The Lathyrus excitotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid is a substrate of the L-cystine/L-glutamate exchanger system xc-.
Beta-N-oxalyl-L-alpha-beta-diaminopropionic acid (beta-L-ODAP) is an unusual amino acid present in seeds of plants from the Lathyrus genus that is generally accepted as the causative agent underlying the motor neuron degeneration and spastic paraparesis in human neurolathyrism. Much of the neuropathology produced by beta-L-ODAP appears to be a direct consequence of its structural similarities to the excitatory neurotransmitter L-glutamate and its ability to induce excitotoxicity as an agonist of non-NMDA receptors. Its actions within the CNS are, however, not limited to non-NMDA receptors, raising the likely possibility that the anatomical and cellular specificity of the neuronal damage observed in neurolathyrism may result from the cumulative activity of beta-L-ODAP at multiple sites. Accumulating evidence suggests that system xc-, a transporter that mediates the exchange of L-cystine and L-glutamate, is one such site. In the present work, two distinct approaches were used to define the interactions of beta-L-ODAP with system xc-: Traditional radiolabel-uptake assays were employed to quantify inhibitory activity, while fluorometrically coupled assays that follow the exchange-induced efflux of L-glutamate were used to assess substrate activity. In addition to confirming that beta-L-ODAP is an effective competitive inhibitor of system xc-, we report that the compound exhibits a substrate activity comparable to that of the endogenous substrate L-cystine. The ability of system xc- to transport and accumulate beta-L-ODAP identifies additional variables that could influence its toxicity within the CNS, including the ability to limit its access to EAA receptors by clearing the excitotoxin from the extracellular synaptic environment, as well as serving as a point of entry through which beta-L-ODAP could have increased access to intracellular targets.


Effectively Identifying Compound-Protein Interactions by Learning from Positive and Unlabeled Examples.
Prediction of compound-protein interactions (CPIs) is to find new compound-protein pairs where a protein is targeted by at least a compound, which is a crucial step in new drug design. Currently, a number of machine learning based methods have been developed to predict new CPIs in the literature. However, as there is not yet any publicly available set of validated negative CPIs, most existing machine learning based approaches use the unknown interactions (not validated CPIs) selected randomly as the negative examples to train classifiers for predicting new CPIs. Obviously, this is not quite reasonable and unavoidably impacts the CPI prediction performance. In this paper, we simply take the unknown CPIs as unlabeled examples, and propose a new method called PUCPI (the abbreviation of PU learning for Compound-Protein Interaction identification) that employs biased-SVM (Support Vector Machine) to predict CPIs using only positive and unlabeled examples. PU learning is a class of learning methods that leans from positive and unlabeled (PU) samples. To the best of our knowledge, this is the first work that identifies CPIs using only positive and unlabeled examples. We first collect known CPIs as positive examples and then randomly select compound-protein pairs not in the positive set as unlabeled examples. For each CPI/compound-protein pair, we extract protein domains as protein features and compound substructures as chemical features, then take the tensor product of the corresponding compound features and protein features as the feature vector of the CPI/compound-protein pair. After that, biased-SVM is employed to train classifiers on different datasets of CPIs and compound-protein pairs. Experiments over various datasets show that our method outperforms six typical classifiers, including random forest, L1- and L2-regularized logistic regression, naive Bayes, SVM and k-nearest neighbor (kNN), and three types of existing CPI prediction models. More information can be found at http://admis.fudan.edu.cn/projects/pucpi.html.


Barriers to the employability of people with disabilities in the South African public service.
South African public sector efforts to employ people with disabilities (PWDs) in the post-apartheid have been less successful, resulting in a poor transformation record during the past 27 years (1994-2021) due to the failure to integrate PWDs into mainstream employment in government departments. The objective of this article is to identify and highlight some of the barriers to the employability of PWDs in the South African public service. The research was framed as a case study within the transformative research paradigm. A typical department in the Western Cape provincial government was selected for the study. In-depth interviews were conducted with selected top managers within the Western Cape provincial government. Convenience sampling technique of the purposive sampling method was adopted to select targeted respondents (n = 10). Thematic analysis was employed to condense the data collected into a small number of significant themes. Atlas.ti version 7 was also used to enhance the analysis. The study found, among others, that there are conceptual, infrastructural, managerial and organisational factors affecting the employability of PWDs in mainstream public service. The study concludes that barriers to the socio-economic progression of PWDs, including infrastructural and psychosocial factors, continue to prevail and cause the socio-economic marginalisation of PWDs. The study contributes towards efforts aimed at the inclusion of PWDs in the workplace by offering both internal and society-wide actions. Internally, successful inclusion of PWDs involves eliminating barriers, removing bureaucracy, initiating management development for disability matters, introducing appropriate talent development measures, and implementing collaborative management of PWDs. External or society-wide measures include campaigns to demystify disability and change attitudes, engage society structures, and improve societal knowledge of disability.


Antimicrobial effects of a borate-based bioactive glass wound matrix on wound-relevant pathogens.
The antimicrobial effects of a borate-based bioactive glass matrix (BBBGM) on clinically relevant microorganisms was investigated for up to seven days in vitro. A total of 19 wound-relevant pathogens were studied using the in vitro AATCC 100 test method. The reduction of viable Gram-negative and Gram-positive bacteria and yeasts at days 4 and 7 post-culture on the BBBGM was significant (> 4log10) in most cases. Mould counts were reduced (<2log10) during the seven-day assessment, indicating that mould viability and reproduction was inhibited. The cell count of each organism was reduced at seven days indicating that the BBBGM not only reduced the viable cell count, but that the cell count did not recover during the seven-day period, indicating a sustained reduction in pathogenic activity. Based on the present results, the use of a BBBGM as a pathogenic barrier should be considered as a tool for combating pathogenic colonisation and infection in acute and hard-to-heal (chronic) wounds.


Variable anatomy of the right coronary artery supply to the left ventricle.
The right coronary artery is "dominant" (contributing to the supply of the left ventricular muscle) in 90% of people. Although the most common pattern is for the right coronary artery to bifurcate at the crux giving the posterior descending (posterior interventricular) artery, a branch may arise before the crux, either as an aberrant acute marginal artery or as an early posterior descending artery, crossing the diaphragmatic surface of the right ventricle. Recognition of this possibility may be important if surgical revascularisation is to be complete. To establish the frequency of these different patterns of blood supply, 22 hearts were studied in the dissecting room, and 100 consecutive coronary angiograms and 100 consecutive operative drawings were reviewed. A vessel arising before the crux contributed to the supply of the left ventricle in one third of cases.


Shellfish toxicity in UK waters: a threat to human health?
The potential for poisoning of humans through their consumption of shellfish which have themselves consumed biotoxin producing marine phytoplankton exists in the UK. Toxins are bio-accumulated within the shellfish flesh allowing them to reach harmful concentrations. This threat is in most part mitigated by monitoring programmes that assess both the presence of potentially harmful phytoplankton and shellfish flesh toxicity. However, the medical profession in the UK remains relatively ignorant of the potential for biotoxin derived shellfish toxicity, preventing quantification of magnitude, frequency, and severity of health effects in the community or the medical significance of more recently discovered toxins. While the current causative species and their toxins are relatively well characterised there remains a lack of understanding of the factors governing the temporal and spatial appearance of harmful phytoplankton. Expansion of shellfish aquaculture is likely both worldwide and in the UK. Better understanding of how harmful phytoplankton interact with their environment to promote the sporadic harmful blooms that we observe is required to underpin risk assessments.


Global expression of simulated microgravity-responsive genes in Xenopus liver cells.
The random positioning machine (RPM) is a method used to generate a simulated-microgravity environment at approximately 0 g. Using an RPM, we analyzed the global gene expression of A8 cells derived from the liver of adult Xenopus laevis. A range of genes on a Xenopus 44K-scale microarray were up- or downregulated two-fold or more: 43 genes (up, 36 genes; down, 7 genes) on culture day 5 in RPM, 74 genes (up, 48 genes; down, 26 genes) on day 8, 105 genes (up, 71 genes; down, 34 genes) on day 10, and 132 genes (up, 98 genes; down, 34 genes) on day 15. Five genes were upregulated two-fold or more throughout culturing in RPM, while only one gene was downregulated over the entire time. We then compared the expression patterns of the RPM-dependent genes in the A8 cells with those in A6 cells established from the kidney of adult Xenopus laevis. Six upregulated genes and three downregulated genes showed the same expression patterns throughout the culturing of A6 and A8 cells in RPM. Such globally responsive genes may play a common role in the cell response to simulated microgravity. We were particularly interested in the downregulation of SPARC in both cell types in RPM, which supported previous observations from simulated-microgravity experiments on earth or microgravity in space. We conclude that SPARC is plays a key role in the response of a cell to microgravity.


Trophic skin ulceration of leprosy: skin and serum zinc concentrations.
Skin and serum zinc measurements have been made in patients with leprosy with and without trophic skin ulceration and in several other groups. Serum zinc concentrations were decreased in leprosy irrespective of the presence or absence of skin ulceration. Serum zinc concentrations in leprosy were also unrelated to smears positive for Mycobacterium leprae and to the clinical type of leprosy. Since a decrease of the serum zinc was also found in patients with dermatitis herpetiformis and pulmonary tuberculosis it seems likely that the decreased serum zinc in leprosy is a nonspecific metabolic consequence of chronic skin and internal disease. The mean skin zinc concentration in leprosy did not differ significantly from the corresponding value in control subjects, the lack of agreement between serum and skin concentrations being possibly related to the presence of nonexchangeable keratin-bound zinc in skin. Though the clinical significance of lowered serum zinc concentrations in leprosy is uncertain therapeutic trials of zinc treatment in leprosy with trophic skin ulceration seem justifiable.


