miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy.

Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.

Nutrition in developmental age: few rules to stay healthy.

The first 1000 days of life represent a critical window for infants' and children's development. Overweight and insulin resistance, at the basis of non-communicable diseases (NCDs), are linked to various risk factors that begin in childhood, including children's diet. Italian data on infants' and children's dietary habits show higher intake of proteins, simple sugars, unhealthy fats and salt than recommended, while the iron intake is below requirement. We reviewed current literature analyzing observational studies, meta-analysis, systematic review and randomized clinical trials of the last 10 years (from 2009) on nutrition in developmental age, providing some few rules to abide by. Exclusive breastfeeding is recommended by World Health Organization for the first 6 months of life and it should be continued alongside the complementary feeding period until 12 months, or even afterward. Complementary feeding should not be started before the 17th week of age with energetically adequate foods, paying attention to limit protein intake and favoring iron-rich foods. Intake of simple sugars should be limited or avoided at all; it has been demonstrated that substituting sugar-sweetened beverages with water decreases body fatness development in adolescence. Quality of the ingested fats is more important than their quantity: polyunsaturated fatty acids should be preferred. Sodium intake should be limited in the first 24 months of life, as first prevention measure of arterial hypertension later in adulthood. Healthy eating habits are the first important step toward the prevention of NCDs.

Longitudinal Relations Among Positivity, Perceived Positive School Climate, and Prosocial Behavior in Colombian Adolescents.

Bidirectional relations among adolescents' positivity, perceived positive school climate, and prosocial behavior were examined in Colombian youth. Also, the role of a positive school climate in mediating the relation of positivity to prosocial behaviors was tested. Adolescents (N = 151; Mage of child in Wave 1 = 12.68, SD = 1.06; 58.9% male) and their parents (N = 127) provided data in two waves (9 months apart). A model of bidirectional relations between positivity and perceived positive school climate emerged. In addition, adolescents with higher levels of perceived positive school climate at age 12 showed higher levels of prosocial behaviors in the following year. Positive school climate related positivity to adolescents' prosocial behavior over time.

Investigation of age and gender effects on positive orientation in Italian twins.

We investigated age and gender effects on "Positive Orientation" (POS)-an individual's tendency to view life with a positive outlook-using a genetically informed design. Study subjects were 1016 twins aged 22-75 from the Italian twin registry. We assessed POS by the recently developed P-scale. First, we used confirmatory factor analysis to investigate scale's measurement invariance by age and gender. Then, we applied biometric modelling to estimate genetic and environmental components of POS score. Overall, we found a satisfactory degree of measurement invariance by both age and gender. Results from these analyses further indicated an increasing mean level of POS across the lifespan. Additive genetic and unshared environmental factors explained respectively 58% and 42% of variance in POS score, with no significant gender differences; furthermore, the pattern of change of gene-environment architecture of POS over time was consistent with a greater plasticity of personality at older ages.

Umbilical cord stump medication with a topical dermo protective powder compared to dry care in healthy full-term and near-term newborns: a two-center prospective cohort study.

BACKGROUND: Proper umbilical cord stump care during the first days of life (both in hospital and at home) should not be overlooked to prevent possible complications (e.g., purulent discharge, granulomas, or periumbilical erythema or omphalitis). Despite the known benefits of its correct execution, the care of umbilical cord stump remains controversial, and many different approaches are described. The World Health Organization suggests the use of dry cord stump care (easy and economic technique) in developed countries, but in many cases in the real life various topical antiseptics are used in combination with dry cord stump. The extracts of Arnica Montana (AM) have been reported to possess antibacterial, anti-inflammatory, antifungal, and immunomodulatory activities, very useful in the management of cord stump in full term infants. METHODS: In our study we evaluated the efficacy of a powder containing AM (study group- GrA) versus dry cord stump (control group-GrB) in a population of healthy newborn >35 weeks of gestational age (GA). RESULTS: Three hundred twenty-six neonates (mean GA 39±1 in both groups and body weight 3200 g and 3400±448 g respectively in GrA and GrB) were enrolled in two standard neonatal care units (163 neonates in GrA and 163 in GrB). At T1 (48 hours after discharge) GrA showed significantly reduced incidence of mild complications in toto, in particular a lower rate of wet umbilical cord stump). No differences between the two groups at T2 (1 week after discharge). CONCLUSIONS: The use of a natural topical dermo-protective powder containing AM reduces the risk of minor complications, both nurse and parental workload in the first days after discharge, but does not have an impact on cord detachment and other complications in neonates >35 weeks GA.

