Enhancement by cyclosporine A and tacrolimus of serotonin-induced formation of small platelet aggregation.
Cyclosporine A (CsA) may increase the incidence of thrombotic events, but whether tacrolimus (Tc) has such effects is still unclear. The serotonergic system has been linked to the thrombotic effects of CsA, but a direct effect of CsA on serotonin-induced platelet aggregation has not been demonstrated because of methodological difficulties. We measured the effects of CsA and Tc on serotonin-induced platelet aggregate formation by particle counting using light scattering. CsA and Tc both enhanced serotonin-induced formation of small platelet aggregates, however, neither CsA nor Tc affected aggregation induced by high or low concentrations of ADP, with or without addition of a serotonin receptor antagonist. Both CsA and Tc enhance platelet aggregation induced via the serotonin pathway.


Effects of cocaine and desipramine on the neurally evoked overflow of endogenous noradrenaline from the rat heart.
1 Stimulation of postganglionic cardiac sympathetic nerves produced a stimulation frequency-dependent overflow of endogenous noradrenaline from the otherwise isolated rat heart. 2 Such nerve stimulation also produced increases in heart rate. There was significant correlation between heart rate increases and corresponding noradrenaline concentrations in the coronary venous effluent. 3 Cocaine (3 X 10(-5)M) caused a significant reduction in both the noradrenaline overflow and the heart rate increase, produced by nerve stimulation for 1 min at 4 Hz. 4 Desipramine (10(-6)M) caused a significant increase in the noradrenaline overflow produced by stimulation for 1 min (4 Hz) with a mean increase of approximately 60%. There was no significant effect on the heart rate increase produced by such stimulation. 5 The opposite effects of cocaine (3 X 10(-5)M) and desipramine (10(-6)M) on noradrenaline overflow are attributed to differences in the local anaesthetic properties of these agents.


The potential value of amlexanox in the treatment of cancer: Molecular targets and therapeutic perspectives.
Amlexanox (AMX) is an azoxanthone drug used for decades for the treatment of mouth aphthous ulcers and now considered for the treatment of diabetes and obesity. The drug is usually viewed as a dual inhibitor of the non-canonical IκB kinases IKK-ɛ (inhibitor-kappaB kinase epsilon) and TBK1 (TANK-binding kinase 1). But a detailed target profile analysis indicated that AMX binds directly to twelve protein targets, including different enzymes (IKK-ɛ, TBK1, GRK1, GRK5, PDE4B, 5- and 12-lipoxygenases) and non-enzyme proteins (FGF-1, HSP90, S100A4, S100A12, S100A13). AMX has been demonstrated to have marked anticancer effects in multiple models of xenografted tumors in mice, including breast, colon, lung and gastric cancers and in onco-hematological models. The anticancer potency is generally modest but largely enhanced upon combination with cytotoxic (temozolide, docetaxel), targeted (selumetinib) or biotherapeutic agents (anti-PD-1 and anti-CTLA4 antibodies). The multiple targets participate in the anticancer effects, chiefly IKK-ɛ/TBK1 but also S100A proteins and PDE4B. The review presents the molecular basis of the antitumor effects of AMX. The capacity of the drug to block nonsense-mediated mRNA decay (NMD) is also discussed, as well as AMX-induced reduction of cancer-related pain. Altogether, the analysis provides a survey of the anticancer action of AMX, with the implicated protein targets. The use of this well-tolerated drug to treat cancer should be further considered and the design of newer analogues encouraged.


[The concept of depression. Evolution of thoughts from Kraepelin until today (author's transl)].
Our concept of depression have been profondly modified during these last decennies. The work of Kraepelin keeps an interest more than historical. By proposing a medical model for thymic troubles, he has opened the avenue for genetic and biochemical research which will confirm or not the nosology based on clinical investigations. Other models have been proposed for affective troubles : psychodynamic, ethological and experimental models. It is not yet possible to make a synthesis integrating psychological and biological parameters.


Hormonal effect on glycosaminoglycans and glycoproteins in uteri of ovariectomized rats.
1. Glycosaminoglycans such as chondroitin sulfate A (or C), chondroitin sulfate B (dermatan sulfate), heparitin sulfate (heparan sulfate) and hyaluronic acid were identified as major glycosaminoglycan components in whole uteri as well as in uterine stroma of rats. Two types of sialoglycoproteins with different electrophoretic mobilities (fast- and slow-migrating) were detected in the glycosaminoglycan fraction from the luminal epithelia. 2. Treatment of ovariectomized rats with estradiol-17beta markedly increased the uterine contents of glycosaminoglycans. Chondroitin sulfate A (or C) was found to increase more than chondroitin sulfate B. Furthermore, it was found that the estrogen treatment specifically increases the fast-migrating sialoglycoprotein level in the luminal epithelia and results in the appearance of it in the uterine fluid. 3. Administration of progesterone to ovariectomized rats slightly increased the uterine glycosaminoglycan content without appreciable alteration of the uterine glycosaminoglycan pattern.


Meta-Analysis Comparing Percutaneous Coronary Revascularization Using Drug-Eluting Stent Versus Coronary Artery Bypass Grafting in Patients With Left Ventricular Systolic Dysfunction.
The relative safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stent (DES) and coronary artery bypass grafting (CABG) in patients with left ventricular (LV) systolic dysfunction remains controversial; therefore we conducted this meta-analysis to identify the optimal strategy for such cohorts. A comprehensive search of the electronic databases including PubMed, EMBASE, and Cochrane Library from January 1, 2003 to March 1, 2018 was performed to identify the eligible adjusted observational studies. The primary end point was all-cause death during the longest follow-up, and the generic inverse variance random-effect model was used to estimate the pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Eight adjusted observational studies involving 10,268 patients were included. Compared with CABG, PCI with DES was associated with higher risk of all-cause mortality (HR 1.36, 95% CI 1.16 to 1.60), cardiac mortality (HR 2.20, 95% CI 1.63 to 2.95), myocardial infarction (HR 1.69, 95% CI 1.28 to 2.24), and repeat revascularization (HR 4.95, 95% CI 3.28 to 7.46) in patients with coronary artery disease and LV systolic dysfunction. Besides, separate analysis of patients with LV ejection fraction <35% or left main and/or multivessel disease obtained similar results compared with the overall analysis. However, DES and CABG shared similar rates of stroke (HR 0.92, 95% CI 0.67 to 1.26). In conclusion, CABG appears to be superior to PCI with DES for patients with coronary artery disease and LV systolic dysfunction, particularly in patients with severe LV systolic dysfunction or those with left main and/or multivessel disease.


Results of long-term follow-up observations of blepharoptosis correction using the palmaris longus tendon.
The frontalis sling procedure is a useful approach for correcting severe blepharoptosis. However, blepharoptosis often recurs after corrective surgery using the tensor fascia lata. Good results without recurrence after a modified Fox method were obtained using the palmaris longus tendon. This study examined the safety and validity of the surgical method using the palmaris longus tendon through long-term follow-up observations. To reduce the rate of recurrence, the highest point on the pentagon of the Fox method was fixed to the frontalis fascia and frontalis muscle. It was fixed once again to the area 1 cm above the highest point. This approach remarkably reduces the incidence of recurrence by fixing the pentagon of the Fox method not only to the palmaris longus tendon but also to the frontalis fascia and again to the frontalis muscle. A modified Fox method using the palmaris longus tendon was used to treat 16 eyelids of 10 patients. A senior surgeon performed the procedure in all cases under local anesthesia. The mean follow-up period was 51 months (range = 18-86 months). There was no case of blepharoptosis recurrence and a good field of view was secured after surgery. Long-term follow-up revealed that the visual field had been well secured with a mean MRD1 of 3.1 mm. The eyelids were well maintained without any postoperative adverse reaction such as exposure keratitis. The palmaris longus tendon as useful donor material does not lead to recurrence of blepharoptosis, which is often encountered when the tensor fascia lata is used. The modified Fox method using the palmaris longus tendon can be an effective and valid surgical approach that produces both immediate and long-term results.


Gene signatures of testicular seminoma with emphasis on expression of ets variant gene 4.
Gene expression patterns of testicular seminoma were analysed applying oligonucleotide microarrays in 40 specimens of different tumour stages (pT1, pT2, pT3) and in normal testes. Transcripts of maternally expressed 3 transcripts were expressed in seminoma without correlation with delta-like 1 homologue expression indicating an impaired imprinting status in seminoma. Interestingly, the transcripts of bromodomain-containing 2 and nuclear autoantigenic sperm protein associated with spermatogenesis were significantly upregulated in progressing tumour stages. Transcription factors TEA domain family member 4 and ETS variant gene 4 (ETV4), weakly expressed in normal testis, were strongly augmented during tumourigenesis. For ETV4 expression, a significant correlation with the increased expression of matrix metalloproteinase 2 and a disintegrin and metalloproteinase domain 15 was determined. The ETV4 protein was localised to nuclei of spermatogonia and revealed an intense staining in seminoma cells. Taken together, we characterised additional transcription factors and spermatogenesis-associated genes involved in the progression of seminoma.


[Polymorphic markers of the dopamine D4 receptor gene promoter region and personality traits in mentally healthy individuals from the Russian population].
The dopamine receptor gene D4 is a highly polymorphic gene, which, according to a number of studies, is associated with the personality traits characterizing human activity. Earlier, a VNTR polymorphic marker in exon 3 and single-nucleotide polymorphism in the promoter region were shown to be associated with novelty seeking. However, these results were not supported by all subsequent studies, which suggest a possible effect of other polymorphic regions of this gene. The aim of the present work was studying the effect of gene DRD4 on activity-related human personality traits in Russians, using in association analysis three polymorphic markers of this gene (-809 G/A, -616 C/G, and -521 C/T) and psychological traits assessed by various tests. Genotyping and psychological examination were conducted in 220 mentally healthy subjects (131 individuals lacking hereditary load of psychic diseases and 89 relatives of patients with psychoses). In Russians, allele frequencies of all markers proved to have no significant difference from the corresponding estimates for European populations. The markers examined were in linkage equilibrium. We have found a significant contribution of genotypes -521 C/T and -809 G/A to the expression of extraversion (Eysenck Personality Inventory (EPI), P = 0.0016) and variation of scores of the Social Introversion scale (Minnesota Multiphase Personality Inventory (MMPI), P = 0.0085). Genotypes -521 C/T and -616 C/G had a joint effect on scores on the Hypomania scale (P = 0.04), while their effect on extraversion was recorded as a trend (P = 0.054). Thus, the results of this study in general support the evidence by other authors showing association of polymorphism at the DRD4 gene promoter to personality traits. We have shown that the traits in question were mainly related to social activity. A reduction in social activity is associated largely with the T(-521 C/T) allele, characterized by low transcription rate.


