Porphyrins and Metalloporphyrins Combined with N-Heterocyclic Carbene (NHC) Gold(I) Complexes for Photodynamic Therapy Application: What Is the Weight of the Heavy Atom Effect?

The photophysical properties of two classes of porphyrins and metalloporphyrins linked to N-heterocyclic carbene (NHC) Au(I) complexes have been investigated by means of density functional theory and its time-dependent extension for their potential application in photodynamic therapy. For this purpose, the absorption spectra, the singlet-triplet energy gaps, and the spin-orbit coupling (SOC) constants have been determined. The obtained results show that all the studied compounds possess the appropriate properties to generate cytotoxic singlet molecular oxygen, and consequently, they can be employed as photosensitizers in photodynamic therapy. Nevertheless, on the basis of the computed SOCs and the analysis of the metal contribution to the involved molecular orbitals, a different influence in terms of the heavy atom effect in promoting the intersystem crossing process has been found as a function of the identity of the metal center and its position in the center of the porphyrin core or linked to the peripheral NHC.

Efficacy and safety of atazanavir-ritonavir plus abacavir-lamivudine or tenofovir-emtricitabine in patients with hyperlipidaemia switched from a stable protease inhibitor-based regimen including one thymidine analogue.

Randomized, open-label, prospective clinical trial assessing efficacy and safety on hyperlipidemia of a switching from a regimen including one protease inhibitor and one thymidine analogue to atazanavir/ritonavir plus abacavir/lamivudine or tenofovir/emtricitabine. Adult HIV-infected patients on their first antiretroviral therapy (of at least 48-week duration), including one protease inhibitor and zidovudine or stavudine, with stable immunovirologic features, and having diagnosis of persisting hyperlipidemia, were randomized to replace current treatment with atazanavir/ritonavir plus abacavir/lamivudine (arm A) or tenofovir/emtricitabine (arm B), and were followed for 48 weeks. Eighty-nine patients were enrolled: 42 patients were randomized to arm A, and 47 to arm B. At the end of the 48-week follow-up, incidence of virologic failure was comparable in both arms, and associated with a poor drug compliance. Increase in CD4 lymphocyte count was significantly higher in arm A after a 24-week study period (62.5 versus 39.2 x 10(6) cells/L; p < 0.05), while immunologic responses were comparable at the end of 48-week follow-up (91.5 versus 83.6; p > 0.05). A statistically significant reduction (-15.4%) in mean triglyceridaemia versus respective baseline values was reported in both groups (p < 0.05), without statistically significant difference between arm A and B. Similar results were reported for total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Safety and tolerability profiles were comparable in both groups. Switching from a protease inhibitor- and thymidine analogue-based antiretroviral regimen to atazanavir/ritonavir plus abacavir/lamivudine or tenofovir/emtricitabine proved effective in the management of hyperlipidemia, without significant differences in lipid-lowering effect, virologic efficacy, and safety profile between these regimens.

Prevalence of antiretroviral drug resistance in untreated persons newly diagnosed with HIV-1 infection.

Current knowledge of HIV-primary resistance indicates that the prevalence of transmitted resistant strains has increased to substantial levels over the past few years, with a wide variation depending upon a number of factors. New infections with a virus strain already resistant to antiretroviral drugs, namely non-nucleoside reverse transcriptase inhibitor (NNRTI), have a negative impact on initial treatment response and also shorten the time to first virologic failure. The aim of this study was to determine the prevalence of antiretroviral drug resistance by a genotypic test in a population with newly diagnosed HIV-1 infection at a clinical centre in Bologna between June 2006 and September 2007.

Paradoxical immune reconstitution inflammatory syndrome associated with previous Cryptococcus neoformans infection in an HIV-positive patient requiring neurosurgical intervention.

