Association Between Personal Activity Intelligence and Mortality: Population-Based China Kadoorie Biobank Study.
To prospectively investigate the association between personal activity intelligence (PAI) - a novel metabolic metric which translates heart rate during physical activity into a simple weekly score - and mortality in relatively healthy participants in China whose levels and patterns of physical activity in addition to other lifestyle factors are different from those in high-income countries. From the population-based China Kadoorie Biobank study, 443,792 healthy adults were recruited between June 2004 and July 2008. Participant's weekly PAI score was estimated and divided into four groups (PAI scores of 0, ≤50, 51-99, or ≥100). Using Cox proportional hazard analyses, we calculated adjusted hazard ratios (AHRs) for cardiovascular disease (CVD) and all-cause mortality related to PAI scores. During a median follow-up of 8.2 (interquartile range, 7.3 to 9.1) years, there were 21,901 deaths, including 9466 CVD deaths. Compared with the inactive group (0 PAI score), a baseline weekly PAI score greater than or equal to 100 was associated with a lower risk of CVD mortality, an AHR of 0.87 (95% CI, 0.81 to 0.94) in men, and an AHR of 0.84 (95% CI, 0.78 to 0.92) in women, after adjusting for multiple confounders. Participants with a weekly PAI score greater than or equal to 100 also had a lower risk of all-cause mortality (AHR, 0.93; 95% CI, 0.89 to 0.97 in men, and AHR, 0.93; 95%, 0.88 to 0.98 in women). Moreover, this subgroup gained 2.7 (95% CI, 2.4 to 3.0) years of life, compared with the inactive cohort. Among relatively healthy Chinese adults, the PAI metric was inversely associated with CVD and all-cause mortality, highlighting the generalizability of the score in different races, ethnicities, and socioeconomic strata.


Alternative somatic cell count traits as mastitis indicators for genetic selection.
The aim of this study was to define alternative traits of somatic cell count (SCC) that can be used to decrease genetic susceptibility to clinical and subclinical mastitis (CM and SCM, respectively). Three kinds of SCC traits were evaluated: 1) lactation-averages of SCC, 2) traits derived from the proportion of test-day SCC above 150,000 cells/mL, and 3) patterns of peaks in SCC. Genetic parameters for these SCC traits and their genetic correlation with CM and SCM were estimated; CM and SCM were scored as binary traits. Two data sets (A and B) depending on CM recording were available. After editing, subset A contained 28,688 lactations from 21,673 cows in 394 herds. Subset B contained 56,726 lactations of 30,145 cows in 272 herds. Variance components for sire and permanent animal effects were estimated. Estimated heritabilities for all mastitis traits were around 0.03. Heritabilities for SCC traits ranged from 0.01 for patterns of peaks in SCC to 0.13 for lactation-average SCC. Genetic correlations between SCC traits and CM or SCM ranged from 0.55 to 0.93 for CM and from 0.55 to 0.98 for SCM. High genetic correlations were estimated between CM and SCC averaged over 250 d in milk (0.87), and between SCM and presence of test-day SCC >150,000 cells/mL (0.98) in subset A. In subset B, a high genetic correlation was estimated between CM and an SCC peak with a quick recovery (0.93) and between SCM and SCC averaged between 151 and 400 d (0.95). Partial genetic correlations were calculated to investigate the additional information of the alternative SCC traits, compared with lactation-average SCC. They showed that some traits remain informative for CM and others for SCM. Therefore, use of information from a combination of different SCC traits may be more successful in improving overall udder health than the traditional single SCC measure.


Evaluation of in vitro antimicrobial activity of Thai basil oils and their micro-emulsion formulas against Propionibacterium acnes.
The aim of this study was to evaluate the efficacy of Thai basil oils and their micro-emulsions, on in vitro activity against Propionibacterium acnes. An agar disc diffusion method was employed for screening antimicrobial activity of the essential oils of Ocimum basilicum L. (sweet basil), Ocimum sanctum L. (holy basil) and Ocimum americanum L. (hoary basil) against P. acnes. Minimum inhibitory concentration (MIC) values of the basil oils were determined using an agar dilution assay. The obtained results indicated that the MIC values of sweet basil and holy basil oils were 2.0% and 3.0% v/v, respectively, whereas hoary basil oil did not show activity against P. acnes at the highest concentration tested (5.0% v/v). Gas chromatography-mass spectrometry analysis revealed that methyl chavicol (93.0%) was the major compound in sweet basil oil, and eugenol (41.5%), gamma-caryophyllene (23.7%) and methyl eugenol (11.8%) were major compounds in holy basil oil. Hoary basil oil contained high amounts of geraniol (32.0%) and neral (27.2%) and small amounts of methyl chavicol (0.8%). The Oil-in-water (o/w) micro-emulsions of individual basil oils with concentrations corresponding to their MIC values were formulated. The stable o/w micro-emulsion system for basil oil consisted of 55.0% v/v water phase, 10.0% v/v oil phase (2.0 or 3.0% v/v sweet basil or 3.0% v/v holy basil oil plus 7.0% v/v isopropyl myristate), 29.2% v/v polysorbate 80 and 5.8% v/v 1,2-propylene glycol. Hydroxyethylcellulose at a concentration of 0.5% w/v was used as thickening agent. According to the disc diffusion assay, the formulations containing sweet basil oil exhibited higher activity against P. acnes than those containing holy basil oil, and the thickened formulations tended to give a lower activity against P. acnes than the non-thickened formulations. The prepared micro-emulsions were stable after being tested by a heat-cool cycling method for five cycles. These findings indicate the possibility to use Thai sweet and holy basil oil in suitable formulations for acne skin care.


TFOS Lifestyle Report Executive Summary: A Lifestyle Epidemic - Ocular Surface Disease.
The Tear Film & Ocular Surface Society (TFOS) Workshop entitled 'A Lifestyle Epidemic: Ocular Surface Disease' was a global initiative undertaken to establish the direct and indirect impacts of everyday lifestyle choices and challenges on ocular surface health. This article presents an executive summary of the evidence-based conclusions and recommendations of the 10-part TFOS Lifestyle Workshop report. Lifestyle factors described within the report include contact lenses, cosmetics, digital environment, elective medications and procedures, environmental conditions, lifestyle challenges, nutrition, and societal challenges. For each topic area, the current literature was summarized and appraised in a narrative-style review and the answer to a key topic-specific question was sought using systematic review methodology. The TFOS Lifestyle Workshop report was published in its entirety in the April 2023 and July 2023 issues of The Ocular Surface journal. Links to downloadable versions of the document and supplementary material, including report translations, are available on the TFOS website: http://www.TearFilm.org.


XRHAMM functions in ran-dependent microtubule nucleation and pole formation during anastral spindle assembly.
The regulated assembly of microtubules is essential for bipolar spindle formation. Depending on cell type, microtubules nucleate through two different pathways: centrosome-driven or chromatin-driven. The chromatin-driven pathway dominates in cells lacking centrosomes. Human RHAMM (receptor for hyaluronic-acid-mediated motility) was originally implicated in hyaluronic-acid-induced motility but has since been shown to associate with centrosomes and play a role in astral spindle pole integrity in mitotic systems. We have identified the Xenopus ortholog of human RHAMM as a microtubule-associated protein that plays a role in focusing spindle poles and is essential for efficient microtubule nucleation during spindle assembly without centrosomes. XRHAMM associates both with gamma-TuRC, a complex required for microtubule nucleation and with TPX2, a protein required for microtubule nucleation and spindle pole organization. XRHAMM facilitates Ran-dependent, chromatin-driven nucleation in a process that may require coordinate activation of TPX2 and gamma-TuRC.


Nickel: a review of its occupational and environmental toxicology.
Nickel and nickel compounds belong to the classic noxious agents encountered in industry, but is also known to affect non-occupationally exposed individuals, especially those handling stainless-steel and nickel plated articles of everyday use. For plants and some vertebrates, specifically for mammals, nickel is indispensable as one of the essential trace elements. The most important health problems due to exposure to nickel and nickel compounds are allergic dermatitis (nickel itch) and increased incidence of cancers of the lungs and nasal mucosa encountered among the workers after a long-term over-exposure to nickel. In this respect the most hazardous nickel compounds appear to be nickel sulfide and nickel oxide. The monitoring of nickel exposure levels can be based on blood serum and urine analyses, but also on nickel determinations in hair which have proved promising even in groups of non-occupationally exposed individuals. Nickel carbonyl is the most toxic of all of the nickel compounds encountered, but because of its relatively short half-life it does not seem to represent any actual biohazard from the standpoint of environmental pollution. To prevent incidence of malignancies it is recommended to include in the routine plan of the preventive medical examinations also the cytologic analysis supplemented, in the case of cytologic positivity, with the bioptic examination for epithelial dysplasia. A systematic medical surveillance of workers with known long-term exposure to nickel is, of course, essential. At present, a major attention is centered on biochemical interactions of nickel with copper, cadmium, iron, iodine and particularly with manganese known to significantly reduce the experimental carcinogenicity of nickel and nickel compounds.


