Susceptibility to AIDS progression appears early in HIV infection.
To investigate whether predictors of AIDS progression are operative very early in the natural history of HIV infection, we conducted a nested case-control study within a cohort of 119 subjects who seroconverted while under observation in a prospective study of homosexual men. For each of the 18 cases who have progressed to AIDS, we randomly selected three controls who had seroconverted within 3 months of the case but who have remained AIDS-free. Cases and controls were compared with regard to laboratory and clinical parameters obtained at the time of the earliest HIV-positive result. The median duration between the estimated date of seroconversion and this first positive result was 4 months for cases and 6 months for controls. Cases exhibited lower CD4 counts (657 versus 774 x 10(6)/l; P = 0.037), lower CD4: CD8 ratios (0.98 versus 1.39; P = 0.003), higher immune complex levels (C1q binding: 25 versus 15%; P = 0.002), lower hemaglobin concentrations (14.8 versus 15.2 g/l; P = 0.011), higher immunoglobulin (Ig) A levels (272 versus 184 mg/dl; P = 0.003), and higher IgG levels (1530 versus 1300 mg/dl; P = 0.037) than controls. Cases exhibited higher CD8 counts of marginal statistical significance (732 versus 597 x 10(6)/l; P = 0.059). No differences were observed with respect to IgM levels, total lymphocyte or white blood cell counts, or the frequency of generalized lymphadenopathy. A total of 27.8% of cases but only 11.5% of controls reported one or more symptoms during the 6-month period preceding the first positive visit (P = 0.027). We conclude that laboratory and clinical abnormalities which are predictive of more rapid progression to AIDS may appear very early in HIV infection. This suggests that some of the factors responsible for more rapid disease progression are present in the host prior to or shortly after infection occurs.


Transcatheter infusion of epirubicin in water-in-oil-in-water emulsion via a cystic artery for the treatment of hepatocellular carcinoma.
We have previously reported the clinical efficacy of water-in-oil-in-water (W/O/W) emulsion containing anticancer agent. The purpose of this study was to evaluate the safety and effectiveness of transcatheter arterial infusion (TAI) of W/O/W emulsion via a cystic artery for hepatocellular carcinoma (HCC). TAI of a W/O/W emulsion was performed at our institute in five patients with Stage III or IV HCC with blood supply from the cystic artery. In all patients, 2-12 ml/O/W emulsion was infused via a cystic artery. Therapeutic effects and complications were evaluated in these patients. Of the five patients treated, one achieved a complete response and two achieved a partial response. After treatment, acute cholecystitis or gallbladder ischemia that required treatment was not encountered in any patient. W/O/W emulsion can be safely infused via a cystic artery without major complications; it is a good therapeutic option for the patients with advanced HCC fed by a cystic artery.


New and future therapies: Changes in the therapeutic armamentarium for SLE.
Following better understanding of molecular pathways involved in the pathogenesis of Systemic lupus erythematosus (SLE), pharmaceutical companies have been investigating new targeted drugs for SLE. The purpose of this scoping review is to provide an updated view of the most promising targeted therapies currently in clinical development or recently approved for SLE treatment as well as of the most promising potential future therapeutic strategies in SLE. In the past several years, two new drugs have been developed for lupus treatment along with an extended indication for belimumab. Anifrolumab, the anti-interferon medication, to treat non-renal lupus; voclosporin, a calcineurin inhibitor, for the treatment of lupus nephritis; and belimumab for lupus nephritis. More than 90 investigational drugs are currently in clinical development for SLE treatment, with various targets including inflammatory cytokines and their receptors, intracellular signaling, B cells or plasma cells, co-stimulation molecules, complement fractions, T cells, plasmacytoid dendritic cells as well as various other immunological targets of interest. Researchers are also actively engaged in the development of new therapeutic strategies, including the use of monoclonal antibodies in combination with bispecific monoclonal antibodies, nanobodies and nanoparticles, therapeutic vaccines, utilizing siRNA interference techniques, autologous hematopoietic stem-cell transplantation and Chimeric Antigens Receptor (CAR)-T cells. The therapeutic management and prognosis of SLE have profoundly evolved with changes in the therapeutic armamentarium. With the broad pipeline of targeted treatments in clinical development and new treatment strategies in the future, current challenges are transitioning from the availability of new drugs to the selection of the most appropriate strategy at the patient level.


Relocation of Maternal-Fetal Medicine Specialists in the United States.
To examine patterns in relocation of maternal-fetal medicine (MFM) specialists during the recent 10 years. This descriptive study analyzed the migration of MFM specialists between 2006 and 2016 based on county locations. Year-to-year comparisons of physicians in active clinical practice were performed. Demographic and county characteristics were gathered from three data resources. A multivariable logistic regression model was used to identify factors associated with relocation. An average of 7.4% (5.5-10.8%) of all 1,104 (1,103-1,115) MFM specialists moved per year. Approximately one in three (36%) relocated during the 10 years, usually once or twice. The likelihood of relocation was higher if the physician was younger, especially under 40 years compared with those aged 60 years and older (odds ratio [OR] = 2.08; 95% confidence interval [CI]: 1.36-3.19). No differences were noted based on gender and race/ethnicity. Physicians in independent group practices were more inclined to relocate, especially when compared with those in a solo or two-physician practice (OR = 0.38; 95% CI: 0.27-0.54). Relocations were primarily between urban counties (95.9%) and showed a significant regional pattern. Approximately one in three MFM specialists relocated in the past 10 years, mostly between urban counties and especially in independent group practices.


Capsaicin prevents ethanol-induced teratogenicity in cultured mouse whole embryos.
Prenatal exposure to alcohol promotes the level of reactive oxygen species within embryos and results in developmental disorders. In this study, we investigated the effect of capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient in red peppers, on ethanol-induced teratogenicity in mouse embryos (embryonic days 8.5-10.5). In response to ethanol administration (1.0 microl/ml), developmental parameters such as yolk sac circulation, allantois, heart, hindbrain, midbrain, forebrain, otic and optic systems, branchial bar, olfactory system, forelimb, hindlimb, and somites decreased significantly in comparison with those of control group (p<0.05). However, the concurrent administration of capsaicin (1 x 10(-8) microg/ml or 1 x 10(-7) microg/ml) and ethanol significantly ameliorated most of the morphological scores excepting yolk sac circulation and hindlimb scores (p<0.05). Furthermore, the levels of superoxide dismutase activity and cytoplasmic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase mRNAs in the ethanol-treated embryos recovered to the levels observed in control embryos by capsaicin co-administration. These results indicate that capsaicin has a protective effect against ethanol-induced teratogenicity via an antioxidative activity.


Insights into the effect of polyethylene terephthalate (PET) microplastics on HER2 signaling pathways.
Plastic pollution poses a significant threat to both ecosystems and human health, as fragments of microscale size are daily inhaled and ingested. Such tiny specks are defined as microplastics (MPs), and although their presence as environmental contaminants is ubiquitous in the world, their possible effects at biological and physiological levels are still not clear. To explore the potential impacts of MP exposure, we produced and characterized polyethylene terephthalate (PET) micro-fragments, then administered them to living cells. PET is widely employed in the production of plastic bottles, and thus represents a potential source of environmental MPs. However, its potential effects on public health are hardly investigated, as the current bio-medical research on MPs mainly utilizes different models, such as polystyrene particles. This study employed cell viability assays and Western blot analysis to demonstrate cell-dependent and dose-dependent cytotoxic effects of PET MPs, as well as a significant impact on HER-2-driven signaling pathways. Our findings provide insight into the biological effects of MP exposure, particularly for a widely used but poorly investigated material such as PET.


Solution and solid phase combinatorial synthesis of peptidomimetic library containing diversified alpha-methylated amino acids.
A combinatorial peptidomimetic library containing diversified alpha-methylated amino acids was generated by the Ugi four component condensation (4cc) reaction from acids, amines, isocyanides and ketones in both solution and solid phase synthetic procedures. This one-pot methodology overall gave fair to good yields, which compare well with multi-step syntheses.


A novel myogenic cell line with phenotypic properties of muscle progenitors.
Skeletal myogenesis is a multistep process starting with progenitor cell proliferation, followed by their exit from the cell cycle, differentiation, alignment, and fusion to form multinucleated myotubes, typical of the differentiated muscle tissue. While the molecular players involved in early myogenesis have been extensively characterized, information about the later steps of the process is scanty. Here, we describe a novel myogenic cell line (MYOP7), composed of highly proliferating Sca-1+ muscle precursor cells, which can be induced to terminally differentiate into spontaneously contracting multinucleated myotubes. By performing high-density microarray analysis on these cells, we identified a series of genes, differentially expressed in proliferating vs differentiating conditions, which are candidates to play a major role in the later phase of myogenesis. In addition, we confirmed that the late stages of muscle differentiation are characterized by a marked upregulation of the cellular receptors for the vascular endothelial growth factor.


Miniaturization in percutaneous nephrolithotomy: What is new?
To summarize recent advancements in mini-percutaneous nephrolithotomy (mini-PCNL) in surgical technique, stone removal strategy, lithotripsy, and surgical model from the current literature. We conducted a narrative review of relevant English-language articles up to October 2022 using the PubMed and Web of Science databases. The following keywords were used in the search: "percutaneous nephrolithotomy", "minimally invasive percutaneous nephrolithotomy", "mini-PCNL", "mini-perc", "mPCNL", and "miniaturization". A series of new progress has been made in many aspects of mini-PCNL, such as further reduction of tract size-needle perc and further improvement of robotic-assisted PCNL-artificial intelligence-powered robotic devices. Many studies and trials have been conducted to reduce morbidity and increase the safety and effectiveness of mini-PCNL. It is crucial to realize that miniaturization of PCNL requires not only a smaller percutaneous tract size, but also an adjustment strategically in renal access, stone removal, lithotripsy, and surgical model in general. More large-scale prospective research needs to be carried out to further validate and optimize the safety and effectiveness of mini-PCNL.