Antiretroviral therapy and pregnancy: effect on cortical bone status of human immunodeficiency virus-infected Caucasian women as assessed by quantitative ultrasonography.

Treatment with antiretroviral agents (ARVs) during pregnancy is important to prevent mother-to-child transmission of the human immunodeficiency virus (HIV), but their use has been associated with low bone mineral density in adult patients. Currently, there are no data regarding the bone status of HIV-infected women who received ARV during pregnancy. The aim of this study was to evaluate cortical bone status at delivery in a group of HIV-infected women who received ARV during pregnancy and to monitor the changes occurring during the first year postpartum. We studied 33 HIV-infected and 116 HIV-uninfected healthy Caucasian women within 4 days from delivery. Follow-up measurements were performed at 4 and 12 months postpartum in 17 HIV-infected and 55 healthy women. Cortical bone status was evaluated by quantitative ultrasonography at the mid-tibia, and bone measurements were expressed as the speed of sound (SOS). HIV-infected women after delivery had a median SOS of 3,985 (3,567-4,242) m/s, while the median SOS of healthy women was 4,025 (3,643-4,250) m/s. The difference was not significant (t = 0.39, P = 0.69). No significant differences were observed between ARV-exposed and control subjects at 4 and 12 months. Our data suggest that ARV during pregnancy and the first year after delivery does not affect negatively cortical bone status.

Effects of breed on preferential intake of hydroxychloride and sulfate sources of trace minerals in growing beef heifers.

This study evaluated the effects of breed on voluntary preferential intake of two sources of Cu, Mn, and Zn when added to white salt-based trace mineral supplement (days 0 to 55; experiment 1) and protein supplement (days 56 to 112; experiment 2). On day 0, Nelore and ½ Angus × ½ Nelore heifers (n = 20/breed) were stratified by breed, body weight (BW = 347 ±â€…82 kg), and age (12 to 30 mo), and randomly allocated into 1 of the 40 drylot pens (1 heifer/pen). Both experiments were divided into washout (days 0 to 27 in experiment 1 and days 56 to 83 in experiment 2) and preferential intake periods (days 28 to 55 in experiment 1 and days 84 to 112 in experiment 2). During the respective preferential intake period, heifers were provided simultaneous free-choice access to sulfate (SUL) and hydroxychloride (HYD) sources of Cu, Mn, and Zn mixed into salt-based trace mineral supplements from days 28 to 55 (experiment 1) and then protein supplements from days 84 to 112 (experiment 2). Heifers were provided free-choice access to Tifton 85 (Cynodon sp.) hay from days 0 to 112. Effects of breed × source × day of the study were detected (P ≤ 0.05) for daily trace mineral intake from days 28 to 56 and days 84 to 112. Angus × Nelore heifers consumed a greater amount of SUL vs. HYD supplements on days 31 to 33 (P = 0.02) and HYD vs. SUL supplements on days 37 to 42 (P ≤ 0.02), whereas Nelore heifers consumed more HYD vs. SUL supplements on days 31 to 33 and 43 to 51 (P ≤ 0.05). Both breeds consumed (P ≤ 0.05) a greater amount of protein supplement containing HYD vs. SUL from days 84 to 112, but the differences in protein supplement intake increased (P ≤ 0.04) in greater magnitude for Nelore vs. Angus × Nelore heifers. Supplement intake coefficient of variation (CV) from days 28 to 41 and days 84 to 97 tended (P = 0.06) to be greater for Nelore vs. Angus × Nelore heifers. Effects of breed × source were detected (P = 0.02) for supplement intake CV from days 84 to 112. Intake CV of supplements added with HYD did not differ (P ≥ 0.40) between Nelore vs. Angus × Nelore heifers but was greater (P < 0.01) for Nelore vs. Angus × Nelore heifers fed SUL supplements. Overall, Nelore heifers had greater preferential intake for mineral and protein supplements containing hydroxychloride vs. sulfate sources compared to Angus × Nelore heifers. Hydroxychloride sources encouraged voluntary intake and reduced variation in supplement consumption compared to SUL sources of the same metals.

Positivity and Self-Efficacy Beliefs Explaining Health-Related Quality of Life in Cardiovascular Patients.

