COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement

Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.     

Predicting toxicity in marine sediment in Taranto Gulf (Ionian Sea,Southern Italy) using Sediment Quality Guidelines and a battery bioassay

The goal of this study was to assess coastal marine pollution in the Mar Piccolo and Taranto Gulf (Ionian Sea, Southern Italy) by combining chemical and toxicological data in order to compare and integrate both approaches. Pollutants levels, traditionally, have limited ability to predict adverse effects on living resources. Moreover, in order to provide information on the ecological impact of sediment contamination on aquatic biota Numerical Sediment Quality Guidelines (SQGs) and sediment toxicity bioassays were carefully recommended. In this study ERL (effect range low)/ERM (effect range medium value) and TEL (threshold effect level)/PEL (probable effect level) guidelines have been used. Bioassays were performed with two species of amphipods Gammarus aequicauda and Corophium insidiosum, one species of isopod Idotea baltica and bivalve Mytilus galloprovincialis larvae. The TEL/PEL analysis suggested that, especially for stations 1 and 2, sediments in Mar Piccolo should contain acutely toxic concentrations of metals. In particular Hg content, in station 1, was about 17 times PEL value. 96 h LC₅₀ and 48 h EC₅₀ values were estimated for cadmium, copper and mercury in these species using the static acute toxicity test. M. galloprovincialis larvae was more sensitive than other species to all the reference toxicants tested (EC₅₀ determined for cadmium copper and mercury were of 0.59, 0.11 and 0.01 mg/l respectively). Significant differences in sensitivity of species tested to all reference toxicants (ANOVA p < 0.001) were recorded. Bioassays with these species allowed to estimated sediment toxicity from the different studied sites. On the basis of results obtained a good agreement was reported between chemical data and response of the biological endpoints tested.     

Design of stereoselective Ziegler-Natta propene polymerization catalysts

After five decades of largely serendipitous (albeit formidable) progress, catalyst design in Ziegler-Natta olefin polymerization, i.e., the rational implementation of new active species to target predetermined polyolefin architectures, has ultimately become a realistic ambition, thanks to a much deeper fundamental understanding and major advances in the tools of computational chemistry. In this article, we discuss, as a case history, a unique class of stereorigid C2-symmetric bis(phenoxy-amine)Zr(IV) catalysts with controlled kinetic behavior. A large variety of polypropylene microstructures have been obtained with these catalysts by modulating the steric demand of one key substituent, without altering the nature and symmetry of the ancillary ligand framework, under the guidance of computer modeling. This unusual achievement is relevant per se and for the perspective implications in catalyst discovery.     

Assessment of Granger Causality by Nonlinear Model Identification: Application to Short-term Cardiovascular Variability

A method for assessing Granger causal relationships in bivariate time series, based on nonlinear autoregressive (NAR) and nonlinear autoregressive exogenous (NARX) models is presented. The method evaluates bilateral interactions between two time series by quantifying the predictability improvement (PI) of the output time series when the dynamics associated with the input time series are included, i.e., moving from NAR to NARX prediction. The NARX model identification was performed by the optimal parameter search (OPS) algorithm, and its results were compared to the least-squares method to determine the most appropriate method to be used for experimental data. The statistical significance of the PI was assessed using a surrogate data technique. The proposed method was tested with simulation examples involving short realizations of linear stochastic processes and nonlinear deterministic signals in which either unidirectional or bidirectional coupling and varying strengths of interactions were imposed. It was found that the OPS-based NARX model was accurate and sensitive in detecting imposed Granger causality conditions. In addition, the OPS-based NARX model was more accurate than the least squares method. Application to the systolic blood pressure and heart rate variability signals demonstrated the feasibility of the method. In particular, we found a bilateral causal relationship between the two signals as evidenced by the significant reduction in the PI values with the NARX model prediction compared to the NAR model prediction, which was also confirmed by the surrogate data analysis. Furthermore, we found significant reduction in the complexity of the dynamics of the two causal pathways of the two signals as the body position was changed from the supine to upright. The proposed is a general method, thus, it can be applied to a wide variety of physiological signals to better understand causality and coupling that may be different between normal and diseased conditions.     

Ventriculostomy-related hemorrhage in patients on antiplatelet therapy for endovascular treatment of acutely ruptured intracranial aneurysms. A meta-analysis

