Nuclear receptors in vascular biology

Nuclear receptors sense a wide range of steroids and hormones (estrogens, progesterone, androgens, glucocorticoid, and mineralocorticoid), vitamins (A and D), lipid metabolites, carbohydrates, and xenobiotics. In response to these diverse but critically important mediators, nuclear receptors regulate the homeostatic control of lipids, carbohydrate, cholesterol, and xenobiotic drug metabolism, inflammation, cell differentiation and development, including vascular development. The nuclear receptor family is one of the most important groups of signaling molecules in the body and as such represent some of the most important established and emerging clinical and therapeutic targets. This review will highlight some of the recent trends in nuclear receptor biology related to vascular biology

Recurring Candida albicans esophagitis in a HIV-infected patient undergoing long-Term antiretroviral therapy, and with absent-negligible immunodeficiency

A patient with HIV infection developed the first episode of AIDS-defining opportunism (severe Candida albicans esophagitis) with an underlying CD4+ lymphocyte count of 1,025 cells/µL. After treatment with a highly active antiretroviral therapy (HAART), taken with insufficient compliance and leaving a residual viral load, our patient suffered from two relapses of esophageal candidiasis, which occurred three months and seven years later, when his CD4+ lymphocyte count was 930 and 439 cells/µL, respectively, and a viral load slightly above 10(4) copies/mL was still present. Also in the HAART era, Candida esophagitis remains one of the most common AIDS-defining diseases, but a presentation with a concurrent CD4+ count above 1,000 cells/µL remains a rare exception, as well as the two isolated, subsequent relapses, occurred with a CD4+ count ranging from 439 to 930 cells/µL, and a residual HIV viremia due to insufficient adherence to the prescribed HAART regimens. Our case report represents the opportunity to revisit the epidemiology and, especially, the pathogenesis of this opportunistic fungal complication in HIV-infected patients and in other subjects at risk, on the ground of an extensive literature review, and to explore possible alternative supporting factors other than the crude absolute CD4+ lymphocyte count, with emphasis on the possible role of a persisting HIV viremia, and other potential contributing factors. Clinicians engaged with immunocompromised patients and subjects with HIV disease, should be aware that a Candida esophagitis may occur and relapse also when the cell-mediated immunity, as measured by a simple CD4+ cell count, do not show relevant abnormalities

Difficult to control atopic dermatitis

Difficult to control atopic dermatitis (AD) presents a therapeutic challenge and often requires combinations of topical and systemic treatment. Anti-inflammatory treatment of severe AD most commonly includes topical glucocorticosteroids and topical calcineurin antagonists used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, the topical calcineurin inhibitors tacrolimus and pimecrolimus are preferred in certain locations. Systemic anti-inflammatory treatment is an option for severe refractory cases. Microbial colonization and superinfection contribute to disease exacerbation and thus justify additional antimicrobial/antiseptic treatment. Systemic antihistamines (H1) may relieve pruritus but do not have sufficient effect on eczema. Adjuvant therapy includes UV irradiation preferably of UVA1 wavelength. "Eczema school" educational programs have been proven to be helpful

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells

Air‐polishing followed by ultrasonic calculus removal for the treatment of gingivitis: A 12‐month, split‐mouth randomized controlled clinical trial

Objective: To evaluate the advantages of a novel protocol involving full-mouth erythritol-powder air-polishing followed by ultrasonic calculus removal in the maintenance of patients treated for gingivitis, with a focus on time and comfort. Methods: Systemically healthy patients with gingivitis were selected. Following a split-mouth design, quadrants 1-4 and 2-3 were randomly allocated to receive air-polishing followed by ultrasonic calculus removal following a protocol known as Guided Biofilm Therapy (GBT) or traditional full-mouth ultrasonic debridement followed by polishing with a rubber cup and prophylactic paste (US + P). Bleeding on probing (BoP) and the plaque index (PI) were collected at baseline (T0), 2 weeks (T1), 4 weeks (T2), 3 months (T3), and 6 months (T4) and 12 months (T5). Following the same randomization, prophylactic therapy was provided at 3 months (T3) and 6 months (T4). Clinical parameters, treatment time and patient comfort and satisfaction were evaluated. Results: A total of 41 patients were selected, 39 completed the study. The clinical parameters were clinically satisfactory for both treatments at every time. At 4 months after treatment, GBT maintained significantly lower BoP and PI. GBT protocol required a significantly lower treatment time, especially at T3 and T4, when it saved 24.5% and 25.1% of the time, respectively. Both treatments were rated positively by most patients. However, GBT was perceived as more comfortable, and a higher number of patients preferred it. Conclusion: No significant difference was observed between GBT and conventional ultrasonic debridement and rubber cup polishing in terms of BoP and PI levels. The GBT protocol allowed less time expenditure and higher patients' perceived comfort

