DGK\u3b1 in Neutrophil Biology and Its Implications for Respiratory Diseases

Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGK\u3b1 and DGK\u3b6 as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGK\u3b1, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGK\u3b1 activation is necessary for migration and a productive response. The role of DGK\u3b1 in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGK\u3b1 transcript. Together with in vitro experiments, this suggests that DGKs may represent potential therapeutic targets for disorders where inflammation, and neutrophils in particular, plays a major role. In this paper we focus on obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), but also rare genetic diseases such as alpha-1-antitrypsin deficiency. Indeed, the biological role of DGK\u3b1 is understudied outside the T lymphocyte field. The recent wave of research aiming to develop novel and specific inhibitors as well as KO mice will allow a better understanding of DGK\u2019s role in neutrophilic inflammation. Better knowledge and pharmacologic tools may also allow DGK to move from the laboratory bench to clinical trials

Enhanced osteogenic differentiation in zoledronate-treated osteoporotic patients

Bisphosphonates are well known inhibitors of osteoclast activity and thus may be employed to influence osteoblast activity. The present study was designed to evaluate the in vivo effects of zoledronic acid (ZA) on the proliferation and osteoblastic commitment of mesenchymal stem cells (MSC) in osteoporotic patients. We studied 22 postmenopausal osteoporotic patients. Densitometric, biochemical, cellular and molecular data were collected before as well as after 6 and 12 months of ZA treatment. Peripheral blood MSC-like cells were quantified by colony-forming unit fibroblastic assay; their osteogenic differentiation potential was evaluated after 3 and 7 days of induction, respectively. Circulating MSCs showed significantly increased expression levels of osteoblastic marker genes such as Runt-related transcription factor 2 (RUNX2), and Osteonectin (SPARC) during the 12 months of monitoring time. Lumbar bone mineral density (BMD) variation and SPARC gene expression correlated positively. Bone turnover marker levels were significantly lowered after ZA treatment; the effect was more pronounced for C terminal telopeptide (CTX) than for Procollagen Type 1 N-Terminal Propeptide (P1NP) and bone alkaline phosphatase (bALP). Our findings suggest a discrete anabolic activity supported by osteogenic commitment of MSCs, consequent to ZA treatment. We confirm its anabolic effects in vivo on osteogenic precursors

Early cardiovascular involvement in Chronic Obstructive Pulmonary Disease

Cardiovascular (CV) disease represents a considerable risk factor in terms of both morbidity and mortality in elderly patients with chronic obstructive pulmonary disease (COPD). In fact, there is a considerable evidence of this association: for only 20 years forced expiratory volume in 1 second (FEV1) has been considered as predictive of cardiovascular mortality especially in elderly patients. At present, the emerging evidence suggests that hypoxia, systemic inflammation, oxidative stress may cause an early sub-clinical cardiovascular involvement in patients with COPD. Aging is a selective process dramatically affecting certain portions of the cardiovascular system for example: diminished beta-adrenergic responsiveness, increased myocardial and vascular stiffness, decreased arterial baroreflex, vagal outflow and compromission of diastolic function. The nature of these interactions is complex and involves not only mechanisms of aging but also multiple defined and undefined (e.g., genetic) risk factors. Cardiovascular diseases are the main causes of mortality among the subjects with impaired lung function. Even mild reductions in expiratory flow volumes amplify the risk of ischemic heart diseases, strokes, and sudden cardiac deaths 2-to 3-fold, independent of other risk factors. The mechanism or mechanisms responsible for this association, however, remain largely unknown

Intrauterine growth pattern and birthweight discordance in twin pregnancies: a retrospective study

