Dynamics and phylogenetic relationships of HIV-1 transmitted drug resistance according to subtype in Italy over the years 2000-14.

Background: Transmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care. Methods: In total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters. Results: Most individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30-45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (<2005-14: 19.5%-38.5%, P < 0.0001), particularly among Italians (<2005-14: 6.5%-28.8%, P < 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (<2005-14: 2%-7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (<2005-14: 12.9%-33.5%, P = 0.001) and non-B subtypes (<2005-14: 18.4%-41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (<2005-14: 14.3%-35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6-19) versus 4 (3-4), P = 0.047]. Conclusions: The epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.

Electron-electron interactions in artificial graphene.

Recent advances in the creation and modulation of graphenelike systems are introducing a science of "designer Dirac materials". In its original definition, artificial graphene is a man-made nanostructure that consists of identical potential wells (quantum dots) arranged in an adjustable honeycomb lattice in the two-dimensional electron gas. As our ability to control the quality of artificial graphene samples improves, so grows the need for an accurate theory of its electronic properties, including the effects of electron-electron interactions. Here we determine those effects on the band structure and on the emergence of Dirac points.

Exact conditions in finite-temperature density-functional theory.

Density-functional theory (DFT) for electrons at finite temperature is increasingly important in condensed matter and chemistry. The exact conditions that have proven crucial in constraining and constructing accurate approximations for ground-state DFT are generalized to finite temperature, including the adiabatic connection formula. We discuss consequences for functional construction.

[Strategies for prevention and control of healthcare related infections by Acinetobacter baumannii]. / Strategie di prevenzione e controllo delle infezioni da Acinetobacter baumannii correlate all'assistenza sanitaria.

The frequent development of acquired antibiotics resistance in bacteria represents a challenge for Public Health in terms of healthcare associated infections control. Apart from the appropriate use of drugs, in particular the choice of proper antimicrobial therapy, increasing interest is, therefore, given to the non-pharmacological prevention of these infections. Acinetobacter (A.) baumannii is a micoorganism that commonly causes infections for patients hospitalized in critical hospital wards (intensive care units, burn centers, surgery, neonatology, etc) potentially severe and difficult to treat, because A. baumannii is resistant to many or sometimes all, available antibiotics (PDR - pan drug resistant). The aim of the present paper was to review the available measures for preventing and controlling the contamination and the spread of these types of bacterial infections in health care scenarios, with particular attention to two methods that stand out for efficiency and safety: hand hygiene and environmental disinfection.

Universal correction for the Becke-Johnson exchange potential.

The Becke-Johnson exchange potential [A. D. Becke and E. R. Johnson, J. Chem. Phys. 124, 221101 (2006)] has been successfully used in electronic structure calculations within density-functional theory. However, in its original form, the potential may dramatically fail in systems with non-Coulombic external potentials, or in the presence of external magnetic or electric fields. Here, we provide a system-independent correction to the Becke-Johnson approximation by (i) enforcing its gauge-invariance and (ii) making it exact for any single-electron system. The resulting approximation is then better designed to deal with current-carrying states and recovers the correct asymptotic behavior for systems with any number of electrons. Tests of the resulting corrected exchange potential show very good results for a hydrogen chain in an electric field and for a four-electron harmonium in a magnetic field.

Multiband superconductivity in Pb, H under pressure and CaBeSi from ab initio calculations.

Superconductivity in Pb, H under extreme pressure and CaBeSi, in the framework of the density functional theory for superconductors, is discussed. A detailed analysis on how the electron-phonon and electron-electron interactions combine together to determine the superconducting gap and critical temperature of these systems is presented. Pb, H under pressure and CaBeSi are multigap superconductors. We will address the question under which conditions does a system exhibits this phenomenon. The presented results contribute to the understanding of multiband and anisotropic superconductivity, which has received a lot of attention since the discovery of MgB(2), and show how it is possible to describe the superconducting properties of real materials on a fully ab initio basis.

Interleukin-12 in early or advanced cancer patients.