Immune reconstitution inflammatory syndrome (IRIS) in HIV-1-infected patients is associated with an exaggerated inflammatory response against an opportunistic infection during highly active antiretroviral therapy. The only review on IRIS associated with Criptococcus neoformans reported 21 episodes including lymphadenitis, necrotizing pneumonitis, breast and cutaneous abscess, and cryptococcomas. To our knowledge this is the first report of IRIS associated with previous meningeal criptococcal infection which required neurosurgical intervention with placement of a ventriculo-peritoneal shunt to drain a CSF cyst formed by exclusion of the temporal horn of the right lateral ventricle. We demonstrate that this procedure is possible without complications such as cryptococcal dissemination into the peritoneum.

Rosuvastatin, pravastatin, and atorvastatin for the treatment of hypercholesterolaemia in HIV-infected patients receiving protease inhibitors.

Highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been independently associated with an abnormal lipid profile, and recent studies have shown an increased risk of cardiovascular complications in patients with prolonged exposure to HAART. Aim of our open-label, randomized, prospective study is to evaluate the role of different statins in the management of PI-associated hypercholesterolaemia. Ninety-four adult patients on a stable PI-based antiretroviral therapy since at least 12 months, and presenting hypercholesterolaemia (total cholesterol level >250 mg/dL) of at least 3-month duration and unresponsive to a hypolipidaemic diet and physical exercise, were randomized to a hypolipidaemic treatment with rosuvastatin (10 mg once daily), pravastatin (20 mg once daily) or atorvastatin (10 mg once daily), and were followed-up for 12 months. Among the 85 subjects who completed the study, rosuvastatin was employed in 26 cases, pravastatin in 31, and atorvastatin in 28. At the close of 1-year follow-up, statins led to a mean reduction of 21.2% and 23.6% versus baseline total cholesterol and LDL cholesterol levels, respectively (p=0.002). Mean decrease in total cholesterol concentration was significantly greater with rosuvastatin (25.2%) than with pravastatin (17.6%; p=0.01) and atorvastatin (19.8%; p=0.03). During these 12 months, all administered statins showed a favourable tolerability profile, and patients' plasma HIV viral load did not present any variation. All used statins showed a significant efficacy and a good tolerability in the treatment of diet-resistant hyperlipidaemia, but rosuvastatin was found to be more effective in reducing total and LDL cholesterol levels.

Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy.

The use of new potent protease inhibitor-based antiretroviral therapies in patients with human immunodeficiency virus (HIV) infection has been increasingly associated with cardiovascular risk factors, including hyperlipidaemia, fat redistribution syndrome, insulin resistance, and diabetes mellitus. The introduction of highly active antiretroviral therapy (HAART) in clinical practice has remarkably changed the natural history of HIV disease, leading to a notable extension of life expectancy, and prolonged lipid and glucose metabolism abnormalities are expected to lead to significant effects on the long-term prognosis and outcome of HIV-infected patients. Prediction modeling, surrogate markers and hard cardiovascular endpoints suggest an increased incidence of cardiovascular diseases in HIV-infected subjects receiving HAART, even though the absolute risk of cardiovascular complications remains still low, and must be balanced against the evident virological, immunological, and clinical benefits descending from combination antiretroviral therapy. Nevertheless, the assessment of cardiovascular risk should be performed on regular basis in HIV-positive individuals, especially after initiation or change of antiretroviral treatment. Appropriate lifestyle measures (including smoking cessation, dietary changes, and aerobic physical activity) are critical points, and switching HAART may be considered, although maintaining viremic control should be the main goal of therapy. Pharmacological treatment of dyslipidaemia (usually with statins and fibrates), and hyperglycaemia (with insulin-sensitizing agents and thiazolidinediones), becomes suitable when lifestyle modifications and switching therapy are ineffective or not applicable.

HIV-1 DNA load analysis in peripheral blood lymphocytes and monocytes from naïve and HAART-treated individuals.