Begging and parental care in relation to offspring need and condition in the barn swallow (Hirundo rustica)

Parents are selected to maximize their fitness by allocating care among their progeny in relation to the differential reproductive value of offspring. Nestlings have been hypothesized to signal need for parental care reliably through their begging behavior, but offspring condition as reflected by their reproductive value may likewise affect begging and hence provisioning. We assessed the relative importance of need and condition in determining begging behavior and feeding rate of nestling barn swallows (Hirundo rustica) through short-term starvation, a challenge to their immune system with a foreign antigen negatively affecting condition, and brood size manipulation. Food deprivation but not condition or brood size manipulation increased nestling begging rate. Parents fed offspring depending on both need and condition but only when feeding broods that were reduced or of normal size. In enlarged broods, offspring received less food per capita than in reduced broods, and parents did not discriminate among nestlings relative to their need or condition. Thus, nestlings signal their need by increased solicitation. Parents allocate food to offspring dependent on both need and condition, with these effects depending on parental workload as determined by experimental brood size

Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat.

Background: Hypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies. Methods: In order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90 min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24 h and 72 h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array. Results: We found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-\u3b1 in CSF showed an upregulation at 24 h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72 h in CSF. At 24 h post-injury, we observed an increase of Edn1, Hif1-\u3b1, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72 h post-injury. Conclusions: Our work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits

Aerosols Contamination in the Dental Practice Following Everyday Procedures: An Observational Study

ObjectiveThe purpose of the present observational study was to evaluate the bacterial load in the air following various dental procedures. MethodsAir contamination following seven aerosol-generating dental procedures was assessed. The air volume was sampled by a wet cyclone collector for 10 min during 10 sessions of the following procedures: air-polishing, ultrasonic instrumentation, manual instrumentation, rubber cup polishing, cavity preparation with a 1:5 red contra-angle, cavity preparation with turbine and Low Volume Evacuator (LVE), and cavity preparation with turbine and High Volume Evacuator (HVE). Contamination of the sampled solution was determined using ATP (Adenosine TriPhosphate) quantification of the viable bacterial count, and compared to baseline measurements. ResultsThe baseline air contamination was 1.45 (0.85-2.04) CFUs/L of air. The highest increase in air contamination was observed after the use of a turbine with LVE, with an average of 7.38 (95% CI 3.87-10.89) CFUs/L of air (p < 0.01). The use of the turbine with HVE and the use of the red hand-piece resulted in non-significant increases in bacterial counts compared to baseline (2.98 [1.34-4.63] and 2.70 [0.18-4.22] CFUs/L of air respectively). The application of air polishing, ultrasonic instrumentation, hand instrumentation and rubber cups did not result in a higher bacterial count than the baseline. ConclusionRoutine professional oral hygiene procedures do not increase air contamination. However, cavity excavation with LVE creates a significantly higher bacterial count in the air

Relationship between Lower Limbs Performance and Spinal Alignment in Parkinson’s Disease Patients: An Observational Study with Cross Sectional Design

Parkinson’s disease (PD) is a progressive neurodegenerative disease determining spinal deformities and muscle rigidity, weakness and dystonia that can be related to a change in muscular output during sit-to-stand tasks (STS). Purpose: The aim of this study was to determine the impacts of spinal alignment on lower limbs performance during STS tasks in Parkinson’s disease (PD) patients and healthy controls. Methods: In total, 43 consecutive PD patients (“PD” Group, 25 males and 18 females; age 73.7 ± 7.1) and 42 people not affected by any type of neurological disease (“CON” Group, 22 males, 20 females; age 69.8 ± 6.0) participated in the observational study. The clinical assessment included: IPAQ (International Physical Activity Questionnaire), Hoehn Yahr score, plumbline distance from the spinous process of C7, kyphosis apex and the spinous process of L3 and S1. We used the Muscle Quality Index test (MQI) to assess muscle power output during STS in both groups. Results: The MQI test measurements of absolute and relative lower limb power was significantly lower in the PD group, in addition to a negative correlation with age and a positive correlation with PL-L3 in that group of patients. Conclusions: A final consideration regarding our results leads to the possibility that the preservation of lumbar lordosis may be one of the factors for maintaining efficient biomechanics of the lower limb muscles, with the preservation of the physiological contractile characteristics of these muscles being the objective for a multidisciplinary rehabilitation based on postural exercises of the spine and a program of training exercises for the lower limb muscles