Molecular differentiation of Erwinia amylovora strains from North America and of two Asian pear pathogens by analyses of PFGE patterns and hrpN genes.
In order to determine a possible genomic divergence of Erwinia amylovora'fruit tree' and raspberry strains from North America, several isolates were differentiated by pulsed-field gel electrophoresis (PFGE) analysis, the size of short DNA sequence repeats (SSRs) and the nucleotide and deduced amino acid sequences of their hrpN genes. By PFGE analysis European strains are highly related, whereas strains from North America were diverse and were further distinguished by the SSR numbers from plasmid pEA29. The E. amylovora strains from Europe showed identical HrpN sequences in contrast to the American isolates from fruit trees and raspberry. Those were related to each other, but distinguishable by their HrpN patterns. The Asian pear pathogens differed in HrpN among each other and from E. amylovora. Erwinia pyrifoliae isolates and the Erwinia strains from Japan were ordered via their HrpN sequences in agreement with the PFGE patterns. For all three pathogens, dendrograms from PFGE and sequence data indicate an evolutionary diversity within the species in spite of a genetic conservation for parts of the hrpN genes suggesting a long persistence of the Asian pear pathogens in Korea and Japan as well as of fire blight in North America. Some of the divergent American E. amylovora isolates share PFGE patterns with the relatively uniform European strains.


Guideline-compliant adjuvant chemotherapy for resected high risk oral cavity cancer: Homefield advantage.
Factors that are associated with failure to receive guideline-compliant adjuvant chemotherapy after resection of high-risk oral cavity cancer are understudied. Here, we performed a retrospective cohort study of surgically treated patients with oral cavity squamous cell carcinoma to determine rates of guideline-compliant adjuvant chemotherapy and to examine patient factors associated with receiving guideline-compliant chemotherapy. Retrospective cohort. Two tertiary care referral centers. Patients with resected high-risk oral cavity squamous cell carcinoma and known adjuvant therapy details were included. Extranodal extension or positive margins were considered high-risk features for which adjuvant chemoradiation was indicated. Patient factors were examined to determine associations with receiving on-guidelines treatment. Univariable and multivariable logistic regression were used to determine significance of associations. 75 patients were included. 36 (48 %) patients received guideline-compliant cisplatin. In total, 39 (52 %) patients did not receive guideline-compliant chemotherapy. On multivariable analysis, meeting with a university medical oncologist was significantly associated with the receipt of guideline-compliant cisplatin (OR 6.38, 95 % CI 2.26-20.0, p < 0.001). Adherence to on-guidelines treatment can be difficult to achieve in patients with advanced stage head and neck cancer. Meeting with university medical oncology is associated with an increased chance of receiving guideline-compliant chemotherapy.


Gender Variations, Generational Effects, and Mental Health of Transgender People in Relation to Timing and Status of Gender Identity Milestones.
Transgender and gender diverse (TGD) people commonly report the following gender identity milestones: feeling different about their gender than expectations for their sex assigned at birth, identifying as TGD, living in their affirmed gender, and, for some, accessing gender-affirming medical care. We explored the average ages of reaching these milestones and variations across gender groups and generational cohorts. We also examined how gender groups, generational cohorts, and endorsement of reaching each of the milestones related to minority stress variables and mental health. This online study included 695 TGD individuals ages 16-73. Boomers+ and Generation X groups were more likely to identify as trans women compared to the younger generational cohorts, who were more varied in their identities. Trans women had later ages of starting to live in their affirmed gender and receiving gender affirming medical care compared to other gender groups. The Boomers+ cohort reported later ages for the milestones compared to other generational cohorts. And, finally, younger generational cohorts had higher levels of internalized stigma, anxiety, and depression, compared to the older cohorts. Gender congruence emerged as a consistent predictor of mental health in the full sample and within each generational cohort. There are important generational differences across identity milestones, minority stress, and mental health that need exploration in future longitudinal research. In addition, beyond the effects of milestone timing, reporting feelings of congruence with one's gender identity is an important consideration for mental health.


Nutrient uptake plasticity in phytoplankton sustains future ocean net primary production.
Annually, marine phytoplankton convert approximately 50 billion tons of dissolved inorganic carbon to particulate and dissolved organic carbon, a portion of which is exported to depth via the biological carbon pump. Despite its important roles in regulating atmospheric carbon dioxide via carbon sequestration and in sustaining marine ecosystems, model-projected future changes in marine net primary production are highly uncertain even in the sign of the change. Here, using an Earth system model, we show that frugal utilization of phosphorus by phytoplankton under phosphate-stressed conditions can overcompensate the previously projected 21st century declines due to ocean warming and enhanced stratification. Our results, which are supported by observations from the Hawaii Ocean Time-series program, suggest that nutrient uptake plasticity in the subtropical ocean plays a key role in sustaining phytoplankton productivity and carbon export production in a warmer world.


The teeth and infective endocarditis.
During 1981 and 1982 544 cases of infective endocarditis were investigated retrospectively by means of a questionnaire. Only 13.7% had undergone any dental procedure within three months of the onset of the illness, and in 42.5% there was no known cardiac abnormality before the onset of the disease. Furthermore, the number of cases occurring annually was about the same as or more than it was before the introduction of penicillin. The mouth and nasopharynx were the most likely sources of the commonest organism, Streptococcus viridans, and it is suggested that it is not dental extractions themselves which are of importance but good dental hygiene. In most patients with infective endocarditis the portal of entry of the organism whatever its nature cannot be identified. If this is so antibiotics are being given to only a small proportion of those at risk, and this would explain why the number of cases is much the same as it was before the introduction of penicillin. Furthermore, the large proportion of patients with no known previous cardiac abnormality adds to the difficulty of providing effective prophylaxis. The evidence suggests that antibiotic prophylaxis should still be given before dental procedures, and a schedule is appended. Much more importance should be given, however, to encouraging people to seek better routine dental care. We also believe that doctors and dentists should appreciate that the pattern of the disease has changed considerably in the past 50 years and that the information given here warrants a revised approach to the problem.


Percentage of anaesthetic fee refunded to patients by schedule-using private medical insurers in New Zealand.
Refunds for anaesthetic services payable to patients by schedule-using private medical insurers or agencies have not been realistically adjusted for inflation or growth in incomes. Patients receive a lower actual refund than that usually implied by the insurers. If private anaesthetic fees had increased in line with award weekly wages, the average refund to patients would have been approximately 50% for most of the period 1968-1981.


Neuronal pyroptosis mediated by STAT3 in early brain injury after subarachnoid hemorrhage.
Neuroinflammation induced by early brain injury (EBI) seriously affects the prognosis of patients after subarachnoid hemorrhage (SAH). Pyroptosis can aggravate inflammatory injury by promoting the secretion of inflammatory cytokines. Meanwhile, STAT3 plays a critical role in the inflammatory response of EBI after SAH. However, whether it plays a pyroptotic role in SAH is mainly unknown. This study aimed to explore the mechanism of STAT3 in pyroptosis in EBI after SAH. C57BL/6J mice were used to establish the SAH model. Brain tissues were collected at different time points for q-RT-PCR and western blot to detect the expression level of STAT3. After intracerebroventricular injection of STAT3 inhibitor S3I-201, they were divided into sham, SAH, SAH + Vehicle, and SAH + S3I-201. Then, the SAH grade, cerebral edema content, blood-brain barrier (BBB) damage, and neurological scores of mice in each group were detected. qRT-PCR and western blot were used to detect related genes and proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of IL-18 and IL-1β. Immunofluorescence staining was used to observe the expression level of proteins. At the same time, S3I-201 was added to the primary neuron cells of the culture medium containing OxyHb to simulate the in vitro experiment, and the relevant indicators consistent with the in vivo experiment were detected. The expression of STAT3 was upregulated after SAH. Inhibition of STAT3 with S3I-201 attenuated neurological deficits, cerebral edema, and BBB damage after SAH. In addition, S3I-201 can also reduce the expression of pyroptosis-related inflammasomes such as GSDMD, NLRP3, Caspase 1, and AIM2 after SAH and the neurological damage caused by IL-18 and IL-1β. Further studies have shown that STAT3 regulates pyroptosis by promoting the nuclear translocation of NF-κB p65. Our finding demonstrated that STAT3 regulates neuronal pyroptosis in EBI after SAH. Inhibition of STAT3 may be a potential target to attenuate the damage that triggers neuroinflammation after SAH.


The Effect of Nest Box Distribution on Sustainable Propagation of Osmia lignaria (Hymenoptera: Megachilidae) in Commercial Tart Cherry Orchards.
The blue orchard bee, Osmia lignaria (Say), is a solitary bee that is an excellent pollinator of tree fruit orchards. Due to the annual rising costs of honey bee hive rentals, many orchardists are eager to develop management tools and practices to support O. lignaria as an alternative pollinator. Establishing O. lignaria pollination as a sustainable industry requires careful consideration of both bee and orchard management. Here, we test the effect of artificial nest box distribution on in-orchard propagation of O. lignaria in Utah commercial tart cherry orchards. Two nest box distributions were compared across three paired, 1.2-ha plots. One distribution, traditionally employed by O. lignaria consultants, included a centrally located tote for mass-nesting with smaller, surrounding 'satellite' nest boxes at orchard margins. The other distribution was composed of smaller, more equally distributed nest boxes throughout the 1.2-ha plots. Significantly higher propagation of O. lignaria was observed in the latter nest box distribution, although all treatments resulted in bee return exceeding the number of bees initially released. These findings provide support for the use of O. lignaria in tart cherry orchards, and demonstrate how simple changes to bee set-up and management can influence propagation efforts.