The risk of ventriculostomy-related hemorrhage among patients requiring antiplatelet therapy (AT) for the endovascular treatment of acutely ruptured intracranial aneurysms needed further investigation. The authors performed a systematic review and meta-analysis of the literature examining the EVD-related hemorrhage rate among patients with and without AT (controls). According to PRISMA guidelines, a comprehensive review of studies published between January 1990 and April 2018 was carried out. The authors identified series with > 5 patients reporting the EVD-associated hemorrhage rate among the AT group and the control group. Variables influencing outcomes were analyzed using a random-effects meta-analysis model. We included 13 studies evaluating 516 (with AT) and 647 (without AT) patients requiring ventriculostomy. EVD-related hemorrhage rates were higher among the AT group (125/516 = 20.9%, 95% CI = 11.9–30%, I2 = 90% vs 57/647 = 9%, 95% CI = 5.5–12.5%, I2 = 45.8%) (p < 0.0001). Major EVD-associated hemorrhage rates were low in both the AT and control group (25/480 = 4.4%, 95% CI = 1.7–7.7%, I2 = 53.9% vs 6/647 = 0.7%, 95% CI = 0.03–1.7%, I2 = 0%) (p < 0.0001). Ventriculostomy before embolization and intraprocedural AT were associated with lower rates of EVD-related bleeding (32/230 = 9.6%, 95% CI = 2.1–17.1%, I2 = 75.4% vs 6/24 = 25.1%, 95% CI = 8.8–41%, I2 = 0%) (p < 0.02). The rate of major hemorrhage was higher after dual AT (CP + ASA) compared to single AT (ASA or CP) used as an intraprocedural loading dose (13/173 = 7%, 95% CI = 3.3–10.7%, I2 = 0% vs 6/210 = 1.7%, 95% CI = 0.1–3.4%, I2 = 0%) (p < 0.009). AT during endovascular treatment of acutely ruptured intracranial aneurysms increases the risk of EVD-related hemorrhages, although most of them are small and asymptomatic. When ventriculostomy is performed before endovascular procedures requiring antiplatelet administration, the hemorrhagic risk is minimized. A single antiplatelet therapy is associated with a lower rate of major bleeding than a dual therapy.     

Evaluation of targetable biomarkers for chimeric antigen receptor T-cell (CAR-T) in the treatment of pancreatic cancer: a systematic review and meta-analysis of preclinical studies

Abstract

One of the cutting edge techniques for treating cancer is the use of the patient’s immune system to prevail cancerous disease. The versatility of the chimeric antigen receptor (CAR) T-cell approach in conjugation with promising treatments in haematological cancer has led to countless cases of research literature for the treatment of solid cancer. A systematic search of online databases as well as gray literature and reference lists of retrieved studies were carried out up to March 2019 to identify experimental animal studies that investigated the antigens targeted by CAR T-cell for pancreatic cancer treatment. Studies were evaluated for methodological quality using the SYstematic Review Center for Laboratory Animal Experimentation bias risk tool (SYRCLE’s ROB tool). Pooled cytotoxicity ratio/percentage and 95% confidence intervals were calculated using the inverse-variance method while random-effects meta-analysis was used, taking into account conceptual heterogeneity. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I² statistic using Stata 13.0. Of the 485 identified studies, 56 were reviewed in-depth with 16 preclinical animal studies eligible for inclusion in the systematic review and 11 studies included in our meta-analysis. CAR immunotherapy significantly increased the cytotoxicity assay (percentage: 65%; 95% CI: 46%, 82%). There were no evidence for significant heterogeneity across studies [P?=?0.38 (Q statistics), I2?=?7.14%] and for publication bias. The quality assessment of included studies revealed that the evidence was moderate to low quality and none of studies was judged as having a low risk of bias across all domains. CAR T-cell therapy is effective for pancreatic cancer treatment in preclinical animal studies. Further high-quality studies are needed to confirm our finding and a standard approach of this type of studies is necessary according to our assessment.     

Semi-structured physical activity intervention in daily life: a good compromise between effectiveness and feasibility

Background

As older-aged population is continuously increasing, it is essential to promote physical activity (PA) to preserve health and autonomy in daily living. Although several methods have been proposed, combining sustainability and efficacy at the same time is still a challenge.

Aims

To evaluate the effects of a semi-structured PA (SSPA) intervention including aerobic as well as strength and flexibility exercise in comparison to generic PA advice (PAAdv) in healthy older adults.

Methods

86 sedentary older adults were divided in two groups, SSPA (n?=?56) and PAAdv (n?=?30). Body weight (BW) and circumferences, blood pressure (BP), submaximal exercise heart rate (HR), as well as Chair Stand Test (CST), Arm Curl Test (ACT), Chair Sit-and-Reach Test (CSRT) and Back Scratch Test (BST) were performed before and after 16 weeks of intervention. SSPA group was further divided in SSPA?>?500 and SSPA?<?500 according to the total amount of PA performed (cut-off level of 500 MET min/week).

Results

Overall, SSPA groups improved more than the PAAdv group on WC, HC, BP, CST, ACT, CSRT and BST. SSPA?>?500 improved more than SSPA?<?500 and PAAdv on CST (+?20.2, +?11.3, +?4.5% respectively), ACT (+?21.5, +?14.9, ??1.3%, respectively), and CSRT (+?3.7, +?0.80, +?0.75 cm, respectively), and similarly to SSPA?<?500 on BST. Submaximal HR values significantly decreased for the SSPA?>?500 and PAAdv groups.

Conclusions

An SSPA program represents an ecological way to enhance fitness in older adults. A greater amount of SSPA (>?500 versus <?500 MET min/week) is associated with higher cardiovascular and muscular fitness benefits.

     

Familial gastric cancer: overview and guidelines for management

Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germline E-cadherin/CDH1 mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germline E-cadherin/CDH1 mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.