Evaluation of two-staged Fowler-Stephens laparoscopic orchidopexy (FSLO) for intra-abdominal testes (IAT).
The best operative intervention for intrabdominal testis (IAT) has not been standardized as yet. The question of whether to bring down an IAT with a single-staged vessel-intact laparoscopic orchidopexy (VILO) or a two-staged laparoscopic Fowler-Stephens orchidopexy (FSLO) is still undergoing debate, with both the procedures being popular. The present study has been designed to evaluate the factors predicting the success or failure of two-staged FSLO for (IAT). 43 boys with 49 non-palpable testes underwent diagnostic laparoscopy out of which 35 underwent two-staged FSLO. Size of the testis was measured with a graduated probe in both stages. Independent variables such as age, height, testis-to-internal ring distance (T-IR), neo internal ring-to-midscrotal distance (NIR-MS), and mobility-to-contralateral ring (MCIR) were analysed. Postoperatively 34 IATs were followed up clinically as well as ultrasonologically after 6 months, to see for the size, position, and vascularity. Based on this, the patients were divided into two groups, Group A (successful) and Group B (Failed). 24 IATs had a successful outcome (Group A) and 11 were failure (Group B). The overall success rate of the study was 68.6%. The difference in mean age of patients in both groups was insignificant (p = 0.89) (Fig. 1), and similarly, the difference in mean height was insignificant (p = 0.61). The difference in mean T-IR in both the groups was insignificant (1.85 versus 2.77 cm; p = 0.09) and mean NIR-MS was 5.41 cm in Group A and 5.10 cm in Group B, and the difference again was insignificant (p = 0.23). The success rate of FSLO was 68.6%. None of the above-described independent variables have any effect on the outcome of two-staged FSLO. While VILO remains the treatment of choice for IAT located at or near the ring, but IAT higher than this, two-staged FSLO gives a better chance for achieving intra-scrotal orchidopexy.


Determination of co-receptor usage of HIV-1.
In addition to CD4, HIV-1 uses chemokine receptors for entry in their target cells. The most important chemokine receptors in this respect are beta-chemokine receptor 5 (CCR5) and alpha-chemokine receptor 4 (CXCR4). Coreceptor usage is an important feature of the biological phenotype of HIV-1 variants. In this chapter, methods are described to determine the co-receptor usage of HIV-1 variants.


A nonhuman primate model for evaluating the potential of antihypertensive drugs to cause orthostatic hypotension.
The potential of several classes of antihypertensive drugs to cause orthostatic hypotension in man was evaluated in a conscious cynomolgus monkey model. Supine and erect blood pressure and heart rate were continuously monitored before and after administration of chlorisondamine (a ganglionic blocking agent); phentolamine and prazosin (alpha-adrenergic blocking agents); propranolol (a beta-adrenergic blocking agent); and minoxidil (a vasodilator). Substantial validation of the model was accomplished when it was observed that these drugs evoked cardiovascular responses in the animal model which were similar to those which had been described in the clinical literature.


Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol.
Patients receiving warfarin who experience minor head injury are at risk of intracranial hemorrhage, and optimal management after a single head computed tomography (CT) scan is unclear. We evaluate a protocol of 24-hour observation followed by a second head CT scan. In this prospective case series, we enrolled consecutive patients receiving warfarin and showing no intracranial lesions on a first CT scan after minor head injury treated at a Level II trauma center. We implemented a structured clinical pathway, including 24-hour observation and a CT scan performed before discharge. We then evaluated the frequency of death, admission, neurosurgery, and delayed intracranial hemorrhage. We enrolled and observed 97 consecutive patients. Ten refused the second CT scan and were well during 30-day follow-up. Repeated CT scanning in the remaining 87 patients revealed a new hemorrhage lesion in 5 (6%), with 3 subsequently hospitalized and 1 receiving craniotomy. Two patients discharged after completing the study protocol with 2 negative CT scan results were admitted 2 and 8 days later with symptomatic subdural hematomas; neither received surgery. Two of the 5 patients with delayed bleeding at 24 hours had an initial international normalized ratio greater than 3.0, as did both patients with delayed bleeding beyond 24 hours. The relative risk of delayed hemorrhage with an initial international normalized ratio greater than 3.0 was 14 (95% confidence interval 4 to 49). For patients receiving warfarin who experience minor head injury and have a negative initial head CT scan result, a protocol of 24-hour observation followed by a second CT scan will identify most occurrences of delayed bleeding. An initial international normalized ratio greater than 3 suggests higher risk.


Gleason Score 6 - Prostate Cancer or Benign Variant?
The leading motivation behind wanting to call a 'malignant' prostate lesion 'benign' is the evidence of indolent prostate cancer that is not associated with a fatal outcome and in part makes therapeutic measures such as surgery and radiotherapy appear like overtreatment for some or possibly the majority of such patients. The present article reviews the definitions of 'precancerous lesion' and 'cancer' from a histopathologic point of view as the basis and gold standard for diagnosis. It is clear that with the 2 modifications implemented since its first publication, the Gleason score as the grading system for prostate cancer has shifted towards a low malignant subgroup diagnosed as Gleason 6. The recommendation of the International Society of Urological Pathology to change the Gleason score to a 5-tiered system, starting with grade group 1, is presented here, and may help doctor-patient communication especially in the active surveillance setting.


Use of a Brief Negotiation Interview in the emergency department to reduce high-risk alcohol use among older adults: A randomized trial.
To determine whether a Brief Negotiation Interview (BNI) performed in the emergency department (ED) can reduce future rates of alcohol use among older adults who are high-risk drinkers. Adults aged 65 years and older in a single academic ED were screened for high-risk alcohol use based on the National Institute for Alcohol Abuse and Alcoholism definition of >7 drinks per week or >3 drinks per occasion. Eligible individuals who were high-risk drinkers who passed a cognitive impairment screener and who consented to enrollment were randomly assigned to receive the BNI versus usual care. Outcomes were assessed at 3, 6, and 12 months. The primary outcome was the rate of high-risk alcohol use at 6 months. Of 2250 ED patients who were screened, 183 (8%) met the criteria for high-risk alcohol use. Of those, 98 (53%) patients met full criteria and consented to participation. Of the participants, 67% were men and 83% were non-Hispanic White. There was no significant difference in the primary outcome of high-risk alcohol use at 6 months between the BNI at 59.1% (95% confidence interval [CI], 45.5%-76.8%) and the control at 49.1% (95% CI, 36.9%-65.2%). However, there was a significant time-effect reduction in alcohol consumption and rates of high-risk alcohol use for both groups. Among older adults who met the criteria for high-risk alcohol use, the BNI in the ED did not result in a reduction in high-risk alcohol use at 6 months, although both groups showed significant reductions after their ED visit. Further work is needed to determine the optimal setting and time to use the BNI to impact high-risk alcohol use in this population.


13,845 home therapy infusions with velaglucerase alfa exemplify safety of velaglucerase alfa and increased compliance to every-other-week intravenous enzyme replacement therapy for Gaucher disease.
Lifelong intravenous (IV) enzyme replacement therapy (ERT) every other week for Gaucher disease is appreciated as decreasing quality of life in a palpable way. To review the Israeli experience with the home therapy option for IV velaglucerase alfa (Shire, Lexington MA USA) infusions every-other-week in the clinical trial context, in the early access program (EAP) during a shortage with the standard commercial ERT, and currently with the commercially available drug (VPRIV, Shire). Among 24 patients participating in trials, 1654 infusions were at home; in the EAP and commercial setting, 12,191 infusions were performed at home for a total of 154 patients with 98.4% compliance. There were no incidents of serious adverse events. This is the first review of experience of 174 patients and 13,845 intravenous infusions of velaglucerase alfa for Gaucher in the home setting, underscoring its safety.


Investigation of nuclear enzyme topoisomerase as a putative molecular target of monohaloacetonitrile disinfection by-products.
Disinfection by-products occur widely as the unintended effect of water disinfection and are associated with toxicity and adverse human health effects. Yet the molecular mechanisms of their toxicity are not well understood. To investigate the molecular basis of hyperploidy induction by monohaloacetonitriles, the interaction of monohaloacetonitriles with topoisomerase II in Chinese hamster ovary cells was examined. We showed a concentration-dependent inhibition of DNA decatenation activity of topoisomerase under acellular conditions while in vitro monohaloacetonitrile treatment expressed mixed results. The working hypothesis, that topoisomerase II is a molecular target of monohaloacetonitriles, was only partially supported. Nevertheless, this research serves as a starting point toward molecular mechanisms of toxic action of monohaloacetonitriles.


rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 and Glycemic Response in Individuals with Type 2 Diabetes Mellitus Receiving Metformin/Sulfonylurea Combination Therapy: 6-Month Follow-Up Study.
Since the treatment outcome with oral anti-diabetics differs between individuals, the objective of this study is to evaluate the significance of rs622342 in SLC22A1, CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910) with regard to the efficacy of metformin/sulfonylurea combination therapy in individuals with type 2 diabetes mellitus (T2DM). Eighty-eight Lebanese individuals with T2DM received metformin/sulfonylurea combination therapy over 3 and 6 months. The clinical and biochemical characteristics were collected. Genotyping of rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 was performed using hybridization probes on real-time polymerase chain reaction (PCR) instrument. Statistical analysis was performed using SPSS 22.0. The levels of fasting blood sugar (FBS) and glycated hemoglobin (HbA1c) showed a statistically significant reduction over 3 and 6 months of follow-up (p < 0.001). An interaction between rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 (p = 0.035) was found associated with reduced levels of HbA1c levels after 3 and 6 months. A significant difference between the means of HbA1c was observed among the different groups after 3 and 6 months (p = 0.004 and p < 0.001, respectively). The most beneficial group was; AA and AC, *1*3, whereas the individuals that benefited the least were CC, *1*3 at 3 and 6 months. In contrast to HbA1c, no interaction was found between the three polymorphisms to affect FBS (p = 0.581). The combination of metformin/sulfonylurea therapy led to the maximum glycemic control in individuals with T2DM carrying AA or AC genotypes in SLC22A1 and *1*3 in CYP2C9.


