Renin-Angiotensin-Aldosterone System Inhibitors, Statins, and Beta-Blockers in Diabetic Patients With Critical Limb Ischemia and Foot Lesions

Medical therapy for secondary prevention is known to be under-used in patients with peripheral artery disease (PAD). Few data are available on the subgroup with critical limb ischemia (CLI). Prescription of cardiovascular preventive therapies was recorded at discharge in a large, prospective cohort of patients admitted for treatment of CLI and foot lesions, stratified for coronary artery disease (CAD) diagnosis. All patients were followed up for at least 1 year. The primary endpoint was major adverse cardiovascular events (MACE). 618 patients were observed for a median follow-up of 981 days. Renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, beta-blockers, and antithrombotic drugs were prescribed in 52%, 80%, 51%, and 99% of patients, respectively. However, only 43% of patients received optimal medical therapy (OMT), defined as the combination of RAAS inhibitor plus statin plus at least one antithrombotic drug. It was observed that the prescription of OMT was not affected by the presence of a CAD diagnosis. On the other hand, it was noticed that the renal function affected the prescription of OMT. OMT was independently associated with MACE (HR 0.688, 95%CI 0.475-0.995, P = .047) and, after propensity matching, also with all-cause mortality (HR 0.626, 95%CI 0.409-0.958, P = .031). Beta-blockers prescription was not associated with any outcome. In conclusion, patients with critical limb ischemia are under-treated with cardiovascular preventive therapies, irrespective of a CAD diagnosis. This has consequences on their prognosis

Serum IgG antibodies from pregnant women reacting to mimotopes of simian virus 40 large T antigen, the viral oncoprotein

Simian virus 40 (SV40) large T antigen (LT) coding sequences were revealed in different human samples, whereas SV40 antibodies (Ab) were detected in human sera of cancer patients and healthy individuals, although with a lower prevalence. Previous studies carried out by the neutralization assay gave a SV40 seroprevalence, in the general population, up to 8%, although higher rates, 12%, were detected in kidney transplant children, in a group of HIV-positive patients, and in healthy females. In this study, serum samples from pregnant women, together with those from non-pregnant women, were analyzed to check the prevalence of IgG Ab reacting to SV40 LT antigens. Serum samples were collected from pregnant and non-pregnant women, with the same mean age. Women were in the range of 15-48 years old. Samples were assayed by an indirect ELISA employing specific SV40 LT mimotopes as antigens, whereas functional analysis was performed by neutralization of the viral infectivity in cell cultures. As a control, sera were analyzed for Ab against BK polyomavirus (BKPyV), which is a human polyomavirus homologous to SV40. Statistical analyses employed chi-square with Yates' correction, and Student's t tests. Indirect ELISAs indicated that pregnant women tested SV40 LT-positive with a prevalence of 17% (23/134), whereas non-pregnant women had a prevalence of 20% (36/180) (P > 0.05). Ab against BKPyV were detected with a prevalence of 80% in pregnant women and with a prevalence of 78% in non-pregnant women. These data indicate that SV40 infects at a low prevalence pregnant women. We may speculate that SV40, or a close human polyomavirus still undetected, could be transmitted from mother to fetus

Neuroendocrine immunity in patients with Alzheimer's disease: toward translational epigenetics

The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a “fast progression” (delta greater than 2 points) or to a “slow progression” group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions

Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from targeting factors that play a continuous role in NAFLD evolution to HCC. Recent work has shown that postprandial liver translation exacerbates lipid accumulation through the activity of a translation factor, eukaryotic initiation factor 6 (eIF6). Here, we test the effect of eIF6 inhibition on the progression of HCC. Mice heterozygous for eIF6 express half the level of eIF6 compared to wt mice and are resistant to the formation of HCC nodules upon exposure to a high fat/high sugar diet combined with liver damage. Histology showed that nodules in eIF6 het mice were smaller with reduced proliferation compared to wt nodules. By using an in vitro model of human HCC, we confirm that eIF6 depletion reduces the growth of HCC spheroids. We also tested three pharmacological inhibitors of eIF6 activity—eIFsixty-1, eIFsixty-4, and eIFsixty-6—and all three reduced eIF6 binding to 60S ribosomes and limited the growth of HCC spheroids. Thus, inhibition of eIF6 activity is feasible and limits HCC formation

Leaf gas exchanges and water relations affect the daily patterns of fruit growth and vascular flows in Abbé Fétel pear (Pyrus communis L.) trees