Centaurea triumfetii essential oil chemical composition, comparative analysis, and antimicrobial activity of selected compounds.
The essential oils from the Centaurea genus are well known for their pharmacological properties. The most abundant and dominant chemical components in Centaurea essential oils are ß-caryophyllene, hexadecanoic acid, spathulenol, pentacosane, caryophyllene oxide, and phytol. However, whether these dominant components are the key drivers for observed antimicrobial activity remains unclear. Thus, the aim of this study was dual. Here we provide comprehensive, literature-based data to correlate the chemical compounds in Centaurea essential oils with the tested antimicrobial activity. Secondly, we characterized the essential oil of Centaurea triumfettii All. squarrose knapweed using coupled system gas chromatography-mass spectrometry and tested its phytochemicals for antimicrobial activity against E. coli and S. epidermis using disc diffusion assay and monitoring their growth in Muller Hinton broth. The most abundant compounds in C. triumfettii essential oil were hexadecanoic acid (11.1%), spathulenol (10.8%), longifolene (8.8%), germacrene D (8.4%), aromadendrene oxide (6.0%) and linoleic acid (5.3%). Based on our analysis of literature data from other Centaurea essential oils, they were positively correlated with antimicrobial activity. Using an agar disk diffusion method, tested chemical constituents did not show experimental evidence to support this positive correlation to antimicrobial activity when we tested them as pure components. The antibacterial effect of essential oil constituents may be related to a complex synergistic, rather than a single component as suggested by performed network pharmacology analysis, underlying the theoretical interactions between the essential oil phytochemicals listed as potentially responsible for antimicrobial activity and should be confirmed in further in-depth studies. This is the first report on the comparative analysis of Centaurea essential oils with good antimicrobial activity, as well as the first analysis of chemical components of the essential oil from C. triumfettii and the first report of antimicrobial activity of the representative, pure components: aromadendrene, germacrene D, spathulenol, longifolene, and the mixture of selected chemical compounds. This work contributes to the body of knowledge on the genus Centaurea and C. triumfettii species.


Differential distribution of vitamin D receptor (VDR) gene variants and its expression in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder that displays an important genetic background. Vitamin D3 (VD3 ) through its receptor (VDR) plays an important immunomodulatory role in autoimmune misbalance, being capable of modulating immune responses. Genetic alterations in VDR gene may contribute to an altered risk in SLE development and clinical manifestations. We investigated VDR SNPs (single nucleotide polymorphisms) frequencies in 128 SLE patients and 138 healthy controls (HC) and mRNA differential expression in 29 patients and 17 HC regarding SLE susceptibility as well as clinical features. We observed that rs11168268 G allele (OR = 1.55, p = .01) and G/G genotype (OR = 2.69, p = .008) were associated with increased SLE susceptibility. The rs2248098 G allele and A/G and G/G genotypes were associated to lower SLE susceptibility (OR = 0.66, p = .01; OR = 0.46, p = .01; OR = 0.44, p = .02, respectively). Regarding clinical features, we observed lower risk for: rs11168268 A/G genotype and nephritis (OR = 0.31, p = .01); rs4760648 T/T genotype and photosensitivity (OR = 0.24, p = .02); rs1540339 T/T genotype and antibody anti-dsDNA (OR = 0.19, p = .015); rs3890733 T/T genotype and serositis (OR = 0.10, p = .01). We identified a significant downregulation in VDR expression levels when compared patients and controls overall (p = 1.04e-7 ), in Cdx-2 A/G and G/G (p = .008 and p = .014, respectively) and in patients with nephritis (p = .016) Our results suggested that VDR SNPs influence upon SLE susceptibility and in particular clinical features, acting on mRNA expression in SLE patients overall and the ones with nephritis.


Successful of the B-Lynch compression suture in the management of massive postpartum hemorrhage: case reports and review.
The authors describe three patients who developed massive primary postpartum hemorrhage and review the case reports. In two patients, primary postpartum hemorrhage was due to uterine atony, and in one patient it was due to atony and thrombophilia. In all three patients, excellent effect was achieved with hemorrhage reduction by a compression B-Lynch suture alone, with bimanual compression following medicamentous uterotonic therapy. B-Lynch suture is an efficient, safe, and simple method for the treatment of primary postpartum hemorrhage during cesarean section, which successfully reduces the number of urgent postpartum hysterectomies, also preserving subsequent fertility. In our opinion, the method should be included in the algorithm of primary postpartum hemorrhage management at all obstetric departments.


DICER1 pleuropulmonary blastoma familial tumour predisposition syndrome: What the paediatric urologist needs to know.
Germline-inactivating DICER1 mutations are responsible of a familial tumour susceptibility syndrome with an increased risk of tumours, mainly pleuropulmonary blastoma (PPB). DICER1 mutations also cause a range of other tumours, some of them in urogenital organs (cystic nephroma [CN], ovarian sex cord-stromal tumours, bladder and cervix embryonal rhabdomyosarcoma [ERMS]). The aim was to clarify the range of urogenital phenotypes associated with DICER1 mutations and to give practical course of action to paediatric urologist that are exposed to DICER1-related conditions. A literature review was performed. Pertinent papers focused on urogenital diseases associated with DICER1 mutations were reviewed. Seventy per cent of CN have a DICER1 germline mutation. The majority of them (80%) have PPB. Like PPB, CN could undergo a malignant progression to a primitive sarcoma. Some rare cases of Wilms tumours were reported. Regarding gonadal manifestations, sex-cord stromal neoplasia of the ovary, especially Sertoli-Leydig cell tumour (SLCT), is the most frequent tumour associated with DICER1 germline mutation. Germline DICER1 mutations also predispose to uterine cervix and bladder ERMS. The presence of unusual tumours suggesting DICER1 mutations may alert clinicians. The first step is to obtain a complete familial history. The variable clinical presentation and the modest penetrance raise concerns about the appropriateness of genetic testing to patients and their relatives. The education of DICER1 mutations carriers about tumour-related symptoms is consensual. In the first 5 years of life, a yearly chest X-ray and abdominal ultrasound are recommended. The presence of a CN, ovarian SLCT or urogenital ERMS in a child should alert the clinician to the possibility of DICER1 mutation and the associated risk of PPB. Individuals with one of the typical DICER1 conditions should be offered DICER1 analysis. Despite the low penetrance, a genetic counselling and testing should be offered to the family of the affected child.


Beta + thalassemia: aberrant splicing results from a single point mutation in an intron.
We have analyzed the molecular basis of beta + thalassemia by studying the expression of a cloned beta-globin gene in HeLa cells. This beta-globin gene was isolated from a beta + thalassemic patient and differs from the normal beta-globin genes by only a single point mutation within the first intron. The beta + thalassemic and the normal beta-globin genes were cloned into an SV40-pBR328 vector and introduced into HeLa cells by calcium phosphate coprecipitation. We assayed the RNA from these transfected HeLa cells by S1 nuclease mapping and cDNA sequencing to detect the nature of the defect in beta-globin gene expression. While the transcripts of the normal beta-globin gene are processed correctly, the first intron of the beta + thalassemic beta-globin gene is incorrectly spliced in about 90% of the mRNA because of an additional 3; splice site that has been created by the point mutation. This incorrectly spliced mRNA is effectively exported to the cytoplasm, where it would conceivably be translated to give a truncated globin chain of 35 amino acids. The remaining 10% of the mRNA transcribed from the beta+ thalassemic globin gene is correctly spliced and can therefore be translated to give normal beta-globin. In addition to the incorrect splicing of the first intron, the splicing of both introns is retarded, which results in the accumulation of unspliced pre-mRNA. This suggests that removal of the first intron might facilitate splicing of the second intron.


EXpert consensus On Diaphragm UltraSonography in the critically ill (EXODUS): a Delphi consensus statement on the measurement of diaphragm ultrasound-derived parameters in a critical care setting.
Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research. To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: "Anatomy and physiology", "Transducer Settings", "Ventilator Impact", "Learning and expertise", "Daily practice" and "Future directions". Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question. Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established. This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established. Trial registration The study was pre-registered on the Open Science Framework with registration digital object identifier https://doi.org/10.17605/OSF.IO/HM8UG .


Dynamic mechanical properties of an inlay composite.
A visible light-cured composite resin (Brilliant DI) has been studied over a wide range of temperature and frequency by a dynamic mechanical flexural method. The derived data of logarithmic modulus and loss tangent (tan delta) show considerable changes following a secondary-cure process applied to the material. This involved the application of heat and intense light with temperatures rising to 120 degrees C in 7 min. Following this oven-cure the resin phase exhibited enhanced stiffness with the activation-energy barrier for molecular motion at the glass-transition rising from 220 to 291 kJ/mol. This study clarifies the nature and extent of the internal molecular changes which may be produced in the fabrication of a composite inlay.