Bedside ultrasound diagnosis of vitreous hemorrhage and traumatic lens dislocation.
We report a case where an emergency physician using bedside ocular ultrasound was able to diagnose vitreous hemorrhage and lens dislocation in an elderly patient. Bedside ultrasound performed by a physician trained in this imaging modality can diagnose ocular emergencies, facilitating appropriate consultation and treatment.


Genomic analysis of SARS-CoV-2 in forensic autopsy cases of COVID-19.
Numerous genomic analyses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been conducted, highlighting its variations and lineage transitions. Despite the importance of forensic autopsy in investigating deaths due to coronavirus disease 2019 (COVID-19), including out-of-hospital deaths, viral genomic analysis has rarely been reported due in part to postmortem changes. In this study, various specimens were collected from 18 forensic autopsy cases with SARS-CoV-2 infection. Reverse-transcription quantitative polymerase chain reaction revealed the distribution of the virus in the body, primarily in the respiratory organs. Next-generation sequencing determined the complete genome sequences in 15 of the 18 cases, although some cases showed severe postmortem changes or degradation of tissue RNA. Intrahost genomic diversity of the virus was identified in one case of death due to COVID-19. The accumulation of single-nucleotide variations in the lung of the case suggested the intrahost evolution of SARS-CoV-2. Lung of the case showed diffuse alveolar damage histologically and positivity for SARS-CoV-2 by immunohistochemical analysis and in situ hybridization, indicating virus-associated pneumonia. This study provides insights into the feasibility of genomic analysis of SARS-CoV-2 in forensic autopsy cases and the potential for uncovering important information in COVID-19 deaths, including out-of-hospital deaths.


Correction: The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP.
[This corrects the article DOI: 10.18632/oncotarget.14928.].


Thoracic or thoracoabdominal approaches to endovascular device removal and open aortic repair.
Endovascular aortic repair is becoming increasingly common and diverse in its application despite ongoing uncertainty about long-term durability. Recent reports detail late conversion to open surgical repair to treat disease progression and repair failure. We describe our experience with using thoracic or thoracoabdominal approaches to endovascular device removal and open aortic repair after previous endovascular procedures. Thirty-five patients underwent open aortic repair through thoracotomy (n=7) or thoracoabdominal incision (n=28) 0.5 to 48 months after undergoing endovascular thoracic (n=27) or abdominal (n=8) aortic procedures. Indications for open repair included expanding aneurysm (n=23), device infection (n=8), fistula (n=5), pseudoaneurysm (n=2), aneurysm rupture (n=2), and restenosis (n=1). Endovascular devices were completely removed in 26 patients and partially removed in 9. Descending thoracic aortic repair was performed in 10 patients, thoracoabdominal aortic repair in 24, and juxtarenal abdominal aortic repair in 1. There were 2 in-hospital deaths (6%), both in patients who presented with endovascular device infection. There were 8 late deaths. Overall 1-year survival was 83%±7%. Among the patients who presented with infected devices, 3 experienced major late complications, including persistent infection, pseudoaneurysm, and recurrent fistula; 2 of these patients succumbed to late deaths. Open surgical repair after previous endovascular aortic procedures is successful in the majority of patients, particularly in those without device infections. Achieving definitive aortic repair in patients with infected endovascular devices is particularly challenging.


Electrodiffusional ATP movement through CFTR and other ABC transporters.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the superfamily of ATP-binding cassette (ABC) transporters, also known as traffic ATPases. Recent studies from our laboratory determined that various members of the ABC family of transport proteins mediate the electrodiffusional movement of the nucleotide ATP. In this report, evidence for the movement of cellular nucleotides by the ABC transporter CFTR and related molecules, including P-glycoproteins (Pgp), is reviewed. The wild-type mdr1 gene product, Pgp, enables the spontaneous release of cellular ATP. However, single amino acid substitutions in both nucleotide-binding sites render a dysfunctional Pgp, whose function can only be reversed by voltage activation. This report includes data indicating that reconstitution of highly purified CFTR from human epithelial origin enables the permeation of both Cl and ATP. The relevance of the ABC domains in ATP transport is also explored, and the hypothesis is forwarded that improper ATP transport by a dysfunctional CFTR is a relevant factor in cystic fibrosis.


Redox signaling in impaired cascades of wound healing: promising approach.
In the aging communities, wound healing management is a quite remarkable problem especially in elderly individuals. The optimal level of healing of wounds developed spontaneously or due to surgery is of critical importance in order to prevent the negative effects that may occur due to delayed healing (for example, organ or system damage caused by infections that may develop in the wound area). The deteriorated subcellular redox signaling is considered to be as the main factor in the chronicity of wounds. The pivotal role of mitochondria in redox regulation reveals the importance of modulation of redox signaling pathways in senescent cells. Secretory factors released upon the acquisition of senescence-associated secretory phenotype (SASP) function in a paracrine manner to disseminate impaired tissue redox status by affecting the redox metabolome of nearby cells, which could promote age-related pro-inflammatory pathologies. Evaluating the wound-site redox regulation in impaired redox signaling pathways may help prevent the formation of chronic wounds and the development of long-term complications of the wounds, especially in the elderly. Using the redox modulatory pharmacologically active substances targeting the senescent cells in chronic wound areas hopefully opens a new avenue in wound management. As the signaling mechanisms of wound healing and its relationship with advanced age become more clearly understood, many promising therapeutic approaches and redox modulator substances are coming into clinical view for the management of chronic wounds.


Rotavirus particles in the extrahepatic bile duct in experimental biliary atresia.
Biliary atresia (BA) is the most common indication for liver transplantation in children. The experimental model of BA, induced by rotavirus infection in neonatal mice, has been widely used to investigate the inflammatory aspects of this disease. We investigated the kinetics and the localization of the viral infection in this murine model. In this study 399 animals were employed for a detailed investigation of rhesus rotavirus (RRV)-induced BA. RRV kinetics was analyzed by rtPCR and its (sub) cellular localization investigated using whole mounts which were further processed for confocal and electron microscopy. The BA mouse model resulted in up to 100% induction of atresia following RRV injection. The kinetics of RRV infection differed between liver and extrahepatic bile ducts. While the virus peak up to day 10 postinfection was similar in both organs, the virus remained detectable in extrahepatic bile duct cells up to day 21. Interestingly, RRV particles were localized not only in cholangiocytes but also in cells of the subepithelial layers, potentially macrophages. RRV remains present in the extrahepatic bile duct cells after an initial virus peak. Viral particles were detected in subepithelial cells in contrast to the described tropism toward cholangiocytes.


Fed-batch production of l-tryptophan from glycerol using recombinant Escherichia coli.
l-tryptophan is an essential amino acid of high industrial interest that is routinely produced by microbial processes from glucose as carbon source. Glycerol is an alternative substrate providing a variety of economic and metabolic advantages. Process performance of the recombinant l-tryptophan producer Escherichia coli NT367 was studied in controlled fed-batch processes. The chromosome of the recombinant l-tryptophan producer was equipped with additional genes coding for enzymes of the aromatic amino acids biosynthetic pathway and l-serine biosynthesis, including genes for feedback-resistant enzyme variants ( trpE fbr , aroFBL, and serA fbr ), deletions of enzymatic steps for the degradation of precursors or the product l-tryptophan ( sdaB and tnaA), and alterations in the regulation of l-tryptophan metabolism (deletion of trpL and trpR). The impact of glycerol supply rates as well as the application of a multicopy plasmid (pF112- aroFBL -kan) were investigated in fully controlled stirred-tank bioreactors on a 15 L scale. The combination of E. coli NT367 carrying pF112- aroFBL -kan and an appropriate biomass-specific glycerol supply-rate resulted in the highest final product concentration of 12.5 g L -1 l-tryptophan with the lowest concentrations of other aromatic amino acids. Fed-batch production of l-tryptophan from glycerol was shown for the first time with recombinant E. coli.


Do quantitative birefringence characteristics of meiotic spindle and zona pellucida have an impact on implantation in single embryo transfer cycles?
The aim of this study was to determine whether quantitative PolScope characteristics of meiotic spindle and zona pellucida could be used as a non-invasive marker to predict implantation success in elective single embryo transfer cycles. Quantitative birefringence parameters; including mean retardance, area, length and polar body deviation angle of meiotic spindle and mean retardance and width of inner zona pellucida belonging to 53 transfer oocytes from elective single embryo transfer cycles were retrospectively analyzed. The relevant PolScope features were compared between 20 conception and 33 non-conception cycles. Meiotic spindle mean retardance, area, length and inner zona pellucida mean retardance and width did not reveal a statistically significant difference between transfer oocytes from conception and non-conception cycles. Deviation angle of the polar bodies was also comparable between the groups. Spindle and inner zona PolScope characteristics of transfer oocytes were not correlated with the maternal age. Quantitative PolScope features of meiotic spindle and inner zona pellucida can not be used as a non-invasive marker to predict assisted reproductive technology success in elective single embryo transfer cycles.


Factors influencing the decision to amputate or reconstruct after high-energy lower extremity trauma.
Factors thought to influence the decision for limb salvage include injury severity, physiologic reserve of the patient, and characteristics of the patient and their support system. Eligible patients were between the ages of 16 and 69 with Gustilo type IIIB and IIIC tibial fractures, dysvascular limbs resulting from trauma, type IIIB ankle fractures, or severe open midfoot or hindfoot injuries. Data collected at enrollment relevant to the decision-making process included injury characteristics and its treatment, and the nature and severity of other injuries. Logistic regression and stepwise modeling were used to determine the effect of each covariate on the variable salvage/ amputation. Of 527 patients included in the analysis, 408 left the hospital with a salvaged limb. Of the 119 amputations performed, 55 were immediate and 64 were delayed. The multivariate analysis confirmed the bivariate analysis: all injury characteristics remained significant predictors of limb status with the exception of bone loss; and soft tissue injury and absence of plantar sensation were the most important factors in accounting for model validity. Soft tissue injury severity has the greatest impact on decision making regarding limb salvage versus amputation.