Interleukin-2 (IL-2) and interleukin-12 (IL-12) may represent the most important antitumour cytokines in human neoplasms. IL-2 blood levels decrease in advanced solid malignancies, but currently there are no data on IL-12 secretion in cancer patients. This study was performed to obtain preliminary data about IL-12 secretion in patients with solid malignant tumours, either in relation to the extension of disease, or to other cytokines, including IL-2, IL-6 and IL-10. The study included 40 solid cancer patients, 24 of whom showed distant organ metastases. Cytokine serum levels were measured by an enzyme immunoassay of blood samples collected during the morning. No patient had abnormally low levels of IL-12, but the levels were high in 14/14 (35%) patients. Mean levels of IL-12 were significantly higher in metastatic patients compared with non-metastatic patients (P < 0.05). Moreover, metastatic patients with high blood concentrations of IL-12 showed significantly lower levels of IL-10 than metastatic patients with normal IL-12 values, while no difference was seen in IL-2 mean concentrations. IL-6 mean levels were lower in metastatic patients with increased IL-12 levels, but this was non-significant. This preliminary study shows that advanced solid cancers are not characterised by a diminished secretion of IL-12, but rather IL-12 levels tend to be abnormally high in metastatic cancer patients.

In vivo biological results of the association between interleukin-2 and interleukin-3 in the immunotherapy of cancer.

The concomitant generation of macrophage-mediated suppressive events, as documented by the increase in neopterin and soluble interleukin-2 (IL-2) receptor (SIL-2R), and the enhanced production of cortisol, would represent the most investigated phenomena responsible for the reduced anticancer efficacy of IL-2 immunotherapy in humans. Based on our preliminary experimental studies suggesting a modulatory role of IL-3 on immune and endocrine effects induced by IL-2, a study was performed to evaluate the influence of IL-3 on biological effects of IL-2 cancer immunotherapy. We have evaluated 12 immunotherapeutic courses with IL-3 plus IL-2, which were performed in 6 patients with metastatic non-small cell lung cancer. The results were compared to those seen in 22 courses with IL-2 alone, carried out in 12 patients with metastatic non-small cell lung cancer. IL-3 was given intravenously at a daily dose of 1 microgram/kg/b.w. at 6 p.m. for 14 consecutive days, starting 7 days before IL-2. IL-2 was given subcutaneously at a dose of 3 million IU twice/daily for 5 days/week for 3 weeks. The increase in serum levels of the specific macrophage marker neopterin, induced by IL-2, was completely blocked by IL-3. The IL-2-induced SIL-2R rise was significantly lower during IL-3 plus IL-2 than under IL-2 alone. The increase in cortisol levels in response to IL-2 was neutralised by IL-3. The increase in lymphocyte, T lymphocyte, natural killer (NK) cell, activated T lymphocyte and eosinophil mean number was significantly higher during IL-3 plus IL-2 than during IL-2 alone. Episodes of fever, asthenia, anorexia, vomiting, anaemia and thrombocytopenia were significantly more frequent in patients receiving IL-2 alone than in those treated with IL-3 and IL-2. This preliminary study would suggest that IL-3 may improve the tolerability of IL-2 immunotherapy and enhance the biological antitumour properties of IL-2 by neutralising cortisol increase and macrophage-mediated suppressive events, with a following potential amplification of Il-2 anticancer efficacy.

Muscle glucose-6-phosphate dehydrogenase deficiency.

Muscle glucose-6-phosphate dehydrogenase (G6PD) deficiency is described in four clinically heterogeneous patients: an athlete who developed myoglobinuria after physical exercise; a 7-year-old, mildly mentally retarded boy, who had episodes of dark urine and high creatine kinase; and two brothers of Sardinian origin, the elder showing moderate exercise intolerance. Histochemical and biochemical studies showed a lack of G6PD activity in muscle biopsy specimens as well as in erythrocytes. G6PD characterization in erythrocytes classified these mutant enzymes as Mediterranean variant in all the patients. The deficiency was confirmed in the patients' myotubes and skin fibroblasts, where residual activity was present. Electrophoretic studies in tissue culture extracts showed that the residual muscle enzyme migrated as a single electrophoretic band like normal human muscle G6PD.

Modulation of cytokine production from TH2-lymphocytes and monocytes by the pineal neurohormone melatonin.