The Use of 3D Printing Technology in Gynaecological Brachytherapy-A Narrative Review.
Radiation therapy, including image-guided adaptive brachytherapy based on magnetic resonance imaging, is the standard of care in locally advanced cervical and vaginal cancer and part of the treatment in other primary and recurrent gynaecological tumours. Tumour control probability increases with dose and brachytherapy is the optimal technique to increase the dose to the target volume while maintaining dose constraints to organs at risk. The use of interstitial needles is now one of the quality indicators for cervical cancer brachytherapy and needles should optimally be used in ≥60% of patients. Commercially available applicators sometimes cannot be used because of anatomical barriers or do not allow adequate target volume coverage due to tumour size or topography. Over the last five to ten years, 3D printing has been increasingly used for manufacturing of customised applicators in brachytherapy, with gynaecological tumours being the most common indication. We present the rationale, techniques and current clinical evidence for the use of 3D-printed applicators in gynaecological brachytherapy.


Critical appraisal of oral calcium load test for indirect assessment of intestinal calcium absorption.
Two methods of oral calcium load or tolerance test for the indirect assessment of calcium absorption were compared. In 16 patients in whom the diagnosis of absorptive hypercalciuria was made independently, an exaggerated urinary total calcium excretion during four hours following calcium load, indicative of increased calcium absorption according to the method of Pak et al., was found in 15 patients. An abnormally high increment in urinary calcium during third and fourth hours post-calcium load, suggestive of enhanced calcium absorption by the criteria of Broadus et al., was encountered in 14 patients. However, an exaggerated urinary total calcium following calcium load was found in all 7 patients with renal hypercalciuria, whereas only 4 were shown to have an enhanced increment in calcium excretion. It is concluded that both methods are equally reliable in the detection of increased calcium absorption in absorptive hypercalciuria. However, the technique of Broadus et al. is probably superior to that of Pak et al. in the disclosure of increased calcium absorption in renal hypercalciuria.


Total venous obstruction following atrioventricular sequential pacemaker implantation.
We describe a case of a 79-year-old woman who developed pain and pitting edema of the upper right extremity due to total venous obstruction following the implantation of an atrioventricular sequential pacemaker. She was treated by arm elevation and anticoagulation after which the pain and edema subsided. To our knowledge, this is the first reported case of this complication occurring following implantation of a dual-chamber pacing system. We recommend that venographic studies be done after implantation if apparent arm swelling occurs, and that anticoagulant therapy be instituted if thrombosis is present.


Phosphatidic acid binds to cytosolic glyceraldehyde-3-phosphate dehydrogenase and promotes its cleavage in Arabidopsis.
Phosphatidic acid (PA) is a class of lipid messengers involved in a variety of physiological processes. To understand how PA mediates cell functions in plants, we used a PA affinity membrane assay to isolate PA-binding proteins from Camelina sativa followed by mass spectrometric sequencing. A cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPC) was identified to bind to PA, and detailed analysis was carried out subsequently using GAPC1 and GAPC1 from Arabidopsis. The PA and GAPC binding was abolished by the cation zinc whereas oxidation of GAPCs promoted the PA binding. PA had little impact on the GAPC catalytic activity in vitro, but the PA treatment of Arabidopsis seedlings induced proteolytic cleavage of GAPC2 and inhibited Arabidopsis seedling growth. The extent of PA inhibition was greater in GAPC-overexpressing than wild-type seedlings, but the greater PA inhibition was abolished by application of zinc to the seedling. The PA treatment also reduced the expression of genes involved in PA synthesis and utilization, and the PA-reduced gene expression was partially recovered by zinc treatment. These data suggest that PA binds to oxidized GAPDH and promotes its cleavage and that the PA and GAPC interaction may provide a signaling link coordinating carbohydrate and lipid metabolism.


Reward cues readily direct monkeys' auditory performance resulting in broad auditory cortex modulation and interaction with sites along cholinergic and dopaminergic pathways.
In natural settings, the prospect of reward often influences the focus of our attention, but how cognitive and motivational systems influence sensory cortex is not well understood. Also, challenges in training nonhuman animals on cognitive tasks complicate cross-species comparisons and interpreting results on the neurobiological bases of cognition. Incentivized attention tasks could expedite training and evaluate the impact of attention on sensory cortex. Here we develop an Incentivized Attention Paradigm (IAP) and use it to show that macaque monkeys readily learn to use auditory or visual reward cues, drastically influencing their performance within a simple auditory task. Next, this paradigm was used with functional neuroimaging to measure activation modulation in the monkey auditory cortex. The results show modulation of extensive auditory cortical regions throughout primary and non-primary regions, which although a hallmark of attentional modulation in human auditory cortex, has not been studied or observed as broadly in prior data from nonhuman animals. Psycho-physiological interactions were identified between the observed auditory cortex effects and regions including basal forebrain sites along acetylcholinergic and dopaminergic pathways. The findings reveal the impact and regional interactions in the primate brain during an incentivized attention engaging auditory task.


[Therapeutic use of tiapride in movement disorders].
Tiapridal was given to twenty-four patients suffering from dyskinesias. Therapeutic efficacity seems to the etiology. Not any fonctitonal improvement was observed in parkinsonism with dyskinesia consecutive to Dopa therapy. On the other hand a good efficacity was found in the treatment of choreas with a quite good tolerance; the functional result will depend of the evolutive state of the disease.


Similarities in the structural organization of the genomes of stumptailed macaque virus (strain HD) and simian virus 40.
Members of the SV40-polyoma subgroup of papovaviruses share homologous sequences which have been conserved during evolution. The genome of HD virus displays homologies both to the origin of SV40 DNA replication and to the region coding for the VPI capsid protein. As in the case of SV40, both regions are discontinuously arranged in the HD genome.


Pre-administration of BAX-inhibiting peptides decrease the loss of the nigral dopaminergic neurons in rats.
In this study, we investigated the effects of Bax-inhibiting peptide (Bip)-V5, an anti-apoptosis membrane-permeable peptide, on the 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model rats. Rats were randomly divided into five groups: Control, 6-OHDA only, Vehicle+6-OHDA, zVAD+6-OHDA, and V5+6-OHDA, that rats were preadministrated with different reagents before 6-OHDA administration. The result showed that intrastriatal preadministration of Bip-V5 significantly decreased the amphetamine-induced rotation of the 6-OHDA model rats and the loss of the nigral dopaminergic (DA) neurons. Moreover, Bip-V5 intrastriatal preadministration not only significantly decreased the expression of activated caspase 9 and activated caspase 3 but also decreased the enhanced expression of AIF and its nuclear translocation in the SNpc. The results in our study provide the first experimental evidence that both caspase-dependent and AIF-dependent apoptosis pathways are involved in the loss of the nigral DA neurons caused by intrastriatal administration of 6-OHDA, and intrastriatal preadministration of Bip-V5 can inhibit the above two apoptosis pathways to protect the nigral DA neurons. Our results provide a new idea that Bax-inhibiting peptide may be a promising preventive or therapeutic method for PD.


Stability, dose uniformity, and palatability of three counterterrorism drugs-human subject and electronic tongue studies.
These studies evaluated the ability of common household food and drink products to mask the bitter taste of three selected anti-terrorism drugs. Three anti-terrorism drugs (doxycycline, ciprofloxacin hydrochloride, and potassium iodide) were mixed with a variety of common household food and drinks, and healthy adult volunteers evaluated the resulting taste and aftertaste. In parallel, the ASTREE Electronic Tongue was used to evaluate taste combinations. Stability of the mixtures over time was monitored, as was the dosage uniformity across preparations. Foods and drinks were identified that satisfactorily masked the bitter flavor of each drug. Dose uniformity and stability were also acceptable over the range studied, although some combinations were significantly less stable than others. The electronic tongue was able to differentiate between tastes, but ranked masking agents in a different order than human volunteers. Doxycycline, potassium iodide, and ciprofloxacin, which are stockpiled in solid tablet form, can conveniently be prepared into more palatable formulations, using common household foods and drinks. The electronic tongue can be used to perform an initial screening for palatability.


Biomarkers and Right Ventricular Dysfunction.
Right ventricular failure is common in critically ill patients, as it frequently results from pulmonary embolism or pulmonary hypertension, and can complicate sepsis and the acute respiratory distress syndrome. Right ventricular dysfunction can be challenging to manage and is associated with poor outcomes in this wide array of disease. Laboratory biomarkers are rapid, noninvasive, accurate, and widely available and thus are useful in the diagnosis and management of right ventricular dysfunction in the critically ill patient. This article discusses the pathophysiology of right ventricular failure and reviews the applications of commonly used biomarkers in right ventricular dysfunction in critical care.


[PERSIRIS study: observational study, postmarketing, prospective, to evaluate the persistence to treatment with monthly risedronate in women with osteoporosis].
To assess the persistence of treatment with monthly risedronate and know the reasons of persistence and nontherapeutic persistence and the profile of the non-persistent patients. Observational, postmarketin and prospective study. Primary care, traumatology, rheumatology, gynecology and geriatrics of Catalonia. Women with osteoporosis treated with monthly risedronate that previously had abandoned weekly bisphosphonate therapy. Percentage of patients on persistent monthly risedronate year of their prescription, reasons for persistent and non persistent and profile of non persistent patients in relation to biodemographic data, clinical data and risk factors for fracture. 289 evaluable patients with a mean age of 68.3. At 12 months of initiation with monthly risedronate, 58.1% of patients remained on treatment. Most frequent reasons for leaving: fear of having side effects and belief that the disease is typical of the age. Reasons remarkable persistence: comfort/ease and dosage. Significant differences were observed between persistent and non-persistent patients relative to: employment status, number of concomitant therapy and height; however the results of possible associated factors must be contextualized within the study characteristics and the difference in size does not seem clinically relevant. The administration of therapeutic patterns more comfortable as monthly risedronate in osteoporosis, could facilitate persistence in patients improving the effectiveness of the drug. However in that persistence can also influence biodemographic and clinical variables and diverse of various kinds.