Background: Twins, compared to singletons, have an increased risk of perinatal mortality and morbidity, due mainly to a higher prevalence of preterm birth and low birthweight. Intrauterine growth restriction (IUGR) is also common and can affect one or both fetuses. In some cases, however, one twin is much smaller than the other (growth discordance). Usually, high birthweight discordance is associated with increased perinatal morbidity. The aim of this study is to describe the epidemiological features of a population of twins at birth, with particular reference to the interpretation and clinical effects of birthweight discordance. Methods: We evaluated retrospectively the clinical features of 70 infants born from twin pregnancies and assessed birthweight discordance in 31 pregnancies where both twins were followed at our institution. Discordance was treated both as a continuous and a categorical variable, using a cutoff of 18%. Possible relationships between birthweight discordance and other variables, such as maternal age, gestational age, birthweight percentile, number of SGA newborns in the pair, Hematocrit (Ht) discordance and neonatal anemia, prevalence of malformations, neonatal morbidity and death, were analyzed. Results: In our cohort birthweight percentile decreased slightly with increasing gestational age. Birthweight discordance, on the contrary, increased slightly with the increase of gestational age. A high discordance is associated to the presence of one SGA twin, with the other AGA or LGA. In our population, all 6 pregnancies in which discordance exceeded 18% belonged to this category (one SGA twin). Ht discordance at birth is associated to the presence of neonatal anemia in a twin, but it is not significantly related to weight discordance. Finally, in our case history, weight discordance is not associated in any way with the prevalence of malformations, morbidity and mortality. Conclusions: Birthweight discordance is an important indicator of complications that act asymmetrically on the two fetuses, affecting intrauterine growth in one of them, and usually determining the birth of a SGA infant. Our case history shows a significant statistical association between pair discordance and IUGR in one of the twins, but we could not demonstrate any relationship between discordance and the prevalence of malformations, morbidity and mortality

In situ formation and size control of gold nanoparticles into chitosan for nanocomposite surfaces with tailored wettability.

The in situ formation of gold nanoparticles into the natural polymer chitosan is described upon pulsed laser irradiation. In particular, hydrogel-type films of chitosan get loaded with the gold precursor, chloroauric acid salt (HAuCl4), by immersion in its aqueous solution. After the irradiation of this system with increasing number of ultraviolet laser pulses, we observe the formation of gold nanoparticles with increasing density and decreasing size. Analytical studies using absorption measurements, atomic force microscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy of the nanocomposite samples throughout the irradiation procedure reveal that under the specific irradiation conditions there are two competing mechanisms responsible for the nanoparticles production: the photoreduction of the precursor responsible for the rising growth of gold particles with increasing size and the subsequent photofragmentation of these particles into smaller ones. The described method allows the loca..

Interrelationship among Obstructive Sleep Apnea,Renal Function and Survival: A Cohort Study

Previous studies showed a bidirectional relationship between renal function decline and obstructive sleep apnea (OSA) syndrome. Continuous Positive Airway Pressure (C-PAP) treatment was shown to preserve the kidney function in OSA patients. This study aims to investigate the progression of long-term renal function in OSA patients treated with different PAP strategies (patients were divided into two groups, fixed C-PAP or other PAP—automatic and bilevel pressure). Comorbidities and 10-years survival were also evaluated. We performed a retrospective, observational, single-center, cohort study, including the first 40 consecutive patients enrolled from 2009 in the Respiratory disease Unit at the Vercelli University Hospital database. The patient inclusion criteria were: age ≥ 18 years with OSA syndrome according to AASM (American Academy of Sleep Medicine) guidelines. Creatinine serum levels (mg/dL) and the estimated Glomerular Filtration Rate (eGFR, mL/min calculated by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration equation)) were measured at 3 different time points: at baseline, 3 years and 8 years after PAP treatment. The Kaplan–Meier survival curves stratified according to PAP treatment and compliance have been reported together with log-rank test estimation. In our study, we found a significant creatinine serum level reduction after 3 years of fixed C-PAP treatment (p value = 0.006) when compared to baseline values. However, we observed that the long-term C-PAP benefit was not significant (p value = 0.060). Our data confirmed the progressive renal function decline in OSA patients, especially in those using other-PAP treatments; nevertheless, OSA treatment with a fixed C-PAP device has shown, in the short term, a significant improvement in renal function. By contrast, in our study, long-term benefits after 8 years are not been demonstrated probably because of the lack of compliance of the patients and the aging effect

Predictive markers of bronchial hyperreactivity in a large cohort of young adults With cough variant asthma

