The acute effect of different frequencies of whole-body vibration on countermovement jump performance.
Whole-body vibration (WBV) has been shown to elicit acute and chronic improvements in neuromuscular function; however, there is little conclusive evidence regarding an optimum protocol for acute WBV. The aim of this study was to compare the effects of acute exposure to different frequencies of WBV on countermovement jump (CMJ) height. Twelve recreationally trained men (age, 31 ± 8 years; height, 177 ± 12 cm; weight, 83.0 ± 6.9 kg) completed maximal CMJs pre- and post-WBV in a half-squat position for 30 seconds. In a blinded design with randomized testing order, participants were exposed on different days to frequencies of 0, 30, 35, and 40 Hz. Significant main effects were found for time (pre-to-post WBV, p < 0.01) and frequency * time interaction (p < 0.01), with post hoc analysis highlighting that there was a significant mean improvement of 6% in CMJ as a result of WBV at 40 Hz but no significant change at other frequencies. This study demonstrates that for recreationally trained men, an acute 30-second bout of vertical WBV at 40 Hz and 8-mm peak-to-peak displacement significantly enhances explosive jumping performance in comparison to other frequencies. Acute vertical WBV for 30 seconds at 40 Hz may be incorporated into strength and conditioning training to enhance explosive power; however, the exact mechanisms for improvements remain to be elucidated and further well-controlled investigations on chronic WBV training and using well-trained athletes are recommended.


pH-dependent substrate preference of pig heart lipoamide dehydrogenase varies with oligomeric state: response to mitochondrial matrix acidification.
Cycling of intracellular pH has recently been shown to play a critical role in ischemia-reperfusion injury. Ischemia-reperfusion also leads to mitochondrial matrix acidification and dysfunction. However, the mechanism by which matrix acidification contributes to mitochondrial dysfunction, oxidative stress, and the resultant cellular injury has not been elucidated. We observe pH-dependent equilibria between monomeric, dimeric, and a previously undescribed tetrameric form of pig heart lipoamide dehydrogenase (LADH), a mitochondrial matrix enzyme. Dynamic light scattering studies of native LADH in aqueous solution indicate that lowering pH favors a shift in average molecular mass from higher oligomeric states to monomer. Sedimentation velocity of LADH entrapped in reverse micelles reveals dimer and tetramer at both pH 5.8 and 7.5, but monomer was observed only at pH 5.8. Enzyme activity measurements in reverse Aerosol OT micelles in octane indicate that LADH dimer and tetramer possess lipoamide dehydrogenase and diaphorase activities at pH 7.5. Upon acidification to pH 5.8 only the LADH monomer is active and only the diaphorase activity is observed. These results indicate a correlation between pH-dependent changes in the LADH reaction specificity and its oligomeric state. The acidification of mitochondrial matrix that occurs during ischemia-reperfusion injury is sufficient to alter the structure and enzymatic specificity of LADH, thereby reducing mitochondrial defenses, increasing oxidative stress, and slowing the recovery of energy metabolism. Matrix acidification may also disrupt the quaternary structure of other mitochondrial protein complexes critical for cellular homeostasis and survival.


Studies on the reuse of waste printed circuit board as an additive for cement mortar.
The recent development in electronic industries has generated a drastic increase in production of printed circuit boards (PCB). Accordingly, the amount of waste PCB from electronic productions and waste electronics and its environmental impact such as soil and groundwater contamination have become a great concern. This study aims to propose a method for reuse of waste PCB as an additive for cement mortar. Although the expansibility of waste PCB powder finer than 0.08 mm in water was observed to be greater than 2.0%, the maximum expansion rates in water for 0.08 to approximately 0.15 and 0.15 to approximately 0.30 mm sized PCB powders were less than 2.0%, which satisfied the necessary condition as an alternative additive for cement mortar in place of sand. The difference in the compressive strength of standard mortar and waste PCB added mortar was observed to be less than 10% and their difference was expected to be smaller after prolonged aging. The durability of waste PCB added cement mortar was also examined through dry/wet conditioning cyclic tests and acidic/alkaline conditioning tests. From the tests, both weight and compressive strength of cement mortar were observed to be recovered with aging. The leaching test for heavy metals from waste PCB added mortar showed that no heavy metal ions such as copper, lead, or cadmium were detected in the leachate, which resulted from fixation effect of the cement hydrates.


The Electrically Evoked Auditory Change Complex Evoked by Temporal Gaps Using Cochlear Implants or Auditory Brainstem Implants in Children With Cochlear Nerve Deficiency.
This study aimed to (1) establish the feasibility of measuring the electrically evoked auditory change complex (eACC) in response to temporal gaps in children with cochlear nerve deficiency (CND) who are using cochlear implants (CIs) and/or auditory brainstem implants (ABIs); and (2) explore the association between neural encoding of, and perceptual sensitivity to, temporal gaps in these patients. Study participants included 5 children (S1 to S5) ranging in age from 3.8 to 8.2 years (mean: 6.3 years) at the time of testing. All subjects were unilaterally implanted with a Nucleus 24M ABI due to CND. For each subject, two or more stimulating electrodes of the ABI were tested. S2, S3, and S5 previously received a CI in the contralateral ear. For these 3 subjects, at least two stimulating electrodes of their CIs were also tested. For electrophysiological measures, the stimulus was an 800-msec biphasic pulse train delivered to individual electrodes at the maximum comfortable level (C level). The electrically evoked responses, including the onset response and the eACC, were measured for two stimulation conditions. In the standard condition, the 800-msec pulse train was delivered uninterrupted to individual stimulating electrodes. In the gapped condition, a temporal gap was inserted into the pulse train after 400 msec of stimulation. Gap durations tested in this study ranged from 2 up to 128 msec. The shortest gap that could reliably evoke the eACC was defined as the objective gap detection threshold (GDT). For behavioral GDT measures, the stimulus was a 500-msec biphasic pulse train presented at the C level. The behavioral GDT was measured for individual stimulating electrodes using a one-interval, two-alternative forced-choice procedure. The eACCs to temporal gaps were recorded successfully in all subjects for at least one stimulating electrode using either the ABI or the CI. Objective GDTs showed intersubject variations, as well as variations across stimulating electrodes of the ABI or the CI within each subject. Behavioral GDTs were measured for one ABI electrode in S2 and for multiple ABI and CI electrodes in S5. All other subjects could not complete the task. S5 showed smaller behavioral GDTs for CI electrodes than those measured for ABI electrodes. One CI and two ABI electrodes in S5 showed comparable objective and behavioral GDTs. In contrast, one CI and two ABI electrodes in S5 and one ABI electrode in S2 showed measurable behavioral GDTs but no identifiable eACCs. The eACCs to temporal gaps were recorded in children with CND using either ABIs or CIs. Both objective and behavioral GDTs showed inter- and intrasubject variations. Consistency between results of eACC recordings and psychophysical measures of GDT was observed for some but not all ABI or CI electrodes in these subjects.


Correlation between chronic hypovitaminosis C in old age and plasma levels of cholesterol and triglycerides.
The possible interrelations between ascorbic acid, cholesterol and plasma triglycerides were studied in the residents of an old people's home. The study lasted about five months, from autumn to spring, and concerned 100 people in good health, both males and females, whose age varied from 70 to 84. Old people's diets proved well balanced and varied to such an extent as to supply them with a satisfying amount of calories and vitamin C. The results of this study showed that the average plasma levels of ascorbic acid [1] approached the lower level of normal values (587 +/- 34 micrograms %), [2] depended on sex (in fact it was significantly lower in males) (p less than 0.01), and [3] depended on diets which varied according to the different seasons when drawings were made (p less than 0.01). Moreover, in all cases there was a significantly negative correlation between ascorbic acid and cholesterol (p less than 0.05), whereas no significant correlation seemed to exist between ascorbic acid and triglycerides. On the contrary, a significant positive correlation between cholesterol and triglycerides was observed (p less than 0.01). The above-mentioned correlations seem to be valid only for males. This study confirmed by partial 3 variant correlations, produced results that point out the risk of hypercholesterolemia connected with chronic hypovitaminosis C, a characteristic feature of old age.