In silico proof of principle of machine learning-based antibody design at unconstrained scale.
Generative machine learning (ML) has been postulated to become a major driver in the computational design of antigen-specific monoclonal antibodies (mAb). However, efforts to confirm this hypothesis have been hindered by the infeasibility of testing arbitrarily large numbers of antibody sequences for their most critical design parameters: paratope, epitope, affinity, and developability. To address this challenge, we leveraged a lattice-based antibody-antigen binding simulation framework, which incorporates a wide range of physiological antibody-binding parameters. The simulation framework enables the computation of synthetic antibody-antigen 3D-structures, and it functions as an oracle for unrestricted prospective evaluation and benchmarking of antibody design parameters of ML-generated antibody sequences. We found that a deep generative model, trained exclusively on antibody sequence (one dimensional: 1D) data can be used to design conformational (three dimensional: 3D) epitope-specific antibodies, matching, or exceeding the training dataset in affinity and developability parameter value variety. Furthermore, we established a lower threshold of sequence diversity necessary for high-accuracy generative antibody ML and demonstrated that this lower threshold also holds on experimental real-world data. Finally, we show that transfer learning enables the generation of high-affinity antibody sequences from low-N training data. Our work establishes a priori feasibility and the theoretical foundation of high-throughput ML-based mAb design.


Cyclodextrin chiral stationary phases for liquid chromatographic separations of drug stereoisomers.
Many active drugs are racemic mixtures. Because the two enantiomers of a racemate often cause different pharmacological responses, the use of optically pure isomers is desirable and may be soon required. Cyclodextrin-bonded silica gel can be used as chiral stationary phase (CSP) in liquid chromatography. The enantiomers of 25 different racemic drugs were separated on such CSPs in the reversed-phase mode. The principal features of the cyclodextrin chiral recognition mechanism are recalled and some information on future trends for cyclodextrin CSPs is provided.


Semiology of skin toxicity associated with epidermal growth factor receptor (EGFR) inhibitors.
Advances in the understanding of the mechanisms involved in oncogenesis have led to the development of so-called targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, which take on an increasingly important role in the management of cancer. These treatments have the advantage not to trigger the adverse effects traditionally encountered with chemotherapy, such as nausea, vomiting or haematological toxicity. However, they do cause new forms of toxicity: the most common one is skin toxicity. It is important to be aware of it because it can be debilitating, adversely impacting patients' quality of life and altering treatment compliance, although it appears to be correlated with treatment response in certain series. Non-specialists can have difficulty in recognising this unusual skin toxicity. The dermatologic side effects most frequently triggered by EGFR inhibitors are discussed in this article. They are divided into three categories depending on their target: inflammation of the pilo-sebaceous follicle, represented by EGFR inhibitor-associated folliculitis, which occurs at an early stage and is frequent; alteration in the skin barrier, primarily responsible for xerosis, fissures and pruritus, which are frequent and delayed; and lesions of the skin appendages (paronychia, pyogenic granuloma, hair changes), which are delayed and less frequent. It is essential for all practitioners concerned to know about these dermatologic side effects in order to ensure better global management of patients, particularly in terms of quality of life.


[Indications and results of parathyroidectomy in the treatment of hyperparathyroidism in dialyzed and kidney transplant patients. Apropos of 68 cases].
Between 1972 and 1985, 78 parathyroidectomies were performed in 60 patients under chronic haemodialysis and in 6 recipients of renal transplants. These patients had severe hyperparathyroidism and radiological evidence of fibrous osteitis. This series shows a recrudescence of tertiary hyperparathyroidism in renal transplant recipients under ciclosporin. The post-operative course was favourable in 55 cases; 13 patients had to be reoperated upon, revealing the presence of supernumerary glands in 6 of them.


A reversible fluorescence "off-on-off" sensor for sequential detection of aluminum and acetate/fluoride ions.
A new rhodamine functionalized fluorogenic Schiff base CS was synthesized and its colorimetric and fluorescence responses toward various metal ions were explored. The sensor exhibited highly selective and sensitive colorimetric and "off-on" fluorescence response towards Al(3+) in the presence of other competing metal ions. These spectral changes are large enough in the visible region of the spectrum and thus enable naked-eye detection. Studies proved that the formation of CS-Al(3+) complex is fully reversible and can sense to AcO(-)/F(-) via dissociation. The results revealed that the sensor provides fluorescence "off-on-off" strategy for the sequential detection of Al(3+) and AcO(-)/F(-).


Inhibitors of apoptosis proteins and IL-1β: a tangled relationship.
Inhibitors of apoptosis proteins (IAPs) are important regulators of both cell death and inflammation. In this issue of Immunity, Vince et al. (2012) report that inhibition of IAPs results in the processing and secretion of IL-1β through RIP3-mediated caspase-1- and caspase-8-dependent pathways.


Prediction of COVID-19 patients in danger of death using radiomic features of portable chest radiographs.
Computer-aided diagnostic systems have been developed for the detection and differential diagnosis of coronavirus disease 2019 (COVID-19) pneumonia using imaging studies to characterise a patient's current condition. In this radiomic study, we propose a system for predicting COVID-19 patients in danger of death using portable chest X-ray images. In this retrospective study, we selected 100 patients, including ten that died and 90 that recovered from the COVID-19-AR database of the Cancer Imaging Archive. Since it can be difficult to analyse portable chest X-ray images of patients with COVID-19 because bone components overlap with the abnormal patterns of this disease, we employed a bone-suppression technique during pre-processing. A total of 620 radiomic features were measured in the left and right lung regions, and four radiomic features were selected using the least absolute shrinkage and selection operator technique. We distinguished death from recovery cases using a linear discriminant analysis (LDA) and a support vector machine (SVM). The leave-one-out method was used to train and test the classifiers, and the area under the receiver-operating characteristic curve (AUC) was used to evaluate discriminative performance. The AUCs for LDA and SVM were 0.756 and 0.959, respectively. The discriminative performance was improved when the bone-suppression technique was employed. When the SVM was used, the sensitivity for predicting disease severity was 90.9% (9/10), and the specificity was 95.6% (86/90). We believe that the radiomic features of portable chest X-ray images can predict COVID-19 patients in danger of death.


p38 MAPK activation, JNK inhibition, neoplastic growth inhibition, and increased gap junction communication in human lung carcinoma and Ras-transformed cells by 4-phenyl-3-butenoic acid.
Human lung neoplasms frequently express mutations that down-regulate expression of various tumor suppressor molecules, including mitogen-activated protein kinases such as p38 MAPK. Conversely, activation of p38 MAPK in tumor cells results in cancer cell cycle inhibition or apoptosis initiated by chemotherapeutic agents such as retinoids or cisplatin, and is therefore an attractive approach for experimental anti-tumor therapies. We now report that 4-phenyl-3-butenoic acid (PBA), an experimental compound that reverses the transformed phenotype at non-cytotoxic concentrations, activates p38 MAPK in tumorigenic cells at concentrations and treatment times that correlate with decreased cell growth and increased cell-cell communication. H2009 human lung carcinoma cells and ras-transformed rat liver epithelial cells treated with PBA showed increased activation of p38 MAPK and its downstream effectors which occurred after 4 h and lasted beyond 48 h. Untransformed plasmid control cells showed low activation of p38 MAPK compared to ras-transformed and H2009 carcinoma cells, which correlates with the reduced effect of PBA on untransformed cell growth. The p38 MAPK inhibitor, SB203580, negated PBA's activation of p38 MAPK downstream effectors. PBA also increased cell-cell communication and connexin 43 phosphorylation in ras-transformed cells, which were prevented by SB203580. In addition, PBA decreased activation of JNK, which is upregulated in many cancers. Taken together, these results suggest that PBA exerts its growth regulatory effect in tumorigenic cells by concomitant up-regulation of p38 MAPK activity, altered connexin 43 expression, and down-regulation of JNK activity. PBA may therefore be an effective therapeutic agent in human cancers that exhibit down-regulated p38 MAPK activity and/or activated JNK and altered cell-cell communication.


Autophagy in the "inflammation-carcinogenesis" pathway of liver and HCC immunotherapy.
Autophagy plays a dual role in many types of cancer, such as hepatocellular carcinoma (HCC). Autophagy seems to be inhibited and functions as a tumor-suppression mechanism in the "inflammation-carcinogenesis" pathway of the liver, including hepatitis B virus and hepatitis C virus, alcoholic steatohepatitis and non-alcoholic steatohepatitis related HCC. However, in established tumors, autophagy plays a tumor-promoting role. Because of the varied function of autophagy in HCC, we hypothesized p62 as a marker to evaluate the autophagic level. Moreover, autophagy is critical in antigen presentation and homeostasis of immune cells and tumor microenvironment. Understanding the intricate relationships of autophagy, inflammation, and immunity provides us with new insights into HCC immunotherapy.


Effects of anti-inflammatory drugs on urinary excretion of prostaglandin metabolites in cotton pellet inflammation.
The influence of cotton pellet inflammation in rats and the effect of prednisolone and indomethacin on the excretion of the main urinary metabolite (MUM)s of prostaglandin (PG) F and E types were studied. After cotton pellet implantation, the excretion of PGE-MUM and F-MUM was progressively increased. In the early phase of inflammation, the excretion of PGE-MUM and PGF-MUM was suppressed by administration of indomethacin. However, prednisolone suppressed only PGF-MUM excretion in the early phase of inflammation. These results indicate that no direct interaction was obtained between the inhibition of the inflammatory response by prednisolone and indomethacin and PGs-MUM excretion in inflamed rats.


Dopamine D2 receptor signalling controls inflammation in acute pancreatitis via a PP2A-dependent Akt/NF-κB signalling pathway.
Dopamine has multiple anti-inflammatory effects, but its role and molecular mechanism in acute pancreatitis (AP) are unclear. We investigated the role of dopamine signalling in the inflammatory response in AP. Changes in pancreatic dopaminergic system and effects of dopamine, antagonists and agonists of D1 and D2 dopamine receptors were analysed in wild-type and pancreas-specific Drd2-/- mice with AP (induced by caerulein and LPS or L-arginine) and pancreatic acinar cells with or without cholecystokinin (CCK) stimulation. The severity of pancreatitis was assessed by measuring serum amylase and lipase and histological assessments. The NF-κB signalling pathway was evaluated, and macrophage and neutrophil migration assessed by Transwell assay. Pancreatic dopamine synthetase and metabolic enzyme levels were increased, whereas D1 and D2 receptors were decreased in AP. Dopamine reduced inflammation in CCK-stimulated pancreatic acinar cells by inhibiting the NF-κB pathway. Moreover, the protective effects of dopamine were blocked by a D2 antagonist, but not a D1 antagonist. A D2 agonist reduced pancreatic damage and levels of p-IκBα, p-NF-κBp65, TNFα, IL-1β and IL-6 in AP. Pancreas-specific Drd2-/- aggravated AP. Also, the D2 agonist activated PP2A and inhibited the phosphorylation of Akt, IKK, IκBα and NF-κB and production of inflammatory cytokines and chemokines. Furthermore, it inhibited the migration of macrophages and neutrophils by reducing the expression of CCL2 and CXCL2. A PP2A inhibitor attenuated these protective effects of the D2 agonist. D2 receptors control pancreatic inflammation in AP by inhibiting NF-κB activation via a PP2A-dependent Akt signalling pathway.


