Low density lipoprotein kinetics in a family having defective low density lipoprotein receptors in which hypercholesterolemia is suppressed.
Heterozygous familial hypercholesterolemia (FH) usually presents with severe elevations of low density lipoprotein (LDL) cholesterol. Recently, a family with FH was described in which several members heterozygous for a mutation in the LDL receptor gene had normal LDL cholesterol levels. Kinetic studies of LDL apolipoprotein B (apo B) were conducted to determine the metabolic differences between the normolipidemic and hypercholesterolemic FH heterozygotes in the family. Studies were performed in 14 family members including the proband (who has homozygous FH), four FH heterozygotes with high LDL levels, four FH subjects with normolipidemia, and five healthy relatives without FH. The proband had a very low fractional catabolic rate (FCR) for LDL (0.15 pool/day). All the FH and non-FH subjects studied, excluding the FH homozygote, had higher than expected FCRs for LDL. The average FCRs for LDL of hypercholesterolemic and normocholesterolemic subjects were not significantly different (0.39 +/- 0.06 versus 0.37 +/- 0.02 pool/day), and these values were 70-80% of those in unaffected relatives. Compared with hypercholesterolemic FH heterozygotes, normolipidemic heterozygotes had much lower input rates for LDL (17.1 +/- author query macros2.6 versus 8.7 +/- 0.9 pools/day, respectively). These low input rates, together with the higher than usual FCRs for LDL, are responsible for the normal concentrations of LDL cholesterol in some of the FH heterozygotes. The low input of LDL could be due to either a decreased secretion of apo B-containing lipoproteins or an enhanced clearance of LDL precursor lipoproteins.


Pulmonary sarcomatous tumors.
Sarcomatous pulmonary neoplasms are a rare and diagnostically challenging group of tumors. Primary pulmonary sarcomas must be distinguished from the more frequent occurrence of sarcoma metastatic to the lung, primary pulmonary sarcomatoid carcinoma, and diffuse malignant mesothelioma involving the lung. In current practice, the general availability of ancillary diagnostic techniques, such as immunohistochemistry and molecular analysis, can reliably classify many sarcomatoid lesions. To review the literature and report on additional primary material about the application of immunohistochemistry and molecular analysis in the differential diagnosis pulmonary sarcomatous neoplasms. Literature review of relevant articles indexed in PubMed (National Library of Medicine) between 1961 and 2007 and primary material from the author's institution. This review discusses specific criteria for the diagnosis of primary lung sarcomas and offers a practical approach to excluding other sarcoma-like lesions involving the lung. The pathologist has an essential role in evaluating these tumors and will often be the first to suggest an unusual, alternative diagnosis, which may have significant implications for patient care, therapy, and prognosis.


Boll weevil eradication.
Some representatives of the cotton industry and of the entomological profession advocate efforts to eradicate the boll weevil. This coalition originated in 1958 from a complex of socioeconomic changes in cotton production and scientific developments in entomology. The results of a pilot eradication experiment (1971 to 1973) were controversial, and the debate was inhibited by social pressures upon the entomological profession. Substantial conceptual difficulties also attend evaluations of eradication experiments. A new trial eradication program is under way. If its evaluation is not to be warped by problems similar to the earlier ones, both the social and scientific aspects of eradication must be recognized and steps must be taken to ensure a full and open debate.


MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.
Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.


Stratiform copper deposit, northern anatolia, Turkey: evidence for early bronze I (2800 B.C.) mining activity.
A stratiform, massive copper sulfide deposit with possible gold, silver, and cobalt credits was discovered by a United Nations reconnaissance team in Paleozoic (?) metamorphic terrain of north central Turkey. The deposit, which is of possible volcanigenic exhalative origin, contains evidence of extensive prehistoric underground mining and smelting activity that, based on radiocarbon data, may date to 2800 B.C. (Early Bronze I Age).


