Long-term survival of HIV-infected patients treated with highly active antiretroviral therapy in Serbia and Montenegro

Background Highly active antiretroviral therapy (HAART) has dramatically changed the prognosis of HIV disease, even in terminally ill patients. Although these patients may survive many years after the diagnosis of AIDS if treated with HAART, some still die during treatment. Methods A retrospective study in a cohort of 481 HIV-infected patients treated with HAART between January 1998 and December 2005 was conducted to compare subgroups of long-term survivors (LTSs) and patients who died during treatment. Results A total of 48 patients survived for more than 72 months (mean 83.8 +/- standard deviation 5.6 months). Thirty patients died during treatment (mean 35.3 +/- 25.0 months), of whom nine died from non-AIDS-related causes, 18 died from AIDS-related causes, and three died as a result of HAART toxicity. Although LTSs were significantly (P=0.015) younger at HAART initiation, age below 40 years was not a predictor of long-term survival. The subgroups did not differ in the proportion of clinical AIDS cases at HAART initiation, in the prevalence of hepatitic C virus (HCV) coinfection, or in pretreatment and end-of-follow-up CD4 cell counts. In contrast, the viral load achieved during treatment was lower in the survivors (P=0.03), as was the prevalence of hepatitis B virus (HBV) coinfection (P=0.03). Usage of either protease inhibitor (PI)-containing regimens [odds ratio (OR) 9.0, 95% confidence interval (CI) 2.2-35.98, P lt 0.001] or all three drug classes simultaneously (OR 7.4, 95% CI 2.2-25.1, P lt 0.001) was associated with long-term survival. Drug holidays incorporated in structured treatment interruption (STI) were also associated with a good prognosis (OR 14.9, 95% CI 2.9-75.6, P lt 0.001). Conclusion Long-term survival was associated with PI-based HAART regimens and lower viraemia, but not with the immunological status either at baseline or at the end of follow up. STI when CD4 counts reach 350 cells/mu L, along with undetectable viraemia, was a strong predictor of long-term survival

Difficulties in neuroborreliosis diagnostics

Neuroborelioza se može manifestirati različitim neurološkim poremećajima koje uzrokuju bakterije Borrelia burgdorferi sensu lato (s.l.). Kliničke manifestacije neuroborelioze nisu patognomonične. Etiološka dijagnoza neuroborelioze uglavnom se temelji na serološkim testovima i određivanju specifičnih protutijela za B. burgdorferi s.l. u likvoru. Fenotipske razlike vrsta B. burgdorferi s.l., razlike u njihovoj antigenoj strukturi, zemljopisnoj rasprostranjenosti te sposobnosti bolesnika za učinkovitu imunoreakciju određuju specifični humoralni odgovor. U dijelu bolesnika s neuroboreliozom protutijela se sintetiziraju samo intratekalno. Stoga je neophodno istovremeno testirati serum i likvor te odrediti indeks protutijela likvor/serum. U ovom radu analizirani su rezultati serološke dijagnostike 28 bolesnika s kliničkom dijagnozom neuroborelioze. Specifična protutijela IgM i IgG za B. burgdorferi s.l. određena su u serumu i likvoru rekombinantnim neizravnim imunoenzimskim testom (rELISA; Biomedica, Wien, Austria) te ELISA metodom »hvatanja« (engl. capture) za procjenu intratekalnih protutijela određivanjem indeksa protutijela (cELISA; IDEIALyme Neuroborreliosis, Dako, Denmark). Svi reaktivni rezultati u serumu potvrđeni su metodom Western blot (WB; Mikrogen, Germany or DPC Biermann GmbH, Germany). Specifični indeks protutijela u cELISA definiran je prema preporuci proizvođača. Intratekalna protutijela za B.burgdorferi s.l. dokazana su u 11 od 28 (39,3%) pacijenata pomoću cELISAi indeksa protutijela likvor/serum. Detektabilna protutijela u likvoru primjenom rELISA nađena su u 21 od 28 (75%) pacijenata. U 19 od 28 (67,9%) pacijenata rezultati rELISA potvrđeni su metodom WB. Sve serološke rezultate treba interpretirati u skladu s kliničkim i epidemiološkim podacima i koristiti ih za potvrdu kliničke dijagnoze, budući da serološki testovi za dokazivanje protutijela za B. burgdorferi nisu još standardizirani.Neuroborreliosis includes a variety of neurological disorders caused by Borrelia burgdorferi sensu lato. Clinical manifestation of neuroborreliosis is not pathognomonic. The etiological diagnosis is based mainly on serological tests and determination of specific anti-B. burgdorferi antibodies in cerebrospinal fluid (CSF). Specific antibodies response is influenced by phenotypic differences among B. burgdorferi species, different antigenic structure, their different geographic spreading, and patient\u27s possibility to react to infection. In some patients with neuroborreliosis antibodies could be produced only intrathecally. Therefore, it is always necessary to test serum and CSF simultaneously and determine the CSF/serum antibody index. In our study serological results of 28 patients with clinical diagnosis of neuroborreliosis were analyzed. Serum and CSF anti-B.burgdorferi IgM and IgG antibodies were determined by recombinant indirect ELISA (rELISA; Biomedica, Wien, Austria) and capture ELISA for intrathecal antibody synthesis detection by CSF/serum antibody index determination (cELISA; IDEIA Lyme Neuroborreliosis, Dako, Denmark). All sera positive results were confirmed by Western blot (WB; Mikrogen, (67,9 %) patients had confirmed rELISA results by WB. All serological results should be interpreted according to clinical and epidemiological data and used to confirm the clinical diagnosis, while serologic assays for anti-B. burgdorferi antibodies have not been standardized yet