Experimental Shigella infections. V. Studies in germ-free guinea pigs.
Formal, Samuel B., (Walter Reed Army Institute of Research, Washington, D. C.), Gustave Dammin, Helmuth Sprinz, Donald Kundel, Herman Schneider, Richard E. Horowitz, and Martin Forbes. Experimental shigella infections. V. Studies in germ-free guinea pigs. J. Bacteriol. 82:284-287. 1961.-Germ-free guinea pigs succumb after oral infection with Shigella flexneri serotype 2a; they survive a similar challenge with either a strain of Escherichia coli or a culture of lactobacillus. Animals monocontaminated with E. coli survive, whereas those monocontaminated with lactobacilli succumb to subsequent challenge with dysentery bacilli. Prior subcutaneous inoculation of heat-killed S. flexneri 2a does not render germ-free guinea pigs resistant to the fatal infection with viable dysentery bacilli.


Emergency treatment of acute psychosis.
The author reviews the evolution of emergency psychiatric practice over the past 20 years--from the concept of high-dose antipsychotic medication to the more rational treatment approach for acute psychosis made possible by modern pharmacodynamic insight and the availability of new pharmacotherapeutic agents. A decision tree for current practice in the rapid tranquilization of agitated, apparently psychotic patients is described.


Issues in the federal funding of rehabilitation research.
An allocation model for funding health research is the framework for highlighting issues concerned with the federal financing of research related to the rehabilitation of handicapped individuals. Discussion focuses upon the policies and practices of the National Institute of Handicapped Research (NIHR) because of its prominent role among the federal agencies that support rehabilitation research. Separate consideration is given to the influence of the 1978 amendments to the Rehabilitation Act, the National Council on the Handicapped, the NIHR long-range plan, the Interagency Committee for Handicapped Research, and procedures for establishing NIHR's annual priorities. NIHR's conduct of peer review is critically reviewed, as is the agency's history of annual appropriations. Reasons are discussed why rehabilitation research has been inadequately funded, and steps are recommended for increasing its federal support.


Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.
Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections.


Practical Risk Scoring System for Predicting Severity of COVID-19 Disease.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, has become an international pandemic with numerous casualties. It had been noted that the severity of the COVID-19 disease course depends on several clinical, laboratory, and radiological factors. This has led to risk scoring systems in various populations such as in China, but similar risk scoring systems based on the American veteran population are sparse, particularly with the vulnerable Veteran population. As a simple risk scoring system would be very useful, we propose a simple Jhala Risk Scoring System (JRSS) to assess the severity of disease risk. A retrospective review of all SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) tests collected and performed at the regional Veterans Administration Medical Center (VAMC) serving the Philadelphia and surrounding areas from March 17th, 2020 to May 20th, 2020. Data was collected and analyzed in the same year. These tests were reviewed within the computerized medical record system for demographic, medical history, laboratory test history, and clinical course. Information from the medical records were then scored based on the criteria of the Jhala Risk Scoring System (JRSS). The JRSS, based on age, ethnicity, presence of any lung disease, presence of cardiovascular disease, smoking history, and diabetes history with laboratory parameters correlated and predicted (with statistical significance) which patients would be hospitalized. The JRSS may play a role in informing which COVID-19 positive patients in the emergency room/urgent care for risk stratification.


Stillbirth in Women Living With HIV Delivering in the United Kingdom and Ireland: 2007-2015.
Women living with HIV have a higher risk of adverse birth outcomes, but questions remain regarding their specific risk factors for stillbirth and the extent to which maternal HIV is associated with stillbirth. Using data on pregnant women with HIV reported within population-based surveillance in the United Kingdom/Ireland, we described stillbirth rates in 2007-2015 stratified by type of antiretroviral therapy (ART) and evaluated risk factors using Poisson regression. General population stillbirth rates by maternal world region of origin were derived from national annual birth statistics, and compared with rates in women with HIV, using standardized stillbirth ratios with the general population as the reference. Between 2007 and 2015, there were 10,434 singleton deliveries in 8090 women with HIV; 75% of pregnancies were in women of African origin; and 49% were conceived on ART. The stillbirth rate was 8.5 (95% confidence interval: 6.9 to 10.5) per 1000 births. Risk factors for stillbirth included pre-eclampsia, diabetes, Asian maternal origin (versus United Kingdom/Ireland), CD4 count <350 cells/mm, older maternal age, and primiparity. Conceiving on ART did not increase the risk. The stillbirth rates (per 1000 births) by type of ART were 14.3, 11.7, 8.3, and 6.0, respectively for NVP + XTC/TDF-, LPV/r + 3TC/ZDV-, NVP + XTC/ABC-, and NVP + XTC/ZDV-exposed pregnancies (P value = 0.40). The standardized stillbirth ratio was 129 (95% confidence interval: 101 to 165) in women with HIV compared with the general population. After adjusting for maternal origin, the stillbirth rate remained higher in women with HIV than the general population. We recommend further studies to understand and prevent this excess.


Age-related changes in satellite cell proliferation by compensatory activation in rat diaphragm muscles.
To investigate the age-related changes in satellite cell (SC) proliferation in vivo, we used a compensatory activation (CAC) model of the hemi-diaphragm muscle. Young (2-month), adult (14-month) and old (24-month) rats were randomly divided into control and CAC groups. In the CAC group, denervation surgery in the left hemi-diaphragm was performed to induce CAC of the right hemi-diaphragm. Six days after the surgery, the CAC diaphragm muscle was removed and separated into two blocks for immunohistochemical staining and real time RT-PCR procedures. The number of SCs in type I and IIa fibers were not affected significantly by the CAC in any age groups, but that in type IIx/b fibers was significantly increased in the young and adult groups. As compared to the age-matched control group, the Pax7 mRNA expression level was significantly higher in the young and adult CAC groups, but not in the old CAC group. These results may suggest that the mechanism of SC proliferation in type IIx/b fibers is impaired in aged diaphragm muscles.


Reproductive uncertainty and the relative competitiveness of simultaneous hermaphroditism versus dioecy.
Hermaphroditism is typically associated with a sedentary existence, whereas dioecy is associated with mobility. This pattern is reflected within flowering plants, as dioecious species commonly possess traits that promote high dispersal. We investigated these associations with three population dynamics models (an individual-based simulation and two mathematical models, one deterministic and the other stochastic) that allowed us to examine competition for space between a hermaphroditic and dioecious species from different perspectives. The competing species are identical in every way but their sexual system. Separation of the sexes increases the variances of pollen import and seed dispersal for the dioecious species. These variances propagate through subsequent reproductive processes and ultimately reduce mean recruitment as a result of nonlinear averaging (Jensen's inequality). A dioecious species could overcome this disadvantage simply by producing more gametes than hermaphrodites; however, in line with the association with mobility, selection on dioecious species should also favor traits that reduce reproductive uncertainty, such as extensive dispersal.


Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.
We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.


Stepwise Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells Enables Analysis of Glaucomatous Neurodegeneration.
Human pluripotent stem cells (hPSCs), including both embryonic and induced pluripotent stem cells, possess the unique ability to readily differentiate into any cell type of the body, including cells of the retina. Although previous studies have demonstrated the ability to differentiate hPSCs to a retinal lineage, the ability to derive retinal ganglion cells (RGCs) from hPSCs has been complicated by the lack of specific markers with which to identify these cells from a pluripotent source. In the current study, the definitive identification of hPSC-derived RGCs was accomplished by their directed, stepwise differentiation through an enriched retinal progenitor intermediary, with resultant RGCs expressing a full complement of associated features and proper functional characteristics. These results served as the basis for the establishment of induced pluripotent stem cells (iPSCs) from a patient with a genetically inherited form of glaucoma, which results in damage and loss of RGCs. Patient-derived RGCs specifically exhibited a dramatic increase in apoptosis, similar to the targeted loss of RGCs in glaucoma, which was significantly rescued by the addition of candidate neuroprotective factors. Thus, the current study serves to establish a method by which to definitively acquire and identify RGCs from hPSCs and demonstrates the ability of hPSCs to serve as an effective in vitro model of disease progression. Moreover, iPSC-derived RGCs can be utilized for future drug screening approaches to identify targets for the treatment of glaucoma and other optic neuropathies. Stem Cells 2016;34:1553-1562.


Applications of Artificial Intelligence and Radiomics in Molecular Hybrid Imaging and Theragnostics for Neuro-Endocrine Neoplasms (NENs).
Nuclear medicine has acquired a crucial role in the management of patients with neuroendocrine neoplasms (NENs) by improving the accuracy of diagnosis and staging as well as their risk stratification and personalized therapies, including radioligand therapies (RLT). Artificial intelligence (AI) and radiomics can enable physicians to further improve the overall efficiency and accuracy of the use of these tools in both diagnostic and therapeutic settings by improving the prediction of the tumor grade, differential diagnosis from other malignancies, assessment of tumor behavior and aggressiveness, and prediction of treatment response. This systematic review aims to describe the state-of-the-art AI and radiomics applications in the molecular imaging of NENs.