Preliminary clinical and experimental studies have suggested that cytokine secretion is not regulated only by immune substances, but also by the neuroendocrine system through the release of immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). The anticancer immune response would also depend on complex interactions between cytokines and neurohormones. IL-2 is one of the most active antitumor cytokines. However, in addition to the generation of cytotoxic antitumor lymphocytes, IL-2 may concomitantly induce suppressive factors, in particular IL-10 by TH2 lymphocytes and IL-6 by both TH2 lymphocytes and monocytes. IL-10 appeared to inhibit IL-2 secretion and activity, whereas IL-6 has been proven to exert both antineoplastic and proneoplastic immune functions. The present experimental study was performed to evaluate the in vitro effects of MLT on IL-10 and IL-6 secretions, either in basal condition or after IL;2 stimulation. Human pure lymphocyte and pure monocyte cultures were obtained from healthy donors and incubated for 3 days with medium alone, MLT (100 pg/ml), IL-2 (100 Cetus U/ml) or IL-2 plus MLT. IL-2 induced a significant increase in mean medium concentrations of both IL-10 and IL-6. MLT alone had no effect on IL-10 levels, but it was able to significantly reduce IL-2-induced IL-10 release. IL-2-induced IL-6 secretion was not abrogated by a concomitant MLT incubation, whereas MLT alone was able to significantly reduce the basal secretion of IL-6 only in the pure monocyte cultures. These results, by showing a modulatory effect of MLT on lymphocyte and monocyte cytokine secretion, would further confirm the rationale of a concomitant administration of cytokines and immunomodulating neurohormones during cancer immunotherapies.

Cytokine regulation of iron metabolism: effect of low-dose interleukin-2 subcutaneous therapy on ferritin, transferrin and iron blood concentrations in cancer patients.

It is known that the anemias of chronic diseases, which often occur in neoplastic and in systemic inflammatory disorders, are characterized by high levels of ferritin associated with generally low iron concentrations, by suggesting an iron transfer defect due to unknown factors. Since both chronic inflammatory diseases and advanced neoplasms are characterized by alterations in the endogenous production of cytokines, a possible involvement of interleukins in chronic disease-related anomalies of iron metabolism cannot at present be excluded. The present study was carried out to investigate the effect of low-dose IL-2 subcutaneous immunotherapy (3 million IU/day for 6 days/week for 4 weeks) on ferritin, transferring and iron serum levels in cancer patients. Six patients with metastatic gastrointestinal carcinomas were evaluated. Ferritin mean levels significantly decreased during IL-2 treatment, and this finding was associated with a significant increase in transferrin values. Iron mean levels increased in response to IL-2, without, however, significant differences in respect to the pretreatment concentrations. These preliminary data, by showing changes in ferritin, transferrin and iron in cancer patients during the immunotherapy with IL-2, would suggest the existence of a cytokine regulation of iron transfer from tissues to blood, perhaps by modulating the macrophage function.

Immunomodulatory properties of a pineal indole hormone other than melatonin, the 5-methoxytryptophol.

Several experiments have suggested that the pineal gland has an antitumor immunomodulatory action. Melatonin (MLT), the best known pineal hormone, has been shown to stimulate anticancer immune defenses during the night, corresponding to the period of its maximum blood levels, whereas it has no effect during the light phase of the day. At present, no study has been performed to investigate possible immunomodulating properties of other pineal indoles, such as 5-methoxytryptophol (5-MTL), whose circadian secretion would be opposite with respect to that of MLT, since it reaches its highest levels during the light phase of the day. In an attempt to analyze possible effects of 5-MTL on anticancer immunity, we have evaluated the action of 5-MTL (1 mg/ day orally at noon for 5 days) in 10 healthy volunteers on the two fundamental suppressive and immunostimulatory cytokines, consisting of IL-6 and IL-2, respectively. Serum levels of IL-2 and IL-6 were measured by an immunoradiometric method. Mean serum concentrations of IL-2 significantly increased on 5-MTL therapy, whereas those of IL-6 significantly decreased in response to 5-MTL. This preliminary study would suggest that the less known pineal indole 5-MTL, as well as MLT, has important immunomodulatory effects on cytokine secretions, including those involved in the antitumor immune response, by further confirming the essential role of the pineal as a central regulation of biological response modifier system. Several pineal alterations have been described in advanced cancer patients. According to the results of this study, the simultaneous administration of MLT during the dark phase and of 5-MTL during the light period of the day could further contribute to correcting pineal functions and to pilot the host anticancer immune reaction in an antitumor direction with respect to MLT alone.