Cough variant asthma (CVA), a common asthma phenotype characterized by nonproductive cough and bronchial hyperreactivity (BHR), is usually detected by bronchial provocation tests (BPTs) which are time-consuming, expensive, and unsafe. The primary study objective was to provide proof of concept for the use of fractional exhaled nitric oxide (FENO), eosinophil count percentage in induced sputum (sEOS%), forced expiratory flow between 25 and 75% of forced vital capacity (FEF25–75%) % predicted value, and FEF25–75% z-scores as surrogate markers predicting BHR in young adults with suspected CVA; the secondary objective was to compare the diagnostic performance of the various techniques. Three hundred and ten subjects (median age 24 years) were included in a cross-sectional study. Subjects were characterized as BHR positive (POS) (n 147) or BHR negative (NEG) (n 163) according to methacholine BPT. Classification accuracies were expressed as areas under the receiver operator characteristic curves (AUC). Compared with BHR NEG, FEF25–75% % predicted value and FEF25–75% z-scores were lower in the BHR POS group (p < 0.001), whereas FENO (p < 0.001) and sEOS% were higher (p < 0.001). AUC values for detecting BHR were as follows: FENO, 0.98 (SD 0.02); sEOS%, 0.98 (SD 0.02); FEF25–75% % pred, 0.93 (SD 0.05); FEF25–75% z scores, 0.92 (SD 0.05). Optimal cutoff values (OCV) for BHR prediction were as follows: FENO, 32.7 ppb (sensitivity 0.93, specificity 0.96), sEOS %, 3.80% (sensitivity 0.94, specificity 0.94), FEF25–75% % predicted value, 80.0% (sensitivity 0.90, specificity 0.87), and FEF25–75% z-score, −0.87 (sensitivity 0.89, specificity 0.87). Non-invasive/semi-invasive airway inflammatory or small airway functional measures might be used as surrogate markers predicting BHR in young adults with suspected CV

Low power saturation of an ISB transition by a mid-IR quantum cascade laser

We demonstrate that absorption saturation of a mid-infrared intersubband transition can be engineered to occur at moderate light intensities of the order of 10-20 kW.$\text{cm}^{-2}$ and at room temperature. The structure consists of an array of metal-semiconductor-metal patches hosting a judiciously designed 253~nm thick GaAs/AlGaAs semiconductor heterostructure. At low incident intensity the structure operates in the strong light-matter coupling regime and exhibits two absorption peaks at wavelengths close to 8.9 $\mu$m. Saturation appears as a transition to the weak coupling regime - and therefore to a single-peaked absorption - when increasing the incident power. Comparison with a coupled mode theory model explains the data and permits to infer the relevant system parameters. When the pump laser is tuned at the cavity frequency, the reflectivity decreases with increasing incident power. When instead the laser is tuned at the polariton frequencies, the reflectivity non-linearly increases with increasing incident power. At those wavelengths the system therefore mimics the behavior of a saturable absorption mirror (SESAM) in the mid-IR range, a technology that is currently missing

Single Inhaler LABA/LAMA for COPD

Chronic obstructive pulmonary disease (COPD) is a common disabling disease characterized by progressive airflow obstruction. Great efforts were spent in the development of drugs able to improve symptoms, quality of life, reduce exacerbations, hospitalizations and the frequency of death of patients with COPD. The cornerstones of treatment are bronchodilator drugs of two different classes: beta agonists and muscarinic antagonists. Currently the Global initiative for COPD suggests the use of long acting beta agonists (LABAs) and long acting muscarinic antagonists (LAMAs) in combination for the majority of COPD patients, thus great interest is associated with the developing of LAMA/LABA fixed combination in the maintenance treatment of stable COPD. Many LAMA/LABA fixed dose combinations have been licensed in different countries and the clinical use of these drugs stimulated the performance of many clinical trials. The purpose of this review is a complete criticism of pharmacological and clinical aspects related to the use of LAMA/LABA single inhalers for the maintenance treatment of stable COPD, with particular mention to the most debated topics and future prospects in the field

SiNAPS: An implantable active pixel sensor CMOS-probe for simultaneous large-scale neural recordings

Abstract Large-scale neural recordings with high spatial and temporal accuracy are instrumental to understand how the brain works. To this end, it is of key importance to develop probes that can be conveniently scaled up to a high number of recording channels. Despite recent achievements in complementary metal-oxide semiconductor (CMOS) multi-electrode arrays probes, in current circuit architectures an increase in the number of simultaneously recording channels would significantly increase the total chip area. A promising approach for overcoming this scaling issue consists in the use of the modular Active Pixel Sensor (APS) concept, in which a small front-end circuit is located beneath each electrode. However, this approach imposes challenging constraints on the area of the in-pixel circuit, power consumption and noise. Here, we present an APS CMOS-probe technology for Simultaneous Neural recording that successfully addresses all these issues for whole-array read-outs at 25 kHz/channel from up to 1024 electrode-pixels. To assess the circuit performances, we realized in a 0.18  μ m CMOS technology an implantable single-shaft probe with a regular array of 512 electrode-pixels with a pitch of 28  μ m. Extensive bench tests showed an in-pixel gain of 45.4 ± 0.4 dB (low pass, F-3 dB = 4 kHz), an input referred noise of 7.5 ± 0.67 μVRMS (300 Hz to 7.5 kHz) and a power consumptio