Delayed increase of cell volume of single pyramidal cells in live rat hippocampal slices upon kainate application.
Cell volume is an important physiologic parameter but is not directly accessible by conventional microscopy in vivo or in slice preparations. After staining of rat hippocampal slices with 1,1'-dioctadecyl-3,3,3',3'-tetramethylinso-carbocyanineperchlor ate (DiI), living single CA1 pyramidal cells were visualized by confocal microscopy while others in the illuminated area were recorded intracellularly. Resting membrane potential and action potentials were not affected by staining with DiI (4 microM) and repeated laser illumination (up to 600 times). A time- and dose-dependent increase of cell volume succeeds membrane depolarization upon bath application of kainate (40 microM and 100 microM) with a delay of several minutes indicating active regulation of cell volume. We conclude that cell swelling as visualized by confocal microscopy is a relatively late event of kainate excitotoxicity.


Atorvastatin treatment increases plasma bilirubin but not HMOX1 expression in stable angina patients.
In vitro and animal studies indicate that statins increase heme oxygenase-1 gene (HMOX1) expression, which then, presumably, increases plasma bilirubin concentration. However, clinical confirmation that statins concomitantly increase HMOX1 expression and plasma bilirubin concentration is lacking. We hypothesized that in patients with stable angina atorvastatin therapy (20 mg/day for 10 weeks) concomitantly increases total bilirubin concentration and HMOX1 expression, as assessed non-invasively by plasma analysis. In 44 patients with stable angina plasma concentrations of total bilirubin, HMOX1 mRNA and HMOX1 protein were measured before and after the statin treatment, as well as plasma concentrations of oxidized low-density lipoprotein (OxLDL), malondialdehyde (MDA), monocyte chemoattractant protein (MCP-1) and C-reactive protein (CRP). Atorvastatin treatment increased total bilirubin concentration (median 6.95 μmol/L vs. 8.55, + 23.02%; p < 0.001), but did not change plasma HMOX1 mRNA and HMOX1 protein concentrations. Plasma concentrations of OxLDL (- 31.85%, p < 0.001), MCP-1 (- 16.20%, p = 0.020) and CRP (- 7.32%, p = 0.010) were decreased but MDA was not decreased (15.32%, p = 0.107). Within subjects, increment of plasma bilirubin concentration did not correlate with the changes in HMOX1 mRNA and protein concentrations, but correlated with low-density lipoprotein cholesterol decrement (r = - 0.374, p = 0.012). Bilirubin increment did not correlate with the changes in oxidative and inflammatory markers. Our prospective observational trial finally confirms that atorvastatin (20 mg/day for 10 weeks) increases plasma total bilirubin concentration. However, it seems that this effect is HMOX1-independent.


Image manipulation and error estimation for MRI analysis.
Manipulation of MRI images prior to volumetric analysis is a common practice that may unwittingly lead to errors in measurement. In this study, we examine the effects of two types of image manipulation: changes in the total number of slices used to obtain volume estimates (slice sampling rate) and image rotation. A phantom containing two regularly-shaped and two irregularly-shaped regions of interest (ROIs) was scanned using an SPGR sequence and 1-mm slices. Changes in slice sampling rate produced marked effects on volume estimation of irregularly-shaped ROls. Comparatively little error was associated with changes in slice sampling rates for regularly-shaped ROIs. In addition, there was an interaction between image rotation in non-orthogonal planes and slice sampling rate. The data suggests that the ability to detect anatomical effects may be influenced by an investigator's choices concerning the number of slices included in a region of interest and image rotation when estimating volumes.


Environmental assessment model for scrubbers versus alternative mitigation systems for feeder vessels in liner shipping.
Implementation of the Global Sulphur Cap (GSC), in January 2020, boosted scrubber installation in vessels to fulfill the new air emission limitations. This increase in scrubbers' use has intensified concern about its environmental performance. Even though achievement of GSC requirements through this mitigation system has been widely proven, the impact of wash water discharge on the marine environment remains under discussion. In this paper, an assessment environmental model is introduced to quantify in monetary terms the performance of feeder vessels that operate with several mitigation systems. This model attempts to improve traditional air emission evaluations by including the impact of scrubbers' discharges on the marine environmental. In this way, the analysis not only allows different mitigations systems to be ranked by considering their capacity to reduce air emissions, but also provides further information about the marine eutrophication and ecotoxicity impact from scrubbers' discharge. Through the model's application to a regular shipping line between the Canary Islands and the Iberian Peninsula, it was found that, the scrubber, regardless of its operation mode (open- or closed loop), is the most efficient mitigation option after the Liquefied Natural Gas (LNG) fuel shift. The impact of scrubbers' discharge was not as significant as expected on the feeder vessel's total pollution since this provides similar relative weight to the methane emissions from a dual-engine option by operating with LNG. The results also show the need to more closely research the marine eutrophication impact of closed-loop scrubbers. Finally, this paper warns about a significant dispersion on the monetary values of marine ecotoxicity and eutrophication, due to a high dependence of the results on the frameworks' localization. Consequently, further research is needed on the homogenization of pollution monetization in the marine environment.


Management of rheumatic and autoimmune blistering disease in pregnancy and postpartum.
The treatment of rheumatic and autoimmune skin disease in women who are pregnant or of childbearing potential can present challenges to the dermatologist. We discuss the current approaches to treating lupus erythematosus, antiphospholipid antibody syndrome, dermatomyositis, morphea and systemic sclerosis, mixed connective tissue disease, rheumatoid arthritis, and autoimmune blistering disease in such patients. In the appropriate setting, topical and systemic corticosteroids, hydroxychloroquine, dapsone, azathioprine, and ultraviolet B phototherapy may be safely and cautiously used during pregnancy. Considerations about contraception, planned conception, therapeutic options, and disease control are paramount in optimizing pregnancy outcomes and minimizing risks to both mother and fetus.


Central effects of angiotensin II in conscious hamsters: drinking, pressor response, and release of vasopressin.
The effects of intracerebroventricular (icv) injections of angiotensin II (ANG II) on water intake, blood pressure, heart rate, and plasma arginine-vasopressin (AVP) concentration were studied in chronically instrumented adult male Syrian golden hamsters (Mesocricetus auratus). Furthermore, the effects of pharmacological ganglionic blockade, and of vascular AVP receptor blockade, on central ANG II-induced cardiovascular responses were investigated. ANG II (1, 10, and 100 ng, icv) elicited dose-dependent increases in water intake and arterial blood pressure. Heart rate showed a biphasic response with a short initial non dose-dependent tachycardic and a subsequent longer lasting bradycardic phase. Plasma AVP concentration was increased two and a half fold with 100 ng ANG II icv. Both ganglionic blockade and vascular AVP receptor blockade significantly attenuated the central ANG II-induced pressor response. The tachycardic phase of the heart rate response was abolished by ganglionic blockade and the bradycardic phase was significantly diminished by AVP receptor blockade. The results support the hypothesis that brain ANG II may participate in the central control of body fluid volume and in central cardiovascular regulation in conscious hamsters.


Post-fire insect fauna explored by crown fermental traps in forests of the European Russia.
Wildfires considerably affect forest ecosystems. However, there is a lack of data on the post-fire status of insect communities in these ecosystems. This paper presents results of a study conducted in 2019 which considered the post-fire status of the insect fauna in a Protected Area, Mordovia State Nature Reserve (Republic of Mordovia, centre of European Russia), considered as regional hotspot of insect diversity in Mordovia. We sampled insects on intact (unburned, control) and fire-damaged (burnt in 2010) sites and compared the alpha-diversity between sites. In total, we sampled and analysed 16,861 specimens belonging to 11 insect orders, 51 families and 190 species. The largest orders represented in the samples were Coleoptera (95 species), Diptera (54 species), Hymenoptera (21 species), and Neuroptera (11 species). Other insect orders were represented by between one and four species. The largest four orders (Coleoptera, Lepidoptera, Diptera and Hymenoptera) represented 96.7% of all studied specimens. We found that in the ninth year after low intensity surface fire damage, the insect diversity had returned to a similar level to that of the control (unburned) sites. Sites damaged by crown wildfire differed considerably from other sites in terms of a negative impact on both species diversity and the number of specimens. This indicates the serious effect of the crown fires on the biodiversity and consequent long-term recovery of the damaged ecosystem.


Sieve element occlusion: Interactions with phloem sap-feeding insects. A review.
Phloem sieve element (SE) occlusion has been hypothesized for decades to be a mechanism of resistance against phloem sap-feeding insects. Few studies have tested this hypothesis although it is likely a widespread phenomenon. This review focuses on SE occlusion by callose and P-proteins. Both are reversible, which would allow the plant to defend itself against phloem sap-feeders when SEs are penetrated and resume normal function when the insects give up and withdraw their stylets. Callose (β-1,3 glucans with some β-1,6 branches) serves many roles in plant physiology in many different tissues, each being under the control of different callose synthase genes; only callose deposited in SE sieve pores is relevant to SE occlusion. The amount of callose in sieve pores (and consequently how much it impedes sap flow) is determined by the balance in activity between callose synthase and β-1,3 glucanase. Sieve pore callose deposition has been shown to provide resistance to some phloem sap-feeders in a few studies, and in one, the difference in resistance between a susceptible and resistant rice variety was due to the ability or inability of the insect to upregulate the plants' β-1,3 glucanase that degrades the callose deposition. P-proteins occur only in dicotyledons and include a variety of proteins, not all of which are involved in SE occlusion. In some plants, P-proteins form distinct bodies in mature functional SEs. In papilionid legumes, these discrete bodies, called forisomes can expand and contract. In their expanded state, they effectively plug SEs and stop the flow of sap while in their contracted state, they provide negligible resistance to sap flow. Expansion of forisomes is triggered by an influx of Ca2+ into the SE. Penetration of a legume (Vicia faba) SE by a generalist aphid not adapted to legumes triggers forisome expansion which occludes the SE and prevents the aphid from ingesting sap. In contrast, a legume specialist aphid, Acyrthosiphon pisum, does not trigger forisome expansion and readily ingests sap from V. faba. P-protein bodies in SEs of non-legumes do not appear to be involved in SE occlusion. In most dicotyledons, P-proteins do not form discrete bodies, but rather occur as filamentous aggregations adhering to the parietal margins of the SE and in response to damage, are released into the lumen where they are carried by the flow of sap to the downstream sieve plate where they back up and clog the sieve pores. Their effectiveness at actually stopping the flow of sap is controversial. In one study, they seemed to provide little resistance to the flow of sap while in other studies, they provided considerable resistance. In response to injury in melon, they completely stop the flow of sap, and in an aphid-resistant melon, penetration of SEs by the melon aphid, Aphis gossypii, triggers P-protein occlusion which prevents the aphids from ingesting sap. The first P-protein described, PP1, occurs only in the genus Cucurbita, and although it has been often cited to function as a SE occlusion protein, experimental evidence suggests it does not play a significant role in SE occlusion. The most common strategy for phloem sap-feeders to mitigate P-protein occlusion seems to be avoid triggering it. A widely cited in vitro study suggested that aphid saliva can reverse P-protein occlusion, but a subsequent study demonstrated that saliva was ineffective at reversing P-protein occlusion in vivo. Lastly, SE callose deposition in wheat triggered by Russian wheat aphid has been hypothesized to create an artificial sink that benefits the aphid, but additional studies are needed to test that hypothesis.