Alkylation of opioid receptors by 5'-naltrindole-isothiocyanate injected into the nucleus accumbens of rats: receptor selectivity and anatomical diffusion.
Subtypes of the delta opioid receptor (Oprd1) have been suggested based on pharmacology studies. However, these subtypes have not been confirmed biochemically using either receptor binding assays or molecular cloning. Naltrindole-5'-isothiocyanate (5'-NTII) is an irreversible opioid antagonist that appears to selectively inhibit the actions of a subset of delta opioid agonists in vivo, referred to as putative delta-2 agonists. The biochemical and anatomical selectivity of wash-resistant inhibition of binding of [(3)H]DAMGO (Oprm1), [(3)H]DPDPE (Oprd1, putative subtype 1 agonist), or [(3)H]deltorphin II (Oprd1, putative subytpe 2 agonist) in coronal sections was assessed using quantitative in vitro autoradiography following injection of 5'-NTII into the nucleus accumbens in rats. 5'-NTII decreased [(3)H]deltorphin II to a greater extent than the binding of the other two radioligands following administration of 0.05-2.5 nmol. The effects of 5'-NTII were largely confined to the nucleus accumbens; however, some loss in the ventral caudate was also noted. In contrast, administration of the nonselective opioid receptor alkylating antagonist beta-chlornaltexamine (beta-CNA) over a similar range of doses was found to be nonselective for either delta radioligand, and produced greater inhibition of Oprm1 relative to Oprd1 binding, consistent with the nonselective pharmacological activity of this antagonist. Although 5'-NTII inhibited [(3)H]deltorphin II binding to a greater extent, the binding of the other two radioligands was decreased over a similar range of doses. Absolute conclusions regarding the involvement of delta-2 opioid receptors in pharmacological or physiological effects based on studies with 5'-NTII should therefore be tempered, and for site-directed studies it would be best to employ doses of 0.5 nmol or lower.


Examining the Impact of COVID-19 on Parental Stress: A Study of Foster Parents.
The overarching purpose of this exploratory study was to understand how foster parents' parenting-related stress levels have changed over the course of the COVID-19 pandemic, including the role of sociodemographic characteristics in exacerbating risk for increased stress. Participants were electronically surveyed about their pre- and post-pandemic parenting-related stress, using an adapted version of the parenting stress scale. Nine-hundred and ninety foster parents (N = 990) participated in the study. Overall, foster parents reported significant increases along three specific domains of stress-namely, parenting stress, lack of control, and parental satisfaction (reverse-scored). Analyses for group differences on the post-only scores indicated that foster parents who are not married, or who report poorer mental health (i.e., "good", versus "very good" or "excellent") or financial circumstances (i.e., as indicated by not reliably having more income than expenses) may face increased risk for exacerbated stress during this pandemic. Findings from this study indicate that parental stress-levels among foster parents have increased since the start of COVID-19. These findings are not only troubling for foster caregivers, but may also have implications for the youth in their care. Ultimately, results from this study indicate the need to better support foster parents, in general, and during public health crises, specifically.


Bystander accessory pathway during AV node re-entrant tachycardia.
Between 1970 and July 1980, wide QRS tachycardia due to re-entry confined to the AV node with bystander involvement of an accessory atrioventricular pathway (AAV) was documented in three of 290 patients with the Wolff-Parkinson-White syndrome studied at Duke Medical Center. In each of the patients, at least one transition between wide and narrow QRS morphology was recorded without change in either the cycle length of tachycardia or the atrial activation sequence. Two of the three patients had a single left-sided AAV (lateral, postero-lateral) showing antegrade conduction only. The third patient had two right-sided AAVs (free wall, septal), each capable of bidirectional conduction. Initiation and termination of repetitive concealed conduction into the ventricular insert of an AAV appeared to be one mechanism determining bystander AAV participation. Documentation of the retrograde sequence of atrial activation during tachycardia, and examination of the effects of interpolated premature depolarizations from both the ventricle and mid-line atrium are the most helpful features in resolving the differential diagnosis of wide QRS tachycardia in patients with W-P-W syndrome.


Severe adenoviral nephritis following bone marrow transplantation: successful treatment with intravenous ribavirin.
Invasive adenovirus infection is recognized as an unusual cause of serious end-organ sequelae following BMT. Because symptomatic therapy may be inadequate for more serious infections, the use of investigational agents is justified. We describe a case of severe, progressive nephritis secondary to adenovirus serotype 11 following BMT. Treatment with i.v. ribavirin led to prompt clinical improvement and resolution of adenovirus excretion.


[In vitro incorporation of radioactive sulfur into proteoglycans of cartilage. Effects of various nonsteroidal anti-inflammatory agents].
Radioactive sulphur (35SO4) is incorporated in the proteoglycans of chicken embryonic cartilage. In fact, the molecular weight of the macromolecules which bind the sulphur corresponds to monomeric proteoglycans and proteoglycan-hyaluronic acid complexes. This incorporation does not take place when the cartilage has been previously killed. The capture of 35S is stimulated by human serum, in a dose-dependent way. At doses less then, equal to and greater than the maximal plasma concentrations observed following a single oral dose (600 mg), acetyl salicylic acid and sodium salicylate inhibit the incorporation of radioactive sulphur in the cartilage. Under the same conditions, tiaprofenic acid and oxametacine have no effect on this metabolic parameter.


[Studies on the synthesis of antiulcer agents. IV. Synthesis and antiulcer activity of dihydrobenzofuranone derivatives].
The derivatives of 3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5-yl]acrylic acid were synthesized and tested for antiulcer activities. As a result, 1-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]piperidine(3t) and 4-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]morpholine(3u) exhibited potent antiulcer activities.


Some aspects of the SOS response system--a critical survey.
The SOS system and SOS mutagenesis are frequently studied, or exploited to obtain an increase in mutagenicity of bacteria. Here a short survey is made of the phenomenon of SOS response with special attention to latest and less discussed data, especially the induction of the SOS system in response to cell starvation or mutation of certain genes and the role of inducible DNA polymerases.


Development of visual cortex in human neonates is selectively modified by postnatal experience.
Experience-dependent cortical plasticity is a pivotal process of human brain development and essential for the formation of most cognitive functions. Although studies found that early visual experience could influence the endogenous development of visual cortex in animals, little is known about such impact on human infants. Using the multimodal MRI data from the developing human connectome project, we characterized the early structural and functional maps in the ventral visual cortex and their development during neonatal period. Particularly, we found that postnatal time selectively modulated the cortical thickness in the ventral visual cortex and the functional circuit between bilateral primary visual cortices. But the cortical myelination and functional connections of the high-order visual cortex developed without significant influence of postnatal time in such an early period. The structure-function analysis further revealed that the postnatal time had a direct influence on the development of homotopic connection in area V1, while gestational time had an indirect effect on it through cortical myelination. These findings were further validated in preterm-born infants who had longer postnatal time but shorter gestational time at birth. In short, these data suggested in human newborns that early postnatal time shaped the structural and functional development of the visual cortex in selective and organized patterns.


Frequency of primary solid malignant neoplasms in different age groups as seen in our practice.
To determine in a large series of surgical biopsies, the frequency of various histologic types of primary solid malignant neoplasms in males and females in different age groups. A retrospective study of 20,000 consecutive surgical biopsies reposted in the section of histopathology, AKU in 2004. Malignant neoplasms are commonest in the fifth and sixth decades of life. The commonest malignant neoplasms in the first decade were Hodgkin's lymphoma and Wilm's tumor in males and females respectively. In the second decade, osteosarcoma in males and Ewing's sarcoma / PNET in females. In the third decade, colorectal adenocarcinoma in males and infiltrating. Ductal carcinoma of breast in females. In the fourth decade, squamous cell carcinoma of oral cavity in males and infiltrating ductal carcinoma of breast in females. In the fifth decade squamous cell carcinoma of oral cavity in males and infiltrating ductal carcinoma of breast in females. In sixth decade, squamous cell carcinoma of oral cavity in males and infiltrating ductal carcinoma of breast in females and in the seventh decade, prostatic adenocarcinoma in males and infiltrating ductal carcinoma of the breast in females. Above age of 70 years, the commonest malignant were again prostatic adenocarcinoma in males and infiltrating ductal carcinoma of breast in females. Malignant neoplasms are commonest in the fourth, fifth and sixth decades of life.


Kindling phenomenon: impairment by auditory stimuli.
By coupling kindling stimuli with tones, it is shown that kindled epileptiform activity is not easily classically conditioned such that it can be evoked by an auditory stimulus. On the contrary, a tone presented 400 msec before and during the kindling stimulus impedes the rate of kindling.


Clinical and Pharmacological Parameters Determine Relapse During Clopidogrel Treatment of Acute Coronary Syndrome.
The therapeutic efficacy of clopidogrel as an antiplatelet drug varies among individuals, being the mainstream hypothesis that its bioavailability depends on the individual genetic background and/or interactions with other drugs. A total of 477 patients receiving double antiaggregation therapy with aspirin and clopidogrel, after suffering a first event, were followed for 1 year to record relapse, as a surrogate end point to measure their therapeutic response, as defined by presenting with an acute coronary event (unstable angina, ST-segment-elevation myocardial infarction, or non-ST-segment-elevation myocardial infarction), stent thrombosis/restenosis, or cardiac mortality. Anthropometric, clinical, and pharmacological variables along with CYP2C19 genotypes were analyzed for their association with the disease relapse phenotype. Only 75 patients (15%) suffered a relapse, which occurred during the first 6 months of therapy, with a peak at 4.5 months. An initial univariate analysis identified that patients in the relapse group were significantly older (67.4 ± 11.0 vs 61.6 ± 12.3 years old) and presented with diffuse coronary disease, insulin-dependent type 2 diabetes mellitus dyslipidemia, and arterial hypertension. A poor clinical response to the platelet antiaggregation regime also occurred more frequently among patients taking acenocoumarol and calcium channel blockers, along with aspirin and clopidogrel, while no association was found according to CYP2C19 genotypes. A retrospective multivariate analysis indicated that patients belonging to the nonresponder phenotype to treatment with aspirin and clopidogrel were older, presented with diffuse coronary disease, a group largely overlapping with type 2 insulin-dependent diabetes mellitus, and were taking dihidropyrimidinic calcium channel blockers.


Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells.
Cigarette smoking is an important risk factor for both vascular disease and various forms of cancer. Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen that is normally expressed only in low levels in normal arteries but may be involved in the progression of both vascular disease and cancer. Some clinical evidence suggests that cigarette smoking may increase plasma VEGF levels, but there is a lack of basic science studies investigating this possibility. We show here, using an intact porcine common carotid artery perfusion culture model, that nicotine and cotinine, the major product of nicotine metabolism, cause a significant increase in endothelial cell VEGF expression. VEGF mRNA levels were compared between groups using reverse transcriptase-polymerase chain reaction, whereas protein level changes were demonstrated with Western blotting and immunohistochemistry. Our results showed significant increases in endothelial cell VEGF mRNA and protein levels because of nicotine and cotinine at concentrations representative of plasma concentrations seen in habitual smokers. VEGF immunostaining also paralleled these results. These findings may give a clue as to the mechanisms by which nicotine and cotinine from cigarette smoking increase vascular disease progression and tumor growth and metastasis.


Polymer scaffold layers of screen-printed electrodes for homogeneous deposition of silver nanoparticles: application to the amperometric detection of hydrogen peroxide.
A method is described for electrochemical oxidation of polymers on the surface of screen-printed electrodes (SPCE). These act as scaffold layers for homogeneous deposition of silver nanoparticles (AgNPs). Hexamethylenediamine (HMDA) and poly(ethylene glycol) were immobilized on the SPCE surface via electrochemical oxidation. AgNPs were then electrodeposited on the scaffolds on the SPCE. This type of different carbon chain containing materials like PEG and HMDA act as big tunnels for electron mobility and are useful for the homogenous deposition of AgNPs on the SPCE surface without agglomeration. The resulting sensor was applied to the determination of hydrogen peroxide (H2O2) as a model analyte. It is found to display favorable catalytic and conductive properties towards the reduction of H2O2. Cyclic voltammetry and amperometry revealed that the modified electrode performs better than other modified SPCEs. Best operated at a potential of around -0.61 V (vs Ag|AgCl), the amperometric response is linear in the 10-180 μM H2O2 concentration range and the detection limit is 1.5 μM. The sensor is stable and reproducible. The resultant sensor was appplied to toothpaste analysis, and good recovery values were gained. Graphical abstractSchematic representation of electropolymerization of poly(ethylene glycol) and hexamethylenediamine scaffold layers on screen-printed electrodes for homogeneous electrodeposition of silver nanoparticles. This electrode was applied for the amperometric determination of hydrogen peroxide.


Conserved sequence elements at putative processing sites in plant mitochondria.
About 50 nucleotides are conserved in two distinct sequence elements at the 5' termini of abundant short transcripts from plant mitochondrial genes with complex transcription patterns. These sequence motifs are found in both structural RNA and protein-coding precursor transcripts, for example, upstream of the mature 26S rRNA and the shortest transcript of the ATPase subunit 9 genes in different plant species. The high degree of sequence similarity in these plant mitochondrial loci suggests a common functional significance in 5' processing site determination and selection.


Modification of plasma membrane protein cysteine residues by ADP-ribose in vivo.
Proteins can be post-translationally modified by ADP-ribose. Previously, two classes of ADP-ribosyl protein linkages have been detected in vivo which have chemical properties indistinguishable from ADP-ribosyl arginine and ADP-ribosyl glutamate or aspartate. Reported here is the detection of a third class of endogenous ADP-ribosyl protein linkage. This class is chemically indistinguishable from ADP-ribose linked to cysteine residues by a thioglycosidic bond. The distribution of ADP-ribosyl cysteine residues was studied in subcellular fractions of rat liver. Proteins modified on cysteine were detected only in the plasma membrane fraction. Pertussis toxin is known to disrupt signal transduction of ADP-ribosylation of cysteine residues of plasma membrane GTP binding proteins. The results described here raise the interesting possibility that the endogenous modification of plasma membrane protein cysteine residues may be involved in signal transduction.


[Use of the reaction of macrophage disappearance from peritoneal exudate for characterizing cellular immunity in Salmonella immunization].
The test of macrophage disappearance from peritoneal exudate quite effectively shows the state of cell-mediated immunity in guinea pigs immunized with both live and killed S. typhimurium culture. The macrophages of the animals immunized with killed S. typhimurium culture react to the protein extract of these bacteria more actively than the macrophages of the animals immunized with killed S. sonnei cultures, which indicates the specificity of this test.


Deletion mutants of the gene encoding delta-endotoxin specific to scarabaeid beetles: minimum region of the gene required to express the activity.
Various deletion genes for the delta-endotoxin protein of Bacillus thuringiensis strain Buibui were made. The truncated proteins were produced in E. coli, and their larvicidal activity against the cupreous chafer was checked. The fifth block of the five blocks described as "conserved" was shown to be necessary for the activity.


Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis.
Netrin-1 has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5H. However, initially the DCC (deleted in colorectal cancer) gene was proposed as a putative tumor suppressor gene. It was then difficult to reconcile the two activities of DCC until the observation that DCC belongs to an emerging family of receptors named dependence receptors. Such receptors share the property of inducing apoptosis in the absence of ligand, hence creating a cellular state of dependence on the ligand. Thus, netrin-1 may not only be a chemotropic factor for neurons but also a survival factor. We will review here the identification of netrin-1 and its receptors, the signaling pathways initiated in the presence or absence of netrin-1. We will suggest some possible roles of netrin-1 in nervous system development, neovascularisation, adhesion and tumorigenesis.


Anterior shoulder dislocation and concomitant fracture of the greater tuberosity: Clinical and radiological results.
Recurrence rates after primary traumatic shoulder dislocation are distinctly high. We hypothesized that concomitant isolated fractures of the greater tuberosity are associated with low rates of persistent instability but decreased range of motion. Between 2007 and 2013, 66 consecutive shoulders in 64 patients were treated for primary shoulder dislocation combined with an isolated fracture of the greater tuberosity with either a nonsurgical (48 shoulders, 72.7%) or surgical (18 shoulders, 27.3%) treatment approach. In all, 55 cases (83.3%) were available for clinical follow-up examination after an average of 59.0 ± 20.7 months (range: 25-96 months) and of these, 48 (72.7%) patients consented to radiological evaluation to determine healing and position of the greater tuberosity. The mean range of motion of the affected shoulder was significantly decreased by 9° of elevation (p = 0.016), 11° of abduction (p = 0.048), 9° of external rotation in 0° of abduction (p = 0.005), and 10° of external rotation in 90° of abduction (p = 0.001), compared with the unaffected shoulder. The mean WOSI score was 373 ± 486 points, the mean Constant and Murley score was 75.1 ± 19.4 points, and the mean Rowe score was 83 ± 20 points. Three cases (5.5%) of re-dislocation were reported among the cohort, all of them were due to a relevant trauma. Radiological evaluation revealed anatomically healed fragments in 31 shoulders (65%), dislocation of the fragment in ten shoulders (21%), impaction into the humeral head in four shoulders (8%), and absorption in three shoulders (6%). A concomitant isolated fracture of the greater tuberosity leads to low recurrence rates along with a significant decrease in range of motion after primary traumatic anterior shoulder dislocation.


Nonlytic Fc-fused IL-7 synergizes with Mtb32 DNA vaccine to enhance antigen-specific T cell responses in a therapeutic model of tuberculosis.
Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (MTB) infection mouse model examining the combined effects of nonlytic Fc-fused IL-7 DNA (IL-7-nFc) and Flt3-ligand fused Mtb32 (F-Mtb32) DNA. Mice were treated with conventional chemotherapy for 6 weeks from 4 weeks after aerosol infection of MTB. Following the start of chemotherapy, DNA immunizations were administered five times with 2-week intervals. Coadministration of IL-7-nFc and F-Mtb32 DNA given during chemotherapy synergistically enhanced the magnitude of Mtb32-specific T cell responses and sustained for one-year after the last immunization assessed by IFN-γ ELISPOT assay. After dexamethasone treatment, a significantly reduced MTB reactivation was observed in mice received both IL-7-nFc and F-Mtb32 DNA, compared with F-MTb32 DNA alone or with control mice. In addition, mice treated with IL-7-nFc and F-Mtb32 DNA together showed improved lung pathology and reduced pulmonary inflammation values relative to F-Mtb32 DNA or saline injected mice. Intracellular cytokine staining revealed that the protection levels induced by combination therapy with IL-7-nFc and F-Mtb32 DNA was associated with enhanced Mtb32-specific IFN-γ secreting CD4(+) T cell responses and CD8(+) T cell responses stimulated with CTL epitope peptide in the lungs and spleens. These data suggest that IL-7-nFc as a novel TB adjuvant may facilitate therapeutic TB DNA vaccine to the clinics through significant enhancement of codelivered DNA vaccine-induced T cell immunity.


CaV2.1 α1 subunit motifs that control presynaptic CaV2.1 subtype abundance are distinct from CaV2.1 preference.
Presynaptic voltage-gated Ca2+ channels (CaV) subtype abundance at mammalian synapses regulates synaptic transmission in health and disease. In the mammalian central nervous system, most presynaptic terminals are CaV2.1 dominant with a developmental reduction in CaV2.2 and CaV2.3 levels, and CaV2 subtype levels are altered in various diseases. However, the molecular mechanisms controlling presynaptic CaV2 subtype levels are largely unsolved. Since the CaV2 α1 subunit cytoplasmic regions contain varying levels of sequence conservation, these regions are proposed to control presynaptic CaV2 subtype preference and abundance. To investigate the potential role of these regions, we expressed chimeric CaV2.1 α1subunits containing swapped motifs with the CaV2.2 and CaV2.3 α1 subunit on a CaV2.1/CaV2.2 null background at the calyx of Held presynaptic terminal. We found that expression of CaV2.1 α1 subunit chimeras containing the CaV2.3 loop II-III region or cytoplasmic C-terminus (CT) resulted in a large reduction of presynaptic Ca2+ currents compared to the CaV2.1 α1 subunit. However, the Ca2+ current sensitivity to the CaV2.1 blocker Agatoxin-IVA, was the same between the chimeras and the CaV2.1 α1 subunit. Additionally, we found no reduction in presynaptic Ca2+ currents with CaV2.1/2.2 cytoplasmic CT chimeras. We conclude that the motifs in the CaV2.1 loop II-III and CT do not individually regulate CaV2.1 preference, but these motifs control CaV2.1 levels and the CaV2.3 CT contains motifs that negatively regulate presynaptic CaV2.3 levels. We propose that the motifs controlling presynaptic CaV2.1 preference are distinct from those regulating CaV2.1 levels and may act synergistically to impact pathways regulating CaV2.1 preference and abundance.