[Role of high-definition and high frequency ultrasonography in determining tumor thickness in cutaneous malignant melanoma].
We investigated the predictive capabilities of high frequency, high resolution ultrasound (US) in the preoperative assessment of tumor thickness in cutaneous malignant melanomas. This evaluation is a valuable help for correct surgical planning. December 1997 to August 1998, we studied with US over 120 pigmented skin lesions and collected the data, including the final histologic diagnosis, of 78 of them, which make our series. Sixty-six of 78 lesions were histologically defined as cutaneous malignant melanomas with superficial spread and the other 12 as melanocytic nevi. All examinations were carried out with an Esaotebiomedica AU 5 Harmonic scanner equipped with a 20-MHz annular array probe and a linear 13-MHz probe; B-mode, color and power Doppler images were always acquired. The statistical analysis of the comparative US and histologic measurements of tumor thickness showed very good agreement, with a high Pearson's coefficient (R: .93). However, US frequently underestimated the actual thickness relative to histology, which is in contradiction with previous literature reports. We could study with US the melanoma in situ, which has never been described before. Last but not least, low-thickness melanomas had very few color and power Doppler signals. US is the correct tool for the preoperative assessment of the thickness of cutaneous malignant melanomas because it provides high agreement with histologic data even in lesions thinner than 1 mm.


Electronic Cigarette or Vaping-Associated Lung Injury Case Report.
Electronic cigarette (e-cigarette) or vaping associated lung injury (EVALI) cases have increased with the popularity of e-cigarettes in the mostly young, healthy population. Some common symptoms associated with EVALI include shortness of breath and chest pain, and the most common diagnostic imaging findings are organizing pneumonia and diffuse alveolar damage seen on computed tomography (CT). Pneumomediastinum is a known sequela of EVALI.1 In the setting of pneumomediastinum in EVALI, EVALI is a diagnosis of exclusion, so other sources of pneumomediastinum need to be evaluated. EVALI has diverse presentations, and this case is a unique representation of a disease process that is becoming more commonplace with the increase in popularity of vaping. It is important to be aware of the clinical symptoms of EVALI, which can be nonspecific and can include gastrointestinal symptoms along with respiratory symptoms. It is equally important to recognize the diverse image findings of EVALI, which can include subcutaneous emphysema and pneumomediastinum. In this case, pneumomediastinum is seen in EVALI, and the patient was successfully treated with empiric antibiotic coverage, steroids, and conservative measures- making sure to limit any coughing or increases in intrathoracic pressure that can cause worsening of pneumomediastinum. EVALI, vaping, pneumomediastinum, E-cigarette, ground-glass opacity.


A programmable optical angle clamp for rotary molecular motors.
Optical tweezers are widely used for experimental investigation of linear molecular motors. The rates and force dependence of steps in the mechanochemical cycle of linear motors have been probed giving detailed insight into motor mechanisms. With similar goals in mind for rotary molecular motors we present here an optical trapping system designed as an angle clamp to study the bacterial flagellar motor and F(1)-ATPase. The trap position was controlled by a digital signal processing board and a host computer via acousto-optic deflectors, the motor position via a three-dimensional piezoelectric stage and the motor angle using a pair of polystyrene beads as a handle for the optical trap. Bead-pair angles were detected using back focal plane interferometry with a resolution of up to 1 degrees , and controlled using a feedback algorithm with a precision of up to 2 degrees and a bandwidth of up to 1.6 kHz. Details of the optical trap, algorithm, and alignment procedures are given. Preliminary data showing angular control of F(1)-ATPase and angular and speed control of the bacterial flagellar motor are presented.


Effect of metoprolol on myocardial apoptosis after coronary microembolization in rats.
Coronary microembolization (CME) is a serious complication following percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The use of metoprolol before PCI can significantly protect ischemic myocardium from myocardial damage, but the function of metoprolol in the treatment of CME is not entirely clear. This study was to explore the effect and significance of metoprolol on myocardial apoptosis and caspase-3 activation after CME in rats. Thirty rats were randomly divided into three groups including sham-operation (control group), CME plus saline (CME group), CME plus metoprolol (metoprolol group), 10 rats for each group. The CME group was induced by injecting 3 000 polyethylene microspheres (42 μm) into the left ventricle during a 10-second occlusion of the ascending aorta; the control group was injected with physiological saline instead of microembolization ball; the metoprolol or saline group was given three intravenous bolus injections before CME. Echocardiography, TUNEL staining, and Western blotting were used to evaluate cardiac function, proportion of apoptotic cells and activation of caspase-3 respectively at 6 hours after operation. Echocardiographic parameters displayed that the metoprolol group improved cardiac function significantly compared with the CME group (P<0.05). The myocardial apoptotic rate of the CME group as well as the contents of activated caspase-3 increased significantly (P<0.05), both of which were ameliorated significantly by metoprolol treatment (P<0.05). This study demonstrates that metoprolol can protect the myocardium during CME in rats by inhibiting apoptosis and improving cardiac function. These results suggest that the inhibition of apoptosis can be a potential therapeutic strategy for the treatment of CME.


Seeds as a production system for molecular pharming applications: status and prospects.
The production of recombinant proteins in seeds is achieved by driving transgene expression using promoters and protein targeting sequences derived from genes encoding abundant seed storage proteins. This approach is advantageous because high yields, stability and containment are conferred by the accumulation of recombinant proteins in specialized storage compartments such as protein bodies and protein storage vacuoles. Seeds are particularly suitable for the production of pharmaceutical proteins in developing country settings because they reduce the costs of production and distribution by avoiding the need for fermenter-based production capacity and a cold chain for storage and distribution, thus increasing access to critical medicines for the poor in rural areas. Seeds are also ideal for the production of oral vaccine antigens, because encapsulation within the seed provides protection that prolongs exposure to the gastric immune system and thus increases the potency of the immune response. In this review we discuss the current state of the art in seed-based molecular pharming and the future potential of production platforms based on seeds.


Fine mapping of qGL5H, a major grain length locus in barley (Hordeum vulgare L.).
A major grain length QTL on chromosome 5H was fine mapped from 180.5 to 1.7 Mb. Quantitative trait loci (QTLs) mapping has been used extensively in barley to detect QTLs that underlie complex traits such as grain size. In the present study, we utilised 312 double haploid lines derived from a cross between two Australian malting varieties, Vlamingh and Buloke, to dissect the genetic control of a number of grain size characteristics. Digital image analysis was used to measure grain size characteristics including length, width, thickness and plumpness which are important traits influencing barley yield and grain physical quality. Using data from four independent environments and molecular marker genotype data, we identified 23 significant QTLs for these four traits, ten of which were consensus QTLs and identified in two or more environments. A QTL region on chromosome 5H designated qGL5H that was associated with grain size was fine mapped to a 1.7 Mb interval. qGL5H was able to explain 21.6% of phenotypic variation for grain length within the population. This major QTL is an appropriate candidate for further genetic dissection.


Reproductive practices by patterns of marriage among Iranian women: study protocol for an explanatory sequential mixed methods design.
Nowadays, nearly half of the world population lives in societies with low fertility or the below-replacement fertility. This potentially grounds the critical situation of reduction in the workforce and causes the aging of population due to an overall increase in life expectancy and standard of living. Hence, population and its transitions including the issue of fertility decline has become a topic of intense debate in the agenda-setting and policy-making processes in both the developed and developing countries. In this view, what can practically be done to respond to the fertility decline that entails effectively addressing the determinants of fertility change? In line with the literature, how people form their marriages or patterns of marriage is amongst influencing factors which potentially affect their reproductive practices as diverse societies recognize different conventions for marriage. This study is to examine women's reproductive practices by the various patterns of marriage using the explanatory sequential mixed methods design. This study has an explanatory sequential mixed methods design, the follow-up explanations variant model, with two strands. This design will be implemented in two distinct phases. In the first phase, a cross-sectional quantitative study will be done using a cluster sampling strategy on 850 married women 15-49 years old living in Babol city, Iran. In order to obtain a deeper understanding of the results of the quantitative phase, researchers will implement a qualitative research in the second phase of this study. This design will provide an explanation of the quantitative research results using the qualitative evidence. As patterns of marriage have implications for the status of women, their health and fertility, the result of this study can provide a rich source of information for the required health-related interventions and policies are required to put the demographic changes on the right track at micro and macro level and improve the reproductive practices of women at micro level.


Ongoing spontaneous activity controls access to consciousness: a neuronal model for inattentional blindness.
Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden "ignition" of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of "inattentional blindness," in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness.


Spontaneous variability and reactive postural beat-to-beat changes of integral ECG body surface potential maps.
There is virtually no information on spontaneous variability of ECG body surface potential maps (BSPMs) and on dynamics of their reactive changes in healthy subjects. This study evaluated quantitatively the depolarization (QRS) and repolarization (QRST) parameters derived from the respective integral BSPMs, constructed beat-to-beat, from continual body surface ECG records in 9 healthy men resting supine, during head-up tilting and sitting. Spontaneous variability of the BSPMs parameters, both at rest and during postural reactions, was characterized by significant respiratory and low frequency oscillations, more pronounced when related to repolarization. Head-up tilting and sitting-up evoked significant decrease in the QRST-BSPM amplitudes, widening of the angle alpha and reduction of nondipolarity indexes, compared to the respective supine values. All these changes were gradual, characterized by transition phenomena and prolonged after-effects. Tilting back to horizontal restored the resting supine values. The postural effects on depolarization were individually more variable and in the average showed a minimal QRS-BSPM amplitude increase. Beat-to-beat analysis of a train of ECG BSPMs provided the first evidence of spontaneous, non-random, respiratory and low frequency oscillations of the ventricular repolarization pattern, and the first insight into the dynamics of body posture associated changes in ventricular recovery.