2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA).
Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).


Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats.
Radiation-induced skin injury remains a serious concern for radiation therapy. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant and anti-apoptotic properties. However, the role of HO-1 in radiation-induced skin damage remains unclear. This study aims to elucidate the effects of HO-1 on radiation-induced skin injury in rats. A control adenovirus (Ad-EGFP) and a recombinant adenovirus (Ad-HO1-EGFP) were constructed. Rats were irradiated to the buttock skin with a single dose of 45 Gy followed by a subcutaneous injection of PBS, 5 × 109 genomic copies of Ad-EGFP or Ad-HO1-EGFP (n = 8). After treatment, the skin MDA concentration, SOD activity and apoptosis were measured. The expression of antioxidant and pro-apoptotic genes was determined by RT-PCR and real-time PCR. Skin reactions were measured at regular intervals using the semi-quantitative skin injury score. Subcutaneous injection of Ad-HO1-EGFP infected both epidermal and dermal cells and could spread to the surrounding regions. Radiation exposure upregulated the transcription of the antioxidant enzyme genes, including SOD-1, GPx2 and endogenous HO-1. HO-1 overexpression decreased lipid peroxidation and inhibited the induction of ROS scavenging proteins. Moreover, HO-1 exerted an anti-apoptotic effect by suppressing FAS and FASL expression. Subcutaneous injection of Ad-HO1-EGFP demonstrated significant improvement in radiation-induced skin injury. The present study provides evidences for the protective role of HO-1 in alleviating radiation-induced skin damage in rats, which is helpful for the development of therapy for radiation-induced skin injury.


Pickering emulsions stabilized solely by layered double hydroxides particles: the effect of salt on emulsion formation and stability.
The formation and stability of liquid paraffin-in-water emulsions stabilized solely by positively charged plate-like layered double hydroxides (LDHs) particles were described here. The effects of adding salt into LDHs dispersions on particle zeta potential, particle contact angle, particle adsorption at the oil-water interface and the structure strength of dispersions were studied. It was found that the zeta potential of particles gradually decreased with the increase of salt concentration, but the variation of contact angle with salt concentration was very small. The adsorption of particles at the oil-water interface occurred due to the reduction of particle zeta potential. The structural strength of LDHs dispersions was strengthened with the increase of salt and particle concentrations. The effects of particle concentration, salt concentration and oil phase volume fraction on the formation, stability and type of emulsions were investigated and discussed in relation to the adsorption of particles at the oil-water interface and the structural strength of LDHs dispersions. Finally, the possible stabilization mechanisms of emulsions were put forward: the decrease of particle zeta potential leads to particle adsorption at the oil-water interface and the formation of a network of particles at the interface, both of which are crucial for emulsion formation and stability; the structural strength of LDHs dispersions is responsible for emulsion stability, but is not necessary for emulsion formation.


Development of core-shell magnetic molecularly imprinted polymer-based electrochemical sensor for sensitive and selective detection of ezetimibe.
A sensitive electrochemical molecularly imprinted polymer (MIP) sensor was fabricated for detection of ezetimibe (Eze) as an effective cholesterol absorption inhibitor on the surface of a screen-printed carbon electrode based on a magnetic nanoparticle decorated with MIP (Fe3O4@MIP). Placing the magnetic nanoparticle inside the MIP increases the biocompatibility, surface-to-volume ratio, and sensitivity of the sensor. Methacrylic acid (MAA) was used as a monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker, and Eze as a template. The fabricated Fe3O4@MIP was characterized using Fourier-transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Detection of Eze was achieved by differential pulse voltammetry. Using this sensor, Eze can be sensitively detected in the range of 1.0 nM-10 μM and detection limit of 0.7 nM. In addition, we have shown that the proposed sensor successfully detects different concentrations of Eze in human serum samples and thus proves its practical application.


Distribution and predictors of 20 toxic and essential metals in the umbilical cord blood of Chinese newborns.
Early-life exposure to heavy metals and/or trace metal imbalances can have negative developmental effects. Here we sought to characterize exposure profiles for 20 heavy metals and trace elements in umbilical cord blood plasma and identify demographic predictors of exposure. Twenty metals were measured in cord plasma from 357 Chinese infants using ICP-MS. Relationships between demographic variables and metals were analyzed using generalized linear models and logistic regression. Ten metals (antimony [Sb], cobalt [Co], cesium [Cs], copper [Cu], lead [Pb], molybdenum [Mo], rubidium [Rb], selenium [Se], strontium [Sr], titanium [Ti], zinc [Zn]) were detected in all samples. Season of birth was the strongest predictor of metals in cord blood across analyses. Infants born in the spring had 0.1-0.2 μg L-1 higher logAs and logCo in their cord blood (β [95%CI] = 0.22 [0.01,0.42], p = 0.04; 0.11 [0.01,0.22], p = 0.04), while infants born in the summer had higher Sb, logB, logHg, and logZn (β [95%CI] = 0.74 [0.24,1.24], p = 0.004; 0.11 [0.00,0.21], p = 0.04; 0.29 [0.08,0.49], p = 0.007; 0.18 [0.06,0.31], p = 0.005), compared to those born in fall/winter. Prenatal heavy metal exposure and/or trace metal deficiencies are global concerns because of increasing awareness of downstream developmental effects.


Meta-adaptive-weighting-based bilateral multi-dimensional refined space feature attention network for imbalanced breast cancer histopathological image classification.
Breast cancer histopathological image automatic classification can reduce pathologists workload and provide accurate diagnosis. However, one challenge is that empirical datasets are usually imbalanced, resulting in poorer classification quality compared with conventional methods based on balanced datasets. The recently proposed bilateral branch network (BBN) tackles this problem through considering both representation and classifier learning to improve classification performance. We firstly apply bilateral sampling strategy to imbalanced breast cancer histopathological image classification and propose a meta-adaptive-weighting-based bilateral multi-dimensional refined space feature attention network (MAW-BMRSFAN). The model is composed of BMRSFAN and MAWN. Specifically, the refined space feature attention module (RSFAM) is based on convolutional long short-term memories (ConvLSTMs). It is designed to extract refined spatial features of different dimensions for image classification and is inserted into different layers of classification model. Meanwhile, the MAWN is proposed to model the mapping from a balanced meta-dataset to imbalanced dataset. It finds suitable weighting parameter for BMRSFAN more flexibly through adaptively learning from a small amount of balanced dataset directly. The experiments show that MAW-BMRSFAN performs better than previous methods. The recognition accuracy of MAW-BMRSFAN under four different magnifications still is higher than 80% even when unbalance factor is 16, indicating that MAW-BMRSFAN can make ideal performance under extreme imbalanced conditions.


The benefits of EVAR planning using a 3D workstation.
To evaluate the influence of planning endovascular aneurysm repair (EVAR) with a three-dimensional (3D) workstation on early and midterm outcomes. All patients undergoing infrarenal EVAR performed between 2006 and 2009 at our institution were included in the current study. Prior to 2008 (group 1), endograft sizing was performed by interrogation of computed tomography angiography axial images. After 2008 (group 2), endograft sizing was routinely performed using a 3D workstation (Aquarius, Terarecon), allowing for multiplanar reconstruction and centerline analysis. Pre-, peri-, postoperative, and follow-up data were prospectively entered in an electronic database. All postoperative complications and subsequent secondary interventions depicted during the 2-year period following EVAR were compared. Secondary intervention and mortality rates were defined at 2 years and compared. Freedom from secondary intervention and overall survival rates were calculated using the Kaplan-Meier method during follow-up and compared by log-rank test. A total of 295 patients (149 patients in group 1 and 146 patients in group 2) were included. All patients had completed a minimum of 2 years of follow-up. During this 2-year period following EVAR, the type 1 endoleak rate was 8.7% in group 1 and 1.4% in group 2 (p = .004) respectively. Secondary intervention rates related to type 1 endoleak was 5.4% in group 1 and 0 in group 2 (p < .001). No difference was observed regarding all-cause mortality, aneurysm-related death, and freedom from secondary intervention rates during follow-up. The routine use of 3D workstations for EVAR planning significantly reduces the rate of type 1 endoleaks and, therefore, the rate of related secondary interventions.


Accuracy of measuring acetabular cup position after total hip arthroplasty: comparison between a radiographic planning software and three-dimensional computed tomography.
Various methods are available for measuring acetabular cup position after total hip arthroplasty (THA) on standard anterior-posterior (AP) radiographs. We compared the accuracy of a commercial radiographic planning software program with that of three-dimensional computed tomography (3D-CT) scans. We obtained plain AP radiographs and 3D-CTs from 65 patients after THA. In addition to calculating cup anteversion and inclination with 3D-CT, we determined the cup position using the radiographic planning software program mediCAD® 2.5 (Hectec, Niederviehbach, Germany). Furthermore, we compared the measurements using the inter-teardrop and bi-ischial lines as pelvic landmarks. The mean difference in anteversion between 3D-CT and mediCAD® software was 0.1° using the inter-teardrop line (standard deviation [SD], 8.8°; range, -21° to 23°; p = 0.97) and 0.4° using the bi-ischial line (SD, 8.8°; range, -23° to 21°; p = 0.72). Inclination showed a mean difference of 0.6° using the inter-teardrop line (SD, 4.4°; range, -9° to 21°; p = 0.24) and 0.5° using bi-ischial line (SD, 4.6°; range, -9° to 22°; p = 0.35). The means for absolute differences were 7.2° for anteversion and 3.1° for inclination. With regard to using the bi-ischial or inter-teardrop line, no significant difference was found between the two pelvic landmarks. The intra-class correlation coefficient (ICC) was analysed for anteversion and inclination using either the inter-teardrop line or the bi-ischial line as radiographic baseline. A radiographic planning software program (mediCAD®) is a helpful tool for measuring cup inclination on AP radiographs. With respect to anteversion, measurements are rather susceptible to mistakes with mean inaccuracies of over 7°. Thus, 3D-CT remains the "gold standard" if a lower tolerance limit (±3°) is required for more complex biomechanical evaluations. As a pelvic landmark, the interteardrop line is preferential to the bi-ischial line because of its lower impact on the position of the pelvis.