Daily patterns of leaf and stem water potentials, leaf gas exchanges (net photosynthesis, stomatal conductance and transpiration), fruit growth, vascular (phloem and xylem) and transpiration in/outflows were determined in two subsequent years at regular time intervals during the season on pear trees of the cv. Abbé Fétel. Leaf gas exchanges showed higher values in the morning, while fruit shrank due to high transpiration water losses which were not balanced by xylem flows. Despite the high rates of transpiration, fruit were fully rehydrated in the afternoon thanks to high xylem flows, while phloem import occurred mostly in the midday hours. During most of the season, fruit growth was sustained above all by the xylem flux which represented upto 85% of fruit total inflows. Later, fruit growth rate decreased while dry matter accumulation increased following a rise in the phloem relative contribution to growth, which reached 50% of fruit total inflows. This is the first report to show how the biophysical mechanism of fruit growth in “Abbé Fétel” pear is based on high water exchanges by xylem and transpiration during most of the season. The simultaneous monitoring of leaf gas exchanges and fruit vascular flows during the day suggests how until about 95 days after full bloom (DAFB), leaves are stronger “sinks” for water in the morning while fruit import water mainly during the afternoon, thanks to the increase in leaf water potential following stomatal closure

Increasing water stress negatively affects pear fruit growth by reducing first its xylem and then its phloem inflow

Drought stress negatively affects many physiological parameters and determines lower yields and fruit size. This paper investigates on the effects of prolonged water restriction on leaf gas exchanges, water relations and fruit growth on a 24-h time-scale in order to understand how different physiological processes interact to each other to face increasing drought stress and affect pear productive performances during the season. The diurnal patterns of tree water relations, leaf gas exchanges, fruit growth, fruit vascular and transpiration flows were monitored at about 50, 95 and 145 days after full bloom (DAFB) on pear trees of the cv. Abbé Fétel, subjected to two irrigation regimes, corresponding to a water restitution of 100% and 25% of the estimated Etc, respectively. Drought stress progressively increased during the season due to lower soil tensions and higher daily vapour pressure deficits (VPDs). Stem water potential was the first parameter to be negatively affected by stress and determined the simultaneous reduction of fruit xylem flow, which at 95 DAFB was reflected by a decrease in fruit daily growth. Leaf photosynthesis was reduced only from 95 DAFB on, but was not immediately reflected by a decrease in fruit phloem flow, which instead was reduced only at 145 DAFB. This work shows how water stress negatively affects pear fruit growth by reducing first its xylem and then its phloem inflow. This determines a progressive increase in the phloem relative contribution to growth, which lead to the typical higher dry matter percentages of stressed fruit

Osteogenic sarcoma of the extremity with detectable lung metastases at presentation - Results of treatment of 23 patients with chemotherapy followed by simultaneous resection of primary and metastatic lesions

BACKGROUND. In the past 20 years, it has been demonstrated that the combination of surgery and chemotherapy improves the prognosis for patients with osteosarcoma of the extremity without detectable metastases at presentation: By contrast, the efficacy of chemotherapy coupled with aggressive surgery has not. yet been well established for patients with metastatic disease at diagnosis. The current study evaluates the efficacy of chemotherapy associated with simultaneous surgery of primary and metastatic lesions in patients presenting with osteosarcoma of the extremity with lung metastases. METHODS. Patients with lung metastases originating from an osteosarcoma of the extremity received chemotherapy (high dose methotrexate, cisplatin, doxorubicin, and ifosfamide) followed by simultaneous resection of primary and metastatic lesions and additional chemotherapy RESULTS. Between January 1993 and lune 1995, 23 patients entered the study. After primary chemotherapy, lung metastases disappeared in three patients, whereas in four patients they remained surgically unresectable. All seven patients received surgical treatment of the primary tumor only. In the remaining 16 patients, a simultaneous resection of the primary and metastatic tumors was performed after chemotherapy. The resection of metastatic lesions resulted in a complete remission in 15 patients and an incomplete remission in 1 patient. All five patients who never achieved tumor free status died within a few months. Of the 18 patients who achieved radiologic remission at a 30-month follow-up (range, 14-50 months), 10 (55.5%) remained continuously free of disease, 7 relapsed with new metastases, and 1 died of to city. In 13 of the 18 patients who underwent a complete simultaneous resection of the primary and the metastatic lesions, or whose pulmonary metastases disappeared after chemotherapy, a strong correlation was found between degree of necrosis of the primary tumor and of the metastatic tumor. CONCLUSIONS. In patients presenting with osteosarcoma of the extremity with lung metastases, the combination of aggressive chemotherapy with simultaneous resection of the primary and metastatic lesions improves traditionally negative outcomes. The strong correlation found between the histologic response of the primary and metastatic tumors supports the strategy, largely used currently in the neoadjuvant treatment of osteosarcoma, of tailoring postoperative chemotherapy on the basis of the histologic response of the primary tumor to preoperative chemotherapy