Multicenter Retrospective Review of Safety and Efficacy of a Novel Minimally Invasive Lumbar Interspinous Fusion Device.
Several treatment options exist for those with spinal stenosis, as well as degenerative changes. This series evaluates the use of an interspinous fixation (ISF) device as performed by interventional pain physicians. This is a retrospective analysis identifying 32 patients with the diagnosis of lumbar degenerative disc disease with secondary diagnosis of lumbar spinal stenosis being treated with ISF with Aurora Spine Zip Interspinous Spacer. Serious adverse events, specifically nerve injury, hematoma, infection, and death, were analyzed quantitatively for reported complications within 90 days from the procedure. In addition, VAS was analyzed for patient reported outcomes. Adverse event rate was 0% with no incidences of reoperation, or device removal. Estimated blood loss was recorded as less than 50 cc for all patients. The preoperative pain assessment demonstrated an average pain score of 8.1 and a postoperative pain score of 2.65 equating to a percentage pain reduction of 67%. This case series demonstrates the success and safety of ISF being performed by interventional pain physicians in an outpatient setting. It is a valuable tool in the treatment of moderate to severe lumbar spinal stenosis and degenerative disc disease that has decreased morbidity and significant efficacy.


Hyperinsulinemia and blood pressure in non-obese middle-aged subjects with normal glucose tolerance.
A possible link between hyperinsulinemia and blood pressure was studied in non-obese subjects with normal glucose tolerance. First, the responses in plasma glucose and serum insulin to an oral glucose load (75-g oral glucose tolerance test) were compared between 42 patients with essential hypertension and 93 normotensive control subjects. Second, of the 93 normotensive subjects, the relations of serum insulin levels to blood pressure, serum cholesterol, and triglycerides concentrations were assessed in 8 hyperinsulinemic (serum insulin level [during fasting, or after glucose loading, or both] greater than 2 S.D. higher than the mean) and 8 pair-matched normoinsulinemic subjects (serum insulin level within 1 S.D. of the mean), individually matched for age, sex, and body mass index. Plasma glucose and serum insulin responses to the glucose load in hypertensive subjects were identical to the respective responses in normotensive subjects, while the mean total serum cholesterol level was slightly higher (p less than 0.05) in hypertensive subjects. The respective values for systolic and diastolic blood pressures, and total serum cholesterol and triglycerides concentrations were comparable in hyperinsulinemic and normoinsulinemic subjects. These results did not suggest a close association between hyperinsulinemia and elevated blood pressure in non-obese middle-aged Japanese subjects with normal glucose tolerance.


First Report of Iris yellow spot virus in Spiny Sowthistle (Sonchus asper) in the United States.
Iris yellow spot virus (IYSV) is a member of the genus Tospovirus in the family Bunyaviridae. Its known host range is very limited, and the currently known hosts include onion, leek, lisianthus, and alstroemeria (2). The virus is vectored by onion thrips (Thrips tabaci). Onion (Allium cepa) is grown as a winter crop in Georgia from September to April and is the only known host commercially grown in the region. However, the virus has been found across the onion-growing region in the state every year since its first occurrence during 2003 (3). Consequently, the virus must oversummer in other host(s) or its insect vector. Accordingly, samples of weeds were collected in the vicinity of onion fields and cull piles in the Vidalia region and tested for the presence of IYSV by a double-antibody sandwich (DAS)-ELISA (Agdia, Inc., Elkhart, IN). One of three nonsymptomatic spiny sowthistle samples tested positive by ELISA for IYSV. Total RNA was extracted from the leaf using the RNeasy Plant Mini Kit (Qiagen, Valencia, CA) following the manufacturer's protocol. Two microliters were used for reverse transcription (RT)-PCR with the forward primer (5'-TCAGAAATCGAGAAACTT-3') and reverse primer (5'-TAATTATATCTATCTTTCTTGG-3') for the IYSV nucleocapsid gene (1). A band of the expected size (approximately 800 bp) was obtained and sequenced. The sequence from the sowthistle (GenBank Accession No. EU078327) matched IYSV sequences from Georgia and Peru in a BLAST search in GenBank (closest matches with Accession Nos. DQ838584, DQ838592, DQ838593, and DQ658242). This is to our knowledge, the first confirmed report of IYSV infecting spiny sowthistle. The distribution of IYSV in sowthistle and its role as an oversummering host for IYSV is currently an on-going study. References: (1) L. du Toit et al. Plant Dis. 88:222, 2004. (2) D. H. Gent et al. Plant Dis. 90:1468, 2006. (3) S. W. Mullis et al. Plant Dis. 88:1285, 2004.


NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review.
NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two- or four-electron reduction of numerous endogenous and environmental quinones (e.g., the vitamin E alpha-tocopherol quinone, menadione, benzene quinones). In laboratory animals treated with various environmental chemicals, inhibition of NQO1 metabolism has long been known to increase the risk of toxicity or cancer. Currently, there are 22 reported single-nucleotide polymorphisms (SNPs) in the NQO1 gene. Compared with the human consensus (reference, "wild-type") NQO1*1 allele coding for normal NQO1 enzyme and activity, the NQO1*2 allele encodes a nonsynonymous mutation (P187S) that has negligible NQO1 activity. The NQO1*2 allelic frequency ranges between 0.22 (Caucasian) and 0.45 (Asian) in various ethnic populations. A large epidemiologic investigation of a benzene-exposed population has shown that NQO1*2 homozygotes exhibit as much as a 7-fold greater risk of bone marrow toxicity, leading to diseases such as aplastic anemia and leukemia. The extent of the contribution of polymorphisms in other genes involved in the metabolism of benzene and related compounds-such as the P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase (GSTM1, GSTT1), microsomal epoxide hydrolase (EPHX1), and other genes-should also be considered. However, it now seems clear that a lowered or absent NQO1 activity can increase one's risk of bone marrow toxicity, after environmental exposure to benzene and benzene-like compounds. In cancer patients, the NQO1*2 allele appears to be associated with increased risk of chemotherapy-related myeloid leukemia. Many other epidemiological studies, attempting to find an association between the NQO1 polymorphism and one or another human disease, have now begun to appear in the medical literature.


Effects of growth hormone and insulin-like growth factor I on salinity tolerance and gill Na+, K+-ATPase in Atlantic salmon (Salmo salar): interaction with cortisol.
The potential roles of growth hormone (GH) and insulin-like growth factor I (IGF-I) in seawater (SW) acclimation of juvenile Atlantic salmon (Salmo salar) were examined. Compared to controls, fish in 12 ppt seawater given one or three injections (2-6 days) of GH (ovine, 0.2 microgram.g-1) or IGF-I (recombinant bovine, 0.05-0.2 microgram.g-1) had significantly greater salinity tolerance as judged by lower plasma sodium, osmolality, and muscle moisture content following transfer to 34 ppt. Single injections of GH and IGF-I in fish in fresh water failed to improve salinity tolerance following transfer to 25 ppt SW. Treatment of fish in 12 ppt with GH or IGF-I for 2-6 days did not increase gill Na+, K(+)-ATPase activity, but treatment with GH prevented decreases in gill Na+, K(+)-ATPase activity that occurred in controls following transfer to 34 ppt seawater. Fish in fresh water administered GH by implants (5.0 microgram.g-1) or osmotic minipumps (0.5 micrograms.g-1 day-1) for 7-14 days had greater gill Na+, K(+)-ATPase activity and salinity tolerance than controls. IGF-I administered by implants (0.5-1.0 microgram.g-1) or osmotic minipumps (0.1 microgram.g-1 day-1) for 4-14 days did not increase salinity tolerance or gill Na+, K(+)-ATPase activity. Cortisol implants (50 micrograms.g-1) also increased gill Na+, K(+)-ATPase activity and salinity tolerance after 14 days, and in combination with GH had a synergistic effect, Although IGF-I and cortisol implants had no significant effect after 7 days, in combination they significantly increased gill Na+, K(+)-ATPase activity. The results indicate that GH and cortisol can increase salinity tolerance and gill Na+, K(+)-ATPase activity of Atlantic salmon and together act in synergy. Although IGF-I can increase salinity tolerance in short-term treatments (2-6 days) in 12 ppt, it is less effective than GH in increasing salinity tolerance and gill Na+, K(+)-ATPase activity in long-term treatments (7-14 days) and in interacting with cortisol.


Enzymatic and Structural Characterization of the Naegleria fowleri Glucokinase.
Infection with the free-living amoeba Naegleria fowleri leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high (∼98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the N. fowleri genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The N. fowleri Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme (Homo sapiens Glck), suggesting that parasite-specific inhibitors with anti-amoeba activity can be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with the greatest activity observed with glucose. The enzyme had apparent Km values of 42.5 ± 7.3 μM and 141.6 ± 9.9 μM for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2-Å resolution, revealing that the enzyme shares greatest structural similarity with the Trypanosoma cruzi Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucose-phosphorylating enzymes and identified several small molecules with 50% inhibitory concentration values of <1 μM that may prove useful as hit chemotypes for further leads and therapeutic development against N. fowleri.