Cognitive behavioral therapy for chronic pain in veterans: Evidence for clinical effectiveness in a model program.
The U.S. Department of Veterans Affairs (VA) has been training clinicians in its cognitive behavioral therapy for chronic pain (CBT-CP) structured protocol since 2012. The aim of this project was to review patient outcomes to determine the effectiveness of the VA's CBT-CP treatment. From 2012-2018, 1,331 Veterans initiated individual CBT-CP treatment as part of the training program. Patient outcomes were assessed with measures of patient-reported pain intensity, pain catastrophizing, depression, pain interference, and quality of life (physical, psychological, social, and environmental). Mixed models of the effects of time indicated significant changes across pretreatment, midtreatment, and treatment conclusion on all outcomes. There was a large effect size (Cohen's d = 0.78) for pain catastrophizing, and there were medium to large effect sizes (d > 0.60) for worst pain intensity, pain interference, depression, and physical quality of life. Systematic training of therapists and implementation of the VA's CBT-CP protocol yielded significant patient improvements across multiple domains. This offers strong support for the VA's CBT-CP as an effective, safe treatment for Veterans with chronic pain and highlights it as a model to increase the availability of training in standardized, pain-focused, evidence-based, behavioral interventions. The findings suggest that the broad dissemination of such training, including in routine, nonpain specialty settings, would improve patient access to effective, nonpharmacological treatment options in both the public and private sectors. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Tick Thioester-Containing Proteins and Phagocytosis Do Not Affect Transmission of Borrelia afzelii from the Competent Vector Ixodes ricinus.
The present concept of the transmission of Lyme disease from Borrelia-infected Ixodes sp. ticks to the naïve host assumes that a low number of spirochetes that manage to penetrate the midgut epithelium migrate through the hemocoel to the salivary glands and subsequently infect the host with the aid of immunomodulatory compounds present in tick saliva. Therefore, humoral and/or cellular immune reactions within the tick hemocoel may play an important role in tick competence to act as a vector for borreliosis. To test this hypothesis we have examined complement-like reactions in the hemolymph of the hard tick Ixodes ricinus against Borrelia afzelii (the most common vector and causative agent of Lyme disease in Europe). We demonstrate that I. ricinus hemolymph does not exhibit borreliacidal effects comparable to complement-mediated lysis of bovine sera. However, after injection of B. afzelii into the tick hemocoel, the spirochetes were efficiently phagocytosed by tick hemocytes and this cellular defense was completely eliminated by pre-injection of latex beads. As tick thioester-containing proteins (T-TEPs) are components of the tick complement system, we performed RNAi-mediated silencing of all nine genes encoding individual T-TEPs followed by in vitro phagocytosis assays. Silencing of two molecules related to the C3 complement component (IrC3-2 and IrC3-3) significantly suppressed phagocytosis of B. afzelii, while knockdown of IrTep (insect type TEP) led to its stimulation. However, RNAi-mediated silencing of T-TEPs or elimination of phagocytosis by injection of latex beads in B. afzelii-infected I. ricinus nymphs had no obvious impact on the transmission of spirochetes to naïve mice, as determined by B. afzelii infection of murine tissues following tick infestation. This result supports the concept that Borrelia spirochetes are capable of avoiding complement-related reactions within the hemocoel of ticks competent to transmit Lyme disease.


The Aspergillus flavus Homeobox Gene, hbx1, is Required for Development and Aflatoxin Production.
Homeobox proteins, a class of well conserved transcription factors, regulate the expression of targeted genes, especially those involved in development. In filamentous fungi, homeobox genes are required for normal conidiogenesis and fruiting body formation. In the present study, we identified eight homeobox (hbx) genes in the aflatoxin-producing ascomycete, Aspergillus flavus, and determined their respective role in growth, conidiation and sclerotial production. Disruption of seven of the eight genes had little to no effect on fungal growth and development. However, disruption of the homeobox gene AFLA_069100, designated as hbx1, in two morphologically different A. flavus strains, CA14 and AF70, resulted in complete loss of production of conidia and sclerotia as well as aflatoxins B₁ and B₂, cyclopiazonic acid and aflatrem. Microscopic examination showed that the Δhbx1 mutants did not produce conidiophores. The inability of Δhbx1 mutants to produce conidia was related to downregulation of brlA (bristle) and abaA (abacus), regulatory genes for conidiophore development. These mutants also had significant downregulation of the aflatoxin pathway biosynthetic genes aflC, aflD, aflM and the cluster-specific regulatory gene, aflR. Our results demonstrate that hbx1 not only plays a significant role in controlling A. flavus development but is also critical for the production of secondary metabolites, such as aflatoxins.


[The study of the risk factors of fungal infection after liver transplantation].
To explore the risk factors of fungal infection so as to provide rationales for the prevention of fungal infection after liver transplantation. The clinical data of 94 cases of fungal infections after liver transplantation from January 1, 2003 to November 30, 2010 at our hospital were collected as the infective group. A total of 603 liver transplant patients without fungal infections during the same period were selected as the control group. χ(2) test and t test were utilized for the analysis of possible risk factors for fungal infection. Fungal infection rate was 13.5% (94/697) after liver transplantation and mortality rate of fungal infection 86.2% (81/94). Candida albicans was the majority infective fungi. And the main site of infection was the lungs. The postoperative acute physiology and chronic health evaluation III (APACHE III) score of the infective group was significantly higher than that of the control group (26.0 ± 5.4 vs 21.5 ± 4.7, P < 0.01). The number of patients with primary liver cancer was lower than that of the control group (26.6% vs 45.8%, P < 0.01). The number of decompensated HBV cirrhosis and diabetics in the infective group was higher than that of the control group at pre-operation (23.4% vs 11.6%, 9.6% vs 2.8%, both P < 0.01). The number of patients with postoperative mechanical ventilation over 10 days, postoperative antibiotics over 14 days, postoperative cardiopulmonary dysfunction and liver function recovery time over 7 days, parenteral nutrition over 12 days and hyperglycemia over 7 days in the infective group were significantly higher than that in the control group (all P < 0.01). Preoperative primary disease, postoperative disease severity, postoperative organ dysfunction, long-term mechanical ventilation, antibiotics and hyperglycemia, etc. may be the important risk factors of fungal infection after liver transplantation.


Localization of arginine synthesis along rat nephron.
Arginine production was measured in isolated rat nephron segments. Segments were incubated with 0.3 mM aspartate and 0.1 mM L-[ureido-14C]-citrulline in a sealed chamber. Arginase and urease were added to the medium to hydrolyze arginine and to release 14CO2, which was trapped in KOH and counted. Arginine synthesis was found only in the proximal tubule, with decreasing intensity from proximal convoluted (PCT) to proximal straight tubule (PST). Results were as follows (in fmol.min-1.mm tubule length-1): PCT, 122 +/- 15; cortical PST, 71 +/- 6; outer medullary PST, 41 +/- 4; all other segments, less than 6. Arginine synthesis changed almost proportionally with precursor concentration of less than or equal to 0.4 mM. We had shown previously that PST but not PCT was able to hydrolyze arginine into urea and ornithine. In this study arginine was further hydrolyzed in cortical (40%) and medullary (64%) PST but not in PCT. These observations suggest that the arginine formed in PCT contributes to the maintenance of the whole body arginine pool, whereas most of the arginine formed in PST might contribute, by its conversion to urea, to the process of urine concentration.


Variability among Tunisian populations of Culex pipiens: genetic structure and susceptibility to a filarial parasite, Brugia pahangi.
Culex pipiens pipiens is a common mosquito found in North Africa and is the primary vector of Bancroftian filariasis in Egypt. Experimental infections with C. p. pipiens have demonstrated that this species supports Brugia pahangi development (parasitic yield 6.3%). In addition, the genetic variation among C. p. pipiens populations from Ben Arrous (in the suburb of Tunis) estimated from isoenzyme polymorphism of five neutral genes (Pgm, Gpi, Hk1, Got-1, and Got-2) was slight (Fst = +0.083). C. p. pipiens from Tunis seems to consist of a homogeneous population that is susceptible to Brugia infection.


A pharmacokinetic-pharmacodynamic model for a muscle relaxant: atracurium.
Our goal was to develop a pharmacokinetic-pharmacodynamic model that describes the fate of atracurium and its metabolite laudanosine as well as the time course of the neuromuscular block. The model was based on the consideration of mass balance of atracurium and was constructed by postulating an effect compartment linked to the central compartment in the previously described open mammillary model for atracurium. The entry and exit rate constants, kCE and kEC, were adjusted to satisfy the requirement that the peak amount in the effect compartment coincides with the peak submaximal block. We used previously published clinical data to arrive at the times to 50% neuromuscular block either during the onset of the block following an ED50 dose or during the recovery following larger doses of atracurium. Laplace transforms were used to define the model, and the solution was obtained by iterative numeric adjustments of the rate constants. The model provides an excellent fit of the observed plasma concentrations of atracurium and laudanosine and simulates well the development and waning of the neuromuscular block. The model projects that the peak amount of atracurium in the effect compartment amounts to 14% of the injected dose and is reached at 7.6 min after the injection.


Diabetes and cognitive decline: investigating the potential influence of factors related to health disparities.
The authors investigated whether factors related to health disparities--race, rural residence, education, perceived racial discrimination, vascular disease, and health care access and utilization--may moderate the association between diabetes and cognitive decline. Participants were 624 community-dwelling older adults (49% African American and 49% rural) who completed in-home mini-mental state examination at baseline and 4-year follow-up. Diabetes at baseline predicted four-year cognitive decline in regression models adjusted for a number of possible confounds. Only perceived discrimination and health utilization showed significant interaction effects with diabetes. Among African Americans who reported experiencing racial discrimination, there was a stronger relationship between diabetes and cognitive decline. Among participants who reported absence of visiting a physician within the past 6 months, the association between diabetes and cognitive decline was substantially larger. Findings suggest that factors related to health disparities may influence cognitive outcomes among older adults with diabetes.