Interleukin-2, melatonin and interleukin-12 as a possible neuroimmune combination in the biotherapy of cancer.

Suppressive events induced by macrophages and TH2 lymphocytes would represent the most important factors responsible for the in vivo reduced efficacy of IL-2 cancer immunotherapy. Previous studies have shown that IL-3 or the pineal hormone MLT may abrogate macrophage-related suppressive events during IL-2 immunotherapy, while TH2-mediated immunosuppression is not neutralized by MLT or IL-3. On the basis of previous experimental data suggesting the inhibitory effect of IL-12 on TH2 activation, this preliminary study has been performed in an attempt to evaluate the influence of IL-12 on TH2 stimulation induced by IL-2 alone or IL-2 plus MLT, by evaluating the release of IL-10, which represents the main suppressive factor produced by TH2 lymphocytes. Pure lymphocyte cultures were incubated for 4 days with IL-2 (100 Cetus U/ml), MLT (100 pg/ml), IL-12 (1 ng/ml), IL-2 plus MLT, IL-2 plus IL-12 or IL-2 plus MLT and IL-12. Mean medium concentrations of IL-10 were measured by Elisa. IL-2 alone significantly stimulated IL-10 secretion with respect to the control medium alone, while no difference was observed with MLT alone or IL-12. IL-2-induced stimulation of IL-10 secretion was not abrogated by a concomitant MLT incubation. On the contrary, IL-12 significantly diminished IL-10 release in response to IL-2, and this inhibitory effect was more pronounced when IL-2 was added in association with both IL-12 and MLT. This preliminary study would suggest that the two most important immunosuppressive events occurring during IL-2 therapy, which are mediated by macrophages and TH2-lymphocytes, may be abrogated by a concomitant administration of MLT and IL-12, respectively. Therefore, the association of IL-12 could further amplify IL-2 efficacy with respect to IL-2 alone or IL-2 plus MLT.

Effects of granulocyte-macrophage colony stimulating factor on soluble interleukin-2 receptor serum levels and their relation to neopterin and tumor necrosis factor-alpha in cancer patients.

SIL-2R levels mainly depend on a T lymphocyte production. The mechanisms responsible for the elevated blood concentrations of SIL-2R in advanced solid tumors are still unknown. To investigate the role played by the monocyte-macrophage system on SIL-2R release, we have evaluated serum levels of SIL-2R in 10 head and neck cancer patients during GM-CSF subcutaneous administration (3 mcg/kg/day for 11 consecutive days). Serum levels of TNF and neopterin, both produced by macrophages, were also measured. SIL-2R mean concentration significantly enhanced in response to GM-CSF, and their rise positively correlated to that in TNF and neopterin values, while lymphocyte mean number did not increase during the study. The present results represent the first in vivo demonstration that SIL-2R release is related to macrophage activation, rather than to depend only on lymphocyte proliferation.

Tumor necrosis factor in solid tumors: increased blood levels in the metastatic disease.

TNF, a cytokine produced by macrophages, is able either to exert an antitumor activity, or to determine severe clinical complications, such as cachexia and septic shock. Increased blood levels of TNF have been described in cancer patients. The present study was performed to better define TNF secretion in patients with solid tumors. The study included 48 cancer patients (lung cancer: 22; colon cancer: 11; breast cancer: 10; renal cancer: 5), and among them 27 showed distant organ metastases. TNF serum levels were measured by IRMA method. The control group comprised 40 healthy subjects. TNF levels were also evaluated in relation to those of SIL-2R, whose increase seems to be associated with an unfavorable prognosis in cancer. High levels of TNF were seen in 27/48 (56%) patients. Mean levels of TNF were significantly higher in cancer patients than in controls. Moreover, within the cancer group, TNF mean values were significantly higher in metastatic patients than in those without metastases; the highest levels were observed in patients with visceral lesions as dominant metastasis sites. Finally, patients with high TNF concentrations showed significantly higher mean levels of SIL-2R than those with normal values. This study shows that the neoplastic metastatic disease is associated with an exaggerated TNF secretion.