Epidemics of vector-borne diseases observed in infectious disease surveillance in Japan, 2000-2005.
Observing the epidemics of vector-borne diseases is important. One or more cases of 6 vector-borne diseases were reported to the National Epidemiological Surveillance of Infectious Diseases in Japan in 2000-2005. The reports of those cases were available. The incidence was observed by region of acquired infection, prefecture reporting, and week and year of diagnosis. The incidence rate per year per 1,000,000 population was 0.36 for dengue fever, 0.04 for Japanese encephalitis, 0.38 for Japanese spotted fever, 0.08 for Lyme disease, 0.74 for malaria, and 3.50 for scrub typhus. There were no cases of dengue fever or malaria derived from domestic infections. The yearly incidence rate increased for dengue fever and Japanese spotted fever, and declined for malaria and scrub typhus. The proportion of cases reported in Tokyo was 44% for dengue fever and 37% for malaria. The number of prefectures reporting one or more cases of Japanese spotted fever increased in western Japan. The cases of scrub typhus increased in autumn-winter in prefectures of eastern Japan, and increased both in autumn-winter and spring in western prefectures. The study reveals the epidemiologic features of both temporal and geographic distributions of cases of 6 vector-borne diseases in Japan, 2000-2005.


Relationship between osteoarthritis of knee and menopause.
To study the difference in the onset of osteoarthritis (OA) between males and females with respect to age and to note the relationship between OA of the knees and menopause and hysterectomy in females. One hundred consecutive patients (50 males and 50 females) were studied for the onset of OA and compared for the statistical difference. In females the relationship between onset of OA and menopause and hysterectomy, if done, was noted. Fifty eight percent of females had onset of symptoms of OA of knees before 50 years of age as compared to only 20% in males (p < 0.05). Sixty four percent of females with OA of knees had the onset of symptoms either perimenopausally or within five years of natural menopause or hysterectomy. There is a definite early peaking of the incidence of OA of knees in women in the fifth decade of life as compared to males. There is an association between OA of knees and menopause and we suggest correlating it with the levels of sex hormones.


Histochemical evidence for inducible nitric oxide synthase in advanced but non-ruptured human atherosclerotic carotid arteries.
In response to cytokine stimulation, the inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide with potential consequences in the pathophysiology of atherosclerosis. Previous investigations have demonstrated the presence of iNOS in human atherosclerotic lesions. The goal of this study was to evaluate the occurrence of the expression of iNOS in ruptured versus non-ruptured human carotid atherosclerotic plaques. Using plastic-embedded sections, we performed in situ hybridization and immunohistochemistry on very advanced atherosclerotic lesions type V (non-ruptured) and type VI (ruptured) from 12 atheromatous carotid arteries from endarterectomy and six non-atherosclerotic internal mammary arteries from aorto-coronary bypass. Only one internal mammary artery expressed iNOS in the endothelium. In contrast, iNOS mRNA and protein were repeatedly expressed in advanced lesions type V in 5/7 cases, particularly in inflammatory regions. Specific cell markers identified iNOS-positive cells as macrophages and T-lymphocytes but also as smooth muscle cells and endothelial cells adjacent to these inflammatory regions. Nitration of protein tyrosines was not always associated to iNOS expression but more likely to the presence of inflammatory cells. In complicated lesions type VI, the occurrence of iNOS mRNA and protein expression diminished drastically (1/5 cases). Combined expression of iNOS mRNA and protein is frequently found in advanced but non-ruptured human atherosclerotic carotid lesions while it becomes rare after the plaque has ruptured. These findings suggest that iNOS could be an active participant in the plaque rupture event.


Vibrational anharmonicities revealed by coherent two-dimensional infrared spectroscopy.
Two-dimensional infrared photon echo spectroscopy has been used to describe the anharmonic nuclear potential of two coupled molecular vibrations. The two-dimensional spectrum shows diagonal and off-diagonal features, each composed of two peaks. The splitting between these peaks is directly related to the anharmonicity, while the relative amplitude of the diagonal and off-diagonal features describes the projection angle between interacting dipoles.


A novel system to diagnose cutaneous adverse drug reactions employing the cellscan--comparison with histamine releasing test and Inf-gamma Releasing Test.
There are several mechanisms to describe allergic drug reactions yet the methods to diagnose them are limited. To compare several conventional clinical and laboratory methods to diagnose skin reactions to drugs to a new method of diagnosing drug reactions by the CellScan system. The study entailed 21 patients who were diagnosed as suffering from drug eruptions, and 105 healthy controls with no history of drug allergy. The drugs were classified into two groups according to suspicion of causing drug allergy: high and low. Most of the patients were on more than one drug, leading to 41 patient-drug interactions (assays). Histamine releasing test (HRT), interferon (INF)-gamma releasing test and CellScan examination were performed on lymphocytes of the patients and controls. The HRTwas interpreted as positive in 9 out of 18 (50%) patients and in 13 out of 35 (37%) assays. Based on the INF-gamma releasing test, positive results were observed in 16 out of 21 (76%) patients and in 24 out of 41 (59%) assays. In the CellScan test (CST), positive results were observed in 17 out of 21 (81%) patients and in 29 out of 41 (71%) assays. The rate of identifying the drug for eruption in the high suspicion level drugs was 9 out of 22 (41%) assays in the HRT, 20 out of 24 (83%) assays in the INF-gamma releasing test, and 21 out of 24 (87%) studies with the CellScan method. The rate of determining of the drug that caused the eruption in the low suspicion level drugs was 4 out of 13 (31 %) in the HRT, 4 out of 17 (24%) assays in the INF-gamma releasing test, and 8 out of 17 (47%) analyses in the CST. When examined in the CellScan, 99 out of 105 (94%) controls were interpreted as negative. This preliminary study indicates that the CellScan seems to be an easy and promising method for the detection of drugs responsible for adverse skin reactions. In contrast to the HRT and to the Interferon-gamma secretion test, the CellScan method is characterized by its ability to track and monitor the reaction of individual cells. By measuring the kinetic parameters of selected cells before and after adding the suspected drug, we were able to identify the culprit drug. The CellScan method had the highest sensitivity, and the interferon-gamma secretion test had the highest specificity for detection of the culprit drug. In contrast, the analysis of 105 normal control sera disclosed a high specificity of 94% for the CellScan method.


Characteristics of Idiopathic Urethral Strictures: A Link to Remote Perineal Trauma?
To characterize the physical features and reconstructive outcomes of a series of idiopathic urethral strictures (IUS) in an effort to elucidate the nature of this common yet poorly understood entity. We retrospectively reviewed our urethroplasty database to identify men undergoing initial urethral reconstruction from 2007 to 2014 at 1 of 3 hospitals (N = 514). Patients were stratified by stricture etiology, including IUS, acute trauma, iatrogenic, hypospadias, balanitis xerotica obliterans, and radiation. IUS that had a known history of subacute or repetitive blunt force to the perineum (horseback riding, avid cycling, motocross, etc.) were subclassified as subacute or repetitive perineal trauma (SRPT). Among 466 men undergoing initial reconstruction with available data, 215 (46%) were IUS cases. The median delay between IUS diagnosis and urethroplasty was 5.2 years, during which time men underwent a median of 2 endoscopic treatments. A total of 51 (24%) IUS cases recalled a distinct history of SRPT. Men with SRPT were slightly younger (median 43 vs 48 years, P = .01) but were remarkably similar in terms of urethral stricture length (2 vs 2 cm, P = .15), location (bulbar 96% vs 89%, P = .41), and treatment success (92% vs 88%; P = .61). Bulbar (-)SRPT and (+)SRPT IUS had similar clinical and morphometric features as those with known acute bulbar trauma with excellent 24-month stricture recurrence-free survival rates (93% vs 92% vs 97%, P = .19). IUS have clinical features suggesting that many may be related to unrecognized or repetitive perineal trauma. Although treatment tends to be delayed, IUS have excellent urethroplasty success because most are short bulbar strictures amenable to anastomotic urethroplasty.


Same-day versus first-day review of intraocular pressure after uneventful phacoemulsification.
To compare the incidence and the spectrum of postoperative complications detected when the intraocular pressure (IOP) is reviewed 4 to 6 hours or the day after uneventful phacoemulsification cataract extraction and intraocular lens (IOL) implantation. Royal Free Hospital, London, United Kingdom. The study cohort consisted of 141 patients who had uneventful phacoemulsification and IOL implantation under regional (peribulbar/topical) or general anesthesia. Postoperative evaluation of the patients was performed by an ophthalmologist using a standard form at 4 to 6 hours or 24 hours. The mean IOP at 4 to 6 hours and 24 hours was 22.85 mm Hg +/- 9.56 (SD) and 19.44 +/- 7.04 mm Hg, respectively. The IOP was more likely to be greater than 30 mm Hg when measured on the same day, resulting in a significantly higher intervention rate than on the first day (P =.037). The best corrected visual acuity was significantly better at 24 hours than at the same-day review (P <.001). There was no significant difference in the extent of anterior chamber activity, patient comfort, or state of the wound between the same- or next-day follow-up. All patients attended a follow-up appointment 3 weeks after surgery, had an IOP of 21 mm Hg or less, and were subsequently discharged. The results indicate that moderate IOP spikes (<40 mm Hg) can be left untreated if they are not associated with corneal edema or patient discomfort as they decline spontaneously. Before they are discharged, patients with compromised optic discs or predisposed to retinal or optic nerve pathology should be carefully evaluated the day after surgery to treat IOP elevations.


