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Background Triple-drug regimens are the gold standard for HIV therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) reducing regimens are used to decrease drugs toxicity, exposure and costs. Aim of our study was to evaluate trends of biochemical and inflammatory indices in patients switching to dual therapy (DT). Methods We included patients that a) switched to a DT from 2007 to 2015 from a tenofovir/abacavir-based triple regimen b) previously maintained a triple and c) subsequently a dual regimen for 12 months with virological suppression. We retrieved data measured at 5 points (at the switch, 6 and 12 months before and after switch). We used platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and CD4/CD8 ratio as inflammatory indices. We assessed temporal trends of viro-immunological, biochemical and inflammatory parameters. Results Overall, 364 and 65 patients switched from a tenofovir- and an abacavir-triple regimen, respectively. In the tenofovir-reducing group, creatinine clearance and lipids raised after the switch. There was a significant increase in both CD4+ cells and CD4/CD8. CD8+ cells rose after the switch, while opposite trend was found for PLR. In the abacavir-reducing group total lipids showed a decrease during the first 6 months after the switch and then stabilized. An increase of CD4+ and a decrease of CD8+ cells was observed during the study period, although not statistically significant. While CD4/CD8 remained stable after simplification, PLR decreased significantly after 6 months, then returning to baseline. CD8+ cells increased in the tenofovir-reducing group despite a viro-immunological response. Intriguingly, PLR decreased, maintaining this trend for 12 and 6 months after tenofovir and abacavir interruption respectively. Conclusions Increased PLR has been linked to hypercholesterolemia and metabolic-syndrome, while high CD8+ cells count to increased risk of non-AIDS-related events regardless of CD4 T-cell recovery and to virological failure. Whether these findings may have clinical implications, and which role DT plays on the immune system and on inflammation should be further investigated.

The availability of direct antiviral agents (DAAs) offers the possibility to treat HCV-infected patients with a high rate of efficacy and a good safety profile. Little is known about the benefit of DAAs on HCV-related hematological diseases and their complications. We describe the case of an HIV/HCV-infected patient with HCV-related chronic lymphoproliferative disease, mixed cryoglobulinemia and hyperviscosity syndrome. Treatment with direct antiviral agents (DAAs) cured HCV infection and its complications, while HCV re-infection caused recrudescence of the associated diseases.

A new class of artificial ionophores has been rationally designed and synthesized linking to a tetrafunctionalized L-treitol spacer two rigid hydrophobic 3ƒÒ-hydroxy-5ƒÑ-23,24-bisnorcholanic units and two flexible hydrophilic oligo(ethyleneglycol) chains. Compounds 1a and 1b were incorporated into phospholipid vesicles and shown to facilitate Na+-transport

The Harderian gland of the green frog contains mast cells. Their number shows annual variations, being more numerous in the winter months. The increase of mast cell number (MCN) is matched by a marked degranulation. No sex differences are found throughout the year. Manipulations of the photoperiod and temperature, either in winter or in summer, suggest that only the latter is responsible for the annual variations. Exposure to higher temperatures causes a decrease in the MCN in the winter frogs, while exposure of the summer frogs to low temperatures provokes the opposite effect. The pituitary gland also influences MCN. Hypophysectomy causes a decrease of MCN, with a return to normal following replacement therapy with homologous pars distalis homogenate. Among pituitary hormones, only ACTH mimics the effect of pars distalis homogenate. However, a possible link seems to exist between environmental (temperature) and hormonal (pituitary) factors, since hypophysectomy prevents the increase of MCN in the summer frogs exposed to low temperatures.

An efficient protocol for the solid-phase synthesis of six members of a new class of extended macrocyclic peptoids (based on ortho-, meta- and para-N-(methoxyethyl)aminomethyl phenylacetyl units) is described. Theoretical (DFT) and experimental (NMR) studies on the free and Na+-complexed cyclic trimers (3–5) and tetramers (6–8) demonstrate that annulation of the rigidified peptoids can generate new hosts with the ability to sequestrate one or two sodium cations with the affinities and stoichiometries defined by the macrocycle morphology. Ion transport studies have been also performed in order to better appreciate the factors promoting transmembrane cation translocation.

Background Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain. Methods We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated. Results Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated. Conclusions These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.