Familial early onset macular degeneration in cynomolgus monkeys (Macaca fascicularis).
The mode of inheritance of macular degeneration was determined with 45 cynomolgus monkeys (18 females and 27 males) who were the offspring of one breeding male with typical macular degeneration. In the first generation, 27 offspring (10 females and 17 males) were born from mating between the macular degeneration-affected founder male and 5 normal female breeders. Among them, 18 monkeys (9 females and 9 males) were judged as having macular degeneration (affected). Next, the distribution of affected offspring was examined with 18 offspring who were born from 3 different mating pairs, normal vs normal, affected vs normal and affected vs affected, when they became 2 years old. All of the 9 monkeys (4 females and 5 males) obtained from the 2 pairs of normal vs normal were normal. On the other hand, 6 affected monkeys (3 females and 3 males) were detected in 8 offspring from the mating pair of affected vs normal, and the single offspring produced by the mating pair of affected vs affected was affected. These results showed that this degeneration must be early onset familial macular degeneration controlled by autosomal dominant gene(s).


Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells.
Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB (NF-κB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes MS formation, upregulating NF-κB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.


The diagnostic and predictive value of fecal calprotectin and capsule endoscopy for small-bowel Crohn's disease: a systematic review and meta-analysis.
there are no clarified non-invasive methods to evaluate small bowel inflammation in Crohn's disease. to evaluate the accuracy of fecal calprotectin and capsule endoscopy for the diagnosis of small bowel Crohn's disease and to predict relapse. a systematic literature search was performed for studies to diagnose and predict relapse of the disease with fecal calprotectin and capsule endoscopy. The relevant pooled data including sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, negative likelihood ratio and area under curve were calculated using Stata 14.0. twenty-one studies were included in the final analyses. The diagnostic accuracy of the disease and relapse were obtained for capsule endoscopy, with a pooled sensitivity of 0.90 and 0.82, specificity of 0.76 and 0.56, diagnostic odds ratio of 33 and 6, and area under curve of 0.92 and 0.82, respectively. Diagnostic accuracy of the disease was calculated for fecal calprotectin values of 50, 100 and 200 ug/g; the sensitivity values were 0.84, 0.66 and 0.45; specificity values were 0.49, 0.74 and 0.87; diagnostic odds ratio were 5, 5 and 5; and area under curve were 0.74, 0.76 and 0.75, respectively. A fecal calprotectin level of 100-140 ug/g for the prediction of relapse had a pooled sensitivity of 0.68, specificity of 0.91, diagnostic odds ratio of 21, and area under curve of 0.77. capsule endoscopy is effective in diagnosing small bowel Crohn's disease and predicting relapse. Fecal calprotectin is an accurate surrogate technique to diagnose small bowel inflammation in Crohn's disease. Furthermore, the best scenario for fecal calprotectin is the prediction of relapse.


Benefits and risks of low molecular weight heparin in patients with acute exacerbation of chronic obstructive pulmonary disease: a meta-analysis of randomized controlled trials.
Low molecular weight heparin (LMWH) is an anticoagulant that has recently been found benefit in the acute exacerbation stage of chronic obstructive pulmonary disease (COPD). But its efficacy is controversial. The objective of this paper is to compare the harm/benefit of LMWH combined with conventional therapy versus single conventional therapy in the acute exacerbation stage of COPD. PubMed, Cochrane Library, EMBASE, CNKI, and Clinical Trials.gov were searched from inception until March 2019. Randomized control trials were included if they reported the use of LMWH for the treatment of COPD. Continuous variable data were reported as mean difference (MD), risk difference (RD), and Peto odds ratio (OR) with corresponding 95% CIs. Twelve RCTs (N = 1086 subjects) were included in the meta-analysis. Pooled results exhibited that LMWH treatment significantly improved the levels of arterial partial pressure of oxygen (PaO2) (MD = 4.58, 95% CI: 1.78-7.39, P = 0.001), forced expiratory volume in 1 s (FEV1) (MD = 0.19, 95% CI: 0.09-0.29, P = 0.0002), and FEV1/forced vital capacity (FVC) (MD = 10.44, 95% CI: 5.40-15.48, P < 0.0001), and significantly reduced the risk of thrombosis (RD, - 0.03; 95% CI, - 0.07 to 0.00; P = 0.05). There was a marginally but nonsignificant improvement in PaCO2 levels vs non-LMWH treatment. Moreover, pooled results exhibited that LMWH may increase the risk of hemorrhage. Subgroup analyses exhibited that LMWH treatment only was associated with a significantly increased risk of minor bleeding but not major hemorrhage. When compared with single conventional therapy, addition of LMWH to conventional therapy may provide more clinical benefits in the acute exacerbation stage of COPD.


Polymeric membranes functionalized with nanomaterials (MP@NMs): A review of advances in pesticide removal.
The excessive contamination of drinking water sources by pesticides has a pernicious impact on human health and the environment since only 0.1% of pesticides is utilized effectively to control the and the rest is deposited in the environment. Filtration by polymeric membranes has become a promising technique to deal with this problem; however, the scientific community, in the need to find better pesticide retention results, has begun to meddle in the functionalization of polymeric membranes. Given the great variety of membrane, polymer, and nanomaterial synthesis methods present in the market, the possibilities of obtaining membranes that adjust to different variables and characteristics related to a certain pesticide are relatively extensive, so it is expected that this technology will represent one of the main pesticide removal strategies in the future. In this direction, this review focused on, - the main characteristics of the nanomaterials and their impact on pristine polymeric membranes; - the removal performance of functionalized membranes; and - the main mechanisms by which membranes can retain pesticides. Based on these insights, the functionalized polymeric membranes can be considered as a promising technology in the removal of pesticides since the removal performance of this technology against pesticide showed a significant increase. Obtaining membranes that adjust to different variables and characteristics related to a certain pesticide are relatively extensive, so it is expected that functionalized membrane technology will represent one of the main pesticide removal strategies in the future.


[Bronchoscopy in children with foreign body aspiration].
Aspiration of foreign body presents a high incidence of mortality during the paediatric life period. Family suspect and detection of specific symptoms and signs determine the need of bronchoscopy. The objective of this study is to establish the clinical parameters that indicate foreign body in airway. Retrospective study in 44 children with foreign body aspiration. We reviewed age, sex, family suspect, blood analysis, chest x-ray, time to consulting, location, type, complications, and time to discharge. Decisive clinical factors that indicate foreign body in airway are family suspect and respiratory clinic. Findings after auscultation and chest x-ray support suspect, but final diagnostic only can be made after bronchoscopy. Bronchoscopy with foreign body removal was performed during first 24 hours in 86.36 % of patients, and founded that those with delayed diagnosis had increased morbidity. Family's suspect is the most important parameter that indicates foreign body located in airway. Bronchoscopy performed during the first hours avoids morbidity. This is a secure technique when performed in adequate place with trained personnel.


The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies.
The aim was to review the worldwide incidence and prevalence of SLE and variation with age, sex, ethnicity and time. A systematic search of MEDLINE and EMBASE search engines was carried out using Medical Subject Headings and keyword search terms for Systemic Lupus Erythematosus combined with incidence, prevalence and epidemiology in August 2013 and updated in September 2016. Author, journal, year of publication, country, region, case-finding method, study period, number of incident or prevalent cases, incidence (per 100 000 person-years) or prevalence (per 100 000 persons) and age, sex or ethnic group-specific incidence or prevalence were collected. The highest estimates of incidence and prevalence of SLE were in North America [23.2/100 000 person-years (95% CI: 23.4, 24.0) and 241/100 000 people (95% CI: 130, 352), respectively]. The lowest incidences of SLE were reported in Africa and Ukraine (0.3/100 000 person-years), and the lowest prevalence was in Northern Australia (0 cases in a sample of 847 people). Women were more frequently affected than men for every age and ethnic group. Incidence peaked in middle adulthood and occurred later for men. People of Black ethnicity had the highest incidence and prevalence of SLE, whereas those with White ethnicity had the lowest incidence and prevalence. There appeared to be an increasing trend of SLE prevalence with time. There are worldwide differences in the incidence and prevalence of SLE that vary with sex, age, ethnicity and time. Further study of genetic and environmental risk factors may explain the reasons for these differences. More epidemiological studies in Africa are warranted.


Residual effects of daytime administration of melatonin on performance relevant to flight.
There is a general consensus that melatonin possesses time-dependent hypnotic effects, but there is no information yet whether it has residual effects on neurobehavioral performance, especially after daytime administration. In the present study we investigated the possible residual effects of 3 mg melatonin on performance relevant to flight and on subjective feelings of sleepiness, arousal, activation and affect after a daytime nap, as a function of nap length. Fifteen reserve pilots of the Israeli Air Force participated in the study. The experiment consisted of four sessions during which either melatonin or placebo was administered at 16:00 h. In two conditions, subjects were allowed to sleep for 2 h (17:00-19:00 h) whereas in the other two only a 0.5-h nap was allowed. After the naps they started performing a flight simulator task every 2 h. Sleep efficiency significantly increased and sleep latency significantly decreased in both melatonin conditions compared to placebo. Flight performance was only mildly affected in the 0.5-h nap condition. Subjective assessment of sleepiness significantly differed between the two treatment conditions, only in the 0.5-h nap condition. Subjects felt sleepier 2-4 h after melatonin administration. To conclude, our data suggest that administration of melatonin before a brief daytime nap (about 0.5 h) may be associated with mild residual effects on psychomotor performance and may significantly affect subjective feeling of sleepiness for 2-4 h.