Nicotinic transmission at functionally distinct synapses in descending reflex pathways of the rat colon.
We examined descending reflex pathways in the rat colon using intracellular recording techniques. Inhibitory junction potentials (IJPs) were recorded from circular smooth muscle when descending pathways were excited by combined mucosal compression and distension. IJPs were reduced to 71% of control when synaptic transmission was blocked in the oral stimulation chamber of a divided organ bath suggesting that two reflex pathways exist, the one involving descending sensory neurones and the other involving descending interneurones. Hexamethonium (200 micromol L(-1)) in the recording chamber abolished reflexly evoked IJPs, while in the stimulation chamber, it was as effective as synaptic blockade. When hexamethonium was added to a chamber lying between the stimulation and recording chambers, it again sharply depressed IJPs to 27% of control; an extent similar to synaptic blockade. A P2 receptor antagonist did not reveal any purinergic neurotransmission. Either granisetron (5-HT3 receptor antagonist, 1 micromol L(-1)) or SB204070 (5-HT4 receptor antagonist, 1 micromol L(-1)) in the stimulation chamber significantly decreased IJPs; these decreases were not additive. We conclude that some sensory neurones and interneurones in rat colon have long anally projecting axons and that acetylcholine, acting via nicotinic receptors, is the primary neurotransmitter from sensory neurones, to inhibitory motor neurones and between interneurones.


Lung cancer survival and deletion of GSTM1 and GSTT1 genes. A case-series from Spain.
Lung cancer has a high incidence, and only 15% of all cases are alive 5 years after the diagnosis. Identifying the role of the genes implicated in the success of chemotherapy agents is crucial to predict survival. The objective of the study was to assess the effect of GSTM1 and GSTT1 gene deletion on lung cancer survival. A consecutive sampling of lung cancer cases was performed in 1999-2000 at the University Hospital of Santiago de Compostela, Spain, and GSTM1 and GSTT1 genes were genotyped. The effect of GSTM1 and GSTT1 deletion on survival was analyzed with the logrank test and with Cox regression. A total of 132 individuals were included, and more than half of them had stage IV lung cancer at diagnosis. Survival was similar irrespective of the presence or absence of the GSTM1 gene, whereas those with deleted GSTT1 had a significantly shorter survival. In multivariate Cox regression analysis, no significant effect was observed for the deletion of any of the genes, although there was a tendency towards a worse survival for those with deletion of GSTT1. The main limitation was that stage at diagnosis could not be considered in the analysis since most of the patients were diagnosed at stage IV. GSTT1 appears to influence lung cancer survival whereas GSTM1 seems to have no effect.


DNA Methylation and Mutation of Small Colonic Neoplasms in Ulcerative Colitis and Crohn's Colitis: Implications for Surveillance.
Stool DNA testing in patients with inflammatory bowel disease (IBD) may detect colorectal cancer and advanced precancers with high sensitivity; less is known about the presence of DNA markers in small IBD lesions, their association with metachronous neoplasia, or contribution to stool test positivity. At a single center in 2 blinded phases, we assayed methylated bone morphogenic protein 3, methylated N-Myc downstream-regulated gene 4, and mutant KRAS in DNA extracted from paraffin-embedded benign lesions, and matched control tissues of patients with IBD, who were followed for subsequent colorectal dysplasia. Stool samples from independent cases and controls with lesions <1 cm or advanced neoplasms were assayed for the same markers. Among IBD lesions (29 low-grade dysplasia, 19 serrated epithelial change, and 10 sessile serrated adenoma/polyps), the prevalence of methylation was significantly higher than in mucosae from 44 matched IBD controls (P < 0.0001 for methylated bone morphogenic protein 3 or methylated N-Myc downstream-regulated gene 4). KRAS mutations were more abundant in serrated epithelial change than all other groups (P < 0.001). Subsequent dysplasia was not associated with DNA marker levels. In stools, the sensitivity of methylated bone morphogenic protein 3 as a single marker was 60% for all lesions <1 cm, 63% for low-grade dysplasia ≥1 cm and 81% for high-grade dysplasia/colorectal cancer, all at 91% specificity (P < 0.0001). Selected DNA markers known to be present in advanced IBD neoplasia can also be detected in both tissues and stools from IBD patients with small adenomas and serrated lesions. Mutant KRAS exfoliated from serrated epithelial change lesions might raise false-positive rates. These findings have relevance to potential future applications of stool DNA testing for IBD surveillance.


Direct demonstration of retroviral recombination in a rhesus monkey.
Recombination may be an important mechanism for increasing variation in retroviral populations. Retroviral recombination has been demonstrated in tissue culture systems by artificially creating doubly infected cells. Evidence for retroviral recombination in vivo is indirect and is based principally on the identification of apparently mosaic human immunodeficiency virus type 1 genomes from phylogenetic analyses of viral sequences. We infected a rhesus monkey with two different molecularly cloned strains of simian immunodeficiency virus. One strain of virus had a deletion in vpx and vpr, and the other strain had a deletion in nef. Each strain on its own induced low virus loads and was nonpathogenic in rhesus monkeys. When injected simultaneously into separate legs of the same monkey, persistent high virus loads and declines in CD4+ lymphocyte concentrations were observed. Analysis of proviral DNA isolated directly from peripheral blood mononuclear cells showed that full-length, nondeleted SIVmac239 predominated by 2 weeks after infection. These results provide direct experimental evidence for genetic recombination between two different retroviral strains in an infected host. The results illustrate the ease and rapidity with which recombination can occur in an infected animal and the selection that can occur for variants generated by genetic recombination.


Rising atmospheric CO2 is reducing the protein concentration of a floral pollen source essential for North American bees.
At present, there is substantive evidence that the nutritional content of agriculturally important food crops will decrease in response to rising levels of atmospheric carbon dioxide, Ca However, whether Ca-induced declines in nutritional quality are also occurring for pollinator food sources is unknown. Flowering late in the season, goldenrod (Solidago spp.) pollen is a widely available autumnal food source commonly acknowledged by apiarists to be essential to native bee (e.g. Bombus spp.) and honeybee (Apis mellifera) health and winter survival. Using floral collections obtained from the Smithsonian Natural History Museum, we quantified Ca-induced temporal changes in pollen protein concentration of Canada goldenrod (Solidago canadensis), the most wide spread Solidago taxon, from hundreds of samples collected throughout the USA and southern Canada over the period 1842-2014 (i.e. a Ca from approx. 280 to 398 ppm). In addition, we conducted a 2 year in situtrial of S. Canadensis populations grown along a continuous Ca gradient from approximately 280 to 500 ppm. The historical data indicated a strong significant correlation between recent increases in Ca and reductions in pollen protein concentration (r(2)= 0.81). Experimental data confirmed this decrease in pollen protein concentration, and indicated that it would be ongoing as Ca continues to rise in the near term, i.e. to 500 ppm (r(2)= 0.88). While additional data are needed to quantify the subsequent effects of reduced protein concentration for Canada goldenrod on bee health and population stability, these results are the first to indicate that increasing Ca can reduce protein content of a floral pollen source widely used by North American bees.


Elevated levels of a high molecular weight antigen detected by antibody W1 in sera from breast cancer patients.
A novel screening assay was used to test 13 previously described antibreast cancer antibodies for those which recognize antigens elevated in serum of breast cancer patients. Binding of three of these antibodies to breast or lung carcinoma cells was inhibited to a significantly greater extent by tumor patient serum than by normal serum, suggesting that the antigens might be useful serum markers. Two of these antibodies, W1 and W9, were shown to recognize nonoverlapping epitopes on a high molecular weight molecule(s) purified from serum from breast cancer patients. A sensitive double determinant immunoassay was developed to measure W1 antigen levels in sera from a total of 389 cancer patients and controls. Forty seven % (37 of 79) of individuals having breast cancer showed elevated serum levels of the W1 antigen, whereas only 4% (1 of 25) of normal controls and 2% (1 of 47) of patients hospitalized for nonmalignant disorders showed elevated levels. These differences were statistically significant (P less than 0.001). The percentage of breast cancer patients showing elevated serum levels was greater for individuals with metastatic disease. Statistically significant numbers of lung, ovarian, and prostate, but not colon, cancer patients also had elevated serum levels of the W1 antigen. These data suggest that measurement of the W1 antigen in serum might provide clinically useful information on the course of metastatic breast and other cancers.


The Association between Glucose 6-Phosphate Dehydrogenase Deficiency and Attention Deficit/Hyperactivity Disorder.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, impacting 4.9% of the population and more prevalent in Mediterranean communities, is a common enzymopathy with potential relevance to Attention Deficit/Hyperactivity Disorder (ADHD). This study investigated this association. The clinical characteristics of 7473 G6PD-deficient patients and 29,892 matched case-controls (selected at a 1:4 ratio) from a cohort of 1,031,354 within the Leumit Health Services database were analyzed using Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. In total, 68.7% were male. The mean duration of follow-up was 14.3 ± 6.2 years at a mean age of 29.2 ± 22.3 years. G6PD deficiency was associated with an increased risk of being diagnosed with ADHD (Odds Ratio (OR) = 1.16 [95% CI, 1.08-1.25], p < 0.001), seeking care from adult neurologists (OR = 1.30 [95% CI, 1.22-1.38], p < 0.001), and consulting adult psychiatrists (OR = 1.12 [95% CI, 1.01-1.24], p = 0.048). The use of stimulant medications among G6PD-deficient individuals was 17% higher for the methylphenidate class of drugs (OR = 1.17 [95% CI, 1.08, 1.27], p < 0.001), and there was a 16% elevated risk for amphetamine use (OR = 1.16 [95% CI, 1.03, 1.37], p = 0.047). G6PD deficiency signals an increased risk of ADHD diagnosis, more severe presentations of ADHD and a greater need for psychiatric medications to treat ADHD.