Background: Glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on creatinine or cystatine C may be more accurate methods especially in patients without chronic kidney disease. There is lack of data on GFR estimated by these methods in patients on highly active antiretroviral therapy. Methods: Antiretroviral-naive HIV-infected patients were randomized to tenofovir/emtricitabine in association with atazanavir/ritonavir (ATV/r) or efavirenz (EFV) Patients had to have an actual creatinine clearance >50 mL/minute (24-hour urine collection) and were followed for 48 weeks. RESULTS: Ninety-one patients (48 ATV/r, 43 EFV) were recruited. Using the CKD-EPI creatinine formula, there was a significant decrease in GFR up to week 48 in patients receiving ATV/r (4.9 mL/minute/m, P = 0.02) compared with a not statistically significant increment in patients prescribed EFV. Using the cystatin C-based equation, we found greater decrease in GFR in both arms, although, in the EFV arm, the decrease was not statistically significant (5.8 mL/minute/m, P = 0.92). At multivariable analysis, ATV/r was a significant predictor of greater decrease in estimated glomerular filtration rate (eGFR) (P = 0.0046) only with CKD-EPI creatinine. Conclusions: ATV/r plus tenofovir caused greater GFR decreases compared with EFV. The evaluation of eGFR by cystatin C confirmed this result, but this method seemed to be more stringent, probably precluding the possibility to detect a significant difference in the pattern of eGFR evolution between the two arms over time. More studies are needed to understand the clinical relevance of these alterations and whether cystatin C is a more appropriate method for monitoring GFR in clinical practice.

Cardiovascular risk in HIV-infected patients is related, at least in part, to serum lipid alterations before and after HAART. Lipoprotein-particle subclasses may also have an effect, but comparative data after standard HAART regimens are limited.This was a substudy of a trial in 91 antiretroviral-naïve patients randomized to tenofovir + emtricitabine + atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Over-time trends from baseline to week 48 in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL particles (HDLp), and TC:HDL-C and TG:HDL-C ratios were analyzed by analysis of covariance (ANCOVA). Furthermore, confidence intervals for differences between the 2 groups at week 48 were calculated. Indications for lipid-lowering interventions and low HDL-C were also studied.ANCOVA showed that, with respect to patients receiving ATV/r, those prescribed efavirenz (EFV) had greater increases reported as mean differences in lipid values at week 48: 14 mg/dL (95% CI, 0.2 to 27) for TC, 14 mg/dL (95% CI, 4 to 25) for LDL-C, 5 mg/dL (95% CI, 2 to 9) for HDL-C, and 2.2 mg/dL (95% CI, 0.4 to 4) for large HDLp. Proportions of subjects with indications for lipid-lowering interventions and with HDL-C40 mg/dL did not differ significantly.Patients prescribed EFV had greater increases in TC, LDL-C, and HDL-C. Although no significant differences were detected between the 2 groups for the TC:HDL ratio and for indications to start lipid-lowering interventions, large HDLp increased more in the EFV group compared to the ATV/r group, suggesting a protective effect associated with EFV use.

The synthesis and screening of neutral and cationic, linear and cyclic peptoids (N-alkylglycine peptidomimetics) is described. Structure-activity relationship studies show that the in vitro activities of the tested peptoids depend on both cyclization and decoration with cationic groups. The most powerful N-lysine cyclopeptoid derivatives showed good antifungal activity against Candida albicans (ATCC90029 and L21) and Candida famata (SA550, Amph B-resistant) and low hemolytic activity. The effects of the cyclic peptoids on membrane permeabilization were evaluated by the propidium iodide exclusion assay.

There is a lack of updated estimates of HIV-2 infection in Italy. Moreover, lack of standardized HIV-2 viral load (VL) and drug resistance tests challenges clinical practice. Among 2941 HIV-positive patients followed in our center (Brescia, Northern Italy), 220 (7.5%) were African at the beginning of the study period. We assessed a population of 151 HIV-Ab positive patients (141 of African origin), presenting for routine blood testing from January 2006 to May 2007. Those found infected with HIV-2 started an appropriate disease management with HIV-2 VL and genotypic drug resistance testing. Sixteen of 151 (10.6%) patients were positive for HIV-2. Of those 16 patients, 14 came from Africa. Among 7 experienced patients, 1 was responding to nelfinavir and 4 to lopinavir/ritonavir-containing regimens. Two patients were failing treatment: 1 patient was switched to a saquinavir/ritonavir-containing regimen and responded. The remaining patient switched to lamivudine+atazanavir+saquinavir+ritonavir did not respond, having had previous experience to multiple ineffective drugs, resulting in a very complex HIV-2 drug-resistance pattern. Accurate screening programs and integration of virological tools must be implemented urgently, given the high prevalence of HIV-2, particularly in immigrant patients. © 2008 Mary Ann Liebert, Inc.