RNA structure: merging chemistry and genomics for a holistic perspective.
The advent of deep sequencing technology has unexpectedly advanced our structural understanding of molecules composed of nucleic acids. A significant amount of progress has been made recently extrapolating the chemical methods to probe RNA structure into sequencing methods. Herein we review some of the canonical methods to analyze RNA structure, and then we outline how these have been used to probe the structure of many RNAs in parallel. The key is the transformation of structural biology problems into sequencing problems, whereby sequencing power can be interpreted to understand nucleic acid proximity, nucleic acid conformation, or nucleic acid-protein interactions. Utilizing such technologies in this way has the promise to provide novel structural insights into the mechanisms that control normal cellular physiology and provide insight into how structure could be perturbed in disease.


Cooperative action of Hsp70, Hsp90, and DnaJ proteins in protein renaturation.
The proteins required for the repair of damaged proteins in the eukaryotic cytoplasm remain largely uncharacterized. The renaturation of thermally denatured firefly luciferase readily occurs in rabbit reticulocyte lysate by an ATP-dependent process. Earlier studies had shown that this chaperoning activity could be reconstituted, in part, using purified preparations of hsp70 and hsp90. We have extended the description of this system by clarifying the importance of hsp70 and hsp90 and have tested for additional factors that enhance renaturation. Using mutant hsp70 proteins, we have shown that hsp70 is required for luciferase renaturation. We have also found that hsp70 and hsp90 preparations purified by common procedures were contaminated with low levels of DnaJ proteins that are essential for the renaturing activity. When hsp70 and hsp90 preparations free of DnaJ proteins are used, the system must be supplemented with a DnaJ protein to obtain renaturation activity. The yeast DnaJ protein, YDJ-1, was found to be very effective for this purpose. Although significant renaturation can occur with only hsp70 and DnaJ proteins, hsp90 also contributes to the renaturation process, both in the complex environment of reticulocyte lysate and in a purified system. However, using highly purified hsp90 and geldanamycin, a specific inhibitor of hsp90 function, we have determined that hsp90 is not an essential component of the renaturation system. The contribution of hsp90 to renaturation is only partially blocked by geldanamycin, suggesting that this protein may influence activity in more than one way. This study indicates that hsp70, hsp90, and DnaJ proteins function cooperatively to renature damaged proteins in the eukaryotic cytoplasm and provides a framework by which additional components can be identified and individual chaperone contributions can be investigated.


Decision aids that facilitate elements of shared decision making in chronic illnesses: a systematic review.
Shared decision making (SDM) is a patient-centered approach in which clinicians and patients work together to find and choose the best course of action for each patient's particular situation. Six SDM key elements can be identified: situation diagnosis, choice awareness, option clarification, discussion of harms and benefits, deliberation of patient preferences, and making the decision. The International Patient Decision Aid Standards (IPDAS) require that a decision aid (DA) support these key elements. Yet, the extent to which DAs support these six key SDM elements and how this relates to their impact remain unknown. We searched bibliographic databases (from inception until November 2017), reference lists of included studies, trial registries, and experts for randomized controlled trials of DAs in patients with cardiovascular, or chronic respiratory conditions or diabetes. Reviewers worked in duplicate and independently selected studies for inclusion, extracted trial, and DA characteristics, and evaluated the quality of each trial. DAs most commonly clarified options (20 of 20; 100%) and discussed their harms and benefits (18 of 20; 90%; unclear in two DAs); all six elements were clearly supported in 4 DAs (20%). We found no association between the presence of these elements and SDM outcomes. DAs for selected chronic conditions are mostly designed to transfer information about options and their harms and benefits. The extent to which their support of SDM key elements relates to their impact on SDM outcomes could not be ascertained. PROSPERO registration number: CRD42016050320 .