Genomics research in the UK--the social science agenda.
We sketch the development of UK genetics and genomics research, and emphasize the UK's key role in the international genetics and genomics research community. We highlight in particular the part played by the UK's Research Councils and other funders. With the move from genomics to post-genomics research, the field is diversifying, and interdisciplinarity becomes increasingly important, as traditional disciplinary boundaries become blurred, or break down, in the face of newly emerging sciences. We consider the changing nature of health and ill health in the developed and developing world, and questions about the complex nature of the relationships between genes and the environment, and their future implications for human health and human populations. We describe the ESRC's activities, stressing the importance of both the social, ethical and legal issues raised by these emerging disciplines, and of public engagement. Finally, we link the data handling and analysis issues raised by these emerging sciences, with other new research areas, in particular the UK's e-Science programme.


Prenatal methylmercury exposure and genetic predisposition to cognitive deficit at age 8 years.
Cognitive consequences at school age associated with prenatal methylmercury (MeHg) exposure may need to take into account nutritional and sociodemographic cofactors as well as relevant genetic polymorphisms. A subsample (n = 1,311) of the Avon Longitudinal Study of Parents and Children (Bristol, UK) was selected, and mercury (Hg) concentrations were measured in freeze-dried umbilical cord tissue as a measure of MeHg exposure. A total of 1135 children had available data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) scores at age 8 years. Multivariate regression models were used to assess the associations between MeHg exposure and IQ and to determine possible gene-environment interactions. Hg concentrations indicated low background exposures (mean = 26 ng/g, standard deviation = 13). Log10-transformed Hg was positively associated with IQ, which attenuated after adjustment for nutritional and sociodemographic cofactors. In stratified analyses, a reverse association was found in higher social class families (for performance IQ, P value for interaction = 0.0013) among whom there was a wider range of MeHg exposure. Among 40 SNPs showing nominally significant main effects, MeHg interactions were detected for rs662 (paraoxonase 1) and rs1042838 (progesterone receptor) (P < 0.05) and for rs3811647 (transferrin) and rs2049046 (brain-derived neurotrophic factor) (P < 0.10). In this population with a low level of MeHg exposure, there were only equivocal associations between MeHg exposure and adverse neuropsychological outcomes. Heterogeneities in several relevant genes suggest possible genetic predisposition to MeHg neurotoxicity in a substantial proportion of the population. Future studies need to address this possibility.


Thyroid nodules.
Thyroid nodules are common entities, clinically important primarily because of their malignant potential. Serum thyrotropin and thyroid ultrasonography are pivotal in evaluating thyroid nodules. Fine-needle aspiration biopsy is the most accurate tool for diagnosing malignancy and selecting candidates for surgery. An approach to the initial evaluation and management of single nodules, functioning nodules, multinodular glands, incidental nodules, and cysts is discussed, as are therapeutic interventions for benign nodules. Thyroid cancer discovered during pregnancy is also discussed.


Manipulation of bubble collapse patterns near the wall of an adherent gas layer.
This paper aims to apply experimental methods to investigate the effect of the thickness of gas layers on the wall on the collapse direction of spark-induced bubbles. In the experiment, two high-speed cameras synchronously record the time evolution of the bubbles and the corresponding parameters such as the normalized collapse position and bubble collapse time. Experiments yielded results for individual bubbles over a range of normalized distances from 0 to 4.0 for different air layer thicknesses. Based on the morphology of the bubbles, the experimental jets were visualized into six different modes, namely, forward jet (FJ), merging jet (MJ), bidirectional jet (BJ), reversing jet (RJ), forward followed by reversing jet (FRJ), and non-directional jet (NDJ). The height of the air layer on the wall is affected by the fluctuation of the bubble volume and shows the opposite trend to the change of the bubble volume. The air film reaches its maximum height when the bubble collapses, which affects the final jet pattern. In addition, as the thickness of the air layer increases, the center of the bubble gradually migrates away from the wall. The different collapse modes and the migration of the bubble centers have positive significance for reducing cavitation erosion in engineering.


Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.
Routine addition of ipratropium bromide to beta-agonist therapy in acute asthma is of uncertain benefit. This study was carried out to evaluate: (1) whether nebulized ipratropium (0.5 mg) plus salbutamol (2.5 mg) (Combivent) confers additional bronchodilation over nebulized salbutamol (2.5 mg) alone in patients with acute asthma and (2) whether adjustment for prognostic indicators of outcome influences any benefit seen with ipratropium. A double-blind, two-center, randomized, single-dose study was performed in 338 patients with asthma, aged 18 to 55 years, who attended the emergency department for treatment of acute asthma. The primary end point was FEV1 at 90 minutes. The mean absolute difference in FEV1 at 90 minutes for Combivent compared with salbutamol was 113 ml (SEM +/- 48 ml, p < 0.05). Independent of the study drug received, a poor response to treatment was predicted by frequent use of inhaled beta-agonist before presentation (p < 0.0001), severity of the attack (p < 0.05), and longer duration of attack (p < 0.05). Subjects who had taken more than 10 puffs of inhaled beta-agonist through a metered-dose inhaler or who had serum salbutamol levels of greater than 2 mmol/L on presentation demonstrated no benefit from the addition of ipratropium. Patients with an FEV1 less than 1 L on presentation also responded less well to Combivent, which was explained by the association between severity of attack and greater use of inhaled beta-agonist therapy. A single dose of nebulized Combivent confers additional bronchodilation over salbutamol alone (p < 0.05) in acute asthma. Patients who exhibited most benefit from the addition of ipratropium were those who had consumed the least inhaled beta-agonist before presentation, not those with the most severe asthma.


Body Mass Index, Smoking and Hypertensive Disorders during Pregnancy: A Population Based Case-Control Study.
While obesity is an indicated risk factor for hypertensive disorders of pregnancy, smoking during pregnancy has been shown to be inversely associated with the development of preeclampsia and gestational hypertension. The purpose of this study was to investigate the combined effects of high body mass index and smoking on hypertensive disorders during pregnancy. This was a case-control study based on national registers, nested within all pregnancies in Iceland 1989-2004, resulting in birth at the Landspitali University Hospital. Cases (n = 500) were matched 1:2 with women without a hypertensive diagnosis who gave birth in the same year. Body mass index (kg/m2) was based on height and weight at 10-15 weeks of pregnancy. We used logistic regression models to calculate odds ratios and corresponding 95% confidence intervals as measures of association, adjusting for potential confounders and tested for additive and multiplicative interactions of body mass index and smoking. Women's body mass index during early pregnancy was positively associated with each hypertensive outcome. Compared with normal weight women, the multivariable adjusted odds ratio for any hypertensive disorder was 1.8 (95% confidence interval, 1.3-2.3) for overweight women and 3.1 (95% confidence interval, 2.2-4.3) for obese women. The odds ratio for any hypertensive disorder with obesity was 3.9 (95% confidence interval 1.8-8.6) among smokers and 3.0 (95% confidence interval 2.1-4.3) among non-smokers. The effect estimates for hypertensive disorders with high body mass index appeared more pronounced among smokers than non-smokers, although the observed difference was not statistically significant. Our findings may help elucidate the complicated interplay of these lifestyle-related factors with the hypertensive disorders during pregnancy.


Self-monitoring of listening abilities in normal-hearing children, normal-hearing adults, and children with cochlear implants.
Self-monitoring has been shown to be an essential skill for various aspects of our lives, including our health, education, and interpersonal relationships. Likewise, the ability to monitor one's speech reception in noisy environments may be a fundamental skill for communication, particularly for those who are often confronted with challenging listening environments, such as students and children with hearing loss. The purpose of this project was to determine if normal-hearing children, normal-hearing adults, and children with cochlear implants can monitor their listening ability in noise and recognize when they are not able to perceive spoken messages. Participants were administered an Objective-Subjective listening task in which their subjective judgments of their ability to understand sentences from the Coordinate Response Measure corpus presented in speech spectrum noise were compared to their objective performance on the same task. Participants included 41 normal-hearing children, 35 normal-hearing adults, and 10 children with cochlear implants. On the Objective-Subjective listening task, the level of the masker noise remained constant at 63 dB SPL, while the level of the target sentences varied over a 12 dB range in a block of trials. Psychometric functions, relating proportion correct (Objective condition) and proportion perceived as intelligible (Subjective condition) to target/masker ratio (T/M), were estimated for each participant. Thresholds were defined as the T/M required to produce 51% correct (Objective condition) and 51% perceived as intelligible (Subjective condition). Discrepancy scores between listeners' threshold estimates in the Objective and Subjective conditions served as an index of self-monitoring ability. In addition, the normal-hearing children were administered tests of cognitive skills and academic achievement, and results from these measures were compared to findings on the Objective-Subjective listening task. Nearly half of the children with normal hearing significantly overestimated their listening in noise ability on the Objective-Subjective listening task, compared to less than 9% of the adults. There was a significant correlation between age and results on the Objective-Subjective task, indicating that the younger children in the sample (age 7-12 yr) tended to overestimate their listening ability more than the adolescents and adults. Among the children with cochlear implants, eight of the 10 participants significantly overestimated their listening ability (as compared to 13 of the 24 normal-hearing children in the same age range). We did not find a significant relationship between results on the Objective-Subjective listening task and performance on the given measures of academic achievement or intelligence. Findings from this study suggest that many children with normal hearing and children with cochlear implants often fail to recognize when they encounter conditions in which their listening ability is compromised. These results may have practical implications for classroom learning, particularly for children with hearing loss in mainstream settings.