Clinical significance of erythrosedimentation rate in cancer in relation to cytokine production: correlation with high IL-6 and low IL-2 blood concentrations.

Despite its well documented unfavourable prognostic significance in several human diseases, including cancer, the cytokinic mechanisms responsible for an increased erythrosedimentation rate (ESR) still remain to be better analyzed and defined. The recent possibility to measure cytokine concentrations in the blood of patients has allowed us to explore the possible relation between ESR values and endogenous cytokine secretions. This preliminary study was performed to evaluate the relationship between ESR values and serum levels of IL-2 and IL-6, which represent the most important cytokines responsible for the activation and the suppression, respectively, of host anticancer immune reaction. The study included 33 consecutive solid tumor patients, 22 of whom showed distant organ metastases. Abnormally high values of ESR were present in 21 patients, including 18/22 metastatic patients and 3/11 nonmetastatic patients. Patients with elevated values of ESR showed significantly higher mean levels of IL-6 and significantly lower mean concentrations of IL-2 with respect to those found in patients with normal ESR values. These results would show that cancer-related increase in ESR values is associated with low levels of IL-2 and high levels of IL-6. Since IL-2 plays an essential role in the anticancer immunity and IL-6 may suppress the antitumor immune defenses, the evidence of low levels of IL-2 and high values of IL-6 in cancer patients with increased ESR values would explain the unfavourable prognostic significance of high ESR values in human neoplasms.

Characterization of cancer-related disseminated intravascular coagulation in relation to tumor necrosis factor-alpha blood concentrations: possible therapeutic role of pentoxifylline.

AIMS AND BACKGROUND: Preliminary experimental data suggest the involvement of tumor necrosis factor (TNF) in determining endothelial damage related to disseminated intravascular coagulation (DIC). The present study was performed to investigate TNF secretion in DIC occurring in metastatic solid tumor patients and to evaluate the possible therapeutic role of pentoxifylline, which has been proven to have a TNF-lowering activity. METHODS: The study included 20 metastatic solid tumor patients who showed clinical and laboratory signs of DIC. Pentoxifylline was given orally at a dose of 1200 mg/day for 28 days. RESULTS: Abnormally high levels of TNF were found in 13/20 patients, and mean TNF serum levels observed in patients were significantly higher than those seen in a control group of 50 healthy subjects. Fibrinogen plasma concentrations were low in 11 cases. Patients with low fibrinogen values showed significantly higher mean TNF levels than those with normal or elevated concentrations. Pentoxifylline therapy induced a significant decrease in mean TNF concentrations and a significant increase in mean platelet number, which returned to within the normal range in 11/20 patients. An increase in platelets in response to pentoxifylline was more evident in patients with elevated pretreatment TNF values. CONCLUSIONS: Our results suggest the existence of abnormally high blood levels of TNF in cancer-related DIC, mainly in the presence of low fibrinogen values. Moreover, they indicate that pentoxifylline therapy may determine a decrease in TNF levels in DIC patients, an event associated with an increase in platelet number.

Construction of the B88 Exchange-Energy Functional in Two Dimensions.

We construct a generalized-gradient approximation for the exchange-energy density of finite two-dimensional systems. Guided by nonempirical principles, we include the proper small-gradient limit and the proper tail for the exchange-hole potential. The observed performance is superior to that of the two-dimensional local-density approximation, which underlines the usefulness of the approach in practical applications.

[NDM-1: the superbug?]. / NDM-1: il superbug?

A novel type of carbapenemase, New Delhi metallo beta-lactamase 1 (NDM 1), was first identified in 2008 in two Enterobacteriacea isolates, both recovered from a Swedish patient transferred from India. The emergence of NDM 1 is now reported from all continents, often in patients with a history of travel or hospitalization in the Indian subcontinent. The NDM 1 producing Gram-negative bacteria are mainly Enterobacteriaceae, which can cause colonization or fatal infections, with worrying antimicrobial susceptibility profiles: some isolates have developed resistance to practically all available antibiotics. Is the NDM-1 the super-bug? Are we in the post-antibiotic era? This review is a summary of currently available knowledge of NDM-1 that draws attention to future antimicrobial resistance scenarios.