Infant word segmentation and childhood vocabulary development: a longitudinal analysis.
Infants begin to segment novel words from speech by 7.5 months, demonstrating an ability to track, encode and retrieve words in the context of larger units. Although it is presumed that word recognition at this stage is a prerequisite to constructing a vocabulary, the continuity between these stages of development has not yet been empirically demonstrated. The goal of the present study is to investigate whether infant word segmentation skills are indeed related to later lexical development. Two word segmentation tasks, varying in complexity, were administered in infancy and related to childhood outcome measures. Outcome measures consisted of age-normed productive vocabulary percentiles and a measure of cognitive development. Results demonstrated a strong degree of association between infant word segmentation abilities at 7 months and productive vocabulary size at 24 months. In addition, outcome groups, as defined by median vocabulary size and growth trajectories at 24 months, showed distinct word segmentation abilities as infants. These findings provide the first prospective evidence supporting the predictive validity of infant word segmentation tasks and suggest that they are indeed associated with mature word knowledge. A video abstract of this article can be viewed at http://www.youtube.com/watch?v=jxzLi5oLZQ8.


[Plasma technologies in surgery of pulmonary echinococcosis].
178 patients were operated over 18 years for pulmonary echinococcosis, 100 of them with standard methods, 78--with plasma technologies (surgical device SUPR-2M). Close echinococcectomy was performed in 22.5% patients, open--in 69.1%, combination of these operations--in 8.4% patients. Plasma technologies were used at pneumolysis, cysts section, antiparasitic treatment of residual cavities, fibrous capsule resection (pericystectomy) or cystpericystectomy, marginal resection of the lung with cyst, bronchotomy, sanation of pleural cavity, zone of operation and margins of operative wound. It is demonstrated that postoperative complications were seen in 34% patients operated by standard methods and in 8.9% patients operated with plasma technologies, lethal outcomes were in 2 (2%) and 1 (1.3%) patients, respectively. Plasma technologies permitted to reduce postoperative complications rate 3.8 times and postoperative treatment by 9.8 bed days or by 45.8%. Long-term results were studied in 61 (78.2%) operated patients followed from 1 month to 7 years, there were no recurrence of echinococcosis.


[Nuclear morphometry and estrogen receptors in infiltrating ductal carcinoma of the breast].
In this study ten cases of breast infiltrating ductal carcinoma have been considered. In all of them the content of ER has been evaluated by using monoclonal antibodies. Five of them were ER positive and five were ER negative. For the morphometric study ten nuclei of each case have been considered. By using the S.A.M. (Shape Analytical Morphometry) work-station an analytical study of the nuclear shape was performed. The first step was the extraction of fundamental shape which describes the basic shape of original contour without its irregularities. It was obtained by using two parametric equations. The second step was the evaluation of shape asymmetry by S.A.E. (Shape Asymmetry Evaluator). Finally the contour irregularities were evaluated by Fourier analysis. Along with analytical parameters, dimensions (area, perimeter and maximum diameter) were considered too. All obtained data were submitted to univariate statistical analysis (Student's T test) to compare the two groups (ER positive and ER negative tumors). Area, perimeter and maximum diameter were significatively greater in ER negative cases while analytical parameters were not discriminant between the two groups.


Human skin-derived keratinocytes and fibroblasts co-cultured on 3D poly ε-caprolactone scaffold support in vitro HSC differentiation into T-lineage committed cells.
In humans, the thymus is the primary lymphoid organ able to support the development of T cells through its three-dimensional (3D) organization of the thymic stromal cells. Since a remarkable number of similarities are shared between the thymic epithelial cells (TECs) and skin-derived keratinocytes and fibroblasts, in this study we used human keratinocytes seeded with fibroblasts on the 3D poly ε-caprolactone scaffold to evaluate their ability to replace TECs in supporting T-cell differentiation from human haematopoietic stem cells (HSCs). We observed that in the multicellular biocomposite, early thymocytes expressing CD7(+)CD1a(+), peculiar markers of an initial T-cell commitment, were de novo generated. Molecular studies of genes selectively expressed during T-cell development revealed that TAL1 was down-regulated and Spi-B was up-regulated in the cell suspension, consistently with a T-cell lineage commitment. Moreover, PTCRA and RAG2 expression was detected, indicative of a recombinant activity, required for the generation of a T-cell receptor repertoire. Our results indicate that in the multicellular biocomposite, containing skin-derived elements in the absence of thymic stroma, HSCs do start differentiating toward a T-cell lineage commitment. In conclusion, the construct described in this study exerts some properties of a lymphoid organoid, suitable for future clinical applications in cell-based therapies.


Differential diagnosis of inflammatory bowel disease: what is the role of colonoscopy?
Colonoscopy plays a crucial role in the diagnosis, treatment and follow-up monitoring of inflammatory bowel disease (IBD). Practitioners should be well informed of the colonoscopic findings of IBD to prevent the misdiagnosis, overtreatment or delayed treatment. Distinguishing between Crohn's disease and ulcerative colitis is essential in terms of pharmacological treatment, surgical decision-making, and prognosis. But there are still lesions with difficulty in differentiation that approximately 10% of the patients fall into the category of indeterminate colitis. Efforts are needed to carefully select treatment approach appropriate for each patient by providing a precise diagnosis on the extent and degree of lesions as well as to accurately delineate the lesions to assure that they are compared in subsequent rounds of follow-up monitoring in order to allow redetermination and adjustment of the treatment.


Standardization of clinical protocols in oral malodor research.
The objective of this study is to standardize protocols for clinical research into oral malodor caused by volatile sulfur compounds (VSCs). To detect VSCs, a gas chromatograph (GC) using a flame photometric detector equipped with a bandpass filter (at 393 nm) is the gold standard (sensitivity: 5 × 10(-11) gS s(-1)). The baselines of VSC concentrations in mouth air varied considerably over a week. When the subjects refrained from eating, drinking and oral hygiene including mouth rinsing, the VSC concentrations remained constant until eating. Over a 6 h period after a meal, VSC concentrations decreased dramatically (p < 0.01). These results point to optimal times and conditions for sampling subjects. Several portable devices were compared with the measurements by the GCs. Portable GCs demonstrated capabilities similar to those of the GCs. We also applied the recommended protocols described below to clinical research testing the efficacy of ZnCl(2) products, and confirmed that using the recommended protocols in a randomized crossover design would provide very clear results. Proposed protocols include: (a) a short-term study rather than a long-term study is strongly recommended, since the VSC concentrations are constant in the short term; (b) a crossover study would be the best design to avoid the effects of individual specificities on each clinical intervention; (c) measurements of VSCs should preferably be carried out using either a GC or portable GCs.


Paget's disease of the vulva: pathology, pattern of involvement, and prognosis.
The aim of this study was to determine prognostic factors and risk factors for recurrence in patients with Paget's disease of the vulva. The medical records of 76 patients with a diagnosis of Paget's disease of the vulva were retrospectively reviewed. The diagnosis in each case was confirmed by reviewing the pathology. Patients were then divided into four groups by diagnosis: intraepithelial Paget's disease (IEP) (n = 46), invasive Paget's disease (IP) (n = 9), intraepithelial Paget's disease with underlying adenocarcinoma (IEPUA) (n = 13), and intraepithelial Paget's disease with a coexisting cancer (CCA) (n = 8). Comorbid conditions, location of disease, pathologic diagnosis, method of treatment, margin status, and current status of the patient were evaluated. Descriptive statistical data and univariate analysis were generated using the Statview statistical package. A diagnosis of IEPUA, IP, or CCA predicted a poor survival (P = 0. 0017). Patients who had received chemotherapy or radiation as treatment had a poor survival (P < 0.0001 and 0.0002). Patients with clitoral Paget's disease had a higher incidence of death from disease (P = 0.026). When death from all causes was considered, patients treated with wide local excision (WLE) had a significantly longer survival than patients treated with other more radical treatments (P = 0.02). Risk factors for recurrence included treatment with WLE (P = 0.004). Patients with IP, IEPUA, or CCA have a poorer prognosis than patients with IEP. Location of Paget's disease is important for prognosis; and patients with clitoral Paget's disease may require more aggressive treatment. WLE is associated with a higher risk of recurrence, but overall patients with WLE tend to survive longer than patients treated more radically.


Choice Boosts Curiosity.
In our connected era, we spend significant time and effort satisfying our curiosity. Often, we choose which information we seek, but sometimes the selection is made for us. We hypothesized that humans exhibit enhanced curiosity in the context of choice. We designed a task in which healthy participants saw two lotteries on each trial. On some trials, participants chose which lottery to play. On other trials, the lottery was selected for them. Participants then indicated their curiosity about the outcome of the to-be-played lottery via self-report ratings (Experiment 1, N = 34) or willingness-to-wait decisions (Experiment 2, N = 34). We found that participants exhibited higher curiosity ratings and greater willingness to wait for the outcome of lotteries they had chosen than for lotteries that had been selected for them (controlling for initial preference). This demonstrates that choice boosts curiosity, which may have implications for boosting learning, memory, and motivation.


The first clinical application of a "hands-on" robotic knee surgery system.
The performance of a novel "hands-on" robotic system for total knee replacement (TKR) surgery is evaluated. An integrated robotic system for accurately machining the bone surfaces in TKR surgery is described. Details of the system, comprising an "active constraint" robot, called Acrobot, a "gross positioning" robot, and patient clamps, are provided. The intraoperative protocol and the preoperative, CT-based, planning system are also described. A number of anatomical registration and cutting trials, using plastic bones, are described, followed by results from two preliminary clinical trials, which demonstrate the accuracy achieved in the anatomical registration. Finally, the first clinical trial is described, in which the results of the anatomical registration and bone cutting are seen to be of high quality. The Acrobot system has been successfully used to accurately register and cut the knee bones in TKR surgery. This demonstrates the great potential of a "hands-on" robot for improving accuracy and increasing safety in surgery.