The effect of chlorinated aromatic compounds on isolated hepatocytes

Ispitan je efekt 1,2-dihlorbenzena, 1,2,3,4- tetrahlorbenzena, 1,2,3,5- -tetrahlorbenzena, pentahlorbenzena, heksahlorbenzena i Arohlora 1254 na aktivnost enzima lipoperoksidaze i ksantinoksidaze, sadržaj citohroma P-450 i glutationa u izolovanim hepatocitima. Vijabilnost hepatocita bila je smanjena kod primene svih ispitivanih supstancija. 1,2- dihlorbenzen je smanjio sadržaj citohroma P-450 kao i aktivnost enzima, a ostali hlorbenzeni povećavali su aktivnosti enzima, ali nisu uticali na sadržaj citohroma P-450. Arohlor 1254 je povećao sadržaj citohroma P-450, a nije uticao na enzimsku aktivnost. Svi ispitivani spojevi su smanjili sadržaj glutationa.The effects of 1,2-dichlorbenzene, 1,2,3,4-tetrachlorbenzene, 1,2,3,5-tetrachlorbenzene, pentachlorbenzene, hexachlorbenzene and Arochlor 1254 on hepatocyte functions were investigated. The viability of hepatocytes as well as glutathione concentration were decreased in all treatments. 1,2- dichlorbenzene diminished the content of cytochrome P-450 and decreased lipoperoxydase and xantinoxydase activities. Under the same conditions the other compounds investigated increased lipoperoxydase and xantinoxydase activities without influencing cytochrome P-450 content. Arochlor 1254 increased the content of cytocrome P-450 in hepatocytes, but had no effect on enzyme activities

Immunological response in Epstein-Barr virus infection

Epstein Barrov virus (EBV) je humani herpesvirus ubikvitaran u općoj populaciji. Poput drugih herpesvirusa ima latentnu i produktivnu fazu životnog ciklusa. U EBV-infekciji razvijaju se protutijela na različite antigene. Dijagnoza i definiranje statusa EBV-infekcije mogući su zbog karakterističnog odgovora specifičnih protutijela koja se mogu određivati komercijalno dostupnim testovima. U primarnoj infekciji počinju se stvarati protutijela IgM i IgG na virusni kapsidni antigen (VCA), detektiraju se protutijela na rane antigene (EA), a izostaju protutijela IgG za EBNA. Protutijela za EBNA i VCA pokazatelj su ranije EBV-infekcije. Reaktivaciju EBV obilježava visoki titar protutijela za EA, porast protutijela za VCA i ranija prisutnost protutijela za EBNA. Kontrola replikacije EBV primarno je posredovana citotoksičnim T-limfocitima i specifičnim protutijelima za EBV-antigene. Akutnu EBV-infekciju karakterizira samoograničavajuća proliferacija pomoćničkih CD4+ te poglavito citotoksičnih CD8+ T-limfocita. Citotoksični CD8+ T-limfociti uništavaju EBV-om zaražene B-limfocite i na taj način eliminiraju akutnu infekciju nakon čega slijedi doživotna latentna infekcija. Posljednjih se godina sve više istražuje EBV-specifična stanična imunost primjenom nove tehnologije MHC tetrametra. U akutnoj fazi EBV-infekcije dolazi do intenzivne proliferacije CD8+ T-limfocita specifičnih za litičke, ali i za latentne epitope ovog virusa. Određivanje EBV-specifične imunosti posebno je značajno za istraživanje patogeneze, ranu dijagnostiku te imunoterapiju post-transplantacijske limfoproliferativne bolesti.Epstein-Barr virus (EBV) is a human herpes virus that is ubiquitous in the adult population. Like all herpes viruses, EBV has latent and productive (lytic) phases in its life cycle. Infection with EBV induces the synthesis of antibodies to various virus antigens. A characteristic pattern of specific antibodies that can be determined by commercially-available assays enables the diagnosis and the definition of EBV profile in infected patients. In primary infection IgM and IgG antibodies to viral capsid antigen (VCA) start to produce; antibodies to early antigens (EA) are detectable; and antibodies to EBNA are not present. High anti-EA antibodies titre, anti-VCA titre rising and anti-EBNA antibodies predispose EBV reactivation. Cytotoxic T-cells and specific anti-EBV antibodies primarily mediate EBV replication control. Acute EBV-infection is characterized by a self-limiting proliferation of both helper-inducer CD4+ and cytotoxic- -suppressor CD8+ T-cells. The CD8+ T-cell immune response is believed to be responsible for the elimination of acute infection. Application of MHC tetramers demonstrated a massive expansion of CD8+ T-cells specific for both lytic and latent EBV proteins at the acute stage of infection. Characterisation of EBV-specific T-cells is an important experimental tool for the investigation of post-transplant lymphoproliferative disease pathogenesis and immunotherapy