Complete mitochondrial genomes of the slugs Deroceraslaeve (Agriolimacidae) and Ambigolimaxvalentianus (Limacidae) provide insights into the phylogeny of Stylommatophora (Mollusca, Gastropoda).
In this study, we sequenced two complete mitogenomes from Deroceraslaeve and Ambigolimaxvalentianus. The mitogenome of Ambigolimaxvalentianus represented the first such data from the family Limacidae. The lengths of the mitogenomes of Deroceraslaeve and Ambigolimaxvalentianus were 14,773 bp and 15,195 bp, respectively. The entire set of 37 mitochondrial genes were identified for both mitogenomes. Compared with the mitogenome of Achatinafulica, the trnP_trnA tRNA cluster was rearranged in both Deroceraslaeve and Ambigolimaxvalentianus. The secondary structures of tRNA and rRNA genes for the two species were predicted. Phylogenetic analyses based on amino acid sequences supported (1) monophyly of Stylommatophora, (2) division of Stylommatophora into the 'achatinoid' clade (i.e., the suborder Achatinina) and the 'non-achatinoid' clade (i.e., the suborder Helicina), (3) placement of the Orthurethra in the 'non-achatinoid' clade, and (4) monophyly of each of the superfamilies Helicoidea, Urocoptoidea, Succineoidea, Arionoidea, Pupilloidea and Limacoidea. The exemplars of Helicidae, Philomycidae and Achatinellidae displayed many more mitochondrial gene rearrangements than other species of Stylommatophora.


Segmental maternal heterodisomy of the proximal part of chromosome 15 in an infant with Prader-Willi syndrome.
Uniparental disomy (UPD) 15, detected in patients with Prader-Willi (PWS) and Angelman syndromes, has to date always involved the entire chromosome 15. We report the first case of segmental maternal uniparental heterodisomy confined to a proximal part of chromosome 15 in a child with clinical features of PWS. This unusual finding can be explained by the rare combination of three consecutive events: a trisomy 15 zygote caused by a maternal meiosis I error, early postzygotic mitotic recombination between maternal and paternal chromatids, and, finally, trisomy rescue by the loss of the rearranged chromosome 15 containing the paternal 15q11-q13 segment.


Accumulation of Paprika Carotenoids in Human Plasma and Erythrocytes.
The accumulation (incorporation) of paprika carotenoid in human plasma and erythrocytes was investigated. A paprika carotenoid supplement (14 mg/day) was ingested for 4 weeks by 5 young healthy volunteers (3 men and 2 women). After 2 weeks of carotenoid ingestion, the carotenoid levels in plasma and erythrocytes increased by 1.2-fold and 2.2-fold, respectively. Characteristic carotenoids found in paprika (capsanthin, cucurbitaxanthin A, and cryptocapsin) were detected in both plasma and erythrocytes. An oxidative metabolite of capsanthin (capsanthone) was also found in both plasma and erythrocytes.


Efficient Biotransformation of Sclareol to Sclareolide by Filobasidium magnum JD1025.
In this study, a newly isolated strain Filobasidium magnum JD1025 was investigated for its production of sclareolide, which was verified to be a valuable raw material in various industrial fields. Together with a comprehensive analysis of the genome sequence, effective fermentation method to convert sclareol to sclareolide via the isolated strain was explored and optimized by taking the selected co-solvent and nitrogen source into account. The results showed that the final conversion rate could be achieved at 88.79 ± 1.06% with the initial sclareol concentration of 30 g·L-1 after 72 h in baffled flask. The corresponding yield concentration of sclareolide was 21.62 ± 0.26 g·L-1 and the conversion rate per unit thallus attained to 6.11 ± 0.06 % g-1·L-1. Overall, the current study suggested a valid method for the application of Filobasidium magnum JD1025 as bio-transformer to produce sclareolide from sclareol.


[Color Doppler echocardiography in the diagnosis for ruptured aneurysm of sinus of Valsalva].
Twenty-five cases with ruptured aneurysm of sinus of Valsava were detected by color Doppler sonography and twenty-four cases undenwent surgical repair. In twenty-three cases, the sonographic findings of the site of the aneurysm and the chambers into which aneurysm ruptured were coincident with the surgical findings. The accuracy was 95.8%. The size of the aneurysm and the diameter of the ruptured site detected by ultrasound were correlated well with surgical findings. The associated lesions obtained by ultrasound were completely identical with surgical findings. Color Doppler flowing imaging has special value in diagnosing the ruptured aneurysm of sinus of Valsalva.


Comparison of sinus conversion rates and body weights after 6 mg adenosine administration in supraventricular tachycardia.
To evaluate the relationship between body weight and the success rate of supraventricular tachycardia (SVT) termination after an initial 6-mg adenosine administration. This retrospective observational study was conducted with medical records of patients who visited a single tertiary emergency department and underwent an electrophysiologic study with an SVT diagnosis. Patients under 18 years of age or those with SVT aberrancy, recurring SVT after radiofrequency catheter ablation, premedication of non-dihydropyridine calcium channel blocker, and signs of shock were excluded. Data from 124 patients were collected. There were 69 women (55.6%); mean age, 49.7 years. The mean weight and height were 66.8 kg and 164.8 cm, respectively. Adenosine dose was 0.09 mg/kg. For the first sinus conversion (SC) success group (83 patients, 67%), the mean weight, height, and adenosine dose were 61.0 ± 11.5 kg, 161.9 ± 8.1 cm, and 0.10 ± 0.02 mg/kg. For the first SC failure group, these values were 78.4 ± 17.0 kg, 170.7 ± 8.9 cm, and 0.079 ± 0.02 mg/kg, respectively. To evaluate factors associated with the first SC, we performed bivariate logistic regression with weight (odds ratio [OR]: 1.093; 95% confidence interval [CI]: 1.045-1.144; P < 0.001) and height (OR: 1.071; 95% CI: 1.008-1.138; P = 0.027). Receiver operating characteristics curves and the cut-off values for adenosine dose and weight were 0.90 mg/kg and 66.5 kg with 71.1% sensitivity and 73.2% specificity (area under the curve: 0.814; 95% CI: 0.73-0.90; P < 0.001). Weight and height were significant predictors of the first SC success rate among SVT patients. Consequentially, it is necessary to consider other adenosine administration methods, including increasing the initial drug dose or changing the flushing strategy after adenosine injection.


Psychotic behavior in children under the institutions for mentally retarded in Denmark.
The purpose of this research project was to identify children with psychotic behavior in the Institutions for the Mentally Retarded in Denmark and to analyze psychotic behavior. The subjects for study were 392 children, partly selected as a representative sample, partly selected as a sample of children with psychotic behavior. A combined observation and interview scheme was constructed containing 17 behavioral items and 6 developmental scales. Scoring systems for psychotic behavior were constructed and their consistency analyzed by the Rasch item-analysis model. Two major behavioral dimensions, "bizarre behavior" and "psychotic withdrawal," were used for the diagnostic grouping of the subjects. The distributions of the children in regard to developmental retardation, organic brain damage, and psychiatric diagnoses were investigated. Conclusions regarding guidelines for reorganization of present services and establishment of new services are proposed.


[Bilateral laryngeal movement disorder and synkinesia: value of botulism toxin. Apropos of a case].
Several years after a subtotal thyroidectomy complicated by bilateral vocal cord paralysis, the patient presented with progressive dyspnea due to laryngeal synkinesis. The impairement of the ventilation status, in spite of laser arytenoidectomy, followed by contralateral posterior transverse cordotomy, suggested a botulinum toxin injection in the intrinsic adductor laryngeal muscles. The rapid improvement in ventilation without phonatory impairement is discussed in the following report.


Identifiable biomarker and treatment development using HIV-1 long term non-progressor sera.
HIV-infected long-term non-progressor (LTNP) subjects can prevent viral replication and may harbor useful information for the development of both antibody and active vaccination treatments. In this study we used LTNP sera to examine the epitopes presented to the gp160 protein, and from this procedure we hope to elucidate potential biomarkers pertaining to the level of resistance a patient may have in developing AIDS after infection with HIV. We used five clinical sera samples from LTNP patients to identify common epitopes by ELISA; peptides with high binding to sera were selected and analyzed for conservation among HIV clades. Antibodies were generated against one identified epitope using a chimeric peptide in BALB/c mice, and both the sera from these mice and LTNP sera were tested for viral inhibition capabilities. A monoclonal antibody, CL3, against one identified epitope was used to compare these epitopes neutralizing capability. LTNP sera was also studied to determine chemokine/cytokine changes in these patients. The sera from LTNP patients 2, 3, 4, and 5 were identified as having the highest titers, and also significantly inhibited syncytia formation in vitro. Finally, the protein cytokine array demonstrated that I-309 and IGFBP-1 decreased in LTNPs, but levels of TIMP-1 and NAP-2 increased significantly. Our results indicate that the use of LTNP samples may be a useful for identifying further anti-viral epitopes, and may be a possible predictor for determining if patients show higher resistances of converting the HIV infection to AIDS.