Chronic infections & coronary artery disease with special reference to Chalmydia pneumoniae.
Studies on cardiovascular diseases (CVD) in India have shown about 10-20 per cent of cases with no obvious risk factors, raising a suspicion of infections as a cause. There is a paucity of data on this possible role of infections. This study was, therefore, undertaken to find out the association between infection due to Chlamydia pneumoniae and other organisms and coronary artery disease (CAD). Patients with CAD were selected in group I (acute myocardial infarction, AMI) and group III (patients undergoing coronary artery bypass graft (CABG) surgery), and normal controls in group II. Routine biochemical, haematological and inflammatory tests [C-reactive protein (CRP), total leucocyte count (TLC), fibrinogen, ESR], serodiagnostic tests for IgA and IgG antibodies to C. pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), Mycoplasma pneumoniae and Parvovirus B-19 by ELISA kits, C. pneumoniae antigen by microimmunofluorescence and PCR from endothelial tissue obtained at CABG were carried out. Aortic punch biopsies were done in patients who underwent CABG. Acute MI patients had a significantly higher association with accepted cardiac risk factors, lipid profile, inflammatory and thrombogenic tests. IgG and IgA antibodies levels against C. pneumoniae were not significantly different in the controls as against the AMI group. However, C. pneumoniae antigen seropositive group had significant association with HDL cholesterol, lipid tetrad index (P<0.001) and with triglycerides. Parvovirus B antigen was detected in 8.3 per cent of tissue specimens by PCR and of 44 patients with AMI (6.8%) were also positive for parvovirus B-19 IgG antibodies. There was no direct evidence of the involvement of C. pneumoniae and other infective agents and viruses in CAD. It is possible that such infections produce an indirect adverse effect on the lipid profile.


Prions and prion-like proteins.
Prions are self-replicating protein aggregates and are the primary causative factor in a number of neurological diseases in mammals. The prion protein (PrP) undergoes a conformational transformation leading to aggregation into an infectious cellular pathogen. Prion-like protein spreading and transmission of aggregates between cells have also been demonstrated for other proteins associated with Alzheimer disease and Parkinson disease. This protein-only phenomenon may therefore have broader implications in neurodegenerative disorders. The minireviews in this thematic series highlight the recent advances in prion biology and the roles these unique proteins play in disease.


Parent Preferences on Screening for Social Determinants of Health in Hospitalized Children.
Although there has been much research on screening families for social determinants of health (SDOH) at pediatric outpatient visits, there is little data on family preferences about SDOH screening during hospitalization. This is of critical importance because unmet SDOH, also known as social needs, are associated with poor health outcomes. Our objective was to assess caregiver preferences for social needs screening in the inpatient pediatric setting. We surveyed a sample of caregivers of admitted patients at our freestanding tertiary-care children's hospital between March 2021 and January 2022. Caregivers were surveyed with respect to the importance of screening, their comfort with screening, and which domains were felt to be acceptable for screening. We enrolled 160 caregivers. More than 60% of caregivers were comfortable being screened for each of the social needs listed. Between 40% and 50% found screening acceptable, even if resources were unavailable. Forty-five percent preferred to be screened in private, 9% preferred to be screened by a health care team member, and 37% were comfortable being screened either in private or with a health care team member. Electronic screening was the most preferred modality (44%), and if by a health care team member, social workers were preferred over others. Many caregivers reported the acceptance of and comfort with social needs screening in the inpatient setting. Our findings may help inform future hospital-wide social needs screening efforts.


AM-FM texture segmentation in electron microscopic muscle imaging.
This paper describes the application of an amplitude modulation-frequency modulation (AM-FM) image representation in segmenting electron micrographs of skeletal muscle for the recognition of: 1) normal sarcomere ultrastructural pattern and 2) abnormal regions that occur in sarcomeres in various myopathies. A total of 26 electron micrographs from different myopathies were used for this study. It is shown that the AM-FM image representation can identify normal repetitive structures and sarcomeres, with a good degree of accuracy. This system can also detect abnormalities in sarcomeres which alter the normal regular pattern, as seen in muscle pathology, with a recognition accuracy of 75%-84% as compared to a human expert.


Functional tissue units and their primary tissue motifs in multi-scale physiology.
Histology information management relies on complex knowledge derived from morphological tissue analyses. These approaches have not significantly facilitated the general integration of tissue- and molecular-level knowledge across the board in support of a systematic classification of tissue function, as well as the coherent multi-scale study of physiology. Our work aims to support directly these integrative goals. We describe, for the first time, the precise biophysical and topological characteristics of functional units of tissue. Such a unit consists of a three-dimensional block of cells centred around a capillary, such that each cell in this block is within diffusion distance from any other cell in the same block. We refer to this block as a functional tissue unit. As a means of simplifying the knowledge representation of this unit, and rendering this knowledge more amenable to automated reasoning and classification, we developed a simple descriptor of its cellular content and anatomical location, which we refer to as a primary tissue motif. In particular, a primary motif captures the set of cellular participants of diffusion-mediated interactions brokered by secreted products to create a tissue-level molecular network. Multi-organ communication, therefore, may be interpreted in terms of interactions between molecular networks housed by interconnected functional tissue units. By extension, a functional picture of an organ, or its tissue components, may be rationally assembled using a collection of these functional tissue units as building blocks. In our work, we outline the biophysical rationale for a rigorous definition of a unit of functional tissue organization, and demonstrate the application of primary motifs in tissue classification. In so doing, we acknowledge (i) the fundamental role of capillaries in directing and radically informing tissue architecture, as well as (ii) the importance of taking into full account the critical influence of neighbouring cellular environments when studying complex developmental and pathological phenomena.


Overexpression of ZNF460 predicts worse survival and promotes metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer.
Zinc finger proteins (ZNFs) are a class of protein containing zinc finger domains, and they play an important role in tumor progression. However, as a member of the ZNFs family, the effect of ZNF460 in colon cancer remains unclear. In this study, we found that the expression of ZNF460 protein were markedly increased in clinical colon cancer tissues compared with para-cancer non-cancerous tissues by tissue immunohistochemistry (IHC) and western blot (WB). We also confirmed this result at the mRNA and protein levels of ZNF460 through bioinformatics analysis. In addition, high expression of ZNF460 was correlated with increased depth of invasion (P<0.05), increased lymph node metastasis (P<0.05), distant metastasis (P<0.05) and high blood serum CA19-9 level (P<0.05). High expression of ZNF460 predicted poor overall survival (OS) and recurrence free survival (RFS) in patients with colon cancer. Moreover, multivariate analyses revealed that ZNF460 was an independent prognostic factor in both OS (hazard ratio [HR]: 1.636; 95% confidence interval [CI], 1.028-2.603; P = 0.038) and RFS (HR: 2.215; 95% CI: 1.227-3.997; P = 0.008). The knockdown of ZNF460 suppressed the invasion and metastasis of colon cancer cells in vitro. Mechanistically, we revealed that ZNF460 promotes the activation of the JAK2/STAT3 signaling pathway in colon cancer cells. Taken together, overexpression of ZNF460 predicted worse survival and promoted metastasis through JAK2/STAT3 signaling pathway in patient with colon cancer, and could be a novel therapeutic target in colon cancer.


Effects of teriparatide versus alendronate for treatment of postmenopausal osteoporosis: A meta-analysis of randomized controlled trials.
Osteoporosis remains a clinical challenge. Teriparatide is an anabolic drug and alendronate is an antiresorptive agent; both are used in the treatment of osteoporosis. Comprehensive reviews investigating the comparative safety and efficacy of teriparatide versus alendronate are scarce. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and efficacy of teriparatide versus alendronate for the treatment of postmenopausal osteoporosis. We conducted a comprehensive literature review of the PubMed, EMBASE, Cochrane Controlled Trials Registry, and the China Academic Journal Network Publishing databases for relevant RCTs of teriparatide versus alendronate in postmenopausal osteoporosis patients. Outcome measures were percentage change in lumbar spine and femoral neck bone mineral density (BMD) and incidence of vertebral and nonvertebral fractures. Effect size was reported as weighted mean differences (WMDs) for continuous outcomes and odds ratios (OR) for dichotomous outcomes, with associated 95% confidence intervals (CIs). Six trials involving 618 patients were included. The meta-analysis demonstrated a significant increase in lumbar spine BMD (WMD: 3.46, 95% CI: 2.15-4.77, P < .00001), but not femoral neck BMD (WMD = 1.50, 95% CI: 0.04-2.95, P = .04), in postmenopausal osteoporosis patients treated with teriparatide compared with alendronate for 6 to 18 months. These beneficial effects were apparent in the lumbar spine at 12 months of treatment (WMD: 4.49, 95% CI: 2.57-6.40, P < .01). Teriparatide was not superior to alendronate in reducing fracture risk (OR: -0.03, 95% CI: -0.12 to 0.07; P = .52). Teriparatide may be superior to alendronate for increasing lumbar spine BMD in postmenopausal osteoporosis. The efficacy and safety of long-term teriparatide and alendronate treatment in postmenopausal osteoporosis should be further investigated in clinical trials.