Rapid cortisol assays improve the success rate of adrenal vein sampling for primary aldosteronism.
We hypothesized that an adrenal vein sampling (AVS) algorithm incorporating rapid cortisol assays, which enables resampling of the adrenal veins, would improve the success rate by a team of radiologists. AVS is the most accurate means to localize aldosterone production in primary aldosteronism (PA). However, cannulation of the right adrenal vein (RAV) is difficult, and success is assumed from venography without the support of steroid assays. Furthermore, few institutions can assign all studies to 1 dedicated and experienced AVS interventional radiologist. Retrospective chart review of patients with PA at our university hospitals who underwent AVS. We compared results for 30 AVS studies incorporating rapid cortisol assays with 30 conventional AVS studies. The success rate for the control period was 73% (22/30 studies). For the first 30 studies after incorporating rapid cortisol assay, the success rate increased to 97% (29/30 studies). Resampling the RAV was required for 2 studies, and prolonged sheath insertion did not cause any complications. High AVS success rates may be achieved by a team of interventional radiologists at 1 center using defined AVS protocols. Rapid cortisol assay allows for resampling of the RAV and improves AVS success rates.


Refractive-turbulence profiles measured by one-dimensional spatial filtering of scintillations.
Stellar scintillations, when appropriately analyzed, yield information about the turbulence throughout the atmosphere. We describe an instrument involving a 36-cm telescope and an on-line minicomputer that provides, after 20 min of observation, the refractive-turbulence profile of the atmosphere. The height resolution is sufficient to divide the atmosphere into about four independent regions. The principal limitation to greater accuracy and resolution is the nonstationary behavior of the atmosphere during the 20-min observing period.


Hemodynamic imaging parameters in brain metastases patients - Agreement between multi-delay ASL and hypercapnic BOLD.
Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, rrm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF (rrm = -0.822) and longer arterial arrival time (AAT; rrm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR (rrm = -0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.


Polymorphous exudates and atypical mononuclear cells in the cerebrospinal fluid of patients with Sjögren's syndrome.
Central nervous system (CNS) complications of Sjögren's syndrome are now well recognized. To determine if any of the pathologic changes in the CNS in patients with Sjögren's syndrome were reflected in the cellular composition of cerebrospinal fluid (CSF), we examined the CSF of 14 patients with Sjögren's syndrome and neurologic symptoms and compared the differential cell counts in those cases with those of 14 control patients with similar neurologic symptoms. Patients with Sjögren's syndrome had polymorphous (mixed) inflammatory exudates in CSF, composed predominantly of lymphocytes, but including variable numbers of plasma cells, neutrophils and erythrocytes. In addition, the CSF of all patients with Sjögren's syndrome contained large, atypical, morphologically distinct mononuclear cells. The mean percentage of these cells in the CSF of patients with Sjögren's syndrome (8.3 +/- 1.9) was significantly higher (p less than 0.001) than that observed in the control patients (0.7 +/- 0.2). These results suggest that involvement by Sjögren's syndrome may be suspected by noting a polymorphous exudate containing characteristic atypical mononuclear cells in CSF obtained by lumbar puncture.


Preparation and characterization of mono- and multilayer films of polymerizable 1,2-polybutadiene using the Langmuir-Blodgett technique.
The essence of this study is to apply the Langmuir-Blodgett (LB) technique for assembling asymmetric membranes. Accordingly, Langmuir films of a (further) polymerizable polymer, 1,2-polybutadiene (1,2-pbd), were studied and transferred onto different solid supports, such as gold, indium tin oxide (ITO), and silicon. The layers were characterized both at the air/water interface as well as on different substrates using numerous methods including cyclic voltammetry, impedance spectroscopy, spectroscopic ellipsometry, atomic force microscopy, X-ray photoelectron spectroscopy, and reflection-absorption Fourier transform infrared spectroscopy. The Langmuir films were stable at the air-water interface as long as they were not exposed to UV irradiation. The LB films formed disorganized layers, which gradually blocked the permeation of different species with increasing the number of deposited layers. The thickness was ca. 4-7 Å per layer. Irradiating the Langmuir films caused their cross-linking at the air-water interface. Furthermore, we took advantage of the reactivity of the double bond of the LB films on the solid supports and graft polymerized acrylic acid on top of the 1,2-pbd layers. This approach is the basis of the formation of an asymmetric membrane that requires different porosity on both of its sides.


Serial analysis of gene expression identifies connective tissue growth factor expression as a prognostic biomarker in gallbladder cancer.
Gallbladder cancer (GBC) is an uncommon neoplasm in the United States, but one with high mortality rates. This malignancy remains largely understudied at the molecular level such that few targeted therapies or predictive biomarkers exist. We built the first series of serial analysis of gene expression (SAGE) libraries from GBC and nonneoplastic gallbladder mucosa, composed of 21-bp long-SAGE tags. SAGE libraries were generated from three stage-matched GBC patients (representing Hispanic/Latino, Native American, and Caucasian ethnicities, respectively) and one histologically alithiasic gallbladder. Real-time quantitative PCR was done on microdissected epithelium from five matched GBC and corresponding nonneoplastic gallbladder mucosa. Immunohistochemical analysis was done on a panel of 182 archival GBC in high-throughput tissue microarray format. SAGE tags corresponding to connective tissue growth factor (CTGF) transcripts were identified as differentially overexpressed in all pairwise comparisons of GBC (P < 0.001). Real-time quantitative PCR confirmed significant overexpression of CTGF transcripts in microdissected primary GBC (P < 0.05), but not in metastatic GBC, compared with nonneoplastic gallbladder epithelium. By immunohistochemistry, 66 of 182 (36%) GBC had high CTGF antigen labeling, which was significantly associated with better survival on univariate analysis (P = 0.0069, log-rank test). An unbiased analysis of the GBC transcriptome by SAGE has identified CTGF expression as a predictive biomarker of favorable prognosis in this malignancy. The SAGE libraries from GBC and nonneoplastic gallbladder mucosa are publicly available at the Cancer Genome Anatomy Project web site and should facilitate much needed research into this lethal neoplasm.


Evaluation and radiotherapy implications of chest relapse patterns in small cell lung carcinoma treated with radiotherapy-chemotherapy: study of 34 cases and review of the literature.
Evaluation and radiotherapy implications of chest relapse patterns in small cell lung carcinoma treated with chemotherapy and radiotherapy to the chest and brain. Emphasis was placed on analysis of patterns of chest disease relapse, chest complications, and sites of initial chest disease relapse in relation to volume treated by radiation. These results were compared with published reports. Of 17 cases with disease limited to the chest (LD), nine (53%) died of chest related complications, seven of these (41%) with chest disease recurrence. However, in five of these seven cases (72%), recurrences appeared initially outside the irradiated volume, in spite of 1-2 cm of safety margin, mostly in the ipsilateral lung, while the primary was without evidence of growth. Hence, chest disease relapse does not necessarily mean radiotherapy failure, as only 2 of the 17 cases (12%) had definite tumor growth in the irradiated field. This point is not properly emphasized in the literature, where marked discrepancies among authors reporting chest disease relapses are present. We elaborate about factors that will affect results, like frequency of follow-up x-rays, tumor size, site of chest disease relapse, and criteria to define tumor relapse. More autopsy and chest diagnostic studies are needed to investigate patterns of tumor spread within the lung. Survival alone is too broad a factor to measure the impact of radiotherapy in treatment. We need more understanding of the mechanisms of chest disease relapse to obtain a better design of radiotherapy ports. Systemic disease was the main cause of death in 17 patients with extensive small cell lung carcinoma, and routine chest irradiation cannot be justified although it might be of help for chemotherapy responders who are expected to have long survival.


Retrospective analysis of hiccups in patients at a community hospital from 1995-2000.
Hiccups are a physiologic phenomenon noted in animals and humans. There is little understanding of what makes hiccups occur and whether or not they have any productive purpose. A retrospective analysis of all patients seen in a community hospital over a 5 year period was conducted to see who is affected by hiccups, evaluate laboratory findings in people with hiccups, and to see what the currently accepted treatment is for hiccups. The vast majority of patients were male, older than 50 years of age, and with co-morbid conditions. Laboratory values appeared to be of little value in determining whether treatment interventions would be effective. Gastroenterology was the service most consulted and EGD the most common procedural intervention conducted, but with little success. No treatments showed a statistically significant effect.


Advances in proteomic prostate cancer biomarker discovery.
Prostate cancer is the most common non-cutaneous cancer in men in the United States. For reasons largely unknown, the incidence of prostate cancer has increased in the last two decades, in spite or perhaps because of a concomitant increase in serum prostate-specific antigen (PSA) screening. While PSA is acknowledged not to be an ideal biomarker for prostate cancer detection, it is however widely used by physicians due to lack of an alternative. Thus, the identification of a biomarker(s) that can complement or replace PSA represents a major goal for prostate cancer research. Screening complex biological specimens such as blood, urine, and tissue to identify protein biomarkers has become increasingly popular over the last decade thanks to advances in proteomic discovery methods. The completion of human genome sequence together with new development in mass spectrometry instrumentation and bioinformatics has been a major driving force in biomarker discovery research. Here we review the current state of proteomic applications as applied to various sample sources including blood, urine, tissue, and "secretome" for the purpose of prostate cancer biomarker discovery. Additionally, we review recent developments in validation of putative markers, efforts at systems biology approach, and current challenges of proteomics in biomarker discovery.


BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study.
Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy. PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234). BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01). BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.


Glutathione pathway gene variation and risk of autism spectrum disorders.
Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case-parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR = 3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary.


Log odds of positive lymph nodes as an independent predictor of overall survival in oral squamous cell carcinoma.
Log odds of positive lymph nodes (LODDS) have been recently demonstrated as a very promising staging model and have outperformed AJCC pN, lymph node ratio (LNR) category in major cancers. Literature is scarce concerning the prognostic ability of LODDS in oral squamous cell carcinoma (OSCC) patients. The present study was aimed to evaluate the importance of LODDS in predicting locoregional recurrence and overall survival (OS) in patients with OSCC compared to LNR. The retrospective study was carried out on 194 patients with OSCC cases treated by surgery ± adjuvant therapy from 2008 to 2014 at our institution. Demographical and clinicopathological details of study cases were recorded. LNR and LODDS were calculated and expressed as a percentage and mean ± standard deviation. The OS analysis was done by the Kaplan-Meier curve followed by log-rank (mantel-cox) test. Univariate and multivariate survival analysis was done to analyze the prognostic ability of LNR% and LODDS after adjusting the clinicopathological parameters by the Cox proportional hazards model. Patients with cut off values of LODDS >-1.2 and LNR% >4 had significantly lower mean OS (P ≤ 0.001). Multivariate analysis indicated that only mean LODDS >-1.2 was significantly associated with poor OS. Although there was a correlation with locoregional recurrence, LODDS and LNR failed to be the independent predictors of locoregional recurrence. LODDS was an independent reliable prognostic indicator for patients with OSCCs than conventional staging systems and LNR.


Alcohol consumption in Estonia and Finland: Finbalt survey 1994-2006.
Alcohol consumption has been regarded as an important contributor to the high premature mortality rates. The objective of this paper was to provide an overview and comparison of alcohol consumption and its socio-demographic determinants among adults in Estonia and Finland. The study was based on a 25-64-year-old subsample of nationally representative postal cross-sectional surveys conducted in Estonia (n = 10,340) and Finland (n = 19,672) during 1994-2006. Abstinence, frequency, and the amount of alcohol consumed were examined. Logistic regression models were used to test the socio-demographic differences in alcohol consumption at least once a week. The effect of socio-demographic factors on pure alcohol consumed per week was calculated using linear regression. The proportion of abstainers was 1.5 times higher among women than men in both countries. Throughout the study period, the amount of alcohol consumed per week increased for both genders in Estonia and for women in Finland, but was stable for men in Finland. In the final study year, medium risk amount of alcohol consumed per week was nearly 1.5 times higher among men in Estonia than in Finland, but about half that among women in Estonia than in Finland. Compared to ethnic majority in Estonia, alcohol consumption at least once a week was lower among men, but amount of pure alcohol drunk per week was higher among women of ethnic minority. In Finland, alcohol consumption at least once a week was more prevalent among women of ethnic minority, but the amount of pure alcohol drunk per week was lower for both gender groups of ethnic minority. Compared to married/cohabiting respondents, alcohol consumption at least once a week was less pronounced among single respondents in Finland, divorced or separated women in both countries, and widowed respondents in Estonia. Greater amount of alcohol consumed per week was more prevalent among single and divorced or separated respondents in Finland, but only among divorced or separated men in Estonia. Frequency of alcohol consumption was lower among less educated than higher educated respondents in Finland, but not in Estonia. The amount of consumed alcohol per week was higher among less educated men in Estonia, but lower among women with basic education in Finland. Alcohol consumption has increased in Estonia and Finland. National alcohol policies should reflect findings of alcohol epidemiology in order to introduce measures that will reduce alcohol related harm in the population effectively.


Oxidative Stress, Sarcopenia, Antioxidant Strategies and Exercise: Molecular Aspects.
Sarcopenia could be currently defined as a geriatric syndrome initially characterized by a decrease in muscle mass that will get worse causing deterioration in strength and physical performance. A negative protein turnover, impaired mitochondrial dynamics and functions, a decreased muscle regeneration capacity, as well as an exacerbation of apoptosis are usually considered to be cellular mechanisms involved in muscle atrophy leading to sarcopenia. In this review, we first present that muscle overproduction of reactive oxygen and nitrogen species (RONS) and oxidative stress observed during aging are associated with sarcopenia, and then discuss how RONS are involved in redox-sensitive signaling pathways leading to sarcopenia. The identification of cost-effectiveness interventions to maintain muscle mass and physical functions in the elderly is one of the most important public health challenges. Here, we also discuss about the efficiency of different kind of antioxidant strategies against sarcopenia. Since exercise is the best strategy to prevent and reverse sarcopenia, we also highlight that exercise acts as an antioxidant.


Two mitogen-activated protein kinase kinases, MKK1 and MEK2, are involved in wounding- and specialist lepidopteran herbivore Manduca sexta-induced responses in Nicotiana attenuata.
In a wild tobacco plant, Nicotiana attenuata, two mitogen-activated protein kinases (MAPKs), salicylic acid-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK), play central roles in modulating herbivory-induced phytohormone and anti-herbivore secondary metabolites. However, the identities of their upstream MAPK kinases (MAPKKs) were elusive. Ectopic overexpression studies in N. benthamiana and N. tabacum suggested that two MAPKKs, MKK1 and MEK2, may activate SIPK and WIPK. The homologues of MKK1 and MEK2 were cloned in N. attenuata (NaMKK1 and NaMEK2) and a virus-induced gene silencing approach was used to knock-down the transcript levels of these MAPKK genes. Plants silenced in NaMKK1 and NaMEK2 were treated with wounding or simulated herbivory by applying the oral secretions of the specialist herbivore Manduca sexta to wounds. MAPK activity assay indicated that after wounding or simulated herbivory NaMKK1 is not required for the phosphorylation of NaSIPK and NaWIPK; in contrast, NaMEK2 and other unknown MAPKKs are important for simulated herbivory-elicited activation of NaSIPK and NaWIPK, and after wounding NaMEK2 probably does not activate NaWIPK but plays a minor role in activating NaSIPK. Consistently, NaMEK2 and certain other MAPKKs, but not NaMKK1, are needed for wounding- and simulated herbivory-elicited accumulation of jasmonic acid (JA), JA-isoleucine, and ethylene. Furthermore, both NaMEK2 and NaMKK1 regulate the levels of trypsin proteinase inhibitors. The findings underscore the complexity of MAPK signalling pathways and highlight the importance of MAPKKs in regulating wounding- and herbivory-induced responses.


Measurement of urinary cobalt as its complex with 2-(5-chloro-2-pyridylazo)-5-diethylaminophenol by liquid chromatography-tandem mass spectrometry for the purpose of anti-doping control.
Cobalt is well known for its ability to stimulate erythropoiesis via stabilization of hypoxia-inducible factors. In sports, this can provide a competitive benefit to athletes, so the World Anti-Doping Agency prohibits the use of cobalt in any form except its cobalamin vitamers. As of now, cobalt in biological fluids is detected by inductively coupled plasma mass spectrometry (ICP-MS), a technique which has very limited availability in anti-doping laboratories. Therefore, a quantitative method based on liquid chromatography-tandem mass spectrometry capable of measuring urinary cobalt in the form of its complex with 2-(5-chloro-2-pyridylazo)-5-diethylaminophenol (5-Cl-PADAP) has been developed and validated. A cobalt complex with deuterium-labeled 5-Cl-PADAP was used as internal standard. The method was found linear over the concentration range of 5-500 ng/ml with a combined standard uncertainty less than 10% at 15, 200, and 450 ng/ml. Stability of cobalt ions in urine was investigated over the course of 2 months; the concentration of free Co2+ was observed to decline by approximately 50% but restored upon hydrolysis with hydrochloric acid. Unlike ICP-MS, this method is practically unaffected by the presence of cyanocobalamin as the latter is resistant to acid hydrolysis. Notwithstanding the lack of formalized threshold concentration of cobalt in urine, it is highly desirable that more anti-doping laboratories engage in testing for cobalt levels to better understand the prevalence of cobalt misuse in athletes. Given that cobalt salts are inexpensive and easily obtainable, the risk of such abuse should not be underestimated.


[Analysis of local lymphogenic spreading of malignant adrenal tumors].
The effectivity of the treatment of malignant adrenal tumors (MAT) depends on primary complete tumor resection with its regional metastases (RM). The possible regional metastases of malignant adrenal tumors in 257 patients have been studied. One third of the patients were diagnosed with regional metastases. Practically, almost all the patients had malignant adrenal tumors metastasizing lymphogenically. It was noted that independently of the tumors' localisation, morphological structure, the regional metastases more often were found in lymph nodes of the renal hilus, paranephral and paraaortical cellular tissue. Consequently, lymph nodes of the renal hilus, paranephral and paraaortical cellular tissue as well as of back muscle should be revised during radical operations in patients with malignant adrenal tumors.