Pleural pressure measured with a rib capsule in anesthetized pneumonectomized rabbits.
Pleural pressure was measured at end expiration in anesthetized rabbits using a rib capsule placed in the right fifth rib. Three groups of rabbits were studied in right and left lateral recumbency at least 8 weeks after surgery; rabbits that had undergone left pneumonectomy (Px, n = 8), rabbits that had undergone left pneumonectomy with wax plombage (Px + W, n = 7), and sham-operated control rabbits (S, n = 6). In S, Px, and Px + W rabbits in the left lateral position (lung and capsule nondependent), pleural pressure was -2.11 +/- 0.88 (mean +/- SD), -2.65 +/- 0.23, and -1.96 +/- 0.55 cmH2O respectively. In S, Px and Px + W rabbits in the right lateral position (lung and capsule dependent), pleural pressure was 0.64 +/- 0.22, 0.85 +/- 1.42, and 0.48 +/- 1.77 cmH2O respectively. In each position, pleural pressure did not differ among groups. This suggests that the compensatory increase in lung volume and reduced lung compliance following pneumonectomy in rabbits (Olson, J. Appl. Physiol. 74: 415-422, 1993) was not simply due to hyperinflation of the remaining lung.


High-Temperature Dielectrics in BNT-BT-Based Solid Solution.
Bi0.5Na0.5TiO3-BaTiO3 (BNT-BT)-based ternary solid solutions were investigated for high-temperature capacitor applications. Through a comprehensive investigation of the (1 - x )(0.92Bi0.5Na0.5TiO3-0.08BaTiO3)- x NaNbO3 [(1 - x )(BNT-BT)- x NN, x = 0 -0.45] system, 0.85(BNT-BT)-0.15NN was selected as the parent matrix due to its relatively high permittivity (>1800) and favorable energy-storage density (0.56 J/cm3 at 7 kV/mm). The effect of bismuth substitution on the dielectric properties of the matrix was further characterized. The introduction of bismuth greatly broadened the operational temperature range of 0.85(BNT-BT)-0.15Na1-3yBiyNbO3 ceramics to over 327 °C for a ±15% tolerance. The dc resistivities were of the order of 108 - [Formula: see text] magnitude from room temperature to 300 °C. An activation energy of 1.1-1.2 eV in 200-350 °C was obtained from dc resistivity data, suggesting that the conduction process in this temperature range may be associated with oxygen vacancy migration. Furthermore, the energy-storage properties were largely improved by the addition of bismuth. When the substitution of Bi over Na achieved was up to 7%, the energy-storage density and efficiency reached 0.62 J/cm3 and 88% at 7 kV/mm, respectively. These results confirm that a BNT-BT-based solid solution is a promising candidate for lead-free high-temperature capacitor applications.


Aquifer recharge viewed through the lens of microbial community ecology: Initial disturbance response, and impacts of species sorting versus mass effects on microbial community assembly in groundwater during riverbank filtration.
Riverbank filtration has gained increasing importance for balancing rising groundwater demands and securing drinking water supplies. While microbial communities are the pillar of vital ecosystem functions in groundwater, the impact of riverbank filtration on these communities has been understudied so far. Here, we followed changes in microbial community composition based on 16S rRNA gene amplicon sequence variants (ASVs) in an initially pristine shallow porous aquifer in response to surface water intrusion during the early stages of induced riverbank filtration over a course of seven weeks. We further analyzed sediment cores for imprints of river-derived ASVs after seven weeks of riverbank filtration. The onset of the surface water intrusion caused loss of taxa and significant changes in community composition, revealing low disturbance resistance of the initial aquifer microbial communities. SourceTracker analysis revealed that proportions of river-derived ASVs in the groundwater were generally <25%, but locally could reach up to 62% during a period of intense precipitation. However, variation partitioning showed that the impact of dispersal of river-derived ASVs on changes in aquifer microbial community composition was overall outweighed by species sorting due to changes in environmental conditions caused by the infiltrating river water. Proportions of river-derived ASVs on aquifer sediments were <0.5%, showing that taxa transported from the river into the aquifer over the course of the study mainly resided as planktonic microorganisms in the groundwater. Our study demonstrates that groundwater microbial communities react sensitively to changes in environmental conditions caused by surface water intrusion, whereas mass effects resulting from the influx of river-derived taxa play a comparatively minor role.


MRI of the upper aerodigestive tract and neck.
The application of new technology has improved the ability of MR to image the upper aerodigestive tract and neck. Improved resolution along with inherent high tissue contrast and multiplanar capability now allow clear definition of detailed anatomic and pathologic tissue planes. MR currently rivals other imaging modalities in this region. At present, it is often better in demonstrating the depth of tumor infiltration and the presence of nodal metastasis. Initial studies also suggest that MR can effectively image postoperative sites and discriminate chronic fibrosis from recurrent tumor. Localization of abnormal parathyroid glands, particularly for re-exploration, is a promising technique. If the present limitations are recognized, such as identification of soft tissue calcification, MR can play an important role in the evaluation of the face and neck. With additional investigation and continued technologic improvements it is likely that this role will continue to increase.


Ligand loop effects on the free energy change of redox and pH-dependent equilibria in cupredoxins probed on amicyanin variants.
In this work, we have determined the thermodynamic parameters of the reduction of four different variants of Thiobacillus versutus amicyanin by electrochemical techniques. In addition, the thermodynamic parameters were determined of the low-pH conformational change involving protonation of the C-terminal histidine ligand and the concomitant dissociation of this histidine from the Cu(I) ion. In these variants, the native C-terminal loop containing the Cys, His, and Met copper ligands has been replaced with the corresponding polypeptide segments of Pseudomonas aeruginosa azurin, Populus nigra plastocyanin, Alcaligenes faecalis S-6 pseudoazurin, and Thiobacillus ferrooxidans rusticyanin. For the reduction reaction, each loop invariably holds an entropic "memory" of the mother protein. The thermodynamics of the low-pH transition vary in a fashion that is species-dependent. When present, the memory effect again shows a large entropic component. In particular, loop elongation tends to favor the formation of the Cu(I)-His bond (hence disfavors His protonation, yielding lower pK(a) values) probably due to an increased flexibility of the loop in the reduced state. Overall, it appears that both reduction and low-pH transition are loop-responsive processes. The spacing between the ligands mostly affects the change in the conformational freedom that accompanies the reaction.


Anatomic and physiologic advantages of totally subfascial breast implants.
For the past 4 years, whenever it was possible to choose between the subglandular or the submuscular location for the implant pocket (in cases with no precise indication for the submuscular location), the authors have opted for the totally subfascial plane (subaponeurotic) to avoid the disadvantages of the other locations and to obtain additional benefits. The subfascial plane lies below the deep thoracic fascia, or deep aponeurosis, which is not only that of the pectoralis (the muscle connecting with the breast in its upper two-thirds only). The implant is placed completely beneath this fascia, which covers, in addition to the pectoralis major muscle, the serratus, the lateral oblique, and the rectus anterior muscles. This study included 100 women who had breast implanted in the subfascial (subaponeurotic) plane. Of these women, 63 were thin patients with little fatty tissue. Textured surface implants were used McGhan style 120 and 110. All procedures were approached through an inferior periareolar incision. Excellent coverage of the implant as well as natural shape and mobility was achieved for all patients. No rippling in the upper half was observed. Two patients had Baker grade 2 capsular contracture (2%). No seromas or infections were seen, and only once was a surgical exploration necessary for excess drainage volume (1%). In the immediate postoperative period, less edema was recorded and recovery was faster than with the other two procedures: submuscular and subglandular. When circumstances indicate a subglandular pocket, the subfascial plane would seem to be the logical place for mammary implants.


Expression of let-7i is associated with Toll-like receptor 4 signal in coronary artery disease: effect of statins on let-7i and Toll-like receptor 4 signal.
Toll-like receptor (TLR) 4 signal plays an important role in immunity in coronary artery disease (CAD). A recent report has demonstrated that one of the let-7 family microRNAs, let-7i, directly regulates Toll-like receptor 4 (TLR4) expression and contributes to immune response. The aim of this study was to determine whether let-7i is expressed with TLR4 in patients with CAD, and whether statins (atorvastatin or rosuvastatin) might affect these levels. To determine the effects of let-7i on TLR4 expression, human THP-1 cells transfected with let-7i were analyzed for TLR4 levels. This study included 98 patients with CAD and 48 subjects without CAD (non-CAD). Patients with CAD were randomized to 12 months of treatment with atorvastatin or rosuvastatin. Monocytes were obtained from peripheral blood at baseline and after 12 months of each type of therapy. Levels of let-7i and TLR4 were measured by real-time RT-PCR and FACS. Functional approaches to let-7i showed that transfection of let-7i into human THP-1 cells resulted in regulation of TLR4 expression. Levels of let-7i were lower in the CAD group than in the non-CAD group (0.98±0.42 vs. 4.65±1.21, P<0.01). There was a negative correlation between let-7i and TLR4 levels in patients with CAD (let-7i vs. TLR4 mRNA: r=-0.60, P<0.01; let-7i vs. TLR4 MFI: r=-0.32, P<0.01). The atorvastatin group had markedly increased let-7i levels and diminished TLR4 levels (all P<0.01), whereas the rosuvastatin group showed no change in these levels. This study suggests that atorvastatin down-regulates TLR4 signal via let-7i expression in CAD patients, possibly contributing to the beneficial effects of atorvastatin on let-7i-mediated TLR4 signal in this disorder.