BACKGROUND: Psychological well-being and health-specific self-regulation have been associated with cardiovascular health. This study aimed to examine the longitudinal relationship of positivity and health-specific self-regulatory variables to health-related quality of life in patients with cardiovascular disease. METHODS: A sample of 550 cardiac patients completed a number of instruments (positivity, regulatory emotional self-efficacy, and cardiac self-efficacy scales, and the general health questionnaire SF-12) on two occasions 9 months apart, assessing their level of positivity, health-specific self-efficacy beliefs, and health-related quality of life. RESULTS: Mediational analyses demonstrated that health-specific self-efficacy beliefs mediate the relationship between positivity and health-related quality of life. In terms of self-efficacy in managing negative affect, the despondency-distress factor showed both direct and indirect effects on health, while the anger factor showed only an indirect effect. The results of the structural equation model demonstrated suitable indices of fit. CONCLUSIONS: Positivity may act as a disposition helps patients to use motivational strategies related to health, be more confident in their ability to regulate their emotions, and follow the recommendations of their cardiac medical team, enabling them to perceive a higher quality of life. These findings indicate the need to promote psychosocial interventions that include these variables.

Long-term evaluation of glucose homeostasis in a cohort of HAART-treated HIV-infected children: a longitudinal, observational cohort study.

BACKGROUND AND OBJECTIVES: Few and mainly cross-sectional studies of glucose homeostasis are available in HIV-infected children treated with highly active antiretroviral therapy (HAART). The aim of the present study was to describe a 4-year course of glucose homeostasis in a cohort of HAART-treated children and adolescents, using glucose and insulin levels during an oral glucose tolerance test (OGTT) as outcome measures. In addition, we investigated possible risk factors, both related and unrelated to antiretroviral therapy, associated with insulin resistance. METHODS: We assessed glucose metabolism yearly for 4 consecutive years in 37 HIV-infected children receiving a protease inhibitor (PI)-based HAART regimen containing lamivudine/stavudine plus indinavir or ritonavir or nelfinavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen containing lamivudine/tenofovir/efavirenz. Generalized estimating equations were used to evaluate the relationship between the loge-transformed area under the serum concentration-time curve (AUC) of insulin during OGTT and antiretroviral therapy, controlling for time, sex, baseline age, puberty, body mass index and CD4+ T cells percentage. RESULTS: Ritonavir-unboosted PI-based HAART regimens were administered to most children at baseline; however, their use decreased during follow-up in favour of an NNRTI-based regimen. The nelfinavir/lamivudine/stavudine (regression coefficient=-0.69, p<0.05) and efavirenz/lamivudine/tenofovir (regression coefficient=-0.93, p<0.05) regimens, but not the ritonavir/lamivudine/stavudine regimen, were negatively associated with loge-transformed insulin AUC compared with indinavir/lamivudine/stavudine. Puberty was positively associated with loge-transformed insulin AUC. CONCLUSIONS: This 4-year prospective study of HAART-treated HIV-infected children shows that: (i) the nelfinavir/lamivudine/stavudine and the efavirenz/lamivudine/tenofovir regimens but not the ritonavir/lamivudine/stavudine regimen were associated with higher insulin sensivity, i.e. lower insulin AUC, compared with indinavir/lamivudine/stavudine; (ii) the treatment switched substantially in favour of NNRTI from the third year on and this change was associated with an improvement in insulin sensitivity compared with the previous HAART-based regimens; and (iii) puberty is a primary determinant of insulin sensitivity.

Successful rescue therapy with a darunavir/ritonavir and etravirine antiretroviral regimen in a child with vertically acquired multidrug-resistant HIV-1.

An increasing prevalence of antiretroviral therapy (ART) resistance in ART-experienced and ART-naive pregnant women has been reported. Some studies suggest that antiretroviral drug-resistant viruses might have decreased replication capacity and transmissibility. However, cases of perinatal transmission of multidrug-resistant HIV type-1 (HIV-1) have been described. Here, we report the case of one child with vertically-acquired multidrug-resistant HIV-1 and the outcome of a rescue therapy with a darunavir/ritonavir- and etravirine-containing antiretroviral regimen. During the 15 months of therapy, the child showed clinical improvement, including no side effects, persistent suppression of viral replication and a great increase in CD4+ T-cell count. Paediatric HIV specialists should be prepared to manage a small, but increasing, number of babies with a 'nightmare' multidrug-resistant virus with no available treatment options. The use of experimental agents might become a compelling issue in vertically HIV-infected children born in the era of highly active ART.

Gastroparesis following bone marrow transplantation.