Advances in paper-based sample pretreatment for point-of-care testing.
In recent years, paper-based point-of-care testing (POCT) has been widely used in medical diagnostics, food safety and environmental monitoring. However, a high-cost, time-consuming and equipment-dependent sample pretreatment technique is generally required for raw sample processing, which are impractical for low-resource and disease-endemic areas. Therefore, there is an escalating demand for a cost-effective, simple and portable pretreatment technique, to be coupled with the commonly used paper-based assay (e.g. lateral flow assay) in POCT. In this review, we focus on the importance of using paper as a platform for sample pretreatment. We firstly discuss the beneficial use of paper for sample pretreatment, including sample collection and storage, separation, extraction, and concentration. We highlight the working principle and fabrication of each sample pretreatment device, the existing challenges and the future perspectives for developing paper-based sample pretreatment technique.


The production of recombinant cationic α-helical antimicrobial peptides in plant cells induces the formation of protein bodies derived from the endoplasmic reticulum.
Synthetic linear antimicrobial peptides with cationic α-helical structures, such as BP100, are valuable as novel therapeutics and preservatives. However, they tend to be toxic when expressed at high levels as recombinant peptides in plants, and they can be difficult to detect and isolate from complex plant tissues because they are strongly cationic and display low extinction coefficient and extremely limited immunogenicity. We therefore expressed BP100 with a C-terminal tag which preserved its antimicrobial activity and demonstrated significant accumulation in plant cells. We used a fluorescent tag to trace BP100 following transiently expression in Nicotiana benthamiana leaves and showed that it accumulated in large vesicles derived from the endoplasmic reticulum (ER) along with typical ER luminal proteins. Interestingly, the formation of these vesicles was induced by BP100. Similar vesicles formed in stably transformed Arabidopsis thaliana seedlings, but the recombinant peptide was toxic to the host during latter developmental stages. This was avoided by selecting active BP100 derivatives based on their low haemolytic activity even though the selected peptides remained toxic to plant cells when applied exogenously at high doses. Using this strategy, we generated transgenic rice lines producing active BP100 derivatives with a yield of up to 0.5% total soluble protein.


An epigenome-wide association study of child appetitive traits and DNA methylation.
The etiology of childhood appetitive traits is poorly understood. Early-life epigenetic processes may be involved in the developmental programming of appetite regulation in childhood. One such process is DNA methylation (DNAm), whereby a methyl group is added to a specific part of DNA, where a cytosine base is next to a guanine base, a CpG site. We meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study (n = 1,086, Rotterdam, the Netherlands) and the Healthy Start study (n = 236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait when examining individual CpG-sites. However, when examining multiple CpGs jointly in so-called differentially methylated regions, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors.


Spirometry use among pediatric primary care physicians.
This study explores the use of spirometry in primary care settings. A 4-page survey was mailed to a national, random sample of office-based family physicians and pediatricians. Survey items addressed knowledge, attitudes, and practices regarding spirometry and standardized clinical vignettes. Data were analyzed by using χ2 tests and multivariate logistic regression. Among the 360 respondents who provided care to children with asthma, 52% used spirometry in clinical practice, whereas 80% used peak flow meters and 10% used no lung function tests. Only 21% routinely used spirometry for all guideline-recommended clinical situations. More family physicians than pediatricians reported using spirometry (75% vs 35%; P<.0001), and family physicians were more comfortable in interpreting spirometric results (50% vs 25%; P<.0001). Only one-half of respondents interpreted correctly the spirometric results in a standardized clinical vignette, and the frequency of underrating asthma severity increased with the inclusion of spirometric results. The most common barriers to the use of spirometry, that is, time and training, were cited more often by physicians who did not use spirometry. Two-thirds of respondents agreed that they would want additional training regarding implementing spirometry in their clinical practices. The use of spirometry in primary care settings for children with asthma does not conform to national guidelines. Widespread implementation of national asthma guidelines likely would require a major educational initiative to address deficiencies in spirometry interpretation and other barriers.


Droplet Magnetofluidic Assay Platform for Quantitative Methylation-Specific PCR.
Early cancer detection requires identification of cellular changes resulting from oncogenesis. Abnormal DNA methylation patterns occurring early in tumor development have been widely identified as early biomarkers for multiple types of cancer tumors. Methylation-Specific PCR (MSP) has permitted highly sensitive detection of these methylation changes at known biomarker locations. MSP requires multiple sample preparation steps including protein digestion, DNA isolation, and bisulfite conversion prior to detection. In this work, we present a streamlined assay platform and instrumentation for integration of all sample processing steps required to obtain quantitative MSP signal from raw biological samples through the use of droplet magnetofluidic principles. In conjunction with this platform, we present a streamlined protocol for solid-phase DNA extraction from cells and bisulfite conversion of genomic DNA, minimizing the processing steps and reagent volume for implementation on a compact assay platform.


Addressable metasurfaces for dynamic holography and optical information encryption.
Metasurfaces enable manipulation of light propagation at an unprecedented level, benefitting from a number of merits unavailable to conventional optical elements, such as ultracompactness, precise phase and polarization control at deep subwavelength scale, and multifunctionalities. Recent progress in this field has witnessed a plethora of functional metasurfaces, ranging from lenses and vortex beam generation to holography. However, research endeavors have been mainly devoted to static devices, exploiting only a glimpse of opportunities that metasurfaces can offer. We demonstrate a dynamic metasurface platform, which allows independent manipulation of addressable subwavelength pixels at visible frequencies through controlled chemical reactions. In particular, we create dynamic metasurface holograms for advanced optical information processing and encryption. Plasmonic nanorods tailored to exhibit hierarchical reaction kinetics upon hydrogenation/dehydrogenation constitute addressable pixels in multiplexed metasurfaces. The helicity of light, hydrogen, oxygen, and reaction duration serve as multiple keys to encrypt the metasurfaces. One single metasurface can be deciphered into manifold messages with customized keys, featuring a compact data storage scheme as well as a high level of information security. Our work suggests a novel route to protect and transmit classified data, where highly restricted access of information is imposed.


The pattern of expression of CD147/neurothelin during human T-cell ontogeny as defined by the monoclonal antibody 8D6.
A novel monoclonal antibody termed 8D6 was generated against the human leukemic T-cell line Molt 13 and was found to recognize the neurothelin structure, recently termed CD147. UM8D6 precipitated a single band from HSB2 cells of molecular weight 35 kDa nonreduced and 40 kDa reduced. CD147 is broadly expressed on human hematopoietic cells and is expressed more intensely on thymocytes than on mature peripheral blood T cells. A clear distinction was found by three-color flow cytometry between antigen density on single positive mature thymocytes subsets compared with the corresponding subset from peripheral blood. The 8D6 antibody did not have direct effects on T-cell activation or apoptosis, and the function of CD147 in development and activation of T cells is not yet clear. Nevertheless, its highly regulated expression during T-cell differentiation and the structural characteristics of this antigen suggest that it has an interesting and important role in T-cell biology.


Alkaline earth atom doping-induced changes in the electronic and magnetic properties of graphene: a density functional theory study.
Density functional theory was used to investigate the effects of doping alkaline earth metal atoms (beryllium, magnesium, calcium and strontium) on graphene. Electron transfer from the dopant atom to the graphene substrate was observed and was further probed by a combined electron localization function/non-covalent interaction (ELF/NCI) approach. This approach demonstrates that predominantly ionic bonding occurs between the alkaline earth dopants and the substrate, with beryllium doping having a variant characteristic as a consequence of electronegativity equalization attributed to its lower atomic number relative to carbon. The ionic bonding induces spin-polarized electronic structures and lower workfunctions for Mg-, Ca-, and Sr-doped graphene systems as compared to the pristine graphene. However, due to its variant bonding characteristic, Be-doped graphene exhibits non-spin-polarized p-type semiconductor behavior, which is consistent with previous works, and an increase in workfunction relative to pristine graphene. Dirac half-metal-like behavior was predicted for magnesium doped graphene while calcium doped and strontium doped graphene were predicted to have bipolar magnetic semiconductor behavior. These changes in the electronic and magnetic properties of alkaline earth doped graphene may be of importance for spintronic and other electronic device applications.


Identification of increased amounts of UDP-glucuronyltransferase protein in phenobarbital-treated chick-embryo liver cells.
UDP-glucuronyltransferase activity of neonatal-chick liver or phenobarbital-treated chick-embryo liver catalysed the glucuronidation of 1-naphthol, 4-nitrophenol and 2-aminophenol. Only low transferase activity towards testosterone was detected, and activity towards bilirubin was not detectable. Liver microsomal transferase activity towards the three phenols was increased approx. 20-50-fold by phenobarbital treatment of chick embryos or by transfer of liver cells into tissue culture. A single form of UDP-glucuronyltransferase, which appears to catalyse the glucuronidation of these three phenols, was purified to near homogeneity from phenobarbital-treated chick-embryo liver microsomal fraction for the first time. The use of this purified enzyme as a standard protein facilitated the identification of this protein in chick-embryo liver microsomal fraction. Further, the accumulation of this microsomal protein was observed following phenobarbital treatment of chick embryos and during tissue culture of chick-embryo liver cells. The value of this model system for the study of the induction of UDP-glucuronyltransferase by drugs and hormones is discussed.