Neuroretinitis associated with cat-scratch disease: a case report

U studenom 2003. godine u Centralnoj prijamnoj ambulanti Klinike za infektivne bolesti »Dr. Fran Mihaljević«, Zagreb liječena je bolesnica s vitritisom i stražnjim uveitisom oba oka te neuroretinitisom lijevog oka, nastalim tijekom bolesti mačjeg ogreba (BMO). Slabljenje vida nastalo je istovremeno s otokom limfnog čvora u aksili, tri tjedna nakon ogreba mačke. Nakon pregleda u jednoj zagrebačkoj klinici za očne bolesti, bolesnica je upućena u našu Kliniku radi etiološke dijagnostike i preporuke za antimikrobno liječenje. Idućeg dana hospitalizirana je na Klinici za očne bolesti. Za vrijeme hospitalizacije liječena je azitromicinom peroralno tijekom pet dana prema preporuci infektologa, uz lokalnu i parenteralnu terapiju kortikosteroidima. Bolest je imala povoljan ishod. Ovo je prvi slučaj neuroretinitisa nastalog tijekom BMO koji je dijagnosticiran u ovoj Klinici, u suradnji s oftalmolozima. Dijagnoza se temeljila na epidemiološkoj anamnezi, regionalnom limfadenitisu s odgovarajućim citološkim nalazom punktata i serološkoj potvrdi protutijela na Bartonellu henselae.In November 2003, a 32-year-old female patient with vitritis and uveitis (pars planitis) of both eyes and neuroretinitis of the left eye, associated with cat-scratch disease (CSD) was treated at the Central Admissions Department of the University Hospital for Infectious Diseases »Dr. Fran Mihaljevic«, Zagreb. Impaired vision occurred simultaneously with axillar lymph node swelling, three weeks after cat scratch. After the patient was examined at the Ophthalmology Clinic in Zagreb, she was referred to our Hospital for etiological diagnostics and recommendation for antimicrobial treatment. The following day the patient was hospitalized at the Ophthalmology Clinic. During hospitalization she was treated with azithromycin p.o. for five days according to recommendation by the infectious disease specialist, with local and parenteral corticosteroid therapy. The disease had favorable outcome. This is the first case of neuroretinitis associated with CSD that was diagnosed in our Hospital in collaboration with colleagues ophthalmologists. The diagnosis was based on epidemiological data, regional lymphadenitis with corresponding cytological finding and serological confirmation of antibodies to Bartonella henselae

Supplementary data for article: Opsenica, I. M.; Verbić, T. Ž.; Tot, M.; Sciotti, R. J.; Pybus, B. S.; Djurković-Djaković, O.; Slavić, K.; Šolaja, B. A. Investigation into Novel Thiophene- and Furan-Based 4-Amino-7-Chloroquinolines Afforded Antimalarials That Cure Mice. Bioorganic and Medicinal Chemistry 2015, 23 (9), 2176–2186. https://doi.org/10.1016/j.bmc.2015.02.061

Supplementary material for: [https://doi.org/10.1016/j.bmc.2015.02.061]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1691

Supplementary data for the article: Terzić, N.; Konstantinović, J.; Tot, M.; Burojević, J.; Djurković-Djaković, O.; Srbljanović, J.; Štajner, T.; Verbić, T.; Zlatović, M.; Machado, M.; et al. Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials? Journal of Medicinal Chemistry 2016, 59 (1), 264–281. https://doi.org/10.1021/acs.jmedchem.5b01374

Supplementary material for: [https://doi.org/10.1021/acs.jmedchem.5b01374]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2036

Herpes zoster as an immune restoration disease in AIDS patients during therapy including protease inhibitors

A prospective study to evaluate the incidence of herpes zoster (HZ) as an immune restoration disease in patients with AIDS during highly active antiretroviral therapy (HAART) was conducted in a series of 115 patients diagnosed with AIDS initiated on HAART between 1 January 2000 and 31 July 2001. Of these, a single dermatomal HZ episode occurred in 14 (12%) patients within one and 15 months of HAART (median eight months). The HZ patients were similar to the non-HZ patients in age, sex, and HIV transmission risk factor, but had a more advanced disease. Compared with the baseline values, the viral loads significantly (P lt 0.01) decreased, while the mean CD4 + T-cell counts increased by almost four-fold (P lt 0.01) in both groups at the time of the HZ episode (or equivalent in non-HZ), but remained below 400/mL in the HZ patients. HZ during HAART is an immunopathological consequence of the improvement of the host immune response, correlating with the beginning of immune restoration