Effects of dietary and pharmacologic alteration of serum lipids on platelet survival time.
Platelet survival time (SURV) (autologous labelling with 51Chromium) was shortened (3 +/- 0.03 days; average t 1/2 +/- SEM; normal t 1/2 3.7 +/- 0.03 days) in 88 out of 128 (69%) men with coronary disease. In 35 out of 47 men with hyperprebetalipoproteinemia, SURV was shortened (3 +/- 0.09 days) (74%). Of 30 men with hyperbetalipoproteinemia, SURV was shortened (2.5 +/- 0.10 days) in 26 (87%). Of 51 men without hyperlipoproteinemia, SURV was normal (3.3 +/- 0.10 days) in 24 (47%). Dietary alteration of serum triglyceride was undertaken in 12 men with hyperprebetalipoproteinemia, and in eight a decrease of triglyceride of more than 75 mg% was achieved (324 +/- 21-219 +/- 18 mg%; P less than 0.001) with an increase of SURV (2.2 +/- 0.11-2.8 +/- 0.13 days; P less than 0.001). In four, serum triglyceride increased by more than 75 mg% (279 +/- 14-451 +/- 28 mg%) and SURV decreased (2.7 +/- 0.16-2.3 +/- 0.21 days). Cholestyramine (16 g g.d.) and diet decreased serum cholesterol (348 +/- 7.6-319 +/- 6.3 mg%; P less than 0.001) in 15 men with hyperbetalipoproteinemia and SURV increased (2.3 +/- 0.08-2.7 +/- 0.07 days; P less than 0.001). Results suggest that SURV is shortened in men with coronary disease, particularly in those with hyperlipoproteinemia, and that alteration of triglyceride and cholesterol are associated with alteration of SURV.


Transoral endoscopic thyroidectomy vestibular approach vs. transoral robotic thyroidectomy: systematic review and meta-analysis.
This study aimed to conduct a systematic review and meta-analysis to compare the surgical outcomes of the transoral endoscopic thyroidectomy vestibular approach (TOETVA) and transoral robotic thyroidectomy (TORT). We carried out a systematic literature search of PubMed, Web of Science, Cochrane Library, and Google Scholar on studies comparing TOETVA and TORT until January 2023. A total of five articles published between 2018 and 2023 that matched the inclusion criteria were included in the systematic review and meta-analysis. The studies included 641 patients (394 TOETVA patients and 247 TORT patients). TOETVA group was associated with a significantly shorter operative time with a mean difference of 60.08 min [95% confidence interval (CI) - 83.95 to - 36.20; P < 0.001). Transient recurrent laryngeal nerve palsy was more common in the TOETVA group than the TORT group (OR 3.00; 95% CI 1.14-7.88; P = 0.03). There were no significant differences in the other outcomes, including the length of hospital stay, postoperative pain scores, number of central lymph nodes retrieved, permanent recurrent laryngeal nerve injuries, and transient and permanent hypoparathyroidism. The TOETVA group was associated with shorter operative time and more transient recurrent laryngeal nerve palsy than the TORT group. Each procedure has its benefits and limitations. The surgical approach should be determined by considering the patient's characteristics and preferences, as well as the surgeon's preference and area of expertise.


Estimating the energy consumption function: evidence from across the globe.
The motivation for the current study stem from the United Nations Sustainable Development Goals (UN-SDGs) such as access to clean (SDG-7) and responsible energy consumption (SDG-12) and climate change mitigation (SDG-12). This chase for these goals is pertinent for sustainable economic growth and environmental sustainability. This becomes necessary given the global demand for energy which comes has it environmental consequences given anthropogenic effect. To this end, the present study seeks to identify the factors determining the energy consumption function for 79 economies across the globe. For empirical investigation, 44 years data of five regions, namely Asia and Pacific, Europe, Africa, Latin America, and the Middle East and Arab States, is analyzed. A multivariate regression model and the method of least squares are employed to achieve set of objectives. The least squares result of the regions and single country of the regions are not significantly different from each other. Every region exhibits a common narrative that economic growth, carbon emissions, and urbanization are the key factors determining the consumption function in most of the sample economies. The empirical findings revealed that energy consumption function is determined by economic growth, urbanization, and carbon emissions. In the light of these findings, it is recommended that energy policy needs to be designed considering the significance of economic growth and environmental quality, and consequently it leads toward the achievement of the sustainable development goals.


Warm and cold signals from the preoptic area: which contribute more to the control of shivering in rats?
1. To find out whether the thermosensitive neurones in the preoptic area that control shivering are predominantly warm or cold sensitive, we tested the effects of injecting the excitatory amino acid L-glutamate at various sites in and adjacent to the preoptic area of anaesthetized rats shivering at ambient temperatures of 15-21 degrees C. 2. L-Glutamate injections (0.2 mM in 0.5-1.0 microliter), as well as preoptic warming and electrical stimulation, suppressed shivering, whereas control saline injections had no effect. Effective sites were restricted to the anterior part of the preoptic area, and a tenfold lower concentration of L-glutamate did not influence shivering. 3. Injections of procaine (0.2 M) into the sites where L-glutamate suppressed shivering did not affect strong shivering activity, but facilitated shivering in three out of seven cases when shivering was weak or absent at higher ambient temperatures (25-30 degrees C). 4. L-Glutamate injections, as well as preoptic warming and electrical stimulation, also elicited vasodilatation of the paw skin and the tail. Procaine elicited vasoconstriction when it was applied during vasodilatation induced by local preoptic warming. 5. These results indicate that the contribution of the preoptic area to the control of shivering and vasomotion is influenced more by signals from warm-sensitive neurones than by signals from cold-sensitive neurones.


Focused ultrasound-mediated drug delivery from microbubbles reduces drug dose necessary for therapeutic effect on neointima formation--brief report.
We hypothesized that (1) neointima formation in a rat carotid balloon injury model could be reduced in vivo following targeted ultrasound delivery of rapamycin microbubbles (RMBs), and (2) the addition of dual-mode ultrasound decreases the total amount of drug needed to reduce neointima formation. Balloon injury was performed in rat carotids to induce neointima formation. High or low doses of RMBs were injected intravenously and ruptured at the site of injury with ultrasound. Compared with nontreated injured arteries, neointima formation was reduced by 0% and 35.9% with 10(8) RMBs and by 28.7% and 34.9% in arteries treated with 10(9) RMBs with and without ultrasound, respectively. Without ultrasound, 10-fold higher concentrations of RMBs were needed to reduce neointima formation by at least 28%, whereas 10(8) RMBs combined with ultrasound were sufficient to achieve the same therapeutic effect, demonstrating that this technology may have promise for localized potent drug therapy.


High-temperature corrosion behavior of high-temperature and high-pressure cavitation processed Cr-Mo steel surface.
In this paper, long-term high-temperature corrosion at 500 °C and high-temperature corrosion at the melting temperature of a corrosive ash mixture were examined because the use of high-temperature equipment such as boilers and gas turbines increases year over year. To investigate the optimum cavitation processing conditions for the specimens used in high-temperature corrosion tests, the surface properties of each processed specimen were examined. In specimens processed using multifunction cavitation (MFC), the compressive residual stress was high when the processing time was 10 min and the Cr content on the surface was greater than on the surface of an unprocessed specimen. On the other hands, in specimens subjected to water-jet peening (WJP), the compressive residual stress was high when the processing time was 10 min. In the present study, the processing time was selected to be 10 min and all high-temperature corrosion tests were conducted by the coating method. In the case of long-term high-temperature corrosion at 500 °C, the corrosion loss of the MFC-processed and WJP-processed specimens was small, whereas the corrosion loss of the unprocessed specimen was large.


Phospholipase A2 activity in endometrium from early pregnant and non-pregnant ewes.
In the ewe, synthesis of the luteolytic factor, prostaglandin F2 alpha, increases from day 13 to the end of the estrous cycle. Availability of free arachidonic acid is usually the rate-limiting step in prostaglandin biosynthesis. Phospholipase A2 (PLA2) may be the key enzyme for the hydrolysis of arachidonic acid from membrane-bound phospholipids. To investigate uterine PLA2 activity during the estrous cycle and early pregnancy, we monitored the release of [14C]oleic acid from the substrate 1-palmitoyl-2-[14C]oleoyl-phosphorylcholine by homogenates and cytosolic fractions of endometrium from ewes on days 12, 14 and 16 of the estrous cycle or pregnancy. We observed that PLA2 activity dropped by 58% (p < 0.02) in day-16 pregnant endometrium compared to day-16 non-pregnant endometrium. We then investigated whether the reduced PLA2 activity was due to induction of a specific inhibitor. The PLA2-inhibitor activity was determined by monitoring the inhibition of release of [14C]oleic acid from the radioactive substrate by porcine pancreatic PLA2. Inhibition by endometrial homogenates of pregnant animals of the control enzyme activity was 27% and only 14% by cyclic ones. Inhibition was dose-dependent and was as high as 53% (p < 0.01) with 1 mg protein from pregnant endometrial homogenates. Endometrial PLA2 behaved as a Michaëlian enzyme in the endometrium of day-16 cyclic ewes (Km = 79.4 mumol/l). Furthermore, the inhibitory activity from pregnant endometrium had characteristics of competitive inhibition. Our results suggest that inhibition of endometrial PLA2 activity could occur in early pregnant ewes.


Neural crest invasion is a spatially-ordered progression into the head with higher cell proliferation at the migratory front as revealed by the photoactivatable protein, KikGR.
Neural crest cell (NCC) invasion is a complex sculpting of individual cells into organized migratory streams that lead to organ development along the vertebrate axis. Key to our understanding of how molecular mechanisms modulate the NCC migratory pattern is information about cell behaviors, yet it has been challenging to selectively mark and analyze migratory NCCs in a living embryo. Here, we apply an innovative in vivo strategy to investigate chick NCC behaviors within the rhombomere 4 (r4) migratory stream by combining photoactivation of KikGR and confocal time-lapse analysis of H2B-mRFP1 transfected NCCs. We find that the spatial order of r4 NCC emergence translates into a distal-to-proximal invasion of the 2nd branchial arch. Lead and trailing NCCs display similar average cell speeds and directionalities. Surprisingly, we find that lead NCCs proliferate along the migratory route and grow to outnumber trailing NCCs by nearly 3 to 1. A simple, cell-based computational model reproduces the r4 NCC migratory pattern and predicts the invasion order can be disrupted by slower, less directional lead cells or by environmental noise. Our results suggest a model in which NCC behaviors maintain a spatially-ordered invasion of the branchial arches with differences in cell proliferation between the migratory front and trailing NCCs.