OBJECTIVE: To evaluate HIV-1 DNA load in PBLs and monocytes from both long-term HAART-treated and antiretroviral naïve HIV-1 infected patients. METHODS: Cross-sectional quantitative analysis of HIV-1 DNA load was performed in PBLs and monocytes, purified from 34 long-term HAART-treated and 34 naïve HIV-1 infected patients, and compared to RNA viral load and CD4+ cell count. RESULTS: HAART-treated patients showed significantly lower levels of viral DNA both in PBLs and monocytes in comparison with naïve individuals. Variable levels of HIV-1 DNA amount in monocytes were detected in all naïve patients but only in 12 of 34 HAART-treated individuals. PBLs HIV-1 DNA load was inversely correlated to CD4+ cell count in naïve and HAART-treated patients whereas no association was detected in monocytes. CONCLUSIONS: Long-term HAART decreased HIV-1 DNA load in PBLs and monocytes demonstrating a valuable inhibitor effect, especially in short-lived reservoirs. In addition, the positive correlation of DNA burden between PBLs and monocytes may suggest a dynamic relation between these reservoirs in the course of disease. HIV-1 DNA load quantitative analysis in PBLs and monocytes may be considered an important approach to study the HIV-1 reservoir and the effectiveness of HAART therapy in HIV-1 seropositive patients.

RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men.

Osteopenia and osteoporosis are common in HIV-1-infected individuals and represent a challenge in clinical and therapeutic management. This report investigated osteopenia/osteoporosis in a group of 31 antiretroviral naive HIV-1-positive men and the role of specific molecules belonging to TNF and the TNF-receptor family in HIV-1-related bone mass loss. Osteoprotegerin (OPG), the receptor activator of NF-kappab-ligand (RANKL), and the TNF-related apoptosis-inducing ligand (TRAIL) were significantly increased in the plasma of antiretroviral naive HIV-1-positive patients compared to a control group of healthy blood donors. In addition, TRAIL and RANKL plasma concentrations were positively correlated to HIV-1-RNA viral load. Measurement of bone mineral density in 20 out of 31 HIV-1-positive subjects disclosed osteopenia/osteoporosis in 40% of these patients. The antiretroviral naive HIV-1-positive subjects with low bone mineral density had a decreased plasma OPG/RANKL ratio and a plasma RANKL concentration >500 pg/ml. Together, these data indicate that plasma concentrations of specific factors involved in bone homeostasis were increased during HIV-1 infection and that RANKL and OPG/RANKL ratio deregulation may be involved in osteopenia/osteoporosis occurring in antiretroviral naive HIV-1 individuals.

A puzzling microbiological and clinical discrepancy in the management of acute, severe skin-soft tissue and joint staphylococcal infection. In vitro antimicrobial susceptibility to glycopeptides, versus in vivo clinical efficacy of linezolid alone.

We present an intriguing case report of a septicemic post-elective surgical staphylococcal knee arthritis and cellulitis which did not respond to long-term courses of associated rifampicin and teicoplanin or vancomycin despite apparently favourable in vitro susceptibility assays, but rapidly resolved after i.v. followed by oral administration of linezolid. The lack of response to a two-week course of glycopeptides cannot be explained by the in vitro mimimum inhibitory concentrations (MIC90) of involved organisms, which showed full susceptibility of Staphylococcus aureus to vancomycin and teicoplanin, and sensitivity of an accompanying Staphylococcus epidermidis isolated from blood cultures to vancomycin and rifampicin, with borderline "intermediate" values found for teicoplanin. Since neither abscess formation nor bone involvement were of concern, effective glycopeptide and rifampicin penetration into infectious tissue should have been ensured. From a clinical point of view, only the introduction of a two-week i.v. linezolid followed by one more week of oral linezolid obtained a complete clinical and microbiological cure, and an unhoped-for functional success. When managing severe multiresistant gram-positive infections, in vitro activity should be carefully evaluated against expected drug penetration rates into the relevant infectious tissues.