Exposure to a rotating virtual environment during treadmill locomotion causes adaptation in heading direction.
The objective of this study was to investigate the adaptive effects of variation in the direction of optic flow, experienced during linear treadmill walking, on modifying locomotor trajectory. Subjects (n=30) walked on a motorized linear treadmill at 4.0 km h(-1) for 24 min while viewing the interior of a 3D virtual scene projected on to a screen 1.5 m in front of them. The virtual scene depicted constant self-motion equivalent to either (1) walking around the perimeter of a room to one's left (Rotating Room group) or (2) walking down the center of a hallway (Infinite Corridor group). The scene was static for the first 4 min and then constant rate self-motion was simulated for the remaining 20 min. Before and after the treadmill locomotion adaptation period subjects performed five stepping trials. In each trial they marched in place to the beat of a metronome at 90 steps min(-1) for a total of 100 steps while blindfolded in a quiet room. The subject's final heading direction (deg) and final X (fore-aft, cm) and final Y (medio-lateral, cm) positions were measured for each trial. During the treadmill locomotion adaptation period subjects' 3D torso position was measured. We found that subjects in the Rotating Room group, as compared with the Infinite Hallway group: (1) showed significantly greater deviation during post-exposure testing in the heading direction and Y position opposite to the direction of optic flow experienced during treadmill walking; and (2) showed a significant monotonically increasing torso yaw angular rotation bias in the direction of optic flow during the treadmill adaptation exposure period. Subjects in both groups showed greater forward translation (in the +X direction) during the post-treadmill stepping task that differed significantly from their pre-exposure performance. Subjects in both groups reported no perceptual deviation in position during the stepping tasks. We infer that viewing simulated rotary self-motion during treadmill locomotion causes adaptive modification of sensorimotor integration in the control of position and trajectory during locomotion, which functionally reflects adaptive changes in the integration of visual, vestibular, and proprioceptive cues. Such an adaptation in the control of position and heading direction during locomotion, because of the congruence of sensory information, demonstrates the potential for adaptive transfer between sensorimotor systems and suggests a common neural site for processing and self-motion perception and concurrent adaptation in motor output.


Secukinumab: A Review in Ankylosing Spondylitis.
Secukinumab (Cosentyx(®)) is a fully human monoclonal antibody against the proinflammatory cytokine interleukin-17A. It is the first drug in its class to be approved for use in patients with active ankylosing spondylitis (AS). This article reviews the efficacy and tolerability of secukinumab in this indication and briefly summarizes its pharmacology. In ongoing phase III trials, 16 weeks' treatment with subcutaneous secukinumab 150 mg was effective in terms of improving the clinical signs and symptoms of disease and health-related quality of life in patients with AS, with these improvements maintained during longer-term (up to 2 years) treatment. In subgroup analyses, secukinumab was effective both in tumour necrosis factor (TNF) inhibitor-naïve patients and in patients intolerant of or refractory to TNF inhibitors. Secukinumab was generally well tolerated, with a tolerability profile consistent with that seen previously in patients with plaque psoriasis. In the absence of head-to-head trials, the position of secukinumab with respect to TNF inhibitors remains to be fully determined. Nevertheless, secukinumab is an effective and generally well tolerated treatment option for patients with AS.


Auxotrophic Salmonella typhi as live vaccine.
Salmonella typhi 541Ty has deletions at aroA and purA, causing requirement for aromatic metabolites (including p-aminobenzoate) and for adenine. None of 36 volunteers who drank 10(8) to 10(10) bacteria of 541Ty or its Vi-negative mutant 543Ty showed any adverse effect; all gave evidence of cellular immune response but only a few had serum titre increases. S. typhimurium experiments (at the Wellcome Research Laboratories and at Stanford) show that adenine requirement may reduce both bacterial survival in mouse tissues and live-vaccine efficacy. S. typhi attenuated only by block(s) in aromatic biosynthesis may be more effective as oral-route live vaccine.


Topical use of prostacyclin in microvascular surgery.
Prostacyclin was investigated for its ability to overcome surgically induced spasm of the femoral artery and to increase blood flow through the rabbit epigastric free flap. Topical prostacyclin (200 ng/ml) and lignocaine (20 mg/ml or 2%) each produced near-maximal vasodilatation of large conducting vessels. This resulted in a significant increase in blood flow after 5 minutes for each form of topical treatment, compared to a saline control. However the vasodilatation obtained from lignocaine tended to wear off over 30 minutes. Treatment with systemic indomethacin did not prevent surgical spasm nor the action of prostacyclin in relieving it. Topical 6-oxo-prostaglandin F1 alpha, the major breakdown metabolite of prostacyclin, was not responsible for the vasodilatory action of prostacyclin. Topical prostacyclin (200 ng/ml) also caused platelet disaggregation and some rebleeding from the anastomotic site, nevertheless there was no significant difference in flap survival between the use of topical prostacyclin and topical lignocaine.


Effects of prenatally administered thyroid hormones or glucocorticoids on maturation of kidney function in newborn rats.
Influences of treatment with thyroid hormones or dexamethasone during pregnancy on development of kidney function were studied in newborn rats. Treatment of dams for 3 days is followed by a higher rate of urine production in newborn rats. A statistically significant raise of sodium/potassium ratio in tetraiodothyronine- or dexamethasone-treated rats indicates a higher degree of maturation of kidney function. Treatment of dams with dexamethasone is followed by an increase of absolute excreted quantities of sodium and potassium in newborn rats. Treatment of dams with triiodothyronine can increase renal excretion of p-aminohippurate in newborn rats.


Portal but not peripheral serum levels of interleukin 6 could interfere with glucose metabolism in patients with pancreatic cancer.
Interleukin 6 (IL-6), an autocrine growth factor for many tumors, seems to favour tumor spread to the liver. Our aims were first to evaluate the pattern of portal and systemic IL-6 levels in patients with pancreatic cancer (PC, n = 18) and chronic pancreatitis (CP, n = 22) compared with controls (CS, n = 20); and second, to ascertain whether there was any relation between IL-6 levels and tumor spread or PC-associated Diabetes mellitus. For all subjects, a fasting serum sample was obtained from a cubital vein; a portal serum sample was obtained from nine PC and three CP patients. In cubital and portal sera we measured IL-6, interleukin 1 beta (IL-1b), CA 19-9, c-reactive protein (CRP) and amylase. Systemic IL-6 levels were significantly higher in PC patients than in CS. In PC, portal IL-6 levels were significantly higher than the corresponding systemic values. The same pattern was found in the three CP patients, whereas IL-1b, CA 19-9, CRP and amylase portal levels were the same as systemic values. No correlation was found between PC stage and systemic or portal IL-6 levels. Portal IL-6 levels were correlated with the corresponding fasting serum glucose values. A significant correlation was found between IL-6 values and CRP, ALT, total bilirubin, GGT and creatinine, but not amylase. (1) Portal IL-6, which is partly of pancreatic origin, is first metabolised in the liver; (2) Systemic IL-6 reflects hepatic and renal functions rather than local conditions in the pancreas; (3) IL-6 does not appear to influence PC spread; (4) IL-6, which is released in large amounts by the inflamed pancreas, may contribute to determining diabetes, thus interfering with the signal transducing pathways involved in glucose metabolism in liver cells.


Significantly Lower Saliva Secretion in Females With Gastroesophageal Reflux Disease and Healthy Subjects Than in Males.
Saliva secretion in healthy subjects is lower in females than in males. The present study investigated sex differences in saliva secretion in patients with gastroesophageal reflux disease (GERD) and healthy controls. This case-control study included 39 (male/female: 16/23) with non-erosive reflux disease (NERD), 49 (25/24) patients with mild reflux esophagitis, 45 (23/22) with severe reflux esophagitis (A1), and 46 (24/22) healthy controls. Saliva secretion was examined as follows: before endoscopy, patients chewed sugar-free gum for three minutes, and the amount and pH of saliva before and after acid loading as an index of acid-buffering capacity were evaluated. The relationships between saliva secretion and body mass index, height, and weight were also examined. The amount of saliva secreted was significantly lower in females than in males in all four groups (NERD, mild reflux esophagitis, severe reflux esophagitis, and healthy controls). Salivary pH and acid-buffering capacity were similar in all groups. The amount of saliva secreted positively correlated with height and body weight, albeit more strongly with height. A sex difference in saliva secretion exists in GERD patients, similar to healthy controls. Saliva secretion was significantly lower in female GERD patients than in male GERD patients.


Behavioral suppressant effects of clonidine in strains of normotensive and hypertensive rats.
The behavioral effects of orally administered clonidine were investigated in Long--Evans (LE), Sprague--Dawley (SD) or Kyoto Wistar (KW) rats assumed to be normotensive and in NIH spontaneously hypertensive (SH) rats. Although clonidine (0.05-1 mg/kg) resulted in the same qualitative effect, i.e., depression of motor activity, the dose of clonidine required to depress motor activity to 50% of control levels (ED50) tended to vary according to strain. An analysis of variance of the dose response curves for the four strains of rats indicated a significant strain effect. When the effects of clonidine on food-reinforced operant responding were investigated it was observed that SD and SH rats differed with regard to rate and temporal pattering of IRT greater than 20 sec responding. Although oral administration of clonidine (0.006-0.1 mg/kg) produced similar percentage decreases from control in SH and SD rats, and analysis of the temporal patterning of responding indicated differences in responsiveness to the behavioral effects of clonidine. These studies demonstrate strain-related differences in responsiveness to the behavioral suppressant effects of clonidine. Marked differences between genetically hypertensive rats and rats assumed to be normotensive were not evident.


Smooth pursuit and saccadic eye movements as possible indicators of nighttime sleepiness.
Sleepiness is associated with specific variations of spontaneous oculomotor activity. During nocturnal sleep onset periods and also during the Multiple Sleep Latency Test (MSLT) a reduction of both rapid eye movements and blinks are recorded. In many operational contexts it might be even more relevant to assess whether and to what extent voluntary visual ocular control is affected by sleepiness due to sleep deprivation and time-of-day effects. In this study we evaluated, in a laboratory simulation of a sudden inversion of the sleep-wake cycle, the nocturnal modifications of smooth pursuit (SP) and saccadic (SAC) eye movements as possible indicators of sleepiness. Levels of sleepiness were objectively measured by means of MSLT and Maintenance of Wakefulness Test (MWT); subjective ratings of sleepiness were also obtained. After a diurnal sleep, five subjects underwent four nocturnal test sessions, each one comprising an SP and a SAC trial. Both the SP variables considered (velocity gain and phase) showed a trend similar to that one of MWT latencies, being significantly impaired only in the last nocturnal trial, when levels of sleepiness were maximal. Saccadic accuracy showed the same trend, being negatively affected by sleepiness only in the last nocturnal session. In addition, percentage of rejected (inappropriate) saccades showed a linear increase during the night, paralleling the shortening of sleep latency at MSLT and the linear increase of subjective ratings of sleepiness. These results, suggesting that saccadic performance, unlike SP, seems to be more sensitive to increasing levels of sleepiness, encourage further research on this topic.