Adapting Citizen Science to Improve Health in an Occupational Setting: Preliminary Results of a Qualitative Study.
Health interventions often do not reach blue-collar workers. Citizen science engages target groups in the design and execution of health interventions, but has not yet been applied in an occupational setting. This preliminary study determines barriers and facilitators and feasible elements for citizen science to improve the health of blue-collar workers. The study was conducted in a terminal and construction company by performing semi-structured interviews and focus groups with employees, company management and experts. Interviews and focus groups were analyzed using thematic content analysis and the elements were pilot tested. Workers considered work pressure, work location and several personal factors as barriers for citizen science at the worksite, and (lack of) social support and (negative) social culture both as barriers and facilitators. Citizen science to improve health at the worksite may include three elements: (1) knowledge and skills, (2) social support and social culture, and (3) awareness about lifestyle behaviors. Strategies to implement these elements may be company specific. This study provides relevant indications on feasible elements and strategies for citizen science to improve health at the worksite. Further studies on the feasibility of citizen science in other settings, including a larger and more heterogeneous sample of blue-collar workers, are necessary.


Management of ground-glass opacities: should all pulmonary lesions with ground-glass opacity be surgically resected?
Pulmonary nodules with ground-glass opacity (GGO) are frequently observed and will be increasingly detected. GGO can be observed in both benign and malignant conditions, including lung cancer and its preinvasive lesions. Atypical adenomatous hyperplasia and adenocarcinoma in situ are typically manifested as pure GGOs, whereas more advanced adenocarcinomas may include a larger solid component within the GGO region. The natural history of GGOs has been gradually clarified. Approximately 20% of pure GGOs and 40% of part-solid GGOs gradually grow or increase their solid component, whereas others remain unchanged for years. Therefore, it remains unclear whether all pulmonary lesions with GGO should be surgically resected or whether lesions without changes may not require resection. To distinguish GGOs with growth from those without growth, a 3-year follow-up observation period is a reasonable benchmark based on the data that the volume-doubling time (VDT) of pure GGOs ranges from approximately 600 to 900 days and that of part-solid GGOs ranges from 300 to 450 days. Future studies on the genetic differences between GGOs with growth and those without growth will help establish an appropriate management algorithm.


Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China.
Data are lacking whether patients with hypertension who are taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have increased severity or risk of mortality during hospitalization for coronavirus disease 2019 (COVID-19). To investigate the association between ACEIs/ARBs and severity of illness and mortality in patients with hypertension hospitalized for COVID-19 infection. Retrospective, single-center case series of the 1178 hospitalized patients with COVID-19 infections at the Central Hospital of Wuhan, China, from January 15 to March 15, 2020. COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction and epidemiologic, clinical, radiologic, laboratory, and drug therapy data were analyzed in all patients. The percentage of patients with hypertension taking ACEIs/ARBs was compared between those with severe vs nonsevere illness and between survivors vs nonsurvivors. Of the 1178 patients with COVID-19, the median age was 55.5 years (interquartile range, 38-67 years) and 545 (46.3%) were men. The overall in-hospital mortality was 11.0%. There were 362 patients with hypertension (30.7% of the total group; median age, 66.0 years [interquartile range, 59-73 years]; 189 [52.2%] were men), of whom 115 (31.8%) were taking ACEI/ARBs. The in-hospital mortality in the patients with hypertension was 21.3%. The percentage of patients with hypertension taking ACEIs/ARBs did not differ between those with severe and nonsevere infections (32.9% vs 30.7%; P = .65) nor did it differ between nonsurvivors and survivors (27.3% vs 33.0%; P = .34). Similar findings were observed when data were analyzed for patients taking ACEIs and those taking ARBs. This study provides clinical data on the association between ACEIs/ARBs and outcomes in patients with hypertension hospitalized with COVID-19 infections, suggesting that ACEIs/ARBs are not associated with the severity or mortality of COVID-19 in such patients. These data support current guidelines and societal recommendations for treating hypertension during the COVID-19 pandemic.