Patients often develop nausea, vomiting and bloating after bone marrow transplantation (BMT). These symptoms may interfere with nutrition and the ability to take oral medications. Gastroparesis is a recognized cause of these symptoms in non-transplant patients but less is known about patients who undergo BMT. Between January 1996 and March 1997, a total of 151 patients underwent BMT. Eighteen patients (12%) developed persistent symptoms suggestive of gastroparesis (persistent nausea, vomiting or bloating). Scintigraphic gastric emptying studies were performed to assess for gastroparesis. Prokinetic agents were administered at the time of study. The records on these patients were compared with those of all other patients undergoing BMT during the same time period without these symptoms. Nine patients who demonstrated delayed gastric emptying were further evaluated with esophagastroduodenoscopy and biopsy. Biopsy samples were reviewed for evidence of graft-versus-host disease (GVHD). Fourteen of 18 patients demonstrated delayed gastric emptying and most responded to prokinetic agents given at the time of study. Age, conditioning regimen, cytomegalovirus antigenemia and acute GVHD did not appear to be associated with the development of gastroparesis. Allogeneic BMT recipients were at higher risk than autologous BMT patients (26% vs 0%, P < 0.0001). of allogeneic bmt recipients, there was a nonsignificant trend of patients receiving tacrolimus to be less likely to experience gastroparesis than those receiving cyclosporine (27% vs 48%, P = 0.08). For the nine patients undergoing upper endoscopy, GVHD on gastric biopsy was an uncommon finding and was mild when present. Gastroparesis appears to be a common cause of nausea, vomiting and bloating following allogeneic BMT. This may occur less often with tacrolimus than cyclosporine because of the former agent's prokinetic properties. Patients usually respond to prokinetic drugs at the time of scintigraphy. GVHD and CMV infection do not appear to be major contributing factors.

Successful salvage using mismatched umbilical cord blood transplant in an adult with recurrent acute myelogenous leukemia failing autologous peripheral blood progenitor cell transplant: a case history and review.

We report a 26-year-old female with AML, FAB classification M5 who was initially treated with induction therapy consisting of idarubicin and cytarabine followed by high-dose cytarabine and autologous peripheral blood progenitor cell (PBPC) transplant for consolidation. The patient remained in remission for 1 month post-PBPC transplant, when relapse was noted. Reinduction therapy with idarubicin, cytarabine and etoposide was unsuccessful, and the patient underwent an unrelated, two-antigen mismatched umbilical cord blood (UCB) transplant for salvage after melphalan plus total body irradiation. Complications post transplant included veno-occlusive disease, delayed engraftment, and acute grade III graft-versus-host disease (GVHD). The patient remains in remission 1 year post transplant. This study demonstrates the salvage capability of UCB transplantation for refractory leukemia and its potential use in adult patients.

Comparison of autologous peripheral blood stem cell dosing by ideal vs actual body weight.

In this retrospective study, we evaluated the predictability of PBSC dose for hematopoietic engraftment comparing that calculated by ideal body weight (IBW) vs another calculated by actual body weight (ABW) for each patient. Sixty-three consecutive patients treated similarly using one transplant protocol were analyzed. While all patients had data available on CFU-GM and nucleated cells (NC), data on CD34+ enumeration was present only in 34 patients. We found that 49% of the patients were greater than 25% over their IBW. In addition, least-squares linear regression was used to assess the strength of the linear relationship between the inverse of cell dose/kg of ABW or IBW and time to AGC or platelet engraftment and showed no difference in r2 values for platelet engraftment, while using dose/kg of IBW greatly improved the ability of NC (r2 improved from 0.19 for ABW to 0.35 for IBW) and CFU-GM (r2 improved from 0.35 for ABW to 0.53 for IBW) to predict time to AGC engraftment, but did not change the CD34 r2. Hazard ratios were estimated using Cox proportional hazards regression and in all instances were found greater than 1.0 indicating that the probability of engraftment increased as cell dose/kg ABW or IBW increased. Finally, our data showed that 10 patients (16%) could have had one less apheresis procedure performed to obtain their set target stem cell dose calculated per kg IBW rather than ABW. In conclusion, PBSC dose per kg IBW is as good or better predictor of engraftment of AGC and may lead to cost savings in a certain subset of patients.

Allogeneic stem cell transplantation (BMT) for AML and MDS following i.v. busulfan and cyclophosphamide (i.v. BuCy).