Does Inflammation Mediate the Association Between Obesity and Insulin Resistance?
In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings.


Improving uptake of vaccines in pregnancy: A service evaluation of an antenatal vaccination clinic at a tertiary hospital in the UK.
Vaccination against pertussis and seasonal influenza is recommended for all pregnant women in the UK. More recently COVID-19 vaccination has also been offered to women in pregnancy. To evaluate the uptake of vaccines in pregnant women within a midwife-led immunisation clinic and to assess factors influencing pregnant women's decisions about accepting vaccination. Uptake of vaccines amongst pregnant women referred to a single UK centre for antenatal care between 01/01/19 and 02/10/19 was assessed. Interviews with 20 pregnant women explored views of antenatal vaccination and experiences of the vaccination service. Amongst 4420 women, uptake was 90.6% for pertussis and 78.8% for influenza vaccines. Factors influencing vaccine-related decision-making amongst 20 interviewed women were: healthcare professional recommendation, perceived susceptibility and risk of infection, and previous experience of vaccination and vaccine-preventable disease. Uptake of pertussis and influenza vaccines within a secondary care immunisation service was higher than the national or regional average. The model of vaccine delivery was associated with high levels of satisfaction. This model of vaccine delivery could be implemented elsewhere to increase vaccine uptake, and should be considered for delivery of COVID-19 vaccines in the future.


Gender, Stereotypes, and Trust in Communication.
Gender differences in dishonesty and mistrust have been reported across cultures and linked to stereotypes about females being more trustworthy and trusting. Here we focus on fundamental issues of trust-based communication that may be affected by gender: the decisions whether to honestly deliver private information and whether to trust that this delivered information is honest. Using laboratory experiments that model trust-based strategic communication and response, we examined the relationship between gender, gender stereotypes, and gender discriminative lies and challenges. Drawing from a student sample, we presented males and females (N = 80) with incentivized stereotype elicitation tasks that reveal their expectations of lies and challenges from each gender, followed by a series of strategic communication interactions within and between genders. Before interacting, both genders stereotyped females as more trustworthy (expected to send more honest messages) and more trusting (expected to accept and not challenge others' messages) than males, in accord with cross-cultural gender differences. In best response to these stereotypes, both genders discriminately accepted or challenged messages based on the sender's gender. However, we find no differences between males' and females' overall rates of lies and challenges. After learning the results of their strategic interactions, males and females revised their stereotypes about lies and challenges expected of each gender; these stereotype revisions resulted in greater predictive accuracy and less disparate gender discrimination. This suggests an important facultative feature of human trust-based communication and gender stereotyping: while the delivery and trust of private information is informed by gender stereotypes, these stereotypes are recalibrated with experience.


Application of triple quadrupole tandem mass spectrometry to the bioanalysis of collision-induced dissociation-resistant cyclic peptides - Ultra-sensitive quantification of the somatostatin-analog pasireotide utilizing UHPLC-MS/MS.
Cyclic peptides are considered collision-induced dissociation (CID)-resistant due to immobile protons, and the necessity of at least two consecutive dissociation reactions to produce fragments with deviating m/z values. Therefore, the bioanalysis of cyclic peptides by tandem mass spectrometry (MS/MS) poses a major challenge, especially on triple quadrupole (TQ) instruments. One of these peptides is the somatostatin analog pasireotide, a cyclic hexapeptide administered to treat Cushing's disease and acromegaly. To support oral formulation development, sub-therapeutic quantification of pasireotide is highly beneficial. Regardless of the considered CID-resistance, we investigated the CID-characteristics of pasireotide and subsequently developed an ultra-sensitive UHPLC-MS/MS assay with a lower limit of quantification (LLOQ) of 5 pg/mL (4.9 pM) when using 100 μL of plasma and validated it according to the guidelines of the FDA and EMA. The achieved sensitivity, which is the highest thus far reported, demonstrates that TQ-MS/MS is a feasible approach to sensitive quantification of cyclic peptides despite their CID-resistance. Pasireotide was fast and efficiently extracted by protein depletion via precipitation using acetonitrile. Correlation coefficients > 0.99 were achieved for all calibration curves with linear regression. Inter-run and intra-run accuracy ranged from 89.4 to 99.3 % with corresponding precision of ≤ 7.5 % in the calibrated range, and from 94.6 to 105.6 % with corresponding precision of ≤ 14.5 % at the LLOQ. Quantification of 10-fold diluted samples showed an accuracy of 90.8 % and corresponding precision of 4.0 %. The assay was applied to the quantification of pasireotide plasma concentrations after intravenous administration to beagle dogs.


Squeezed exponential kinetics to describe a nonglassy downhill folding as observed in a lattice protein model.
We previously studied the so-called strange kinetics in the two-dimensional lattice HP model. To further study the strange kinetics, folding processes of a 27-mer cubic lattice protein model with Gō potential were investigated by simulating how the bundle of folding trajectories, consisting of a number of independent Monte Carlo simulations, evolves as the folding reaction proceeds, covering a wide range of temperature. Three realms of folding kinetics were observed depending on temperature. Although at temperatures where folding was two-state-like, the kinetics was conventional single exponential, we found that the time course data were well represented by a squeezed (or "shrunken") exponential function, exp [-(t/tau)beta] with beta > 1, at temperatures lower than the folding temperature, where folding was fastest and of a nonglassy downhill type. The squeezed exponential kinetics was found to pertain to the subdiffusion on the nonglassy downhill free energy surface and presents a marked contrast both to the single exponential kinetics and to the stretched exponential kinetics that was observed at lower temperatures where folding was also downhill but topological frustration came into effect. The observed temperature dependence of the folding kinetics suggests that some small single-domain proteins may follow the squeezed exponential kinetics at about the room temperature.


Effects of female sex hormones on the activity of serum hyaluronidase.
The activities of serum hyaluronidase from female rats were measured during pregnancy. In pregnant female rats, the activity of serum hyaluronidase was found to increase initially and to fall to a minimum by the last day of the gestation period, but the activity of the enzyme increased after delivery and was similar to normals at 21 days post-partum. The activity of hyaluronidase obtained from bovine leucocytes was significantly increased when leucocytes were incubated with various concentrations of progesterone. It is suggested that female sex hormones affect lysosomal membranes making them lyse more readily and hence release hyaluronidase.


Regional vascular resistance and heart rate responses mediated through H1- and H2-histamine receptors in the unanaesthetised rabbit.
The effects of histamine infusions (10-100 microgram/kg/min) on heart rate and hindlimb, carotid, mesenteric and renal vascular resistance were investigated in unanaesthetised rabbits after "total" autonomic effector block to abolish reflex effects. Histamine caused a rise in heart rate that was predominately due to stimulation of H2-receptors (blocked by metiamide). Hindlimb and carotid vascular resistance did not change significantly during histamine infusion. However, after blocking H2-receptors with metiamide histamine infusions produced dose-related vasoconstriction in these beds while after H1-receptor block with mepyramine histamine caused dose-related vasodilatation indicating that H1- and H2-RECEPTORS MEDIATED OPPOSITE VASCULAR EFFECTS WHICH WERE OF SIMILAR MAGNITUDE. By contrast, histamine infusion caused vasodilatation in both the mesenteric and renal vasculature before giving antagonists. This dilatation was mediated by both H1- and H2-RECEPTORS AS EITHER RECEPTOR ANTAGONIST ATTENUATED THE RESPONSE. These studies suggest that H1-receptors in the same species mediate vasoconstriction in som- beds and vasodilatation in others while H2-receptors mediate vasodilatation in all the beds studied and also account for most of the increase in heart rate.


Transient proliferative diabetic retinopathy during intensified insulin treatment.
Two women aged 22 and 19 years who had had diabetes for 11 and four years, respectively, developed proliferative retinopathy after five to seven months of significantly improved metabolic control. They were participants in two separate prospective studies including 97 insulin-dependent patients. At inclusion, one patient showed minimal background retinopathy and the other showed no retinopathy. Their level of glycosylated hemoglobin was initially high (14.3% and 17.5%) but within five to six months had fallen by 5.7% and 7.5%. The improved metabolic control was obtained by home blood glucose monitoring and insulin pump in the older patient and by home blood glucose monitoring only in the other. By maintaining near normoglycemia, regression of the proliferative retinopathy was achieved. Photocoagulation was not performed. After five and two years of follow-up, respectively, only mild background retinopathy has been noted in both patients. We concluded that a significant lowering of blood glucose may provoke proliferative retinopathy and that sustained good metabolic control may reverse this retinopathy without photocoagulation.


Valve prostheses in children: a reassessment of anticoagulation.
We have previously published evidence that children with St. Jude Medical prostheses on the left side of the heart may not require anticoagulation. Between March 1979 and September 1986, we followed up 48 patients who had no anticoagulant therapy for up to 7 years after valve replacement, an aggregate of 122 patient-years. The 25 male and 23 female patients ranged in age at implantation from 5 months to 21 years (12 +/- 6 years, mean +/- standard deviation). Five patients (all with complex associated malformation) died in the hospital (10%), and nine died late (22%). None of the early and one of the late deaths was associated with a thrombosed prosthesis. During follow-up, seven thrombotic (one mitral, one aortic) or thromboembolic (two mitral, three aortic) events occurred (5.7 +/- 2.1 per 100 patient-years). Of these seven events, five occurred within the last 14 months of the study. There was no relation of these events to age of patient at implantation, age at the time of even, gender, or site of implantation. Concurrently, we have followed up 340 adult patients with St. Jude Medical prostheses who had warfarin sodium (Coumadin) anticoagulation for 875 patient-years. By the end of this study, the children who did not receive anticoagulants were significantly less free of thrombotic and thromboembolic events than the adults who did receive anticoagulants (p less than 0.01).


Determination of di-(2-ethylhexyl)phthalate in human placenta.
A simple method has been devised for the analysis of di-(2-ethylhexyl)phthalate (DEHP) in human placenta which relies entirely on three rapid partition steps prior to gas chromatography with electron capture detection. The use of adsorption chromatography with all its attendant disadvantages for sample clean-up is eliminated in this procedure. Placental samples taken from women who had given birth to a normal baby contained 0.06 +/- 0.02 ppm of DEHP. The principal limitation of this method, and of any others, is the high blanks given by laboratory equipment and solvents. The reduction of contamination to workable levels is described.