Interferon potentiates cytotoxic effects of 5-fluorouracil on cell proliferation of established human cell lines originating from neoplastic tissues.
A potentiation of the cytotoxic effects of 5-fluorouracil (5-FU) on human tumor cells by interferon was examined. The human neoplastic cell lines used were HeLa (uterine cervical cancer), MCF-7 (mammary cancer), WI-38 CT-1 (embryonic lung fibroblasts transformed in culture by Co-60 gamma-ray irradiation), KMM-1 (myeloma) and Raji (Burkitt's lymphoma). The normal human cell strain used was WI-38 (normal human lung fibroblasts). The cytotoxic effects were determined by colony formation for HeLa, MCF-7, WI-38 CT-1 and WI-38 cells, and by cell growth for KMM-1 and Raji cells. Each cell line was different in sensitivity to interferon or 5-FU. Interferon potentiated synergistically the cytotoxic effects of 5-FU on HeLa, WI-38 CT-1 and KMM-1 cells. In the case of Raji cells, the cytotoxic effects of the combination of interferon and 5-FU were additive. Neither synergistic nor additive lethal effects of the combination of the 2 agents were observed in MCF-7 and WI-38 cells. The present results indicate a possibility that interferon and 5-FU can mutally reduce the amount of the other needed to treat cancer patients.


Redox Potential and Antioxidant Capacity of Bovine Bone Collagen Peptides towards Stable Free Radicals, and Bovine Meat Lipids and Proteins. Effect of Animal Age, Bone Anatomy and Proteases-A Step Forward towards Collagen-Rich Tissue Valorisation.
Collagen antioxidant peptides are being widely studied. However, no research has paid attention to biological parameters such as the age and anatomy of collagen-rich tissues, which can determine a change in tissue structure and composition, and then in bioactivity. Moreover, only few research works have studied and assessed peptides antioxidant activity on the food matrix. This work aimed to investigate the effect of bovine's bone age and anatomy, and of six different enzymes, on the antioxidant activity of collagen peptides. Collagen was extracted from young and old bovine femur and tibia; six different enzymes were used for peptides' release. The redox potential, the quenching of stable free radicals, and the antioxidant capacity on bovine meat lipids and proteins was evaluated, under heating from ambient temperature to 80 °C. Age and anatomy showed a significant effect; the influence of anatomy becomes most important with age. Each enzyme's effectiveness toward age and anatomy was not the same. The greatest amount of peptides was released from young bones' collagen hydrolysed with papain. The antioxidant activity was higher at higher temperatures, except for meat proteins. Assessing the effect of age and anatomy of collagen-rich tissues can promote a better application of collagen bioactive peptides.


Na+, K(+)-ATPase, glutathione, and hydroxyl free radicals in cadmium chloride-induced testicular toxicity in mice.
Cadmium chloride (CdCl2)-induced biochemical changes were characterized in male, CD-1 mouse testes. CdCl2 inhibited the testes microsomal Na+,K(+)-ATPase activity in vitro and in vivo. The inhibitory range was 30-50 microns and the concentration for half maximal inhibition (IC50 value) was 90 microns over 5 min preincubation. CdCl2 (2mg/kg/day, s.c.) for 2 days significantly inhibited testes Na+,K(+)-ATPase (near 90% inhibition). The content of testicular GSH and the ratio of reduced glutathione (GSH)/GSSG (oxidized glutathione) decreased in CdCl2-treated groups. Using salicylate as a trapping agent and high pressure liquid chromatography with electrochemical detection (LCED), we measured the OH production in vivo. 2,5-dihydroxybenzoic acid (2,5-DHBA) and 2,3-dihydroxybenzoic acid (2,3-DHBA) as indices of hydroxyl free radical formation significantly increased after 5 days CdCl2 exposure. Pretreatment with vitamin E (20 mg/kg, s.i.d., i.m., 7d) protected CdCl2-induced increase in OH. generation in testes. From this study, it was demonstrated that CdCl2 induced testicular toxicity could possibly be mediated by a significant increase in hydroxyl free radical formation and a reduction in GSH content and Na+,K(+)-ATPase activity. Vitamin E seems to prevent the CdCl2 induced increase in hydroxyl free radical generation.


Cardiotonic activity of milrinone, a new and potent cardiac bipyridine, on the normal and failing heart of experimental animals.
Milrinone (Win 47203) is a potent cardiac bipyridine with inotropic and vasodilator properties. Its effects were studied in anesthetized and unanesthetized dogs and in isolated cardiac tissues from guinea pigs. In the anesthetized dog, the intravenous injection of milrinone (0.01-0.1 mg/kg) increased cardiac contractile force (CF) (23 +/- 6.1 to 87 +/- 8.9%), maximum left ventricular pressure development (24 +/- 5.8 to 119 +/- 16.1%), and cardiac output (16 +/- 4.5 to 33 +/- 8.9%), with less than a 30% increase in heart rate (HR). Significant decreases in systolic and diastolic blood pressures were seen at 0.3-3 mg/kg i.v. Oral doses of milrinone (0.1-1.0 mg/kg), in unanesthetized dogs, increased cardiac CF by 35 +/- 7.0 to 99 +/- 17.0%, with a maximum increase in HR of 40 +/- 7.1% and no significant change in blood pressure. Milrinone was effective in the presence of ouabain and dopamine without enhancing their arrhythmogenic properties. It was also effective in reversing propranolol-, verapamil-, or pentobarbital-induced heart failure. The inotropic response does not seem to involve the stimulation of the autonomic receptors, the release of endogenous catecholamines, histamine, or prostaglandins, or the inhibition of Na+,K+-adenosine triphosphatase. Milrinone is an inhibitor or cardiac adenosine 3',5'-monophosphate (cAMP) phosphodiesterase, with resultant increases in cardiac cAMP levels. However, the time course for this increase does not seem to correspond to the increase in muscle developed tension, and, therefore, it is unlikely to be responsible for the initiation of the inotropic response. Milrinone is a potent cardioactive agent which should be beneficial in the treatment of acute and chronic congestive heart failure.


[Migrant health and ethical requirements].
Migrants' health is a subject that is often called up for aspects that are often presented as negative (insecurity, carelessness of public finances, major cultural replacement) in the name of which suspicion and rejection take hold. This vision does not survive the factual analysis of public health, social and economic data. Nevertheless, National Consultative Ethics Committee in its opinion 127 in 2017 draws up a serious, and still topical, assessment of the situation with regard to the health of migrants. In it, he denounced the use of migrant health care as an instrument for political purposes and advocated hospitality and fraternity.


Response of Rambouillet Lambs to an Artificial Gastrointestinal Nematode Infection.
Gastrointestinal nematodes (GIN) threaten the productivity and health of sheep worldwide, prompting the need for genetic selection to reduce GIN susceptibility. Fecal egg count (FEC), packed-cell volume (PCV), and various production traits were examined in parasitized Rambouillet sheep and compared to sire FEC estimated breeding value (EBV). Rambouillet lambs (n = 77) were inoculated with 10,000 H. contortus L3 larvae. Subsequently, FEC, PCV, and body weight (BW) were captured at seven-day intervals for six weeks. Lambs were sired by one of two rams with post-weaning FEC EBV of −9% or +9%. Mean FEC differed (p = 0.0132) with lambs from the lower EBV sire ("Sire L") being reduced, versus those from the higher EBV sire ("Sire H"), being 2135 ± 211 vs. 2912 ± 207 eggs per gram, respectively. Males and females did not differ for FEC, but females exhibited a higher mean PCV than males, (33.74 vs. 29.65%, p < 0.0001). Lambs were shorn ~120 d post artificial infection and wool measurements were captured. A negative correlation between FEC and grease fleece weight was observed. Our results describe the response of Rambouillet lambs to artificial H. contortus infection and suggest FEC EBV can reduce susceptibility to GIN in this breed.


Effects of Complex Modification by Sr-Sb on the Microstructures and Mechanical Properties of Al-18 wt % Mg₂Si-4.5Cu Alloys.
This research was carried out to investigate the influence of Sr-Sb on the microstructures and mechanical properties of Al-18 wt % Mg₂Si-4.5Cu alloys. After the addition of 0.2 wt % Sr-Sb, the morphologies of primary Mg₂Si transformed from equiaxed dendrite to cube in as-cast alloys and the average size of primary Mg₂Si decreased from ~50 to ~20 μm. The shape of eutectic Mg₂Si changed from Chinese script to short rod. After extrusion and T6 heat treatment, the ultimate tensile strength of modified alloy at room temperature (RT) and 100 °C increased respectively from 229 to 288 MPa, and from 231 to 272 MPa. The elongation-to-failure only slightly improved from 2.9% to 3.8% and from 3.3% to 3.7% at RT and 100 °C, respectively. The tensile fracture surface revealed a transition from brittle fracture to ductile fracture after modifying by 0.2 wt % Sr-Sb.


Public's approach to surrogate consent for dementia research: cautious pragmatism.
To describe how members of the older general public deliberate with one another in finding solutions to the dilemma of involving persons with decisional incapacity in dementia research. One hundred sixty persons age 50 years and older who participated in an all-day deliberative democracy session on the ethics of surrogate consent for dementia research. The deliberative democracy day consisted of both extensive, interactive education with experts in clinical research and ethics, as well as small group deliberations. Audiotaped small group deliberations were transcribed and analyzed and the main thematic elements were coded. During deliberation, participants acknowledged the limitations of advanced research directives and discussed ways to improve their use. Although there was consensus about the necessity of surrogate consent, the participants recognized potential pitfalls and looked for ways to safeguard the process. Participants supporting surrogate consent for research emphasized societal and individual benefits, the importance of assent, and trust in surrogates and the oversight system. Other participants felt that the high risk of some research scenarios was not sufficiently offset by benefits to patients or society. Members of the older general public are able to make use of in-depth education and peer deliberation to provide reasoned and informed opinions on the ethical use of surrogate consent for dementia research. The public's approach to surrogate consent is one of cautious pragmatism: an overall trust in science and future surrogates with awareness of the potential pitfalls, suggesting that their trust cannot be taken for granted.