Assistive technology access in longitudinal datasets: a global review.
Functional limitations become more prevalent as populations age, emphasising an increasingly urgent need for assistive technology (AT). Critical to meeting this need trajectory is understanding AT access in older ages. Yet few publications examine this from a longitudinal perspective. This review aims to identify and collate what data exist globally, seeking all population-based cohorts and repeated cross-sectional surveys through the Maelstrom Research Catalogue (searched May 10, 2022) and the Disability Data Report (published 2022), respectively. Datasets incorporating functional limitations modules and question(s) dedicated to AT, with a wave of data collection since 2009, were included. Of 81 cohorts and 202 surveys identified, 47 and 62 meet inclusion criteria, respectively. Over 40% of cohorts were drawn from high-income countries which have already experienced significant population ageing. Cohorts often exclude participants based on pre-existing support needs. For surveys, Africa is the most represented region (40%). Globally, 73% of waves were conducted since 2016. 'Use' is the most collected AT access indicator (69% of cohorts and 85% of surveys). Glasses (78%) and hearing aids (77%) are the most represented AT. While gaps in data coverage and representation are significant, collating existing datasets highlights current opportunities for analyses and methods for improving data collection across the sector.


Risk markers of incident atrial fibrillation in patients with coronary heart disease.
In patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and biomarkers with incident AF in patients with CHD. Around 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial. The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios. In patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD.


Mechanical Circulatory Support Devices for Acute Right Ventricular Failure.
Right ventricular (RV) failure remains a major cause of global morbidity and mortality for patients with advanced heart failure, pulmonary hypertension, or acute myocardial infarction and after major cardiac surgery. Over the past 2 decades, percutaneously delivered acute mechanical circulatory support pumps specifically designed to support RV failure have been introduced into clinical practice. RV acute mechanical circulatory support now represents an important step in the management of RV failure and provides an opportunity to rapidly stabilize patients with cardiogenic shock involving the RV. As experience with RV devices grows, their role as mechanical therapies for RV failure will depend less on the technical ability to place the device and more on improved algorithms for identifying RV failure, patient monitoring, and weaning protocols for both isolated RV failure and biventricular failure. In this review, we discuss the pathophysiology of acute RV failure and both the mechanism of action and clinical data exploring the utility of existing RV acute mechanical circulatory support devices.


[Role of lysosome permeability disorders in the mechanism of the low-temperature inhibition of protein biosynthesis in the rat liver].
The effect of the supernatants of lysosomes subjected to a rapid or slow freezing and thawing on the protein-synthesizing activity of the rat liver postmitochondrial supernatant (S15) has been studied. It has been found that the addition of supernatants obtained after a slow freezing or thawing to a cell-free system results in a significant inhibition of 14C-leucine incorporation that is in a good agreement with their RNase activity. However, the RNase activity of lysosomal supernatants or Triton-lysate appears to be higher that the inhibitory effect on protein biosynthesis. The damaging effect of supernatants obtained after 2-hour storage at 2-4 degrees C of the frozen-thawed lysosomes has not virtually changed.


Substituent exchange reactions of trimeric and tetrameric aryloxycyclophosphazenes with sodium 2,2,2-trifluoroethoxide.
Substituent exchange reactions of sodium 2,2,2-trifluoroethoxide with trimeric and tetrameric aryloxycyclophosphazenes with phenoxy, 4-formylphenoxy, 4-cyanophenoxy and 4-nitrophenoxy side groups were conducted at 66 °C in THF and monitored by (31)P NMR and mass spectrometry. These are model reactions for their counterparts with high polymeric linear organophosphazenes. The ease of displacement of OAr in cyclic trimeric and tetrameric molecules by CF(3)CH(2)O increased significantly with the presence of electron-withdrawing substituents in the polyphosphazene in the order, phenoxy ≪ 4-formylphenoxy < 4-cyanophenoxy ≈ 4-nitrophenoxy. Fully substituted 2,2,2-trifluoroethoxyphosphazene trimer and tetramer were formed by side group exchange, but these reactions were followed by an attack by the nucleophile on the α-carbon of the 2,2,2-trifluoroethoxy groups linked to phosphorus to give a species in which one trifluoroethoxy group had been replaced by an ONa unit, and bis(trifluoroethyl) ether was formed as a side product. On the other hand, only partly exchanged species were formed when sodium phenoxide reacted with the trifluoroethoxy phosphazene trimer and tetramer, but again a product with an ONa side group was formed eventually together with phenyltrifluoroethyl ether generated via alpha-carbon attack. The relative sensitivity of 2,2,2-trifluoroethoxy and phenoxyphosphazene cyclic trimers and tetramers to the presence of trifluoroethoxide was established.


Synthesis, Characterization, and Bioactivity of Schiff Bases and Their Cd(2+), Zn(2+), Cu(2+), and Ni(2+) Complexes Derived from Chloroacetophenone Isomers with S-Benzyldithiocarbazate and the X-Ray Crystal Structure of S-Benzyl- β -N-(4-chlorophenyl)methylenedithiocarbazate.
Two bidentate Schiff base ligands having nitrogen sulphur donor sequence were derived from the condensation of S-benzyldithiocarbazate (SBDTC) with 2-chloroacetophenone and 4-chloroacetophenone to give S-benzyl- β -N-(2-chlorophenyl)methylenedithiocarbazate (NS2) and S-benzyl- β -N-(4-chlorophenyl)methylenedithiocarbazate (NS4) isomers. Each of the ligands was then chelated with Cd(2+), Zn(2+), Cu(2+), and Ni(2+). The compounds were characterized via IR spectroscopy and melting point while the structure of NS4 was revealed via X-ray crystallography. Finally, the compounds were screened for antimicrobial activity to investigate the effect that is brought by the introduction of the chlorine atom to the benzene ring. X-ray crystallographic analysis showed that the structure of NS4 is planar with a phenyl ring that is nearly perpendicular to the rest of the molecules. The qualitative antimicrobial assay results showed that NS4 and its complexes lacked antifungal activity while Gram-positive bacteria were generally inhibited more strongly than Gram-negative bacteria. Furthermore, NS4 metal complexes were inhibited more strongly than the ligand while the opposite was seen with NS2 ligand and its complexes due to the partial solubility in dimethyl sulfoxide (DMSO). It was concluded that generally NS2 derivatives have higher bioactivity than that of NS4 derivatives and that the Cd complexes of both ligands have pronounced activity specifically on K. rhizophila.


Optical coherence tomography and non-linear microscopy for paintings - a study of the complementary capabilities and laser degradation effects.
This paper examines for the first time the potential complementary imaging capabilities of Optical coherence tomography (OCT) and non-linear microscopy (NLM) for multi-modal 3D examination of paintings following the successful application of OCT to the in situ, non-invasive examination of varnish and paint stratigraphy of historic paintings and the promising initial studies of NLM of varnish samples. OCT provides image contrast through the optical scattering and absorption properties of materials, while NLM provides molecular information through multi-photon fluorescence and higher harmonics generation (second and third harmonic generation). OCT is well-established in the in situ non-invasive imaging of the stratigraphy of varnish and paint layers. While NLM examination of transparent samples such as fresh varnish and some transparent paints showed promising results, the ultimate use of NLM on paintings is limited owing to the laser degradation effects caused by the high peak intensity of the laser source necessary for the generation of non-linear phenomena. The high intensity normally employed in NLM is found to be damaging to all non-transparent painting materials from slightly scattering degraded varnish to slightly absorbing paint at the wavelength of the laser excitation source. The results of this paper are potentially applicable to a wide range of materials given the diversity of the materials encountered in paintings (e.g. minerals, plants, insects, oil, egg, synthetic and natural varnish).


Suppression of tumor growth and angiogenesis by a specific antagonist of the cell-surface expressed nucleolin.
Emerging evidences suggest that nucleolin expressed on the cell surface is implicated in growth of tumor cells and angiogenesis. Nucleolin is one of the major proteins of the nucleolus, but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in cell proliferation, differentiation, adhesion, mitogenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, here we show that the growth of tumor cells and angiogenesis are suppressed in various in vitro and in vivo experimental models. HB-19 inhibited colony formation in soft agar of tumor cell lines, impaired migration of endothelial cells and formation of capillary-like structures in collagen gel, and reduced blood vessel branching in the chick embryo chorioallantoic membrane. In athymic nude mice, HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in nude mice, and in some cases eliminated measurable tumors while displaying no toxicity to normal tissue. This potent antitumoral effect is attributed to the direct inhibitory action of HB-19 on both tumor and endothelial cells by blocking and down regulating surface nucleolin, but without any apparent effect on nucleolar nucleolin. Our results illustrate the dual inhibitory action of HB-19 on the tumor development and the neovascularization process, thus validating the cell-surface expressed nucleolin as a strategic target for an effective cancer drug. Consequently, the HB-19 pseudopeptide provides a unique candidate to consider for innovative cancer therapy.


Misuse of odds ratios in obesity literature: an empirical analysis of published studies.
Odds ratios (ORs) are widely used in scientific research to demonstrate the associations between outcome variables and covariates (risk factors) of interest, and are often described in language suitable for risks or probabilities, but odds and probabilities are related, not equivalent. In situations where the outcome is not rare (e.g., obesity), ORs no longer approximate the relative risk ratio (RR) and may be misinterpreted. Our study examines the extent of misinterpretation of ORs in Obesity and International Journal of Obesity. We reviewed all 2010 issues of these journals to identify all articles that presented ORs. Included articles were then primarily reviewed for correct presentation and interpretation of ORs; and secondarily reviewed for article characteristics that may have been associated with how ORs are presented and interpreted. Of the 855 articles examined, 62 (7.3%) presented ORs. ORs were presented incorrectly in 23.2% of these articles. Clinical articles were more likely to present ORs correctly than social science or basic science articles. Studies with outcome variables that had higher relative prevalence were less likely to present ORs correctly. Overall, almost one-quarter of the studies presenting ORs in two leading journals on obesity misinterpreted them. Furthermore, even when researchers present ORs correctly, the lay media may misinterpret them as relative RRs. Therefore, we suggest that when the magnitude of associations is of interest, researchers should carefully and accurately present interpretable measures of association--including RRs and risk differences--to minimize confusion and misrepresentation of research results.