Lithium and electrolytes plasma/RBC ratio and paradoxical lithium neurotoxicity.
1. Although lithium neurotoxicity and EEG disturbances are known to be associated with toxic plasma lithium levels, it may also be paradoxically manifested when plasma lithium levels are within the therapeutic range. 2. Plasma and RBC lithium and electrolytes levels were measured in 50 patients with affective disorders during the course of lithium therapy. Seventeen of them suffered from lithium neurotoxicity. 3. It is suggested that in the course of lithium treatment, in the manic and depressed phases as well as during prophylaxis, lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium alone, even when the plasma lithium levels are within the therapeutic range. 4. In addition, an increase in the intra-erythrocyte sodium/potassium ratio was observed in toxic patients in comparison to non-toxic patients.


Cholinesterase of rats experimentally infected by Cryptococcus neoformans: Relationship between inflammatory response and pathological findings.
The aim of this study was to assess the role of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as biomarkers of inflammation and tissue injury on rats experimentally infected by Cryptococcus neoformans. For this purpose, 20 male rats were divided into two groups: 10 animals representing the uninfected control group (Group A) and 10 C. neoformans var. grubii infected animals (Group B). Blood and brain samples were collected on days 10 (A10 and B10), and 30 (A30 and B30) post-infection (PI) for hematological analyses; AChE (in lymphocytes and brain) and seric BChE activity; interleukins (IL-1, IL-6, and IL-10); nitrite/nitrate (NOx) levels; and markers of protein oxidation (AOPP) and lipid peroxidation (TBARS). As a result, when animals of Group A were compared to animals of Group B, it was observed leukocytosis (P<0.05) on day 10 PI; AChE activity increase (P<0.05) in lymphocytes (day 30 PI) and in brain (days 10 and 30 PI); BChE activity decrease (P<0.05) on day 10 PI; IL-1 and IL-6 increase (P<0.01) in both periods, while IL-10 had reduced levels (P<0.01) in the same periods; NOx levels increased (P<0.05) significantly on days 10 and 30 PI, while AOPP and TBARS levels increased significantly on day 30 PI; as well as pneumonia on infected rats. Therefore, based on the results obtained, it was possible to conclude that AChE and BChE behavior lead to a proinflammatory reaction evidenced by the enhancement of IL-1, IL-6, and NOx throughout the experiment associated with reduction on IL-10 levels, and cellular damage.


Extensor mechanism failure associated with total knee arthroplasty: prevention and management.
Extensor mechanism complications are the most commonly reported reasons for revision surgery after total knee arthroplasty and are a frequent source of postoperative morbidity. Patellofemoral instability is the most commonly reported extensor mechanism complication and has multiple etiologies, including prosthetic malalignment and soft-tissue imbabalce. Patellar fracture or rupture of either the quadriceps or patellar tendon can cause catastrophic disruption of the extensor mechanism. Although some stable fractures can be successfully managed nonsurgically, displaced fractures or tendon rupture often lead to poor results. Other complications include patellar clunk and soft-tissue adhesions, prosthetic wear or loosening, and osteonecrosis. Increased understanding of implant alignment, rotation, and soft-tissue balance, as well as improved design of the trochlear groove of femoral implants and patellar components, has resulted in a decline in extensor mechanism complications. Appropriate prosthetic selection and meticulous surgical technique remain the keys to avoiding unsatisfactory results and revision surgery.


Separation of Doppler radar-based respiratory signatures.
Respiration detection using microwave Doppler radar has attracted significant interest primarily due to its unobtrusive form of measurement. With less preparation in comparison with attaching physical sensors on the body or wearing special clothing, Doppler radar for respiration detection and monitoring is particularly useful for long-term monitoring applications such as sleep studies (i.e. sleep apnoea, SIDS). However, motion artefacts and interference from multiple sources limit the widespread use and the scope of potential applications of this technique. Utilising the recent advances in independent component analysis (ICA) and multiple antenna configuration schemes, this work investigates the feasibility of decomposing respiratory signatures into each subject from the Doppler-based measurements. Experimental results demonstrated that FastICA is capable of separating two distinct respiratory signatures from two subjects adjacent to each other even in the presence of apnoea. In each test scenario, the separated respiratory patterns correlate closely to the reference respiration strap readings. The effectiveness of FastICA in dealing with the mixed Doppler radar respiration signals confirms its applicability in healthcare applications, especially in long-term home-based monitoring as it usually involves at least two people in the same environment (i.e. two people sleeping next to each other). Further, the use of FastICA to separate involuntary movements such as the arm swing from the respiratory signatures of a single subject was explored in a multiple antenna environment. The separated respiratory signal indeed demonstrated a high correlation with the measurements made by a respiratory strap used currently in clinical settings.


The plasminogen activator inhibitor-1 (PAI-1) promoter haplotype is related to PAI-1 plasma concentrations in lean individuals.
Elevated plasminogen activator inhibitor-1 (PAI-1) concentrations are associated with cardiovascular diseases. PAI-1 antigen levels are influenced by environmental factors such as body mass index (BMI), and by genetic factors. The PAI-1 promoter of the PAI-1 gene contains two common polymorphisms (-844A/G and -675(4G/5G)) and the 4G allele of the -675(4G/5G) variation has been associated with elevated PAI-1 concentrations and on some occasions with an increased risk of cardiovascular disease. The aim of our study was to investigate the effect of the PAI-1 promoter haplotype on PAI-1 concentrations and to determine the role of BMI. The association between the PAI-1 promoter haplotype and PAI-1 antigen levels was investigated in two independent populations, each including 600 healthy Caucasians. Furthermore, to assess the effect of the PAI-1 promoter haplotype on PAI-1 promoter activity, in vitro reporter gene assays were performed in HepG2 and BAEC cells. We observed significantly higher PAI-1 concentrations in A-4G homozygotes than in G-5G carriers in lean subjects (BMI in the lowest quartile). In these lean subjects, the PAI-1 concentrations in A-4G/G-5G heterozygotes were reduced to 60-75%, and the concentrations in G-5G homozygotes to 45-55%, compared to the PAI-1 concentrations of A-4G homozygotes (p < 0.01). PAI-1 concentrations increased approximately four-fold from the lowest to the highest BMI quartile (p < 0.01). The reporter gene assays did not support a direct effect of the PAI-1 promoter haplotype on promoter activity in HepG2 or BEAC cells. Our study suggests that the PAI-1 promoter haplotype and BMI affect PAI-1 concentrations and that BMI is a stronger determinant than PAI-1 promoter variation.


Prediction of solubility parameters using partial least square regression.
The total solubility parameter (delta) values were effectively predicted by using computed molecular descriptors and multivariate partial least squares (PLS) statistics. The molecular descriptors in the derived models included heat of formation, dipole moment, molar refractivity, solvent-accessible surface area (SA), surface-bounded molecular volume (SV), unsaturated index (Ui), and hydrophilic index (Hy). The values of these descriptors were computed by the use of HyperChem 7.5, QSPR Properties module in HyperChem 7.5, and Dragon Web version. The other two descriptors, hydrogen bonding donor (HD), and hydrogen bond-forming ability (HB) were also included in the models. The final reduced model of the whole data set had R(2) of 0.853, Q(2) of 0.813, root mean squared error from the cross-validation of the training set (RMSEcv(tr)) of 2.096 and RMSE of calibration (RMSE(tr)) of 1.857. No outlier was observed from this data set of 51 diverse compounds. Additionally, the predictive power of the developed model was comparable to the well recognized systems of Hansen, van Krevelen and Hoftyzer, and Hoy.


Progress in the DNA diagnosis of hemophilias.
DNA diagnosis of hemophilias has received much attention in recent years, and different methods are presently available to analyze the coagulation factor IX and VIII genes. This review is intended to serve as a brief guide to current and emerging diagnostic strategies.


Increase in S-wave amplitude during ischemic ST-segment depression in stable angina pectoris.
In 50 patients with chronic stable angina and in 10 asymptomatic young male volunteers, the behavior of S-wave amplitude was studied during episodes of ischemic ST-segment depression, both induced by exercise testing and occurring during ambulatory electrocardiographic monitoring. With exercise, all patients showed diagnostic ST-segment depression (0.16 +/- 0.05 mV) which, in 49, was associated with an increase in S-wave amplitude. No consistent changes in R-wave amplitude were observed. S-wave amplitude also increased in all control subjects during exercise, but the sum of R and S wave remained constant, while it increased in 42 patients. In the 10 study patients undergoing Holter monitoring we identified 170 episodes of ischemic ST-segment depression, of which 169 were associated with increased S-wave amplitude. Isolated increases in S-wave amplitude without ST-segment changes occurred in 3 of 4 normal subjects. Dipyridamole echocardiography revealed regional wall motion abnormalities in 12 of 21 patients; the changes were invariably associated with increased S-wave amplitude but not necessarily with diagnostic ST-segment depression. An increase in S-wave amplitude is almost invariably associated with subendocardial ischemia, sometimes in the absence of ST-segment changes; this sign could represent a sensitive (although less specific) additional marker of myocardial ischemia.


Visuo-motor skill and visual perception in left and right handed children of superior intelligence.
It was thought possible that the proximity of the right parietal cortex to the leading hand area in left handed subjects may confer an advantage in tasks requiring visuo-motor function. However, the study showed the left handed group to be defective in the performance of the Wechsler Block-design Sub-test. As some mature left handed individuals may excel in tasks requiring refined visuo-motor skill, it is suggested that any constitutional deficiency is not fixed, but may be expected to disappear with increased maturity, or as the result of training.


[Percutaneous endoscopic gastrostomy: indications, techniques and complications].
We present a revision of techniques, indications and complications of percutaneous endoscopic gastrostomy, with emphasis in technical aspects who allows to perform a safe and simple procedure. It can be done with modification of Pezzer canullas, and easily obtained items who can be collected by any trained endoscopist.