Anion transport across phospholipid membrane is a typical supramolecular function involving dynamic recognition of the substrate during the whole translocation process. Supramolecular chemists, taking inspiration by the natural anion transporters, have designed artificial systems able to mimic, at the functional level, several features of the natural ion channels. The scope of this research is twofold: on one hand to get insight on the molecular basis of recognition and transport, and on the other hand to get control of the biomedical relevant processes. The present review focuses on the synthetic systems promoting anion transport, covering both artificial channels and carriers that operate in phospholipid membrane. The design principles of such systems will be discussed together with the potential biomedical applications.

1,3-Alternate cationic calix[4] arene 1 proved highly selective for proton/ halogens symport transport and showed antiproliferative activity against murine monocyte/macrophage J774.A1 cancer cells.

1,3-Alternate calix[4]arenes, decorated with four nonpolar 'all-trans' tetracyclic nuclei and cation-stabilizing beta-methoxyethoxy appendages, were synthesized from commercially available starting materials and through straightforward functional groups transformations/couplings. Their Na+-transport activities, when compared with those exerted by the known conformationally-rigidified 1,3-alternate calix[4]-arene AB/cis cholic acid conjugates, suggest that the cation conductance is related to the morphology of the pendant steroids.

The synthesis of five steroid-oligo(ethyleneglycol) conjugates ( 1 – 5 ) has been accomplished starting from commercially available epi -androsterone ( 8 ) and known 3β-[( tert -butyldiphenylsilyl)oxy]-5α-23,24-bisnorchol-16-en-6α,7β,22-triol ( 27 ). The synthetic strategy was based on a convergent approach including stereoselective C-17 side chains construction and standard coupling reactions. The activities of the head-to-tail amphiphiles, once incorporated in 95:5 egg PC/PG vesicular membranes, have been assessed by direct determination of transported species by NMR techniques ( 23 Na + ) and fluorescence spectroscopy (H + ). The sodium and proton transmembrane transport was compared to those evaluated for the polyene macrolide antibiotic amphotericin B and those shown by the known related C 2 -symmetric sterol-polyether conjugates 6 and 7 .

The synthesis of the C-2-symmetric bis-(20S)-5alpha-23,24-bisnorchol-16-en-3beta,6alpha,7beta-triol-22-terephthaloate (1), active as Na+-transporting transmembrane channel, has been achieved in 16 steps (10% overall yield) starting from the commercially available androst-5-en-3beta-ol-17-one (3). The straightforward stereospecific functionalization of the side-chain, via the 'ene' reaction, and the successful regioselective terephthaloylation of the C-22 hydroxy group, illustrate the efficiency of the synthetic strategy.

The Harderian gland of the lizard Podarcis sicula sicula (Raf) contains connective tissue type mast cells whose numbers vary during the year showing two peaks, one in spring the other in winter. No sex differences are found throughout the year. Thermal and photoperiodic manipulations indicate that only temperature influences mast cell number (MCN) both in winter and in summer but not in spring. In animals exposed to high temperatures in February (but not in May) MCN declined, while exposure to low temperature in July had the opposite effect. Estradiol treatment of the February and April lizards increased MCN, an effect counteracted by the synthetic antiestrogen tamoxifen; in July lizards, this did not occur. In animals exposed to a high temperature in February, estradiol had no effect, as in animals exposed to low temperatures in July. These data suggest that in spring MCN seems to be more responsive to hormonal stimuli rather than external cues (temperature), while in summer MCN is more sensitive to temperature than to hormonal stimuli (estradiol). Both humoral and external factors are concluded to influence mast cell numbers in the Harderian gland of the lizard P. sicula sicula.

SummaryMast cells of connective tissue type are scattered in the interstitial compartment of the lizard Podarcis s. sicula. Their number varies during the year, showing peaks in spring and in winter, respectively.Thermal manipulation affects mast cell number (MCN): high temperature decreased MCN in both January and May, while low temperature increased MCN only in January. Ethane dimethane sulphonate, a toxin which specifically destroys Leydig cells, induced an increase in MCN on days 3 and 7 of treatment. Oestradiol treatment provoked a strong increase in MCN that was blocked by tamoxifen. Blocking androgen receptors with cyproterone acetate resulted in an increase in MCN, while testosterone injection provoked a strong decrease. These results suggest a relationship between the presence of mature Leydig cells and mast cell proliferation and/or differentiation.