Age-Varying Associations between Child Maltreatment, Depressive Symptoms, and Frequent Heavy Episodic Drinking.
Child maltreatment represents a prevalent public health issue that has been shown to predict both adolescent and young adult depressive symptoms and heavy episodic drinking; however, little is known regarding how associations between specific types of maltreatment (e.g., physical abuse, sexual abuse, care neglect, supervisory neglect) and depressive symptoms and heavy episodic drinking change across adolescence and into young adulthood. Similarly, there is lack of research that has examined how an accumulation of child maltreatment types relates to depressive symptoms and heavy episodic drinking across ages. Time-varying effect models-a statistical approach that allows researchers to pinpoint specific ages where the association between two variables is strongest-were used in the current study to address these gaps. Nationally representative data came from the first four waves of the National Longitudinal Study of Adolescent to Adult Health (Add Health; N = 16,053; 49.4% female; 51.0% European American/White, 21.0% African American, 10.2% Biracial, 9.1% Hispanic; MAGE W1 = 17.00). Results suggested that certain types of maltreatment are more predictive of negative outcomes than others and that different types of maltreatment confer greater risk in different developmental periods. In addition, while victims of between one and three types of maltreatment had comparable prevalence of depressive symptoms and heavy episodic drinking across adolescence and young adulthood, victims of four types of maltreatment had a much higher prevalence of these outcomes indicating the extreme risk that accompanies an accumulation of maltreatment.


On information coded in gene-environment independence in case-control studies.
For analysis of case-control genetic association studies, it has recently been shown that gene-environment independence in the population can be leveraged to increase efficiency for estimating gene-environment interaction effects in comparison with the standard prospective analysis. However, for the special case in which data on the binary phenotype and genetic and environmental risk factors can be summarized in a 2 × 2 × 2 table, the authors show here that there is no efficiency gain for estimating interaction effects, nor is there an efficiency gain for estimating the genetic and environmental main effects. This contrasts with the well-known result assuming that rare phenotype prevalence and gene-environment independence in the control population for the same data can lead to efficiency gain. This discrepancy is counterintuitive, since the 2 likelihoods are also approximately equal when the phenotype is rare. An explanation for the paradox based on a theoretical analysis is provided. Implications of these results for data analyses are also examined, and practical guidance on analyzing such case-control studies is offered.


Androgen receptor activity at the prostate specific antigen locus: steroidal and non-steroidal mechanisms.
Ligand-activated androgen receptors (ARs) occupy target genes and recruit histone modifiers that influence transcriptional competency. In LNCaP prostate cancer cells, the natural ligand 5alpha-dihydrotestosterone (DHT) activates transiently transfected AR-responsive promoter constructs; concurrent treatment with the protein kinase A activator forskolin enhanced AR stimulation induced by DHT. Additional treatment with the cytokine IL-6, purportedly an AR activator, markedly inhibited receptor activity. To assess AR activity on natural chromatin-integrated promoters/enhancers, we determined AR occupancy of the endogenous prostate specific antigen (PSA) promoter/enhancer as well as PSA expression in LNCaP cells treated with DHT; AR occupancy of the PSA enhancer was rapid (within 1 h of stimulation), robust (10-fold over background), and sustained (8-16 h). In contrast, AR occupancy of the PSA promoter was only increased by 2-fold. Histone H3 acetylation at both the enhancer and promoter was evident 1-2 h after DHT treatment. Detectable pre- and mature PSA mRNA levels appeared after 1 and 6 h treatment, respectively. Substantial qualitative and quantitative differences in PSA expression and AR occupancy of the PSA enhancer were observed when DHT-induced and ligand-independent activations of the AR were compared; forskolin stimulated PSA mRNA and protein expression, whereas IL-6 inhibited both DHT- and forskolin-stimulated expression. IL-6 did not diminish DHT-dependent AR occupancy of the PSA enhancer but inhibited CBP/p300 recruitment, histone H3 acetylation, and cell proliferation. These findings provide a contextual framework for interpreting the contribution of non-steroidal activation of the AR to signaling in vivo, and have implications for prostate cancer cell growth.


Intracorporeal ileocolic anastomosis: a review.
This study is a narrative review of the current literature regarding intracorporeal ileocolic anastomosis in laparoscopic right colon resection for benign or malignant diseases of the right colon and terminal ileum. The search strategy included Medline, Embase, CINAHL, ACP Journal Club, and Cochrane databases with laparoscopic right colectomy and intracorporeal anastomosis as keywords. All retrieved references were screened by two independent blinded reviewers. Thirteen papers including 611 patients undergoing laparoscopic right colon resection with intracorporeal ileocolic anastomosis for benign or malignant diseases of the right colon and terminal ileum were identified. There were eight case series and five case control studies. Anastomoses were fashioned as antiperistaltic or isoperistaltic, totally stapled or stapled/handsewn. The mesenteric defect was mostly left open. Overall operating time ranged from 53 to 360 min. The most common specimen extraction site locations were periumbilical, suprapubic, or transvaginal with a median incision length ranging from 3 to 6 cm. The overall rate of surgical site infection was 2.7 %. The anastomotic leak rates varied from 0 to 8.5 %. Postoperative mortality was 0.12 %. Intracorporeal ileocolic anastomosis following laparoscopic resection of the right colon is not commonly performed, but offers potential benefits if carried out by experienced surgeons in selected patients.


[Electron microscopic study of the action of submicroscopic levorin structures on Candida guillermondii].
In the course of preparation of aqueous solutions of the polyene antibiotic levorin, the latter is recovered in the solid phase forming granular submicroscopic structures. If the cells of Candida guilliermondii are treated with submicroscopic granular structures (SMGS) of levorin, the structures are adsorbed on the surface of the yeast cell walls. Some visible changes occur in the ultrastructure of the yeast cells incubated with SMGS of levorin for 5 min: the inner layer of the cell wall becomes loose, the periplasmic space appears, the cytoplasmic membrane becomes thicker, the mitochondria swell, and fragmentation of the mitochondrial cristae takes place. Dense round alien bodies 20--40 mn in size can be discerned in the periplasmic space of such cells. If the yeast cells are treated with the levorin structures for a longer period of time (15--60 min), the cell ultrastructure is entirely disorganized.


αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression.
Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.


Substrate-dependent breast cancer resistance protein (Bcrp1/Abcg2)-mediated interactions: consideration of multiple binding sites in in vitro assay design.
In vitro assays are frequently used for the screening of substrates and inhibitors of transporter-mediated efflux. Examining directional flux across Madin-Darby canine kidney (MDCK) II cell monolayers that overexpress a transporter protein is particularly useful in identifying whether or not a candidate compound is an inhibitor or substrate for that transport system. Studies that use a single substrate or inhibitor in competition assays can be challenging to interpret because of the possible multiple mechanisms involved in substrate/inhibitor-protein interactions. During our previous studies of substrate-inhibitor-transporter interactions, we observed differences in breast cancer resistance protein (BCRP) inhibition, depending on the substrate and the inhibitor. Therefore, we investigated BCRP-mediated interactions with a 4 x 4 matrix of substrates and inhibitors using monolayers formed from MDCKII cells transfected with murine BCRP (Bcrp1/Abcg2). The selective BCRP inhibitor 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino [1',2':1,6] pyrido [3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143) effectively inhibited the Bcrp1-mediated transport of all substrates examined. However, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), nelfinavir, and Pluronic P85 exhibited differences in inhibition depending on the substrate examined. Our findings support recent reports suggesting that the interactions of substrate molecules with BCRP involve multiple binding regions in the protein. The nucleoside substrates zidovudine and abacavir seem to bind to a region on BCRP that may have little or no overlap with the binding regions of either prazosin or imatinib. In conclusion, the choice of substrate or inhibitor molecules for an in vitro assay system can be crucial for the optimal design of experiments to evaluate transporter-mediated drug-drug interactions.


Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus.
Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus. To evaluate the effects of acarbose, an alpha-glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients. Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE). Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) excretion rate as early as after 8 weeks and at each subsequent time point (between-group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11-dehydro-TXB(2) urinary excretion rate (beta = 0.39, P = 0.002) and MAGE the only predictor of 8-iso-PGF(2alpha) urinary excretion rate (beta = 0.42, P = 0.001). Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time-dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.


The Medical University of Vienna and the legacy of Pernkopf's anatomical atlas: Elsevier's donation of the original drawings to the Josephinum.
Eduard Pernkopf (1888-1955) became head of the Second Anatomical Institute in 1933, dean of the medical faculty in 1938 with the Annexation of Austria into Nazi Germany, and rector of the University of Vienna in 1943. He gained worldwide recognition with his anatomical atlas, which many consider unequaled to this day. In the decades that followed, suspicion arose that the drawings were made using corpses of people who had been victims of Nazi persecution and, following international inquiries and critique, the University of Vienna appointed a historical commission to the matter. The commission published its results in 1998, concluding that anatomical specimens used for the illustrations in Pernkopf's atlas had in all likelihood been made using corpses of victims of the Nazi judicial system. In total, the Anatomical Institute received the corpses of at least 1377 executed people, including many members of the anti-Nazi resistance. Through the acquisition of Pernkopf's original publisher Urban & Schwarzenberg in 2003, the original drawings and the publishing rights went to Elsevier. While existing copies of Pernkopf's Anatomy remain in use, printing or licensing of the atlas or its illustrations were stopped in 1994, inducing an effective ban on publishing the illustrations in other contexts, for example in works dealing with history and ethics of anatomy. In December 2019, Elsevier donated the remaining original drawings and proofs to the Medical University of Vienna, ensuring that these returned to the institution where they originated. They are now part of the university's historical collections held at the Josephinum. Moreover, the transfer of the originals to Vienna ensures appropriate archiving and conservation, cataloging and digitization, as well as access to the illustrations for historical and related research.