Admission of foreign citizens to the general teaching hospital of Bologna, northeastern Italy: an epidemiological and clinical survey.

BACKGROUND: The emergency regarding recent immigration waves into Italy makes continued healthcare monitoring of these populations necessary. METHODS: Through a survey of hospital admissions carried out during the last five years at the S. Orsola-Malpighi General Hospital of Bologna (Italy), all causes of admission of these subjects were evaluated, together with their correlates. Subsequently, we focused on admissions due to infectious diseases. All available data regarding foreign citizens admitted as inpatients or in Day-Hospital settings of our teaching hospital from January 1, 1999, to March 31, 2004, were assessed. Diagnosis-related group (DRG) features, and single discharge diagnoses, were also evaluated, and a further assessment of infectious diseases was subsequently made. RESULTS: Within a comprehensive pool of 339,051 hospitalized patients, foreign citizen discharges numbered 7,312 (2.15%), including 2,542 males (34.8%) and 4,769 females (65.2%). Males had a mean age of 36.8+/-14.7 years, while females were aged 30.8+/-12.2 years. In the assessment of the areas of origin, 34.6% of hospitalizations were attributed to patients coming from Eastern Europe, 15.3% from Northern Africa, 7.3% (comprehensively) from Western Europe and United States, 6.9% from the Indian subcontinent, 5.9% from sub-Saharan Africa, 5.7% from Latin America, 4.1% from China, 2.5% from the Philippines, and 1.1% from the Middle East. Among women, most hospitalizations (58.8%) were due to obstetrical-gynecological procedures or diseases, including assistance with delivery (27.1%), and pregnancy complications (18.7%), followed by psycho-social disturbances (5.9%), malignancies (5.1%), gastrointestinal diseases (4.7%), and voluntary pregnancy interruption (4.4%). Among men, the most frequent causes of admissions were related to trauma (15.9%), followed by gastroenteric disorders (12%), heart-vascular diseases (8.9%), psycho-social disorders (8.4%), respiratory (7.1%), kidney (6.1%), liver (5.2%), and metabolic (4.9%) diseases, and alcohol or substance abuse (4.2%). Infectious diseases (alone or with concurrent disorders) were reported in 881 discharged individuals, representing 12.1% of the 7,312 DRGs attributed to foreign patients. The comprehensive patient population discharged from our hospital with at least one infectious disease diagnosis had lower rates of respiratory tract infections, followed by chronic viral hepatitis, HIV infection and related diseases, enterocolitis, pulmonary tuberculosis, pyelonephritis, severe skin and soft tissue infection, meningoencephalitis, and malaria, as the most frequently-reported disorders. CONCLUSIONS: Our survey, through a combined analysis of both DRGs and discharge diagnoses, allowed us to conclude that 12.1% of foreign citizens hospitalized at our General teaching Hospital of Bologna (Italy) suffered from at least one infectious disease. Respiratory tract, liver, and gastrointestinal infections, and HIV infection, were found with an appreciable frequency among discharge diagnoses, while the frequency of malaria and meningoencephalitis was lower, compared with other series. Among disorders other than infectious diseases, obstetric-gynecological conditions and post-traumatic episodes (for male patients) were the most frequent causes of hospitalization.

Multiple, severe lung infiltrates due to Mycobacterium avium-intracellulare in a patient with decompensated liver cirrhosis: Spontaneous resolution after a two-year follow-up.