Frailty, gaps in care coordination, and preventable adverse events.
Older US adults often receive care from multiple ambulatory providers. Seeing multiple providers may be clinically appropriate but creates challenges for communication. Whether frailty is a risk factor for gaps in communication among older adults and subsequent preventable adverse events is unknown. We conducted a cross-sectional analysis of community-dwelling US adults ≥ 65 years of age in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who attended an in-home study examination in 2013-2016 and completed a survey on experiences with healthcare in 2017-2018 (n = 5,024). Using 5 frailty indicators (low body mass index, exhaustion, slow walk, weakness, and history of falls), we characterized participants into 3 mutually exclusive groups: not frail (0 indicators), intermediate-frail (1-2 indicators), and frail (3-5 indicators). We used survey data on self-reported gaps in care coordination and self-reported adverse events that participants attributed to poor communication among providers (a drug-drug interaction, repeat testing, an emergency department visit, or a hospital admission). Overall, 2,398 (47.7%) participants were not frail, 2,436 (48.5%) were intermediate-frail, and 190 (3.8%) were frail. The prevalence of any gap in care coordination was 37.0%, 40.8%, and 51.1% among participants who were not frail, intermediate-frail and frail, respectively. The adjusted prevalence ratio (PR) for any gap in care coordination among intermediate-frail and frail versus not frail participants was 1.09 (95% confidence interval [95%CI] 1.02-1.18) and 1.34 (95%CI 1.15-1.56), respectively. The prevalence of any preventable adverse event was 7.0%, 11.3% and 20.0% among participants who were not frail, intermediate-frail and frail, respectively. The adjusted PR for any preventable adverse event among those who were intermediate-frail and frail versus not frail was 1.47 (95%CI 1.22-1.77) and 2.24 (95%CI 1.60-3.14), respectively. Among older adults, frailty is associated with an increased prevalence for self-reported gaps in care coordination and preventable adverse events. Targeted interventions to address patient-reported concerns regarding care coordination among intermediate-frail and frail older adults may be warranted.


Synthesis, characterization and biological evaluation of two cyclometalated iridium(III) complexes containing a glutathione S-transferase inhibitor.
The cyclometalated iridium(III) compounds have been intensively studied for health-related applications due to their outstanding luminescent properties and multiple anticancer modes of action. Herein, two iridium(III) compounds Ir-1 and Ir-3 containing glutathione S-transferase inhibitor (GSTi) were developed and studied together with two unfunctionalized compounds Ir-2 and Ir-4 as a comparison. Biological study indicated that GSTi-bearing complexes Ir-1 and Ir-3 exert a synergistic effect on the inhibition of cancer cells. The photophysical properties of Ir-1 ∼ Ir-4 were investigated by UV/vis absorption and fluorescence spectroscopy and rationalized with TD-DFT calculations. As expected, GSTi-bearing complexes Ir-1 and Ir-3 exhibited considerable cytotoxicity against both A549 and cisplatin-resistant A549/cis cancer cells, much higher than the unfunctionalized iridium compounds Ir-2 and Ir-4. Further study indicated that Ir-1 and Ir-3 mainly localize in the mitochondria of tumor cells, and exert their cytotoxicity via generating ROS and inhibiting GST activity. The flow cytometry investigations demonstrated that Ir-1 and Ir-3 can arrest the cell cycle in S phase and induce the cell death through apoptosis process. Overall, the complexation of GST inhibitors with cyclometalated iridium(III) agents provides an effective way for potentiating the cytotoxicity of iridium(III) anticancer agents and resensitizing the efficacy against cisplatin resistant cancer cells.


Identification of native endophytic Trichoderma spp. for investigation of in vitro antagonism towards Armillaria mellea using synthetic- and plant-based substrates.
To isolate endophytic Trichoderma species and investigate the potential for biological control of the root rot pathogen Armillaria mellea. In all, 40 Trichoderma isolates were obtained from a range of host plants and identities were confirmed by ITS, rpb2 and tef1 sequence. When tested in dual culture assays for antagonism against A. mellea, Trichoderma isolates overgrew the A. mellea colonies within four days and by eight days 38 Trichoderma isolates significantly reduced A. mellea colony size. Armillaria mellea was unable to be recovered from five of eight co-cultivations tested, suggesting Trichoderma had killed the A. mellea in these cases. Pre-colonized hazel disks were used to determine what happens in a more heterogeneous situation with A. mellea and a refined set of eight Trichoderma isolates. Similar to plate-based assays, Trichoderma quickly covered A. mellea stopping any further growth and two Trichoderma isolates were able to eradicate A. mellea. Of the Trichoderma spp. tested, endophytic isolates of Trichoderma virens and T. hamatum offered the greatest antagonism towards A. mellea. Using pre-colonized hazel disks was of great importance for this work to demonstrate the fungal interactions in plant material. Controlling Armillaria root rot is difficult with chemical treatments, thus an environmentally benign and cost-effective alternative is required. This study highlights the prospect of biological control as an effective, environmentally friendly alternative to chemicals.


Bivalent separation into univalents precedes age-related meiosis I errors in oocytes.
The frequency of chromosome segregation errors during meiosis I (MI) in oocytes increases with age. The two-hit model suggests that errors are caused by the combination of a first hit that creates susceptible crossover configurations and a second hit comprising an age-related reduction in chromosome cohesion. This model predicts an age-related increase in univalents, but direct evidence of this phenomenon as a major cause of segregation errors has been lacking. Here, we provide the first live analysis of single chromosomes undergoing segregation errors during MI in the oocytes of naturally aged mice. Chromosome tracking reveals that 80% of the errors are preceded by bivalent separation into univalents. The set of the univalents is biased towards balanced and unbalanced predivision of sister chromatids during MI. Moreover, we find univalents predisposed to predivision in human oocytes. This study defines premature bivalent separation into univalents as the primary defect responsible for age-related aneuploidy.


Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia.
The anatomical basis of schizophrenia involves the cytoarchitecture of the cerebral cortex, but the phenotype of the affected neurons and synapses remains unclear. In mice, the presynaptic protein complexin I is a marker of axosomatic (inhibitory) synapses, whereas complexin II is a marker of axodendritic (mainly excitatory) synapses. These findings suggest that the complexins might be useful in the investigation of the synaptic pathology of schizophrenia. We characterised the expression of the complexins in tissue taken at necropsy from human medial temporal lobe (hippocampus, parahippocampal gyrus) and cerebellum using in-situ hybridisation and immunoautoradiography. We then measured the concentrations of the complexins and their messenger RNAs (mRNAs) in the medial temporal lobe of 11 patients with schizophrenia and 11 non-schizophrenic controls. The distribution of complexin I and II was consistent with the data on mice, with predominant expression of complexin I by inhibitory neurons, and complexin II by excitatory neurons. The amounts of both complexin mRNAs were lower in schizophrenic than in control patients (p<0.001), but the difference of complexin II mRNA was greater. The amount of complexin I protein was unchanged in schizophrenia, but complexin II protein was decreased (p<0.001). For both mRNA and protein, the complexin II/complexin I ratio was lower in schizophrenia, confirming the relatively greater loss of the excitatory marker. The findings did not seem attributable to medication. The synaptic pathology of schizophrenia, at least in medial temporal lobe, primarily affects excitatory (glutamatergic) neurons. The inferred imbalance between excitatory and inhibitory circuitry may contribute to the involvement of this region in the pathophysiology of the disorder.


Relationship between breast-feeding and adiposity in infants and pre-school children.
We aimed to establish associations of duration of breast-feeding with mean BMI and waist circumference, as well as the likelihood of being overweight/obese, during early childhood. Cross-sectional, population-based study. Height, weight and waist circumference were measured and BMI calculated. Interviewer-administered questionnaire determined whether the child was ever breast-fed and the duration of breast-feeding. Sydney, Australia. Infants and pre-school children (n 2092) aged 1-6 years were examined in the Sydney Paediatric Eye Disease Study during 2007-2009. Of the children aged 1-6 years, 1270 had been breast-fed compared with 822 who were never breast-fed. After multivariable adjustment, 1-6-year-old children who were ever breast-fed compared with those who were not had significantly lower BMI, 16·7 (se 0·1) kg/m2 v. 17·1 (se 0·2) kg/m2 (P = 0·01). Decreasing BMI was associated with increasing duration of breast-feeding (P trend = 0·002). After multivariable adjustment, each month increase in breast-feeding was associated with an average BMI decrease of 0·04 kg/m2 (P = 0·002) and 0·03 kg/m2 (P = 0·03) among children aged 1-2 years and 3-4 years, respectively. In 1-2-year-old children, each month increase in breast-feeding duration was associated with a 0·06 cm decrease in waist circumference (P = 0·04). Significant associations were not observed among 5-6-year-old children. Children who were ever breast-fed v. those never breast-fed were less likely to be overweight/obese (multivariable-adjusted OR = 0·54; 95 % CI 0·36, 0·83). We demonstrated a modest influence of breast-feeding on children's BMI during early childhood, particularly among those aged less than 5 years.


EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma.
Endometrial carcinosarcomas are aggressive biphasic neoplasms traditionally treated as a high-grade uterine sarcoma. Epidermal growth factor receptor (EGFR) and HER2/neu (HER2) tyrosine kinases have been implicated in the development and progression of several human cancers and are targets for therapeutic intervention. The aim of this study was to evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed endometrial carcinosarcoma were immunostained with commercially available antibodies to EGFR and HER2. Fluorescent in situ hybridization for HER2 gene amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR expression were correlated with several prognostic variables. EGFR expression was identified in the majority of tumors (45/55, 82%). HER2 overexpression (3+) was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11 (20%) cases. EGFR expression and HER2 gene amplification did not show significant correlation with disease progression, disease-free survival or overall survival. The carcinomatous component of tumors more frequently showed HER2 overexpression as compared to the sarcomatous component (25% vs. 4%, P = 0.008). The sarcomatous component of tumors more frequently showed EGFR overexpression as compared to the carcinomatous component (44% vs. 24%, P = 0.04). EGFR and HER2 appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous and sarcomatous elements of these tumors showed consistent differences in HER2 and EGFR expression patterns supporting biologic differences between these components. Studies evaluating the clinical utility of HER2 or EGFR targeted therapy in these tumors appear warranted.