Systematic evidence review of newborn screening and treatment of severe combined immunodeficiency.
Severe combined immunodeficiency (SCID) is a group of disorders that leads to early childhood death as a result of severe infections. Recent research has addressed potential newborn screening for SCID. To conduct a systematic review of the evidence for newborn screening for SCID, including test characteristics, treatment efficacy, and cost-effectiveness. We searched Medline and the OVID In-Process & Other Non-Indexed Citations databases. We excluded articles if they were reviews, editorials or other opinion pieces, or case series of fewer than 4 patients or if they contained only adult subjects or nonhuman data. The remaining articles were systematically evaluated, and data were abstracted by 2 independent reviewers using standardized tools. For topics that lacked published evidence, we interviewed experts in the field. The initial search resulted in 719 articles. Twenty-six met inclusion criteria. The results of several small studies suggested that screening for SCID is possible. Interviews revealed that 2 states have begun pilot screening programs. Evidence from large case series indicates that children receiving early stem-cell transplant for SCID have improved outcomes compared with children who were treated later. There is some inconclusive evidence regarding the need for donor-recipient matching and use of pretransplant chemotherapy. Few data on the cost-effectiveness of a SCID-screening program. Evidence indicates the benefits of early treatment of SCID and the possibility of population-based newborn screening. Better information on optimal treatment and the costs of treatment and screening would benefit policy makers deciding among competing health care priorities.


Effect of gamma radiation and oregano essential oil on murein and ATP concentration of Staphylococcus aureus.
The study was carried out to evaluate the effects of gamma-irradiation alone or in combination with oregano essential oil on murein composition of Staphylococcus aureus and on the intracellular and extracellular concentration of ATP. The bacterial strain was treated with 3 irradiation doses: 1.2 kGy to induce cell damage, 2.9 kGy to obtain a viable but nonculturable state, and 3.5 kGy to cause cell death. Oregano essential oil was used at 0.010% and 0.013% (w/v), which is the minimum inhibitory concentration (MIC). All treatments had a significant effect (P < or = 0.05) on the murein composition, although some muropeptides did not seem to be affected by the treatment. Each treatment influenced differently the relative percentage and number of muropeptides. There was a significant (P < or = 0.05) correlation between the reduction of intracellular ATP and increase in extracellular ATP following treatment of the cells with oregano oil. The reduction of intracellular ATP was even more important when essential oil was combined with irradiation. Also, irradiation alone of S. aureus induced a significant decrease (P < or = 0.05) of the internal ATP and a significant increase (P < or = 0.05) of the external ATP. However, no significant difference (P > 0.05) was observed in ATP concentrations between different radiation doses. Transmission electron microscopic observation revealed that oregano oil and irradiation have an effect on cell wall structure.


Onion and a mixture of vegetables, salads, and herbs affect bone resorption in the rat by a mechanism independent of their base excess.
Prevention of low bone mass is important to reduce the incidence of osteoporotic fractures. In man, the consumption of fruits and vegetables is associated with greater bone mineral density (BMD), an effect that is claimed to be caused by their base excess buffering metabolic acid, thought to dissolve bone. We showed previously that in the rat the consumption of several vegetables, salads, and herbs inhibits bone resorption and that onion increases bone mass. In this study we show that, although the intake of onion is associated with a decrease in urinary noncarbonic acid excretion and a concomitant inhibition of bone resorption of similar magnitude, the two findings are not causally related. Onion retains its bone resorption inhibitory activity in the rat even when added to a vegetarian diet with typical base excess. Onion and a mixture of vegetables, salads, and herbs retain their inhibitory activity even when metabolic acid is buffered with potassium citrate. In addition, neither the pH nor the potassium content of individual ashed vegetables, salads, and herbs correlates with inhibition of bone resorption. The effect of vegetables, salads, and herbs, which inhibit bone resorption in the rat, therefore is not mediated by their base excess but possibly by a pharmacologically active compound(s).


Granulosa Cell Tumors: Novel Predictors of Recurrence in Early-stage Patients.
Granulosa cell tumors (GCTs) comprise 2% to 5% of ovarian neoplasms, with unpredictable patterns of recurrence. The HER family, GATA4, and SMAD3 genes are reportedly involved in GCT proliferation and apoptosis and may serve as new predictors of recurrence. The aim of the study was to evaluate novel predictors of recurrence in GCT from a large single institution cohort. Patients diagnosed with GCTs (n=125) between 1975 and 2014 were identified. Clinicopathologic parameters were obtained and immunohistochemical evaluation was performed of calretinin, inhibin, HER2, CD56, SMAD3, and GATA4. Statistical analyses were conducted using Fisher exact test and Kaplan-Meier survival curves and Cox regression analysis. The median follow-up period was 120 months (range, 1-465 mo). Recurrence was noted in 12/125 (9.6%) patients. Kaplan-Meier analysis showed a shorter mean disease-free interval in whites versus blacks (P=0.001), stage III-IV versus stage I-II (P=0.0001), patients treated with surgery+chemotherapy versus surgery (P=0.0001), mitotic rate ≥4 (P=0.005), severe nuclear pleomorphism (P=0.013), high HER2 expression (P=0.001), high CD56 expression (P=0.001), and high SMAD3 expression (P=0.001). On Cox regression analysis, SMAD3 and type of treatment received were the only 2 independent prognostic factors for disease-free interval (P=0.03 and P=0.007, respectively). On subanalysis for early-stage (stage I) GCTs, the need for adjuvant chemotherapy and high expression of SMAD3 continued to be independent predictors of recurrence (HR=10.2, P=0.01 and HR=8.9, P=0.001, respectively).


Sustainable nurse-led care for people with dementia including mild cognitive impairment and their family in an ambulatory care setting: A scoping review.
This review aimed to determine the characteristics of a nurse-led intervention for people with dementia including mild cognitive impairment and their family in an ambulatory care setting. Enhancing the role of nurses in a multidisciplinary team of ambulatory care follow-up after a diagnosis of dementia is thought to lead to successful dementia care. This is a scoping review. MEDLINE, CINAHL, EMBASE, Cochrane, JBI, Japan Medical Abstracts Society, PsycINFO and Web of Science were searched on 14 March 2019. This scoping review was conducted using the Joanna Briggs Institute methodology, followed the PRISMA-ScR checklist and considered studies that included interventions conducted by nurses and included outcomes regarding dementia symptoms or family care burden. Eleven studies were included. Of these, all interventions were multifactorial and reported effective results. Educational interventions were most common, and the content of education included the characteristics of dementia and how to interact with patients with dementia. The roles of nurses included caregiver education, assessment, care plan creation for continuous monitoring and team building. This scoping review suggested that effective nurse-led interventions in the ambulatory care of people with dementia are continuous patient and family supports, primarily caregiver education within multidisciplinary teams.


Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial.
To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.


The Brain Metabolic Signature in Superagers Using In Vivo 1H-MRS: A Pilot Study.
Youthful memory performance in older adults may reflect an underlying resilience to the conventional pathways of aging. Subjects having this unusual characteristic have been recently termed "superagers." This study aimed to explore the significance of imaging biomarkers acquired by 1H-MRS to characterize superagers and to differentiate them from their normal-aging peers. Fifty-five patients older than 80 years of age were screened using a detailed neuropsychological protocol, and 25 participants, comprising 12 superagers and 13 age-matched controls, were statistically analyzed. We used state-of-the-art 3T 1H-MR spectroscopy to quantify 18 neurochemicals in the posterior cingulate cortex of our subjects. All 1H-MR spectroscopy data were analyzed using LCModel. Results were further processed using 2 approaches to investigate the technique accuracy: 1) comparison of the average concentration of metabolites estimated with Cramer-Rao lower bounds <20%; and 2) calculation and comparison of the weighted means of metabolites' concentrations. The main finding observed was a higher total N-acetyl aspartate concentration in superagers than in age-matched controls using both approaches (P = .02 and P = .03 for the weighted means), reflecting a positive association of total N-acetyl aspartate with higher cognitive performance. 1H-MR spectroscopy emerges as a promising technique to unravel neurochemical mechanisms related to cognitive aging in vivo and providing a brain metabolic signature in superagers. This may contribute to monitoring future interventional therapies to avoid or postpone the pathologic processes of aging.


A More Accurate Kinetic Monte Carlo Approach to a Monodimensional Surface Reaction: The Interaction of Oxygen with the RuO2(110) Surface.
The theoretical study of catalysis would substantialy benefit from the use of atomistic simulations that can provide information beyond mean-field approaches. To date, the nanoscale understanding of surface reactions has been only qualitatively achieved by means of kinetic Monte Carlo coupled to density functional theory, KMC-DFT. Here, we examine a widely employed model for oxygen interaction with the RuO2(110) surface, a highly anisotropic system. Our analysis reveals several covert problems that render as questionable the model's predictions. We suggest an advanced approach that considers all the relevant elementary steps and configurations while smoothing the intrinsic errors in the DFT description of oxygen. Under these conditions, KMC provides quantitative agreement to temperature-programmed desorption experiments. These results illustrate how KMC-based simulations can be pushed forward so that they evolve toward being the standard methodology to study complex chemistry at the nanoscale.