A unique case of severe, multiple, microbiologically-confirmed pulmonary Mycobacterium avium-intracellulare lesions occurred in a female with decompensated liver cirrhosis, and went to cure after around 2 y despite the impossibility to deliver an effective antimicrobial chemotherapy, owing to the patient's intolerance. From an extensive literature review, we underline a possible mechanism prompting mycobacterial disease during advanced liver disease, while we retrieved only 2 described cases of possible spontaneous resolution of Mycobacterium terrae lung disease, although both were reported in patients without end-organ liver disease, who received a specific combined chemotherapy for an appreciable time period. On the other hand, while decompensated liver cirrhosis is more frequently complicated by a peritoneal localization of bacteria and very infrequently mycobacteria, the reported case represents the first severe pulmonary localization of multiple lesions due to Mycobacterium avium-intracellulare. Moreover, this extraordinary episode resolved spontaneously within the 2-y follow-up, as documented by bronchoalveolar lavage, culture, high-resolution CT scans, and scintigraphic examination.

Bladder carcinoma and HIV infection during the highly active antiretroviral therapy era: A rare, but intriguing association. Two case reports and literature review.

Two very rare case reports of bladder transitional cell carcinoma associated with HIV infection in patients treated with combined antiretroviral therapy are described, and discussed on the ground of the most relevant and updated literature resources. Only 13 cases of vesical carcinoma have been reported to date in the setting of HIV infection, but only 3 anecdotal single reports (the last in the y 2001) described clinical, therapeutic, and outcome issues of this rare disease association in some detail. In our patients, micro- or macro-haematuria was the clue for in-depth diagnosis and prompt treatment, which was limited to multiple local interventions in 1 case, but finally required a radical cystectomy in the second patient. No relationship was found with the very favourable underlying HIV-related virological and immunological status, and the present 8-12-month follow-up did not show disease relapses.

Fatal long-term immunosuppressive therapy with uncontrolled repeat prescription.

A case of nephrotic syndrome treated with associated cyclophosphamide and corticosteroids came to our attention after over 2 years of self-administered immunosuppressive therapy which remained unchanged and uncontrolled during this period. The self-administered therapy resulted in a severe cell-mediated immunodeficiency (as expressed by a nadir CD4 lymphocyte count of 2 cells/muL). This led to a rapid unfavorable progression of hepatitis B, which was recently acquired and subsequently evolved into a severe cholestatic and fibrosing chronic hepatitis, causing multiple end-organ failure, and ultimately, death. This process was not reversed by lamivudine therapy, hemodialysis, and the use of a Molecular Adsorbent Recirculating System. The role played by repeated drug prescriptions from general practitioners without appropriate clinical and laboratory controls, and that of our patient's depression are discussed. Current literature related to the presented case and the ongoing debate regarding repeated prescriptions are considered in this study.

[Screening of adult patients with fever of unknown origin. A prospective study on the role of primary cytomegalovirus infection]. / Screening di pazienti adulti con febbre di origine indeterminata. studio prospettico sul ruolo dell'infezione primaria da cytomegalovirus.

PATIENTS AND METHODS: In a three-year prospective survey of 135 consecutive adult patients referred for fever of unknown origin often associated with a broad spectrum of constitutional signs and symptoms, 21 (15.5%) were found to have a primary Cytomegalovirus infection. RESULTS: In the majority of cases, this syndrome was consistently associated with altered white blood cell count, abnormal T-lymphocyte subsets and hepatosplenomegaly. On the other hand, altered white blood cell differential and serum hepatic enzymes, and constitutional signs and symptoms were absent with a rate ranging from 11.1% to 27.4% of cases, and an initial laboratory cross-reaction with anti-Epstein-Barr IgM antibodies was detected in 48.1% of episodes. Non-specific signs and symptoms were the only features in 27.4% of patients, thus confirming that this disorder may be still clinically underestimated in its real frequency, until virologic assays are carried out. An extensive and varied spectrum of subjective disturbances, sometimes of duration prolonged beyond six months involved nearly 30% of subjects, and lasted for 3-15 months after recovery of acute, primary Cytomegalovirus disease. CONCLUSIONS: In a multidisciplinary (clinical, laboratory, and instrumental) workup for a fever of unknown origin, a rapid recognition of a primary Cytomegalovirus disease is useful to exclude alternative diagnoses, avoid unnecessary exposure to antimicrobial agents, and reassure patients of the benign and self-limiting course of their illness.