Orthognathic surgery. Review of mandibular body procedures.
In a clinical diagnostic approach to orthognathic deformities, the patient's past medical and dental histories and the indications and potential complications of mandibular body ostectomy and osteotomy are important considerations. The need for a team approach in the diagnostic, orthodontic, and surgical phase of the treatment is also important. The mandibular body procedure has a definite place in the armamentarium of the oral surgeon because certain mandibular deformities can be corrected only by this method. Predictable and stable results can be expected in indicated cases if one adheres to the principles of exacting surgical technique, precision immobilization, and neuromuscular balance. Presurgical and postsurgical orthodontic treatment enhances the functional and esthetic correction and furnished indispensable surgical fixation appliances for precision segment immobilization.


Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation.
Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide-specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide-specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo.


[Computer tomographic ventriculography (author's transl)].
A method for elucidating complex abnormalities of CSF circulation by using a positive contrast medium (metrizamide) and computer tomography is described. The technique for the method, the results and their clinical significance is demonstrated. The value of this method is compared with traditional ventriculography and with computer tomography without the use of contrast medium. It is shown that the technique represents an important extension of the scope of computer tomography.


Resting State Functional Connectivity Is Associated With Motor Pathway Integrity and Upper-Limb Behavior in Chronic Stroke.
Background. Resting state functional connectivity (RSFC) is a developmental priority for stroke recovery. Objective. To determine whether (1) RSFC differs between stroke survivors based on integrity of descending motor pathways; (2) RSFC is associated with upper-limb behavior in chronic stroke; and (3) the relationship between interhemispheric RSFC and upper-limb behavior differs based on descending motor pathway integrity. Methods. A total of 36 people with stroke (aged 64.4 ± 11.1 years, time since stroke 4.0 ± 2.8 years) and 25 healthy adults (aged 67.3 ± 6.7 years) participated in this study. RSFC was estimated from electroencephalography (EEG) recordings. Integrity of descending motor pathways was ascertained using transcranial magnetic stimulation to determine motor-evoked potential (MEP) status and magnetic resonance imaging to determine lesion overlap and fractional anisotropy of the corticospinal tract (CST). For stroke participants, upper-limb motor behavior was assessed using the Fugl-Meyer test, Action Research Arm Test and grip strength. Results. β-Frequency interhemispheric sensorimotor RSFC was greater for MEP+ stroke participants compared with MEP- (P = .020). There was a significant positive correlation between β RSFC and upper-limb behavior (P = .004) that appeared to be primarily driven by the MEP+ group. A hierarchical regression identified that the addition of β RSFC to measures of CST integrity explained greater variance in upper-limb behavior (R2 change = 0.13; P = .01). Conclusions. This study provides insight to understand the role of EEG-based measures of interhemispheric network activity in chronic stroke. Resting state interhemispheric connectivity was positively associated with upper-limb behavior for stroke survivors where residual integrity of descending motor pathways was maintained.


Occupational exposure to arsine. An epidemiologic reappraisal of current standards.
In an evaluation of chronic occupational exposure to arsine (AsH3), an epidemiologic survey was conducted at a lead-acid battery manufacturing plant. Personal (breathing zone) air samples were obtained for the measurement of exposure to arsine and particulate arsenic (As), and area air samples were also collected for the determination of arsenic trioxide (As2O3) vapor concentrations. For the quantification of arsenic absorption, total arsenic content was determined in duplicate 24-h urine samples. Arsine in 177 breathing-zone air samples ranged from nondetectable to 49 micron/m3. The highest levels were found in the battery formation area, where arsine is generated by the reaction of battery acid with lead-arsenic alloy. Exposures to particulate arsenic (maximum 5.1 micron/m3) and to As2O3 (maximum (20.5%) of 39 production workers had urinary arsenic concentrations (corrected to a specific gravity of 1.024) of 50 micron/1 (0.67 mumol/1) or above, indicating increased arsenic absorption. None of eight office staff had elevated urinary arsenic levels. A close correlation was found between urinary arsenic concentration and arsine exposure (N = 47; r = 0.84; p = 0.0001). Arsine levels above 15.6 micron/m3 were associated with urinary arsenic concentrations in excess of 50 micron/1 (0.67 mumol/1). No correlation was found between urinary arsenic content and exposures to particulate arsenic or to As2O3. Consumption of neither seafood, red wine, tobacco, nor contaminated drinking water accounted for urinary arsenic excretion. It was concluded that the current arsine exposure standard, 200 micron/m3, fails to prevent chronic increased absorption of trivalent arsenic from the inhalation of arsine.


Puromycin-sensitive aminopeptidase is required for C2C12 myoblast proliferation and differentiation.
The ubiquitin-proteasome system is a major protein degradation pathway in the cell. Proteasomes produce several peptides that are rapidly degraded to free amino acids by intracellular aminopeptidases. Our previous studies reported that proteolysis via proteasomes and aminopeptidases is required for myoblast proliferation and differentiation. However, the role of intracellular aminopeptidases in myoblast proliferation and differentiation had not been clarified. In this study, we investigated the effects of puromycin-sensitive aminopeptidase (PSA) on C2C12 myoblast proliferation and differentiation by knocking down PSA. Aminopeptidase enzymatic activity was reduced in PSA-knockdown myoblasts. Knockdown of PSA induced impaired cell cycle progression in C2C12 myoblasts and accumulation of cells at the G2/M phase. Additionally, after the induction of myogenic differentiation in PSA-knockdown myoblasts, multinucleated circular-shaped myotubes with impaired cell polarity were frequently identified. Cell division cycle 42 (CDC42) knockdown in myoblasts resulted in a loss of cell polarity and the formation of multinucleated circular-shaped myotubes, which were similar to PSA-knockdown myoblasts. These data suggest that PSA is required for the proliferation of myoblasts in the growth phase and for the determination of cell polarity and elongation of myotubes in the differentiation phase.


Prognostic Biomarkers of Sarcoidosis: A Comparative Study of Serum Chitotriosidase, ACE, Lysozyme, and KL-6.
Sarcoidosis is a systemic granulomatous disease with unknown etiology. Many clinical presentations have been reported, and acute disease needs to be distinguished from subacute and chronic disease. The unpredictable clinical course of the disease prompted us to evaluate the clinical utility of biomarker serum detection in sarcoidosis follow-up. Serum concentrations of chitotriosidase, ACE, KL-6, and lysozyme were analyzed by different methods in a population of 74 sarcoidosis patients (46 on steroid therapy at sampling) regularly monitored at Siena Sarcoidosis Regional Referral Centre and in a group of controls with the aim of comparing their contribution to clinical management of sarcoidosis patients. KL-6 concentrations were significantly elevated in sarcoidosis patients with lung fibrosis and were significantly correlated with DLco and CPI score, while chitotriosidase was significantly higher in patients with extrapulmonary localizations. With a cut-off value of 303.5 IU/ml, KL-6 showed the best sensitivity (78%), while chitotriosidase reported the best specificity (85%) among the biomarkers. KL-6 is a reliable biomarker of fibrotic lung involvement in sarcoidosis patients. Among biomarkers, KL-6 showed the best sensitivity and serum chitotriosidase the best specificity, even in patients on chronic steroid therapy, and seemed to correlate with extrapulmonary localizations.


Forward masking in the amplitude-modulation domain for tone carriers: psychophysical results and physiological correlates.
Wojtczak and Viemeister (J Acoust Soc Am 118:3198-3210, 2005) demonstrated forward masking in the amplitude-modulation (AM) domain. The present study examined whether this effect has correlates in physiological responses to AM at the level of the auditory midbrain. The human psychophysical experiment used 40-Hz, 100% AM (masker AM) that was imposed on a 5.5-kHz carrier during the first 150 ms of its duration. The masker AM was followed by a 50-ms burst of AM of the same rate (signal AM) imposed on the same (uninterrupted) carrier, either immediately after the masker or with a delay. In the physiological experiment, single-unit extracellular recordings in the awake rabbit inferior colliculus (IC) were obtained for stimuli designed to be similar to the uninterrupted-carrier conditions used in the psychophysics. The masker AM was longer (500 ms compared with 150 ms in the psychophysical experiment), and the carrier and modulation rate were chosen based on each neuron's audio- and envelope-frequency selectivity. Based on the average discharge rates of the responses or on the temporal correlation between neural responses to masked and unmasked stimuli, only a small subset of the population of IC cells exhibited suppression of signal AM following the masker. In contrast, changes in the discharge rates between the temporal segments of the carrier immediately preceding the signal AM and during the signal AM varied as a function of masker-signal delay with a trend that matched the psychophysical results. Unless the physiological observations were caused by species differences, they suggest that stages of processing higher than the IC must be considered to account for the AM-processing time constants measured perceptually in humans.