Characteristics of Centenarians in the Irish Hip Fracture Database.
Aim Hip fractures are common amongst older people and result in significant morbidity and mortality. The Irish Hip Fracture Database (IHFD) collects data, from the 16 trauma orthopaedic units in Ireland, on patients aged 60 years and older who sustain hip fractures. This study aims to describe the characteristics of those patients aged 100 years and older in this database. Methods A retrospective analysis of the IHFD from 2012 to 2017. Characteristics of those patients aged 100 years and over were collected and analysed. Results 57 patients were identified for inclusion, 52 (91%) of which were women. Mean age was 101, while mean length of stay was 22.6 days. 51 (89%) fractures were due to low velocity trauma, consistent with likely high rates of osteoporosis in this group. The great majority underwent operative intervention. 50 (88%) were discharged alive. Fracture type varied widely. Only 24 (42%) patients were documented to have been seen by a geriatrician during admission. There were low reported rates of co-morbid medical conditions, likely due to lack of recorded data, rather than true low rates of co-morbidities in this group. Discussion This study provides insight into this distinct group of people, with important implications for future healthcare planning and budgeting.


Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs. By combining mtGLP with structured illumination microscopy to monitor mitochondrial dynamics, we discover the formation of nucleoid condensates in damaged mitochondria. We further reveal that nucleoid condensates promoted the peripheral fission of damaged mitochondria via asymmetric segregation. Through simulations, we find that the peripheral fission events occurred when the nucleoid condensates interacted with the highly curved membrane regions at the two ends of the mitochondria. Overall, we show that mitochondrial nucleoid condensates utilize peripheral fission to maintain mitochondrial homeostasis.


[Perception of ischemic and pressing pain in young women during menstrual cycle. Association with humor and cortisol levels].
The aim of the present study was to investigate the modulation of pain perception, estimate by both threshold and tolerance to ischemic and pressure stimuli, by cortisol and humor states across the menstrual cycle. Threshold and tolerance pain to ischemic and pressure stimuli were determined in eighteen healthy young women. The menstrual cycle phases were determined using oral temperature, documentation of the first and last day of menstruation and plasma levels of progesterone and estradiol. Statistical analysis using linear regression model (R2) indicate which hormonal variables (estradiol, progesterone and cortisol) and/or variables obtained from the questionnaire Profile of Mood States (POMS) (fatigue, tension, anger, vigor, confusion and depression) explain, isolated or together, each one of the pain parameters during the five phases of the menstrual cycle. In the follicular, periovulatory, early-to-middle luteal and menstrual phases hormones and subjective variables from POMS explained the responses for pain threshold and tolerance to ischemic and pressure stimulus. Estradiol (during follicular, peri-ovulatory and menstrual phases) and cortisol (during follicular, early-to-mid luteal and mestrual phases) explain only the pain perception to pressure. The differential participation of the hormones in the two types of pain suggests that estradiol, and probably cortisol, modulate the pathways related to pressure but not those related to ischemic pain. On the other hand only the mood states variables explained pain perception during late luteal phase. The analysis of hormonal and subjective variables (POMS) together, associated to detailed characterization of the menstrual cycle suggest that participation of estradiol and cortisol modulate pain perception to pressure stimulus but not to ischemic one. Indeed, suggest that in healthy women with regular menstrual cycles, only subjective variables explained pain perception during late luteal phase of menstrual cycle.


Early Childhood Neurocognition in Relation to Middle Childhood Psychotic Experiences in Children at Familial High Risk of Schizophrenia or Bipolar Disorder and Population-Based Controls: The Danish High Risk and Resilience Study.
Familial high-risk (FHR) studies examining longitudinal associations between neurocognition and psychotic experiences are currently lacking. We hypothesized neurocognitive impairments at age 7 to be associated with increased risk of psychotic experiences from age 7 to 11 in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and population-based controls (PBC), and further, impaired functioning in some neurocognitive functions to be associated with greater risk of psychotic experiences in children at FHR-SZ or FHR-BP relative to PBC. Neurocognition was assessed at age 7 (early childhood) and psychotic experiences from age 7 to 11 (middle childhood) in 449 children from the Danish High Risk and Resilience Study. The neurocognitive assessment covered intelligence, processing speed, attention, visuospatial and verbal memory, working memory, and set-shifting. Psychotic experiences were assessed through face-to-face interviews with the primary caregiver and the child. Set-shifting impairments at age 7 were associated with greater risk of psychotic experiences from age 7 to 11 in children at FHR-SZ. Children at FHR-BP and PBC showed no differential associations. Working memory and visuospatial memory impairments were related to increased risk of psychotic experiences across the cohort. However, adjusting for concurrent psychopathology attenuated these findings. Early childhood neurocognitive impairments are risk markers of middle childhood psychotic experiences, of which impaired set-shifting appears to further increase the risk of psychotic experiences in children at FHR-SZ. More research is needed to examine longitudinal associations between neurocognitive impairments and psychotic experiences in FHR samples.


Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes (n = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in C3 rs2230199 and CFH rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for CFH rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1, validated between the iAMD vs. normal comparison, and AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292, validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes C3 and CFH suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.


Comparison of methods for the rapid recognition of cholera vibrios.
A comparison was made of three methods of bacteriological diagnosis during the outbreak of cholera due to Vibrio El Tor in the Republic of the Philippines in the last quarter of 1961. Although the disease was clinically indistinguishable from cholera caused by V. cholerae the etiological agent was a haemolytic, cholera-related vibrio which differed in some respects from what is classically regarded as V. cholerae. Of the three techniques evaluated, the selective-enrichment/fluorescent-antibody technique provided the most rapid and the greatest number of positive results in the 481 specimens examined in parallel. The oblique-light technique was second in sensitivity and rapidity, while the gelatin-agar method also had some advantages.


Potentially inappropriate medications among older patients with Parkinson's disease: a cross-sectional analysis of a national health insurance database in China.
With the rapid aging trend of China's population, the issue of drug rational use in older adults has become more and more prominent. Parkinson's disease (PD) is the one of the most common age-related neurodegenerative disorders. Pharmaceutical treatment plays a cardinal role in alleviating motor and non-motor symptoms to improve the quality of life of patients with PD. Patients with PD have complex medical needs yet little is known about the use of potentially inappropriate medications (PIM) among them in China. We quantify the prevalence of PIM use and identify its predictors among older persons with PD in China. We conducted a cross-sectional analysis using a national representative database of all medical insurance beneficiaries across China, extracting records of ambulatory visits of older adults with PD between 2015 and 2017. Beneficiaries aged 65 and above were eligible for inclusion. The prevalence of patients exposed to overall PIMs and PIMs related to motor and cognitive impairment was calculated based on Beers Criteria 2015 version. Potential predictors of PIM concerning patients' characteristics were estimated using multivariate logistic regression. A total of 14,452 older adults with PD were included. In total, 8,356 (57.8%) patients received at least one PIM; 2,464 (17.1%) patients received at least one motor-impairing PIM and 6,201 (42.9%) patients received at least one cognition-impairing PIM. The prevalence of overall PIM use was higher in patients of older age group (54.7% [65-74] vs. 59.5% [75-84; OR, 1.22; 95% CI, 1.14-1.31] vs.65.5% [≥ 85; OR, 1.58; 95% CI, 1.38-1.80) and females (61.4% [female] vs. 55.0% [males; OR, 0.77; 95% CI, 0.72-0.82). Prescribing PIMs for older adults with PD was common in China, especially for females and older age groups, yet younger patients were more inclined to be prescribed with motor or cognition-impaired PIMs. Our findings represent a clear target awaiting multidimensional efforts to promote the rational prescribing of medications for this vulnerable population.


Solution structure of the Mycobacterium tuberculosis complex protein MPB70: from tuberculosis pathogenesis to inherited human corneal desease.
The closely related mycobacteria responsible for tuberculosis produce an unusually high number of secreted proteins, many of which are clearly implicated in pathogenesis and protective immunity. Falling within this category are the closely related proteins MPB70 and MPB83. The structure of MPB70 reveals a complex and novel bacterial fold, which has clear structural homology to the two C-terminal FAS1 domains of the cell adhesion protein fasciclin I, whose structures were reported very recently. Assessment of the surface features of MPB70, the sequence divergence between MPB70 and MPB83, the conservation of residues across a group of FAS1 domains, and the locations of disease-inducing mutations in betaig-h3 strongly suggests that MPB70 and MPB83 contain two functional surfaces on opposite faces, which are probably involved in binding to host cell proteins. This analysis also suggests that these functional surfaces are retained in the FAS1 proteins associated with mediating interactions between cells and the extracellular matrix (fasciclin I, periostin, and betaig-h3) and furthermore that some of the human corneal disease-inducing substitutions identified in betaig-h3 will perturb interactions at these sites.