Admission of foreign citizens to the general teaching hospital of bologna, northeastern Italy: an epidemiological and clinical survey

BACKGROUND: The emergency regarding recent immigration waves into Italy makes continued healthcare monitoring of these populations necessary. METHODS: Through a survey of hospital admissions carried out during the last five years at the S. Orsola-Malpighi General Hospital of Bologna (Italy), all causes of admission of these subjects were evaluated, together with their correlates. Subsequently, we focused on admissions due to infectious diseases. All available data regarding foreign citizens admitted as inpatients or in Day-Hospital settings of our teaching hospital from January 1, 1999, to March 31, 2004, were assessed. Diagnosis-related group (DRG) features, and single discharge diagnoses, were also evaluated, and a further assessment of infectious diseases was subsequently made. RESULTS: Within a comprehensive pool of 339,051 hospitalized patients, foreign citizen discharges numbered 7,312 (2.15 percent), including 2,542 males (34.8 percent) and 4,769 females (65.2 percent). Males had a mean age of 36.8±14.7 years, while females were aged 30.8±12.2 years. In the assessment of the areas of origin, 34.6 percent of hospitalizations were attributed to patients coming from Eastern Europe, 15.3 percent from Northern Africa, 7.3 percent (comprehensively) from Western Europe and United States, 6.9 percent from the Indian subcontinent, 5.9 percent from sub-Saharan Africa, 5.7 percent from Latin America, 4.1 percent from China, 2.5 percent from the Philippines, and 1.1 percent from the Middle East. Among women, most hospitalizations (58.8 percent) were due to obstetrical-gynecological procedures or diseases, including assistance with delivery (27.1 percent), and pregnancy complications (18.7 percent), followed by psycho-social disturbances (5.9 percent), malignancies (5.1 percent), gastrointestinal diseases (4.7 percent), and voluntary pregnancy interruption (4.4 percent). Among men, the most frequent causes of admissions were related to trauma (15.9 percent), followed by gastroenteric disorders (12 percent), heart-vascular diseases (8.9 percent), psycho-social disorders (8.4 percent), respiratory (7.1 percent), kidney (6.1 percent), liver (5.2 percent), and metabolic (4.9 percent) diseases, and alcohol or substance abuse (4.2 percent). Infectious diseases (alone or with concurrent disorders) were reported in 881 discharged individuals, representing 12.1 percent of the 7,312 DRGs attributed to foreign patients.

Reactivation of severe, acute pulmonary tuberculosis during treatment with pegylated interferon-alpha and ribavirin for chronic HCV hepatitis.

The unexpected observation of severe pulmonary tuberculosis after a 7-month combined pegylated interferon-ribavirin for chronic hepatitis C, prompted us to search an eventual immunodeficiency (lymphopenia and/or depletion of CD4+ T-lymphocytes. The retrieval of a chest radiograph incidentally performed 11 y before and showing a probable primary tuberculosis, paralleled a negligible clinical history. The enlargement of interferon indications needs careful evaluation for prior (usually missed) tuberculosis, to prevent or avoid its possible reactivation. Latent tuberculosis is increasingly reported because of extended life expectancy, immigration, and recent availability of cure for multiple chronic disorders, which are often borne by primary-secondary immunodeficiency.

Long-term statin use does not act on the temporal trend of CD4 cell count in patients on virologically effective HAART.

Pleiotropic features are attributed to statins and fibrates, and effects on laboratory markers of HIV disease progression have been claimed. To assess whether statins/fibrates have long-term effects on the immune recovery of patients on virologically effective HAART, a prospective, comparative study was conducted on 267 dyslipidemic patients treated with either statins, fibrates, or on a dietary exercise programme only. Quarterly assessment of CD4 cell counts showed no differences between groups, thus excluding in-vivo negative immunological effects during effective HAART.