An international multicenter propensity-score matched and coarsened-exact matched analysis comparing robotic versus laparoscopic partial liver resections of the anterolateral segments.
Robotic liver resections (RLR) may have the ability to address some of the drawbacks of laparoscopic liver resections (LLR) but few studies have done a head-to-head comparison of the outcomes after anterolateral segment resections by the two techniques. A retrospective study was conducted of 3202 patients who underwent minimally invasive LR of the anterolateral liver segments at 26 international centres from 2005 to 2020. Two thousand six hundred and six cases met study criteria of which there were 358 RLR and 1868 LLR cases. Perioperative outcomes were compared between the two groups using a 1:3 Propensity Score Matched (PSM) and 1:1 Coarsened Exact Matched (CEM) analysis. Patients matched after 1:3 PSM (261 RLR vs 783 LLR) and 1:1 CEM (296 RLR vs 296 LLR) revealed no significant differences in length of stay, readmission rates, morbidity, mortality, and involvement of or close oncological margins. RLR surgeries were associated with significantly less blood loss (50 mL vs 100 ml, P < .001) and lower rates of open conversion on both PSM (1.5% vs 6.8%, P = .003) and CEM (1.4% vs 6.4%, P = .004) compared to LLR. Though PSM analysis showed RLR to have a longer operating time than LLR (170 minutes vs 160 minutes, P = .036), this difference proved to be insignificant on CEM (167 minutes vs 163 minutes, P = .575). This multicentre international combined PSM and CEM study showed that both RLR and LLR have equivalent perioperative outcomes when performed in selected patients at high-volume centres. The robotic approach was associated with significantly lower blood loss and allowed more surgeries to be completed in a minimally invasive fashion.


Escherichia coli enterotoxin. Purification and partial characterization.
Enterotoxin, a diarrheagenic protein elaborated by pathogenic Escherichia coli strains has been isolated from the supernatant of fermenter cultures of E. coli strain P263, a porcine enteropathogen. Purification steps involving Bio-Gel agarose A-5m, Sephadex G-75 chromatography, and preparative isotachophoresis were used in the isolation. The resulting product appears to be pure according to immunoelectrophoretic, disc electrophoretic, ultracentrifugal, and immunologic criteria. The entertoxin has an apparent molecular weight of 102,000 as judged by gel filtration and sodium dodecyl sulfate polyacrylamide gel electrophoresis, and its isoelectric point is 6.90. The isolated product is highly active in inducing experimental diarrhea in adult rabbits and piglets. It also elicits, in small dosage, a marked increase in adenylate cyclase activity in broken cell preparations of cat heart tissue. The enterotoxin activity is acid-labile and is destroyed by heating at 65 degrees for 30 min. It is suggested that the heat-stable enterotoxin material is derived from heat-labile enterotoxin by forming a complex with endotoxin or capsular material present in the culture supernatant.


How do young children determine location? Evidence from disorientation tasks.
Previous studies show that following disorientation children use the geometry of an enclosed space to locate an object hidden in one of the corners [e.g. (Hermer, L., & Spelke, E. (1996). Modularity and development: A case of spatial reorientation. Cognition, 61, 195-232)]. These studies have used a disorientation procedure that involves rotating the viewer (with eyes closed). Here, we examine 18- to 25-month-olds' spatial coding in two disorientation tasks--involving either viewer or space rotation. Importantly, the rotational movements in both tasks could not be visually tracked. Children were tested in either task (viewer- or space-movement) from either inside or outside a triangular (isosceles) space (with one unique and two equivalent corners). In the viewer-movement task, performance was above chance, regardless of which corner contained the object. In the space-movement task, performance was above chance at only the unique corner. On both tasks, performance was better from inside the space than from outside. The implications for how children determine location are discussed.


The clinical and bioinformatics analysis for the role of antihypertension drugs on mortality among patients with hypertension hospitalized with COVID-19.
Comorbidities such as hypertension could exacerbate symptoms of coronaviral disease 2019 (COVID)-19 infection. Patients with hypertension may receive both anti-COVID-19 and antihypertension therapies when infected with COVID-19. However, it is not clear how different classes of anti-hypertension drugs impact the outcome of COVID-19 treatment. Herein, we explore the association between the inpatient use of different classes of anti-hypertension drugs and mortality among patients with hypertension hospitalized with COVID-19. We totally collected data from 278 patients with hypertension diagnosed with COVID-19 admitted to hospitals in Wuhan from February 1 to April 1, 2020. A retrospective study was conducted and single-cell RNA-sequencing (RNA-Seq) analysis of treatment-related genes was performed. The results showed that Angiotensin II receptor blocker (ARB) and calcium channel blocker (CCB) drugs significantly increased the survival rate but the use of angiotensin-converting enzyme inhibitor/β-block/diuretic drugs did not affect the mortality caused by COVID-19. Based on the analysis of four public data sets of single-cell RNA-Seq on COVID-19 patients, we concluded that JUN, LST1 genes may play a role in the effect of ARB on COVID-19-related mortality, whereas CALM1 gene may contribute to the effect of CCB on COVID-19-related mortality. Our results provide guidance on the selection of antihypertension drugs for hypertensive patients infected with COVID-19.


Nitric oxide, prostaglandins and angiotensin II in the regulation of renal medullary blood flow during volume expansion.
Regulation of medullary blood flow (MBF) is essential in maintaining renal function and blood pressure. However, it is unknown whether outer MBF (OMBF) and papillary blood flow (PBF) are regulated independently when extracellular volume (ECV) is enhanced. The aim of this study was to determine whether OMBF and PBF are differently regulated and whether there is an interaction between nitric oxide (NO), prostaglandins (PGs) and angiotensin II (Ang II) in regulating OMBF and PBF when ECV is enhanced. To achieve these goals, OMBF and PBF were measured by laser-Doppler in volume-expanded rats treated with a cyclooxygenase inhibitor (meclofenamate, 3 mg/kg) and/or a NO synthesis inhibitor (L-nitro-arginine methyl ester (L-NAME), 3 μg/kg/min) and/or Ang II (10 ng/kg/min). OMBF was unchanged by NO or PGs synthesis inhibition but decreased by 36 % (P < 0.05) when L-NAME and meclofenamate were infused simultaneously. PBF was similarly reduced by L-NAME (12 %), meclofenamate (17 %) or L-NAME + meclofenamate (19 %). Ang II did not modify OMBF, but it led to a similar decrease (P < 0.05) in OMBF when it was administered to rats with reduced NO (32 %), PGs (36 %) or NO and PGs (37 %) synthesis. In contrast, the fall in PBF induced by Ang II (12 %) was enhanced (P < 0.05) by the simultaneous PGs (30 %) or PGs and NO (31 %) synthesis inhibition but not in L-NAME-treated rats (20 %). This study presents novel findings suggesting that blood flows to the outer medulla and renal papilla are differently regulated and showing that there is a complex interaction between NO, PGs and Ang II in regulating OMBF and PBF when ECV is enhanced.


Nitric oxide synthases are crucially involved in the development of the severe cardiomyopathy of caveolin-1 knockout mice.
Targeted ablation of caveolin-1 (cav-1) results in a severe cardiomyopathy. How the loss of cav-1 mediates these abnormalities is currently under investigation. Mounting evidence indicates that cav-1 acts as a negative regulator of endothelial nitric oxide synthase resulting in a constitutive hyperactivation of the nitric oxide (NO)-pathway in cav-1 knockout mice (cav-1 ko). In this context we hypothesized that disturbed NO signalling is implicated in these changes. To explore this question cav-1 ko were compared with knockout counterparts experiencing 2 month postnatal NO synthase inhibition by N(G)-nitro-l-arginine methyl ester (l-NAME) treatment. Chronic l-NAME treatment resulted in significant improvements in heart function and exercise capacity in cav-1 ko. Furthermore, we found evidence for an enhanced radical stress in hearts of cav-1 ko which was markedly reduced by l-NAME treatment. Collectively, these findings suggest that NO synthases play a crucial role in the evolution of heart failure evident in cav-1 ko.


Identification and characterization of two subpopulations of Encephalitozoon intestinalis.
Microsporidia are obligate intracellular protozoa that have been shown to be pathogenic to most living creatures. The development of in vitro cell culture propagation methods has provided researchers with large numbers of spores and facilitated the study of these organisms. Here, we describe heterogeneity within cell culture-propagated Encephalitozoon intestinalis suspensions. Flow cytometer histograms depicting the log side scatter and forward-angle light scatter of spores from nine suspensions produced over 12 months consistently showed two populations differing in size. The suspensions were composed primarily of the smaller-spore subpopulation (76.4% +/- 5.1%). The presence of two subpopulations was confirmed by microscopic examination and image analysis (P < 0.001). Small subpopulation spores were noninfectious in rabbit kidney (RK13) cell culture infectivity assays, while the large spores were infectious when inocula included > or = 25 spores. The small spores stained brilliantly with fluorescein isothiocyanate-conjugated monoclonal antibody against Encephalitozoon genus spore wall antigen, while the large spores stained poorly. There was no difference in staining intensities using commercial (MicroSporFA) and experimental polyclonal antibodies. Vital-dye (DAPI [4',6'-diamidino-2-phenylindole], propidium iodide, or SYTOX Green) staining showed the spores of the small subpopulation to be permeable to all vital dyes tested, while spores of the large subpopulation were not permeable in the absence of ethanol pretreatment. PCR using primers directed to the 16S rRNA or beta-tubulin genes and subsequent sequence analysis confirmed both subpopulations as E. intestinalis. Our data suggest that existing cell culture propagation methods produce two types of spores differing in infectivity, and the presence of these noninfective spores in purified spore suspensions should be considered when designing disinfection and drug treatment studies.