Three-Dimensional Histology Volume Reconstruction of Axonal Tract Tracing Data: Exploring Topographical Organization in Subcortical Projections from Rat Barrel Cortex.
Topographical organization is a hallmark of the mammalian brain, and the spatial organization of axonal connections in different brain regions provides a structural framework accommodating specific patterns of neural activity. The presence, amount, and spatial distribution of axonal connections are typically studied in tract tracing experiments in which axons or neurons are labeled and examined in histological sections. Three-dimensional (3-D) reconstruction techniques are used to achieve more complete visualization and improved understanding of complex topographical relationships. 3-D reconstruction approaches based on manually or semi-automatically recorded spatial points representing axonal labeling have been successfully applied for investigation of smaller brain regions, but are not practically feasible for whole-brain analysis of multiple regions. We here reconstruct serial histological images from four whole brains (originally acquired for conventional microscopic analysis) into volumetric images that are spatially registered to a 3-D atlas template. The aims were firstly to evaluate the quality of the 3-D reconstructions and the usefulness of the approach, and secondly to investigate axonal projection patterns and topographical organization in rat corticostriatal and corticothalamic pathways. We demonstrate that even with the limitations of the original routine histological material, the 3-D reconstructed volumetric images allow efficient visualization of tracer injection sites and axonal labeling, facilitating detection of spatial distributions and across-case comparisons. Our results further show that clusters of S1 corticostriatal and corticothalamic projections are distributed within narrow, elongated or spherical subspaces extending across the entire striatum / thalamus. We conclude that histology volume reconstructions facilitate mapping of spatial distribution patterns and topographical organization. The reconstructed image volumes are shared via the Rodent Brain Workbench (www.rbwb.org).


Control of the acute phase response. Demonstration of C-reactive protein synthesis and secretion by hepatocytes during acute inflammation in the rabbit.
To determine the cell of origin of C-reactive protein (CRP) and to cast light on the mechanisms leading to the acute phase response, we used an immunoenzymatic technique to visualize this protein in livers from rabbits at intervals after intramuscular injection of turpentine. CRP was detected only in hepatocytes. 8 h after turpentine injection, CRP was demonstrated in occasional periportal hepatocytes. With time, larger numbers of positive cells were detected successively in perilobular, midlobular, and centrilobular areas. On electron microscopy, CRP was detected in rough endoplasmic reticulum (RER), smooth endoplasmic reticulum (SER), and Golgi apparatus (GA). When colchicine was administered to inhibit cellular secretion of CRP, intensity of reaction and number of CRP-containing hepatocytes were substantially greater than without colchicine, but the sequence of intralobular distribution was similar. At peak serum response 38 h after turpentine injection, CRP could be demonstrated in most hepatocytes. Electron microscopic studies showed accumulation of CRP on membranes and lumina of RER, SER, GA, and in cytoplasmic vacuoles. These findings indicate that CRP is produced by progressively increasing numbers of hepatocytes after inflammatory stimulus and suggest that a mediator, acting initially in portal zones, is responsible for recruitment of cells to CRP production.


Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020.
Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a BRCA1/2 mutation. Inhibition of PARP, the key enzyme in base excision repair, is based on synthetic lethality whereby alternative DNA repair pathways in tumor cells that are deficient in homologous recombination is blocked, rendering them unviable and leading to cell death. The Australia New Zealand Gynaecological Oncology Group (ANZGOG) is the national gynecological cancer clinical trials organization for Australia and New Zealand. ANZGOG's purpose is to improve outcomes and quality of life for women with gynecological cancer through cooperative clinical trials and undertaking multidisciplinary research into the causes, prevention and treatments of gynecological cancer. This review summarizes current ovarian cancer research and treatment approaches presented by Australian and New Zealand experts in the field at the 2020 ANZGOG webinar series entitled "Ovarian Cancer systems of Care".


Increasing the Spatial Resolution of Visual Field Tests Without Increasing Test Duration: An Evaluation of ARREST.
The Australian Reduced Range Extended Spatial Test (ARREST) approach was designed to improve visual field spatial resolution while maintaining a similar test duration to clinically used testing algorithms. ARREST does not completely threshold visual field locations with sensitivity < 17 dB, and uses the presentations saved to test new locations in areas of steep gradient within the visual field. Previous assessments of ARREST's performance have used computer simulation. In this study, we cross-sectionally assessed the performance of ARREST in people with visual field loss. We tested 23 people with glaucoma (mean age: 71 ± 8 years) with established visual field loss. Three visual field procedures were performed using the Open Perimetry Interface: cZEST and ARREST on the Octopus 900 perimeter (Haag-Streit AG, Switzerland), and a reference standard (best available estimate [BAE]) on the Compass perimeter (CenterVue SpA, Italy). ARREST was compared against the cZEST and the BAE. On average, ARREST added seven new locations (range = 0-15) to a visual field test. There was no significant difference in the number of stimulus presentations between procedures (mean = 259 ± 25 [ARREST] vs. 261 ± 25 [cZEST], P = 0.78). In classifying threshold values < 17 dB, ARREST performed similarly when compared against BAE. This study provides empirical evidence to support conclusions from previous computer simulations that ARREST can be used to increase spatial sampling in regions of interest without increasing test time. ARREST is a new approach that augments current visual field testing procedures to provide better spatial description of visual field defects without increasing test duration.


Psychoactive Substances Taken with Mephedrone and HCV Infection.
In recent years, the observed frequency of hospitalization of patients taking mephedrone with other psychoactive substances has increased. There are no data in the literature on the effect of mephedrone use on liver function in patients, including the frequency of HCV infection. We have analysed the impact of taking mephedrone together with other psychoactive substances on the incidence of HCV infection. We have also analysed the effect of taking mephedrone with heroin, alcohol, and benzodiazepines on liver enzyme levels. The study included patients taking mephedrone with: alcohol (n = 115), heroin (n = 85) and benzodiazepines (n = 130) hospitalized in 2010-2018. The control group consisted of patients addicted to alcohol (n = 180), heroin (n = 221) and benzodiazepines (n = 152). Clinical data and laboratory findings were collected from medical records. Taking mephedrone together with benzodiazepines is a statistically significant predictor of HCV infection in this group of patients, OR (8.44); 95% CI 5.63-12.64; p < 0.001). A statistically significant interaction of the group with HCV infection was observed, i.e., for the level of alanine transaminase (p < 0.001) and aspartate transaminase (p < 0.001). Increased levels of liver enzymes in each of the studied groups was characteristic in patients with HCV infection (p < 0.001). Taking additional mephedrone by this group of patients did not increase the level of liver enzymes. HCV infection is a statistically significant factor affecting the increase in liver enzymes levels in the group of patients taking mephedrone.


High-Performance Organic Solar Cells Featuring Double Bulk Heterojunction Structures with Vertical-Gradient Selenium Heterocyclic Nonfullerene Acceptor Concentrations.
In this study, we prepared organic photovoltaics (OPVs) featuring an active layer comprising double bulk heterojunction (BHJ) structures, featuring binary blends of a polymer donor and concentration gradients of two small-molecule acceptors. After forming the first BHJ structure by spin-coating, the second BHJ layer was transfer-printed onto the first using polydimethylsiloxane stamps. A specially designed selenium heterocyclic small-molecule acceptor (Y6-Se-4Cl) was employed as the second acceptor in the BHJ. X-ray photoelectron spectroscopy revealed that the two acceptors formed a gradient concentration profile across the active layer, thereby facilitating charge transportation. The best power conversion efficiencies (PCEs) for the double-BHJ-structured devices incorporating PM6:Y6-Se-4Cl/PM6:Y6 and PM6:Y6-Se-4Cl/PM6:IT-4Cl were 16.4 and 15.8%, respectively; these values were higher than those of devices having one-BHJ structures based on PM6:Y6-Se-4Cl (15.0%), PM6:Y6 (15.4%), and PM6:IT-4Cl (11.6%), presumably because of the favorable vertical concentration gradient of the selenium-containing small-molecule Y6-Se-4Cl in the active layer as well as some complementary light absorption. Thus, combining two BHJ structures with a concentration gradient of the two small-molecule acceptors can be an effective approach for enhancing the PCEs of OPVs.


Social accountability and health systems' change, beyond the shock of Covid-19: drawing on histories of technical and activist approaches to rethink a shared code of practice.
Recognition of the value of "social accountability" to improve health systems performance and to address health inequities, has increased over the last decades, with different schools of thought engaging in robust dialogue. This article explores the tensions between health policy and systems research and practice on the one hand, and health equity-focussed activism on the other, as distinct yet interacting processes that have both been impacted by the shock effects of the Covid-19 pandemic. This extended commentary brings multidisciplinary voices seeking to look back at health systems history and fundamental social-institutional systems' behaviors in order to contextualize these current debates over how best to push social accountability efforts forward. There is a documented history of tension between long and short processes of international health cooperation and intervention. Social accountability approaches, as a more recent strategy to improve health systems performance, intersect with this overarching history of negotiation between differently situated actors both global and local on whether to pursue sustained, slow, often community-driven change or to focus on rapid, measurable, often top-down interventions. Covid-19, as a global public health emergency, resulted in calls for urgent action which have unsurprisingly displaced some of the energy and aspiration for systemic transformation processes. A combination of accountability approaches and mechanisms have their own legitimacy in fostering health systems change, demanding collaboration between those that move both fast and slow, top-down and bottom-up. We argue that social accountability, much like all efforts to strengthen health systems, is "everybody's business" and that we must understand better the historical processes that have shaped the field of practice over time to move forward. These differences of perspective, knowledge-base and positioning vis-a-vis interventions or longer-term political commitment should not drive a conflict of legitimacy but instead be named, subsequently enabling the development of a shared code of conduct that applies to the breadth of actors involved in social accountability work. If we are concerned about the state of/status of social accountability within the context of "building back better" we must approach collaboration with a willingness to create dialogue across distinct disciplinary, technical and politically-informed ways of working.