Myocardial cell hypertrophy or hyperplasia.
Growth of the vertebrate heart during embryonic and fetal life is characterized by hyperplasia of myocardial cells; these cells increase in number to a value characteristic for each species. Shortly after birth myocardial cells lose the capability of dividing, and further growth of the heart is due to myocardial cell hypertrophy and nonmuscle cell hyperplasia. This process, which is referred to as hypertrophic growth, results in a 30- to 40-fold increase in volume of individual myocardial cells during normal postnatal growth and maturation. The transition from hyperplastic to hypertrophic growth is related to formation of binucleated myocardial cells as a result of karyokinesis without cytokinesis. The molecular mechanism of this transition is uncertain. The response of the heart to increased metabolic demands or to an increased workload depends on the age of the animal at the time the stress is imposed. Increased myocardial workloads due to systemic hypertension, chronic hypoxia, or carbon monoxide exposure in fetal or early neonatal life lead to cardiac enlargement by causing an increased rate of hyperplasia of myocardial cells or continuation of hyperplasia beyond the normal period of hyperplastic growth. In contrast, imposition of increased loads on the hearts of older animals results in cardiac hypertrophy due to enlargement of myocardial cells and hyperplasia of nonmuscular components. In addition to cellular enlargement, structural remodeling of the myocardial cells, including alterations in the relative proportions of cellular organelles and in the ultrastructure of individual organelles, occurs during the development of hypertrophy in the adult heart.(ABSTRACT TRUNCATED AT 250 WORDS)


Medicare Part D: where we are and where we're going.
Achieving optimum outcomes for our patients clearly is going to require more than making the correct diagnosis and writing the right prescription. If patients cannot access the prescriptions needed to achieve the desired outcome, providers will be judged falling short of the mark. Achieving optimum outcomes requires not only understanding Medicare Part D, but also using this knowledge to develop an efficient and effective office system to gain access to all medically necessary prescriptions.


The FIM instrument in the United States and Italy: a comparative study.
To compare FIM instrument ratings between Italy and the United States. This study utilized 169,835 United States and 4,536 Italian FIM instrument records for stroke with the left side of the body affected, stroke with the right side of the body affected, and orthopedic conditions. Case-mix, patient age, and admission and discharge FIM instrument scores were similar. The delays between onset of disability and admission to rehabilitation and lengths of stay in rehabilitation were 2-4 times longer in Italy. In Italy, some 88-95% of the subjects were discharged to the community vs. 74-88% in the United States. Hierarchies of FIM instrument ratings across the motor and cognitive items were similar, but there were interesting differences. The hierarchical patterns showed that dressing, bathing, perineal hygiene, and tub or shower transfer were relatively more difficult in Italy compared with the Unites States, whereas walking was easier in Italy compared to the United States. The Italian health care payment system offers less incentive for early discharges from acute care and rehabilitation. In Italy, nursing homes are less accessible, whereas family support is more available. Apparently less intensive treatment is applied in Italy, where a minimum time per day for rehabilitation services is not mandatory for payment. Occupational therapy is not used in Italy and the focus is more on physical therapy.


Reduced workforce participation 5 years prior to first Parkinson's disease sick-leave.
The importance of understanding the prodromal phase of Parkinson's disease (PD) by systematic recording of prediagnostic symptoms and reductions in body functions has been highlighted. The aim of this study was to investigate whether persons later diagnosed with PD exhibit increased physician-certified sickness absence 1, 2, and 5 years prior to a first sick-leave episode attributed to PD. A case-control study was performed to analyze data from all nontrivial (exceeding 14 days) sick-leave episodes in Sweden between 2008 and 2014. The 537 incident PD sick-leave episodes were identified as PD sick-leave cases and compared to 537 sick-leave controls identified by matching age, sex, and date of the first day of the sick-leave episode. The total sickness absence and sickness absence due to musculoskeletal diagnoses were found to be increased among the PD sick-leave cases from 5 years prior to the first sick-leave episode ascribed to PD when compared to the controls. No differences between PD sick-leave cases and sick-leave controls were found with regard to mental and behavioral diagnoses. We conclude that the capacity to participate in working life is reduced already at the early prediagnostic stages of PD. This finding can be used as a basis for further research into the process of identifying individuals at risk for developing PD, particularly in combination with further investigation into biochemical, genetic, and imaging biomarkers.


The role of class II molecules in human B cell activation. Association with phosphatidyl inositol turnover, protein tyrosine phosphorylation, and proliferation.
Cross-linking class II molecules on resting human B cells can initiate phosphatidyl inositol turnover and an increase in intracellular calcium concentration levels comparable with that seen with the cross-linking of surface Ig receptors. The calcium response is most evident on dense B cell fractions: buoyant cells are less responsive, even though the levels of class II expression are similar on dense and buoyant tonsillar B cells. Human B cell lines exhibit the same absence of correlation between intensity of the calcium signal and levels of surface class II expression, indicating that responsiveness is related to the state of differentiation of the cell rather than the amount of class II expressed. Cross-linking class II on normal B cells or B cell lines caused accumulation of inositol phosphates, suggesting class II induces calcium release from intracellular stores, rather than through direct regulation of calcium channels. The calcium response mediated through class II was completely abolished by bringing the protein tyrosine phosphatase, CD45, into close proximity with surface class II. This result indicated that protein tyrosine phosphorylation might regulate the signal transduced through this molecule. In support of this notion we found that tyrosine phosphorylation is induced when small dense tonsillar B cells are stimulated with either anti-Ig or with antibodies to class II. Finally, in B cell proliferation assays we show that cross-linking class II molecules on dense tonsillar B cells synergize strongly with suboptimal concentrations of PMA or IL-4. The significance of these results is discussed with regard to the cognate signal between B and T lymphocytes.


The benefit of heart rate variability biofeedback and relaxation training in reducing trait anxiety.
Previous research studies have indicated that biofeedback treatment and relaxation techniques are effective in reducing psychological and physical symptoms (Hammond, 2005; Manzoni, G. M., Pagnini, F., Castelnuovo, G., & Molinari, E., 2008). However, dearth of studies has compared heart rate variability (HRV) biofeedback treatment and relaxation training to reduce trait anxiety. The objective of this study was to determine the effect of HRV biofeedback treatment and relaxation training in reducing trait anxiety compared to control group without any treatment using students in a science and engineering university of South Korea. For the present study, a total of 15 graduate students with moderate level of trait anxiety were recruited for 4 individual sessions every two weeks. They were randomly assigned into three groups: biofeedback treatment (n = 5), relaxation training (n = 5), and no treatment control group (n = 5). Our results revealed significant difference in change score of trait anxiety between the HRV biofeedback treatment and the no treatment control group. However, no significant difference was found between the relaxation training group and the no treatment control group. In addition, there was no significant difference between the HRV biofeedback treatment and the relaxation training. Results of the present study indicate that there is potential benefit in utilizing HRV biofeedback treatment for stress management programs and/or anxiety reduction treatment.


CRISPR/Cas9-mediated gene mutation of EcIAG leads to sex reversal in the male ridgetail white prawn Exopalaemon carinicauda.
In the culture of crustaceans, most species show sexual dimorphism. Monosex culture is an effective approach to achieve high yield and economic value, especially for decapods of high value. Previous studies have developed some sex control strategies such as manual segregation, manipulation of male androgenic gland and knockdown of the male sexual differentiation switch gene encoding insulin-like androgenic gland hormone (IAG) in decapods. However, these methods could not generate hereditable changes. Genetic manipulation to achieve sex reversal individuals is absent up to now. In the present study, the gene encoding IAG (EcIAG) was identified in the ridgetail white prawn Exopalaemon carinicauda. Sequence analysis showed that EcIAG encoded conserved amino acid structure like IAGs in other decapod species. CRISPR/Cas9-mediated genome editing technology was used to knock out EcIAG. Two sgRNAs targeting the second exon of EcIAG were designed and microinjected into the prawn zygotes or the embryos at the first cleavage with commercial Cas9 protein. EcIAG in three genetic males was knocked out in both chromosome sets, which successfully generated sex reversal and phenotypic female characters. The results suggest that CRISPR/Cas9-mediated genome editing technology is an effective way to develop sex manipulation technology and contribute to monosex aquaculture in crustaceans.


IFN-γ Rα is a key determinant of CD8+ T cell-mediated tumor elimination or tumor escape and relapse in FVB mouse.
During the past decade, the dual function of the immune system in tumor inhibition and tumor progression has become appreciated. We have previously reported that neu-specific T cells can induce rejection of neu positive mouse mammary carcinoma (MMC) and also facilitate tumor relapse by inducing neu antigen loss and epithelial to mesenchymal transition (EMT). Here, we sought to determine the mechanism by which CD8+ T cells either eliminate the tumor, or maintain tumor cells in a dormant state and eventually facilitate tumor relapse. We show that tumor cells that express high levels of IFN-γ Rα are eliminated by CD8+ T cells. In contrast, tumor cells that express low levels of IFN-γ Rα do not die but remain dormant and quiescent in the presence of IFN-γ producing CD8+ T cells until they hide themselves from the adaptive immune system by losing the tumor antigen, neu. Relapsed tumor cells show CD44+CD24- phenotype with higher rates of tumorigenesis, in vivo. Acquisition of CD44+CD24- phenotype in relapsed tumors was not solely due to Darwinian selection. Our data suggest that tumor cells control the outcome of tumor immune surveillance through modulation of the expression of IFN-γ Rα.


Are a set of microarrays independent of each other?
Having observed an m x n matrix X whose rows are possibly correlated, we wish to test the hypothesis that the columns are independent of each other. Our motivation comes from microarray studies, where the rows of X record expression levels for m different genes, often highly correlated, while the columns represent n individual microarrays, presumably obtained independently. The presumption of independence underlies all the familiar permutation, cross-validation, and bootstrap methods for microarray analysis, so it is important to know when independence fails. We develop nonparametric and normal-theory testing methods. The row and column correlations of X interact with each other in a way that complicates test procedures, essentially by reducing the accuracy of the relevant estimators.