Gamekeeper's thumb. Evaluation by arthrography and stress roentgenography.
We reviewed 197 previously reported cases of acute rupture of the ulnar collateral ligament of the metacarpophalangeal joint with respect to anatomy, diagnosis, surgical findings, and management. A standardized roentgenographic technique in stress abduction of the thumb was developed from thirty normal patients. The correlation between the abduction arc as recorded by our technique, the arthogram, and surgical pathology in twenty patients is reported.


Serum histamine-releasing activity in a patient with idiopathic pulmonary haemosiderosis.
idiopathic pulmonary haemosiderosis (IPH) is a rare disorder characterized by intermittent, diffuse alveolar bleeding. The pathogenesis of the diseases is unclear, although an association with milk or gluten hypersensitivity has been described, and an immune-mediated damage of alveolar capillaries has been suggested. A previous report showed the release of histamine after cow's milk intake in a newborn with cow's milk intolerance and IPH. here, we report the detection of serum histamine-releasing activity (HRA) in a 30-year-old woman with IPH. The serum taken during an active phase of the disease induced histamine release from basophils of two normal donors; conversely, when the patient was receiving prednisone and azathioprine, and the disease was in remission, the serum HRA was reduced. Serum fractions with a MW lower than 100 kDa displayed an enhanced HRA; in contrast, serum fractions with MW above 100 kDa were not able to induce histamine release, suggesting that the activity was due to a cytokine and not to an immunoglobulin. the detection of serum HRA provides further evidence that the immune system is activated in the course of IPH and supports an immunologic basis for the alveolar capillary damage, which is responsible for alveolar bleeding.


HIV disease progression in Australia in the time of combination antiretroviral therapies.
To examine the effect of recent developments in antiretroviral therapy on HIV disease progression and survival. Retrospective cohort study. Two cohorts of people with HIV were defined retrospectively from the records of a large immunology laboratory. The first cohort were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L during 1990, and the second were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L in 1994. HIV disease progression and survival was determined over a minimum three years of follow-up for each cohort (i.e., 1990-1993; 1994-1997). 346 subjects were included in the analysis (193 subjects from 1990 and 153 from 1994). The relative risk of progression to AIDS in the 1994 cohort compared with the 1990 cohort was 0.57 (95% confidence interval, 0.35-0.91; P = 0.018) and the relative risk of death was 0.20 (95% confidence interval, 0.08-0.49; P < 0.001). There were 43% fewer AIDS cases and 80% fewer deaths in the time following the increased availability of combination antiretroviral therapy in Australia.


Weight regaining: From statistics and behaviors to physiology and metabolism.
Achieving maintenance of weight loss is crucial to combat obesity. However, most individuals tend to regain weight. Data from successful maintainers show that they remain vigilant and constantly apply techniques to oppose the course of regaining. On the other hand, current advances in obesity research show that the reduced obese state is a state of altered physiology in terms of energy balance. This review describes the physiological adaptations occurring after weight loss that predispose to regaining. Specifically, changes regarding body composition, hormonal background, energy expenditure and control of food intake are discussed. Moreover, metabolites that can act as regain predictors and dietary techniques to oppose regaining are presented.


Tripodal squaramide conjugates as highly effective transmembrane anion transporters.
Two tripodal squaramide conjugates having 4-(trifluoromethyl)phenyl and 3,5-bis(trifluoromethyl)phenyl substituents were synthesized and found to exhibit highly efficient transmembrane anion transport with the EC50 values being 0.14 and 0.75mol%, respectively. Though one of them has been reported to act as a strong anion receptor, in particular for sulfate anions, these two compounds exhibit no significant selectivity with respect to the tested monovalent anions and a very low level of activity in the presence of sulfate anions.


The Relativistic Car: Applying Metaethics to the Debate about Self-Driving Vehicles.
Almost all participants in the debate about the ethics of accidents with self-driving cars have so far assumed moral universalism. However, universalism may be philosophically more controversial than is commonly thought, and may lead to undesirable results in terms of non-moral consequences and feasibility. There thus seems to be a need to also start considering what I refer to as the "relativistic car" - a car that is programmed under the assumption that what is morally right, wrong, good, bad, etc. is determined by the moral beliefs of one's society or culture. My investigation of this idea involves six steps. First, I explain why and how the moral universalism/relativism debate is relevant to the issue of self-driving cars. Second, I argue that there are good reasons to consider accident algorithms that assume relativism. Third, I outline how a relativistic car would be programmed to behave. Fourth, I address what advantages such a car would have, both in terms of its non-moral consequences and feasibility. Fifth, I address the relativistic car's disadvantages. Finally, I qualify and conclude my considerations.


Finite element modeling of damage accumulation in trabecular bone under cyclic loading.
A two-dimensional finite element model of an idealized trabecular bone specimen was developed to study trabecular bone damage accumulation during cyclic compressive loading. The specimen was modeled as a two-dimensional honeycomb-like structure made up of an array of hexagonal cells. Each trabecula was modeled as a linearly elastic beam element with the same material properties as cortical bone. Initial microcracks were assumed to exist within the oblique trabeculae and to grow according to the Paris law. Forces and moments were computed in each trabecula and the microcracks were allowed to propagate until fracture occurred. Between cycles, fractured trabeculae were removed from the finite element mesh, and force and moment distributions were calculated for the next cycle. This iterative process was continued until the simulated trabecular bone specimen showed a 10% reduction in modulus. Creep failure was also studied using a single cell analysis, in which a closed-form solution was obtained after prescribing the creep properties of the trabeculae. The results of the crack propagation analysis showed that fractures of only a small number of individual trabeculae can cause a substantial reduction in the modulus of the trabecular bone specimen model. Statistical tests were performed to compare the slopes and intercepts of the S-N curves of our model predictions to those of experimentally derived S-N curves for bovine trabecular bone. There was no significant difference (p > 0.2 for both slope and intercept) between our model predictions and the experimentally derived S-N curves for the low-stress, high-cycle range. For the high-stress, low-cycle range, the crack propagation model overestimated the fatigue life for a given stress level (for slope, p < 0.001), while the creep analysis agreed well with the experimental data (for slope, p > 0.2). These findings suggest that the primary failure mechanism for low-stress, high-cycle fatigue of trabecular bone is crack growth and propagation, while the primary failure mechanism for high-stress, low-cycle fatigue is creep deformation and fracture. Furthermore, our results suggest that the modulus of trabecular bone at the specimen level may be highly sensitive to fractures of individual trabeculae.


Minimizing the effect of precipitation in clarifying the responses of leaf N and P stoichiometry to temperature.
How terrestrial ecosystem responds to global warming has received wide attention. Plant stoichiometry has the potential to reflect ecosystem responses to climate change, thus, investigating the variations in plant stoichiometry with temperature is important and necessary for revealing the responses of terrestrial ecosystem to global warming. Although many studies had explored the relationships between plant N, P stoichiometry and temperature, previous field investigations did not eliminate the interference of precipitation effect with these observed relationships. To minimize the effect of precipitation on leaf N, P stoichiometry, this investigation was conducted across a temperature gradient over broad geographical scale along the 400 mm isohyet, which extends about 6000 km in China. This study showed that leaf N did not vary, whereas leaf P decreased and leaf N:P ratio increased with increasing mean annual temperature (MAT). The responses of leaf N and P stoichiometry to MAT observed in this study might be general patterns; because they were almost ubiquitous across functional groups, genera and species examined, and moreover, they were independent of vegetation and soil type. It could be inferred from this study that global warming in future will have no effect on leaf N, but reduce leaf P and increase leaf N:P ratio. Stable leaf N and varied leaf P with changing MAT suggested that leaf N and P decoupled with changing temperature.


The effect of cholestyramine on lipoprotein lipids in patients with primary type IIA hyperlipoproteinemia.
The effect of 3 months' treatment with cholestyramine on lipoprotein lipids was investigated in 12 patients. VLDL, LDL and HDL were separated by preparative ultracentrifugation. There was a significant decrease of serum cholesterol and phospholipids and an increase of serum triglycerides. All the VLDL-lipids increased by nearly 30%. The LDL-lipids decreased with a tendency for normalisation of their atypical lipid composition. The small but significant alterations of HDL triglycerides and cholesterol are correlated with the corresponding alterations of the other lipoproteins; the HDL-phospholipids were unchanged. The LDL/HDL-lipid ratios were decreased but not normalised. The 30% decrease of LDL-cholesterol is negatively correlated with an increase in all the VLDL-lipids.


The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue.
Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.


Specificity and binding capacity of human blood serum for tetrahydropterins.
Binding behaviour of labelled biopterin, 6,7-dimethylpterin, 2,4-diamino-6,7-dimethylpteridin, and of their 5,6,7,8-tetrahydro derivatives was studied with human serum proteins. Binding capacity of serum proteins is in the range of 5 x 10-10--10-3 M without saturation for all these pteridines. Preincubation or competition with tetrahydrobiopterin does not influence binding of tetrahydro-6,7-dimethylpterin in these concentrations. The bulk of pteridines is bound through unspecific adsorption. Only at concentrations of less than 0.8 x 10-8 M does high affinity binding seem to be possible, corresponding to about 300 pmol/g protein, whereas physiological biopterin concentration is near 2 x 10-8 M. The binding proteins are very sensitive to ageing and lose their capacity during purification, whereas unspecific binding to serum proteins is only weakly influenced by alteration of salt concentration, pH, or temperature. Attempts to partially purify the binding proteins by ion exchange, dextran gel (Sephadex G-200), or affinity chromatography, demonstrate a specificity of tetrahydropterins for the alpha2-macroglobulin fraction. Due to the high lability of this protein fraction and of pteridine binding, purification of a protein which specifically binds tetrahydrobiopterin was not achieved.


The mammalian pseudoautosomal region.
Despite being morphologically dissimilar, mammalian sex chromosomes pair in male meiosis. Molecular studies of the X and Y chromosomes in humans and mice have identified the pseudoautosomal region, a genetically unique region of shared, recombining sequences that fall within the meiotic pairing region. Complete meiotic and physical maps of the human pseudoautosomal region have been produced and the pseudoautosomal boundary has been cloned and sequenced. These studies have provided clues to mammalian sex chromosome function and evolution.