Characteristics of neurogenic bowel in spinal cord injury and perceived quality of life.
To investigate the association between characteristics of individuals with spinal cord injury and neurogenic bowel and their perceived quality of life. The study design is an exploratory, descriptive correlational design. To measure the variables of the study the Quality of Life Survey developed by Randell et al. (2001) was used to measure perceived quality of life related to bowel management. Individual bowel management preferences and subjective costs and benefits of the preferences were gathered through the Neurogenic Bowel Characteristics Survey. PARTICIPANTS/METHOD: Data were collected from a random half of the individuals who met the inclusion criteria from the patient database (n=1193). Two hundred and forty one surveys were analyzed for this study. More than half of the sample (n=134) provided their own bowel management consisting of digital stimulation, suppositories, and other aids; 8% (n=19) had a colostomy. Regardless of the bowel management program 54% (n=127) were satisfied with current methods. Although time reported to complete bowel programs ranged from 1 to 120 minutes, there was no difference in rating of satisfaction with time. There was a statistically significant difference between those satisfied and dissatisfied with current bowel management and quality of life; those satisfied demonstrated a higher quality of life on three subscales, work function (p= .021), bowel problems (p< .001), and social function (p< .001). Those dissatisfied with their bowel program perceived a lower quality of life and indicated problems of time (p= .001), pain or discomfort (p= .033), and poor results (p< .001). Research data provide the patient's perspective on bowel management characteristics, complications, satisfaction, and their perceived quality of life. Results of this research will be incorporated into bowel management education and possible modification of the current inpatient bowel management program.


Serum chloride is an independent predictor of mortality in hypertensive patients.
Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.


Sexual differences in survival rates of adult pipistrelle bats (Pipistrellus pipistrellus) in South Sweden.
A pipistrelle bat (Pipistrellus pipistrellus) population in southernmost Sweden was studied for eight consecutive breeding seasons by means of bat boxes. Survival rates were calculated using Cormack's stochastic technique. The mean survival rate of adult females exceeded that of territorial males. Annual variations in survival rates were most evident in males, low rates being observed in years following wet autumns. Energy constraints imposed on territorial males by the mating system, a resource defence polygyny, were assumed to account for the differences obtained in survival rates between the sexes.


Location of double bonds in two unsaturated forms of phytanic acid from Refsum disease as determined by mass spectrometry.
A monounsaturated and a triunsaturated form of phytanic acid (3,7,11,15-tetramethylhexacosanoate) were isolated from plasma lipids of a patient with Refsum disease. Both were converted to their methyl esters, oxidized to polyhydroxy acids by treatment with OsO4 and converted to their vicinal trimethylsilyl ethers. These derivatives were analyzed by gas chromatography-mass spectrometry using both electron impact ionization (at 21 and 70 eV) and chemical ionization conditions to obtain clear evidence to establish the structure of the monounsaturated form of phytanic acid as 3,7,11,15-tetramethylhexadec-15-monoenoic acid and that of the triunsaturated form of phytanic acid as 3,7,11,15-tetramethylhexadec-6,10,14-trienoic acid. The possible metabolic and dietary sources for these novel fatty acids are discussed.


1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis).
There is a significantly higher incidence of cardiovascular disease (CVD) among type 1 diabetic (T1D) patients than among non-diabetic subjects. T1D is associated with hyperketonemia, a condition with elevated blood levels of ketones, in addition to hyperglycemia. The biochemical mechanism by which vitamin D (VD) may reduce the risk of CVD is not known. This study examines whether VD can be beneficial in reducing hyperketonemia (acetoacetate, AA) induced oxidative stress in endothelial cells. HUVEC were pretreated with 1,25(OH)2D3, and later exposed to the ketone body acetoacetate. The increases in ROS production, ICAM-1 expression, MCP-1 secretion, and monocyte adhesion in HUVEC treated with AA were significantly reduced following treatment with 1,25(OH)2D3. Interestingly, an increase in glutathione (GSH) levels was also observed with 1,25(OH)2D3 in ketone treated cells. The effects of 1,25(OH)2D3 on GSH, ROS, and monocyte-endothelial adhesion were prevented in GCLC knockdown HUVEC. This suggests that 1,25(OH)2D3 inhibits ROS, MCP-1, ICAM-1, and adherence of monocytes mediated by the upregulation of GCLC and GSH. This study provides evidence for the biochemical mechanism through which VD supplementation may reduce the excess monocyte adhesion to endothelium and inflammation associated with T1D.


Population structure of pierid butterflies : II. A "Native" population of Colias philodice eriphyle in Colorado.
The structure of a bivoltine, discrete-generation population of Colias philodice eriphyle, occurring in relatively undisturbed habitat, has been examined by mark-release-recapture techniques. The population's general ecology is briefly discussed. Males eclose before females as in other Colias, and a measure of physical wear on adults is related to age of individuals and to the overall position of a sample in the flight period, again as in other Colias. Densities of adults fluctuate drastically, with the first (overwintering) brood always being less dense than the second brood. Dispersal radius of those dispersing does not vary with brood, sex, or year, although the proportion of dispersants does: more males than females disperse in the first brood, while the reverse is true in the second. A tentative behavioral explanation for this is proposed. Adult mortality is unusually high compared to other Colias. The population displays area continuity with adjacent population areas. The Wrightian neighborhood size varies in geographic extent, due to change in dispersant proportions, from 70 to 260 hectares. In adult numbers, it varies from 4-500 (or possibly fewer in very severe first-brood conditions) to upwards of 20,000 in some second broods (though not all adults present always reproduce successfully). Two possible models for the dispersal behavior of Colias are presented. One, the "excited state" model, is so far supported over the other, "continuous activity" model, by the present data and by earlier work on C. alexandra. The adult mortality level is consistent with the conclusion that this population is ecologically marginal for the species. Possible selective pressures preventing further extension of the species' distribution, including possible competition with other Colias, are discussed.


Scaling-up attention to nonmalaria acute undifferentiated fever.
Studies have reported that only a small fraction of fever cases in malaria-endemic areas are actually caused by malaria. Much greater emphasis is now needed to step up attention to the appropriate management of nonmalarial acute undifferentiated febrile illness. There is an overlap at the start of clinical manifestations of different febrile illnesses which makes it difficult to adhere to the clinical guidelines. The development of rigorous guidelines based on high quality research and a consensus from the core group of content experts are needed. An innovative financing mechanism for universal access to such appropriate management should also be considered.


Treatment motivation in drug users: a theory-based analysis.
Motivation for drug use treatment is widely regarded as crucial to a client's engagement in treatment and success in quitting drug use. Motivation is typically measured with items reflecting high treatment readiness (e.g., perceived need for treatment and commitment to participate) and low treatment resistance (e.g., skepticism regarding benefits of treatment). Building upon reactance theory and the psychotherapeutic construct of resistance, we conceptualized these two aspects of treatment motivation - readiness and resistance - as distinct constructs and examined their predictive power in a sample of 1295 drug-using offenders referred to treatment while on probation. The sample was 60.7% African Americans, 33.5% non-Hispanic Whites, and 21.2% women; their ages ranged from 16 to 63 years old. Interviews occurred at treatment entry and 6 months later. Readiness (but not resistance) predicted treatment retention during the 6-month period. Resistance (but not readiness) predicted drug use, especially among offenders for whom the treatment referral was coercive. These findings suggest that readiness and resistance should both be assessed among clients entering treatment, especially when the referral is coercive. Intake and counseling protocols should address readiness and resistance separately.


Renal function in hypertension.
Hypertension certainly accelerates the age-related changes in renal structure and function, mainly in the glomerulus. Both sodium handling and the renin-angiotensin system are involved in the aging process. Among the available classes of antihypertensive agents, the eventual deterioration of renal function induced by angiotensin-converting enzyme inhibitors in bilateral stenosis and stenosis of a single functioning kidney suggests that changes in glomerular pressure may participate in the changes of renal function. In essential hypertension and other conditions, it is possible that at a certain stage an increase in intraglomerular capillary pressure plays a role in the acceleration of the loss in renal function. As a consequence, it is proposed that in treating hypertension we should aim at reducing systemic blood pressure together with an attempt to reduce intraglomerular pressure using agents that act predominantly on post-glomerular resistance in order to have renal protection.


[Thoracic kidney: traumatic hernia or post-traumatic diaphragmatic hernia (author's transl)].
The discovery of a thoracic kidney a few months after a rupture of the diaphragm repaired as an emergency raises the problem of its congenital or acquired origin. In the latter case, treatment should be adopted?


"Exercise dependence"--a problem or natural result of high activity?
To compare physical activity (PA) and exercise dependence (ED) in 267 weight-loss maintainers (WLM) and 213 normal-weight (NW) controls. PA and ED assessed via accelerometery and the Exercise Dependence Questionnaire. WLM had higher PA levels and ED scores than those of NW (P< 0.0001). WLM status (P=.006) and higher PA (P=.0001) were independently related to higher ED, although effect sizes were larger for PA. Exercising for weight control was the ED domain that most discriminated WLM from NW. WLM have higher ED scores than do NW, but this is mostly due to exercising for weight control.