Pretransplant conditioning therapy with i.v. BuCy followed by allogeneic hematopoietic stem cell transplantation (BMT) was investigated in a phase II trial in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We gave i.v. Bu at a dose of 0.8 mg/kg every 6h x 16 doses, followed by Cy 60 mg/kg daily for 2 days. Twenty-six AML patients (18 males/eight females) were treated, only eight of whom were in CR1. The rest were either refractory to induction chemotherapy (four patients) or in a more advanced stage of their disease (14 patients). In addition, nine patients with MDS (1M/8F) were treated. Their median age was 41 years (range 21-64). Engraftment to > or =500 neutrophils/microl was reached at 14 days (range 10-29 days) post BMT, and the median time of neutropenia was only 11 days (range 4-28 days). The most common regimen-related toxicity was grade 2-3 nausea. In the post-BMT period (including BMT day +30), two patients died, one each from pulmonary hemorrhage secondary to CMV pneumonia and hepatic veno-occlusive disease (VOD), for an early treatment-related mortality (TRM) of 5.7%. Three patients developed VOD and two of them died. There was no direct regimen-related pulmonary or neurologic toxicity. Overall, the clinical side-effect spectrum was analogous to what would be expected from a high-dose oral Bu-based regimen; there was no unique toxicity experienced with the used solvent system. The disease-free survival in the high-risk subgroup (all patients not in CR1) at 1 and 2 years post transplant was 44% and 31%, respectively. The 13 patients still alive in CR have been followed for a median of 24 months (range 18-32). Pharmacokinetic analysis showed very good interdose reproducibility, and limited interpatient variability in area under the plasma concentration vs time curve, peak concentration, and clearance of Bu after this i.v. formulation. We conclude, that this new i.v. Bu formulation is well tolerated; it has an impressive safety profile, and we suggest that it should be considered as appropriate replacement for oral busulfan in pretransplant conditioning therapy prior to allogeneic BMT for patients with AML or MDS.

A phase II trial of paclitaxel in the treatment of recurrent or metastatic soft tissue sarcomas or bone sarcomas.

The study aimed to determine the activity and toxicity of taxol in the treatment of recurrent or metastatic soft tissue sarcomas or osteosarcomas. The major findings are that five patients had stable disease after two cycles of chemotherapy but two of these patients were subsequently removed from the study at their own request. The other three patients progressed after an additional two cycles of chemotherapy. Seven patients progressed during the first two cycles and were removed from the study. One patient completed only one cycle of therapy and was deemed inevaluable for study response. There were eight episodes of grade 3 or 4 neutropenia and two episodes of grade 3 thrombocytopenia. One patient experienced grade 3 neurological toxicity and one patient grade 3 mucositis. Two patients are currently alive with progressing disease and one patient is alive with no evidence of disease after undergoing surgery and radiotherapy. The principal conclusions are that Paclitaxel is ineffective in treating recurrent or metastatic soft tissue sarcoma and osteosarcoma. Treatment at this dose is quite myelosuppressive, but toxicity is generally manageable. Further study of this agent is not justified in this setting.

Failure of intravenous ribavirin in the treatment of invasive adenovirus infection following allogeneic bone marrow transplantation: a case report.

We report a case of fatal adenovirus infection in a 37-year-old female who underwent allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML). Post BMT she developed acute grade II graft-vs.-host disease (aGVHD) requiring high-dose steroids and anti-thymocyte globulin. Additionally, her clinical course was complicated with adenovirus-associated haemorrhagic cystitis and viraemia. Intravenous ribavirin was obtained and administered for 5 days without success; the patient's mental status deteriorated rapidly and she died on day 69 post-transplant. Radiological imaging revealed diffuse cortical necrosis. At autopsy adenovirus was identified in her bladder, kidneys and lungs.

Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of HIV-infected youths.

BACKGROUND: Decreased bone mineral density (BMD) has been associated with the use of tenofovir disoproxil fumarate (TDF) in HIV-infected adults. The data in HIV-infected children are conflicting. The aim of this study was to assess the safety of a TDF-containing antiretroviral (ARV) regimen on BMD in paediatric patients. We report the results of a longitudinal 60-month follow-up study. METHODS: A total of 21 vertically HIV-infected Caucasian youths (10 male and 11 female) on ARV treatment containing lamivudine, efavirenz and TDF were enrolled (age range 4.9-17.9 years at baseline). BMD was measured at the lumbar spine and in the whole skeleton by DXA. Bone-specific alkaline phosphatase (BAP) was measured as a bone formation marker and urinary N-telopeptide of type-I collagen (NTx) was measured as a bone resorption index. RESULTS: Baseline mean (±sd) BMD measurements of HIV-infected patients expressed as z-scores were -0.7 (±0.9) for lumbar spine and -0.13 (±1.0) for the whole skeleton. BMD measurements did not change significantly during the 60-month observation period. Both BAP and NTx concentrations were higher than a reference group of controls at baseline and remained unchanged throughout the study. CONCLUSIONS: Our data indicate that a TDF-containing regimen does not decrease the BMD of HIV-infected youths.