Complex frequency-dependent polarizability through the π → π* excitation energy of azobenzene molecules by a combined charge-transfer and point-dipole interaction model.
The complex frequency-dependent polarizability and π → π* excitation energy of azobenzene compounds are investigated by a combined charge-transfer and point-dipole interaction (CT/PDI) model. To parametrize the model, we adopted time-dependent density functional theory (TDDFT) calculations of the frequency-dependent polarizability extended with excited-state lifetimes to include also its imaginary part. The results of the CT/PDI model are compared with the TDDFT calculations and experimental data demonstrating that the CT/PDI model is fully capable to reproduce the static polarizability as well as the π → π* excitation energy for these compounds. In particular, azobenzene molecules with different functional groups in the para-position have been included serving as a severe test of the model. The π → π* excitation is to a large extent localized to the azo bond, and substituting with electron-donating or electron-attracting groups on the phenyl rings results in charge-transfer effects and a shift in the excitation energy giving rise to azobenzene compounds with a range of different colors. In the CT/PDI model, the π → π* excitation in azobenzenes is manifested as drastically increasing atomic induced dipole moments in the azo group as well as in the adjacent carbon atoms, whereas the shifts in the excitation energies are due to charge-transfer effects.


Oxidative cross-coupling processes inspired by the Chan-Lam reaction.
The Cu-catalyzed oxidative cross-coupling of N- and O-nucleophiles with aryl boronic acids (the Chan-Lam reaction) remains among the most useful approaches to prepare aniline and phenol derivatives. The combination of high chemoselectivity, mild reaction conditions, and the ability to use simple Cu-salts as catalysts makes this process a valuable alternative to aromatic substitutions and Pd-catalyzed reactions of aryl electrophiles (Buchwald-Hartwig coupling). Despite the widespread use of Chan-Lam reactions in synthesis, the analogous carbon-carbon bond forming variant of this process had not been developed prior to our work. This feature article describes our discovery and application of Cu-catalyzed oxidative coupling reactions of activated methylene derivatives or carboxylic acids with nucleophiles including aryl boronic esters and amines.


Intervening in GERD: the phases of management.
The discomforts and histologic changes of gastroesophageal reflux disease call for a stepped approach consisting of four phases: lifestyle modification, initiation of pharmacologic therapy, intensification of drug therapy, and in some cases antireflux surgery. Decisions are guided by symptom patterns, which serve to suggest the predominant pathophysiologic mechanisms.


[The flow cytometry in diagnostic of sepsis in children of first year of life with congenital heart disease and operated in conditions of artificial circulation].
The study was organized to evaluate sensitivity and specificity of CD64 index and relative amount of HLA-DR+ monocytes in diagnostic of sepsis in children of first year of life after surgery correction if congenital heart disease in conditions of artificial circulation. To detect CD64 index the kit Leuko64 (Beckman Coulter USA) was applied. The relative amount of HLA-DR+ monocytes was measured by flow cytofluorimeter Navios (Beckman Coulter, USA) using combination of monoclonal antibodies CD14-APC, HLA-DR-PacificBlue, CD45-KrOr. The results of study established that CD64 index in the group with confirmed or supposed sepsis consisted 2.29 (1.96:3.32) that statistically is reliably higher (p = 0.001) than in group without sepsis. The study established no statistically reliable differences in concentration of C-reactive protein in blood serum (p-0.123), absolute amount of leukocytes in peripheral blood (p = 0.128), relative amount of HLA-DR+ monocytes (p = 0.789). It is demonstrated that value of CD64 index higher than 2.00 increases the risk of development of sepsis up to 9.4 times and can be used as a diagnostic criterion of sepsis (AUC = 0.895) with sensitivity up to 80% and specificity up to 90%. The negative prognostic significance of CD64 index and content of procalcitonin in relation to development of sepsis in children of first year of life operated in conditions of artificial circulation amounted to 74% and 76% and 77% and 64% in case of positive prognostic significance correspondingly.


Environmental Stressors and the PINE Network: Can Physical Environmental Stressors Drive Long-Term Physical and Mental Health Risks?
Both psychosocial and physical environmental stressors have been linked to chronic mental health and chronic medical conditions. The psycho-immune-neuroendocrine (PINE) network details metabolomic pathways which are responsive to varied stressors and link chronic medical conditions with mental disorders, such as major depressive disorder via a network of pathophysiological pathways. The primary objective of this review is to explore evidence of relationships between airborne particulate matter (PM, as a concrete example of a physical environmental stressor), the PINE network and chronic non-communicable diseases (NCDs), including mental health sequelae, with a view to supporting the assertion that physical environmental stressors (not only psychosocial stressors) disrupt the PINE network, leading to NCDs. Biological links have been established between PM exposure, key sub-networks of the PINE model and mental health sequelae, suggesting that in theory, long-term mental health impacts of PM exposure may exist, driven by the disruption of these biological networks. This disruption could trans-generationally influence health; however, long-term studies and information on chronic outcomes following acute exposure event are still lacking, limiting what is currently known beyond the acute exposure and all-cause mortality. More empirical evidence is needed, especially to link long-term mental health sequelae to PM exposure, arising from PINE pathophysiology. Relationships between physical and psychosocial stressors, and especially the concept of such stressors acting together to impact on PINE network function, leading to linked NCDs, evokes the concept of syndemics, and these are discussed in the context of the PINE network.


Evidence for patchy lipid layers on gold nanoparticle surfaces.
Gold nanoparticles bearing multiple surface ligands are becoming favored candidates as multifunctional targeting, imaging, and therapeutic vehicles for biomedicine. The question of spatial location of different ligands on nanoparticle surfaces, especially with those of diameters less than 100 nm, is an important one that is difficult to quantitatively address. Here we functionalize the surface of 20, 50, and 90 nm gold nanoparticles with two different lipids, both single and mixed, using two different surface chemical procedures. Mass spectrometry supports the presence of both lipids in the mixed-lipid systems on nanoparticles, while electron microscopy evidence shows domain sizes for one lipid apparently a quarter to a half the projected diameter for 50 and 90 nm particles; but for 20 nm particles, there is no evidence for the existence of patches of the two lipids. Larger gold nanoparticles (90 nm) can be decorated with an array of 12 nm gold nanoparticles by use of a third lipid and antibody-antigen connectors; the display of the 12 nm particles about the 90 nm particles can be controlled to some extent by the initial surface chemistry and is quantified via a new angle analysis procedure.


An epidemiological modelling approach for COVID-19 via data assimilation.
The global pandemic of the 2019-nCov requires the evaluation of policy interventions to mitigate future social and economic costs of quarantine measures worldwide. We propose an epidemiological model for forecasting and policy evaluation which incorporates new data in real-time through variational data assimilation. We analyze and discuss infection rates in the UK, US and Italy. We furthermore develop a custom compartmental SIR model fit to variables related to the available data of the pandemic, named SITR model, which allows for more granular inference on infection numbers. We compare and discuss model results which conducts updates as new observations become available. A hybrid data assimilation approach is applied to make results robust to initial conditions and measurement errors in the data. We use the model to conduct inference on infection numbers as well as parameters such as the disease transmissibility rate or the rate of recovery. The parameterisation of the model is parsimonious and extendable, allowing for the incorporation of additional data and parameters of interest. This allows for scalability and the extension of the model to other locations or the adaption of novel data sources.


How to Prevent Vaccines Falling Victim to Their Own Success: Intertemporal Dependency of Incidence Levels on Indirect Effects in Economic Reevaluations.
Incremental cost-effectiveness analyses may inform the optimal choice of healthcare interventions. Nevertheless, for many vaccines, benefits fluctuate with incidence levels over time. Reevaluating a vaccine after it has successfully decreased incidences may eventually cause a disease resurgence if switching to a vaccine with lower indirect benefits. Decisions may successively alternate between vaccines alongside repeated rises and falls in incidence and when indirect effects from historic use are ignored. Our suggested proposal aims to prevent suboptimal decision making. We used a conceptual model of demand to illustrate alternating decisions between vaccines because of time-varying levels of indirect effects. Similar to the concept of subsidies, we propose internalizing the indirect effects achievable with vaccines. In a case study over 60 years, we simulated a hypothetical 10-year reevaluation of 2 oncogenic human papillomavirus vaccines, of which only 1 protects additionally against anogenital warts. Our case study showed that the vaccine with additional warts protection is initially valued higher than the vaccine without additional warts protection. After 10 years, this differential decreases because of declines in warts incidence, which supports switching to the nonwarts vaccine that causes a warts resurgence eventually. Instead, pricing the indirect effects separately supports continuing with the warts vaccine. Ignoring how the observed incidences depend on the indirect effects achieved with a particular vaccine may lead to repeated changes in vaccines at successive reevaluations, with unintended resurgences, economic inefficiencies, and eroding vaccine confidence. We propose internalizing indirect effects to prevent vaccines falling victim to their own success.