Effect of verapamil on postischemic "stunned" myocardium: importance of the timing of treatment.
Timely administration of verapamil has been shown to reduce indexes of ischemic injury in experimental models of prolonged coronary artery occlusion, yet its effect on contractile function of reversibly injured (that is, "stunned") myocardium remains unknown. The objective of the present study was to determine whether verapamil--administered either 30 min before coronary artery occlusion, at the time of reperfusion or 30 min after reperfusion--could attenuate the regional contractile dysfunction and alterations in high energy phosphate metabolism produced by 15 min of transient coronary artery occlusion in anesthetized, open chest dogs. All treatment groups exhibited passive systolic bulging during occlusion. In the control dogs receiving saline solution, segment shortening in the previously ischemic tissue averaged only 31 +/- 8% of normal baseline values after 3 h of reperfusion. In addition, endocardial adenosine triphosphate (ATP) stores were depleted by -8.7 +/- 0.8 nmol/mg cardiac protein to 26.5 +/- 1.1 nmol/mg protein, and endocardial creatine phosphate content increased by 9.6 +/- 4.3 nmol/mg cardiac protein over normal values. Pretreatment with verapamil essentially ablated the phenomenon of postischemic stunning: segment shortening was restored to 115 +/- 8% of normal after 3 h of reflow (p less than 0.01 versus control), endocardial ATP stores were partially preserved (30.6 +/- 1.2 nmol/mg protein; p less than 0.05 versus control) and creatine phosphate overshoot was blunted (endocardial creatine phosphate content decreased by -5.6 +/- 2.9 nmol/mg protein; p less than 0.05 versus control). Verapamil administered at or after reperfusion also attenuated postischemic contractile dysfunction: segment shortening for both groups recovered to 65 +/- 9% of baseline at 3 h after reperfusion (p less than 0.05 versus control). Verapamil given at or after reperfusion had no beneficial effect, however, on high energy phosphate stores. Thus, even when treatment was "delayed," that is, initiated at or after reperfusion, administration of verapamil significantly increased contractile function of the postischemic stunned myocardium.


Role of endogenous glucagon-like peptide-1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes.
To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin on glycaemic and energy expenditure responses during intraduodenal fat infusion, as well as the contribution of endogenous glucagon-like peptide-1 (GLP-1) signalling, in people with type 2 diabetes (T2DM). A total of 15 people with T2DM managed by diet and/or metformin (glycated haemoglobin 49.3 ± 2.1 mmol/mol) were studied on three occasions (two with vildagliptin and one with placebo) in a double-blind, randomized, crossover fashion. On each day, vildagliptin 50 mg or placebo was given orally, followed by intravenous exendin (9-39) 600 pmol/kg/min, on one of the two vildagliptin treatment days, or 0.9% saline over 180 minutes. At between 0 and 120 minutes, a fat emulsion was infused intraduodenally at 2 kcal/min. Energy expenditure, plasma glucose and glucose-regulatory hormones were evaluated. Intraduodenal fat increased plasma GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and energy expenditure, and decreased plasma glucose (all P < 0.05). On the two intravenous saline days, plasma glucose and glucagon were lower, plasma intact GLP-1 was higher (all P < 0.05), and energy expenditure tended to be lower after vildagliptin (P = 0.08) than placebo. On the two vildagliptin days, plasma glucose, glucagon and GLP-1 (both total and intact), and energy expenditure were higher during intravenous exendin (9-39) than saline (all P < 0.05). In well-controlled T2DM during intraduodenal fat infusion, vildagliptin lowered plasma glucose and glucagon, and tended to decrease energy expenditure, effects that were mediated by endogenous GLP-1.


Screening for infants with developmental deficits and/or autism: a Swedish pilot study.
The purpose of this study was to develop an instrument (SEEK) for the early detection of developmental deficits and/or autistic spectrum disorders among children by the age of 8 months at eight child health care centers in southern Sweden. Health visitors, trained by the research team, screened 312 infants. SEEK captured 5 infants with several points. Twenty-one percent of the infants obtained at least one SEEK point. At the 18-month follow-up, 5 children still showed more obvious signs of developmental problems. The health visitors found SEEK to be very satisfactory and easy and quick to use and its items and questions to be easy to administer. The results have indicated a new systematic methodology to examine infants, which is to be further developed.


Acute retinal arterial ischaemia: silent brain infarcts prevalence and short-term recurrence.
The purpose was to evaluate, in a consecutive series of patients with isolated acute retinal ischaemia, the proportion of patients with acute silent brain infarcts (SBIs) on diffusion-weighted imaging (DWI) and to assess risk of recurrence within 3 months. In all, 103 consecutive patients with isolated acute retinal ischaemia (central retinal artery occlusion, branch retinal artery occlusion or transient monocular vision loss) were included between January 2015 and December 2016. They all had cerebral magnetic resonance imaging including DWI as well as a standardized aetiological workup and 3 months of follow-up. The presence of DWI-positive cerebral lesions was recorded. Main clinical and radiological characteristics between DWI-positive and DWI-negative patients were compared. Of the 103 patients (including 42 transient monocular vision loss), 20 (19.5%) had SBIs on DWI, which were ipsilateral to the acute retinal ischaemia in 30% and involved different and/or multiple vascular territories in 70% of cases. Ipsilateral carotid stenosis and occlusion were respectively identified in 17 and eight patients whereas cardioaortic embolism was found in 19 patients. Overall, patients with and without acute SBIs were comparable. The topography of SBIs was related to the aetiology of the acute retinal ischaemia. At 3 months of follow-up, one patient suffered from ischaemic stroke and five had recurrent retinal ischaemia. Irrespective of the baseline characteristics of the patients, SBIs are present in about 20% of patients with isolated acute retinal ischaemia and may be of interest in the aetiological workup. Overall risk of recurrence is low, favoured by rapid aetiological workup and appropriate treatment.


A stochastic two-stage model for cancer risk assessment. II. The number and size of premalignant clones.
Mathematical expressions are derived, under different dosing patterns, for the number and size of premalignant clones within the framework of a two-mutation model for carcinogenesis, which has previously been shown to be consistent with a large body of epidemiologic and experimental data.


Implementation and feasibility considerations of an avatar-based intervention for military family caregivers.
Military family caregivers (MFCGs) are a growing population with well-being and quality of life (QOL) challenges. New technologies can help meet their needs while minimizing disruption to caregiving responsibilities. Preliminary research needs to address intervention implementation challenges before larger-scale efficacy studies are conducted. This study aimed to evaluate the feasibility of implementing an avatar-based intervention and preliminarily investigate outcomes. One-hundred twenty-four MFCGs were recruited to participate in this feasibility study. Sixty-four MFCGs completed the intervention. Data were analyzed using repeated-measures analysis of variance to assess 3- and 6-month differences. Meeting the a priori goal of 50 MFCGs completing the program supported feasibility. Preliminary results indicated significant reductions in depression, anxiety, and somatic symptoms, and significant improvements in physical health and overall QOL. Findings support for the feasibility of implementing an avatar-based intervention for MFCGs and present promising findings related to improving caregiver well-being and overall QOL.


Management of low-grade gliomas of the optic nerve and chiasm.
Thirty-six patients were evaluated between 1965 and 1983 for glioma of the optic nerves and/or chiasm. Median follow-up was 10.2 years. Pathologic verification was obtained in 32 patients. Tumor initially confined to the optic nerve recurred in one of five patients after complete resection. The actuarial survival for 25 patients irradiated for biopsy-proven glioma of the optic chiasm was 96%, 90%, and 90% at 5, 10, and 15 years, respectively, and the progression-free survival was 87% at 5, 10, and 15 years. Vision stabilized or improved in 86% of patients after radiotherapy. Patients irradiated to a dose greater than a NSD of 1385 ret had a significantly improved progression-free survival (P = 0.015). One serious complication occurred after a dose of 1533 ret. The recommended radiation dose for optic glioma is 45 to 50 Gy with 1.8 Gy fractions.


Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology.
Cancer is a major threat to human health. Among various treatment methods, precision therapy has received significant attention since the inception, due to its ability to efficiently inhibit tumor growth, while curtailing common shortcomings from conventional cancer treatment, leading towards enhanced survival rates. Particularly, organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles, locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects. In this review, we comprehensively discuss history and recent advances in targeted therapies on organelles, specifically including nucleus, mitochondria, lysosomes and endoplasmic reticulum, while focusing on organelle structures, organelle-mediated cell death signal pathways, and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms. Furthermore, a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented. Through demonstrating recent developments in organelle-targeted therapies, we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.


Diminished responses to mRNA-based SARS-CoV-2 vaccines in individuals with rheumatoid arthritis on immune-modifying therapies.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that causes debilitating swelling and destruction of the joints. People with RA are treated with drugs that actively suppress one or more parts of their immune system, and these may alter the response to vaccination against SARS-CoV-2. In this study, we analyzed blood samples from a cohort of patients with RA after receiving a 2-dose mRNA COVID-19 vaccine regimen. Our data show that individuals on the cytotoxic T lymphocyte antigen 4-Ig therapy abatacept had reduced levels of SARS-CoV-2-neutralizing antibodies after vaccination. At the cellular level, these patients showed reduced activation and class switching of SARS-CoV-2-specific B cells, as well as reduced numbers and impaired helper cytokine production by SARS-CoV-2-specific CD4+ T cells. Individuals on methotrexate showed similar but less severe defects in vaccine response, whereas individuals on the B cell-depleting therapy rituximab had a near-total loss of antibody production after vaccination. These data define a specific cellular phenotype associated with impaired response to SARS-CoV-2 vaccination in patients with RA on different immune-modifying therapies and help inform efforts to improve vaccination strategies in this vulnerable population.


Biomarker negative pancreatitis caused by InfluenzaB infection. A case presentation and review of the literature.
Influenza B is considered to cause milder illness compared to influenza A. There has been no known association between influenza B and acute pancreatitis. We present a case of an influenza B infection complicated with acute pancreatitis. Furthermore, the biochemical markers that are used to diagnose pancreatitis were normal in this case. We present the case that Influenza B can present with severity compared to this of Influenza A. We review the literature on infectious causes and diagnostic criteria for acute pancreatitis and on acute pancreatitis with normal pancreatic enzymes. Influenza B can rarely cause acute pancreatitis. The absence of biochemical confirmation should not exclude the diagnosis of pancreatitis in the appropriate clinical setting.