Balance Training With a Vibrotactile Biofeedback System Affects the Dynamical Structure of the Center of Pressure Trajectories in Chronic Stroke Patients.
Haptic-based vibrotactile biofeedback (BF) is a promising technique to improve rehabilitation of balance in stroke patients. However, the extent to which BF training changes temporal structure of the center of pressure (CoP) trajectories remains unknown. This study aimed to investigate the effect of vibrotactile BF training on the temporal structure of CoP during quiet stance in chronic stroke patients using detrended fluctuation analysis (DFA). Nine chronic stroke patients (age; 81.56 ± 44 months post-stroke) received a balance training regimen using a vibrotactile BF system twice a week over 4 weeks. A Wii Balance board was used to record five 30 s trials of quiet stance pre- and post-training at 50 Hz. DFA revealed presence of two linear scaling regions in CoP indicating presence of fast- and slow-scale fluctuations. Averaged across all trials, fast-scale fluctuations showed persistent dynamics (α = 1.05 ± 0.08 for ML and α = 0.99 ± 0.17 for AP) and slow-scale fluctuations were anti-persistent (α = 0.35 ± 0.05 for ML and α = 0.32 ± 0.05 for AP). The slow-scale dynamics of ML CoP in stroke patients decreased from pre-training to post-BF training (α = 0.40 ± 0.13 vs. 0.31 ± 0.09). These results suggest that the vibrotactile BF training affects postural control strategy used by chronic stroke patients in the ML direction. Results of the DFA are further discussed in the context of balance training using vibrotactile BF and interpreted from the perspective of intermittent control of upright stance.


Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment.
Dysfunctional tear syndrome (DTS) is a common and complex condition affecting the ocular surface. The health and normal functioning of the ocular surface is dependent on a stable and sufficient tear film. Clinician awareness of conditions affecting the ocular surface has increased in recent years because of expanded research and the publication of diagnosis and treatment guidelines pertaining to disorders resulting in DTS, including the Delphi panel treatment recommendations for DTS (2006), the International Dry Eye Workshop (DEWS) (2007), the Meibomian Gland Dysfunction (MGD) Workshop (2011), and the updated Preferred Practice Pattern guidelines from the American Academy of Ophthalmology pertaining to dry eye and blepharitis (2013). Since the publication of the existing guidelines, new diagnostic techniques and treatment options that provide an opportunity for better management of patients have become available. Clinicians are now able to access a wealth of information that can help them obtain a differential diagnosis and treatment approach for patients presenting with DTS. This review provides a practical and directed approach to the diagnosis and treatment of patients with DTS, emphasizing treatment that is tailored to the specific disease subtype as well as the severity of the condition.


Compassion meditation enhances empathic accuracy and related neural activity.
The ability to accurately infer others' mental states from facial expressions is important for optimal social functioning and is fundamentally impaired in social cognitive disorders such as autism. While pharmacologic interventions have shown promise for enhancing empathic accuracy, little is known about the effects of behavioral interventions on empathic accuracy and related brain activity. This study employed a randomized, controlled and longitudinal design to investigate the effect of a secularized analytical compassion meditation program, cognitive-based compassion training (CBCT), on empathic accuracy. Twenty-one healthy participants received functional MRI scans while completing an empathic accuracy task, the Reading the Mind in the Eyes Test (RMET), both prior to and after completion of either CBCT or a health discussion control group. Upon completion of the study interventions, participants randomized to CBCT and were significantly more likely than control subjects to have increased scores on the RMET and increased neural activity in the inferior frontal gyrus (IFG) and dorsomedial prefrontal cortex (dmPFC). Moreover, changes in dmPFC and IFG activity from baseline to the post-intervention assessment were associated with changes in empathic accuracy. These findings suggest that CBCT may hold promise as a behavioral intervention for enhancing empathic accuracy and the neurobiology supporting it.


Emotional memory in pregnant women at risk for postpartum depression.
Postpartum depression (PPD) is associated with debilitating effects on mothers and their infants. A previous history of depression is considered the strongest risk factor for PPD. Depressed individuals recall more negative than positive content and higher levels of stress hormones released during encoding are associated with enhanced recall of emotional stimuli. This study examined the impact of a previous history of major depressive disorder (MDD) and pregnancy on emotional memory. Seventy-seven participants completed the study [44 pregnant women in the second trimester of pregnancy with and without a lifetime history of MDD and 33 non-pregnant women with and without a lifetime history of MDD]. All completed an encoding task and provided salivary cortisol (sCORT) and alpha-amylase (sAA) samples. Participants returned one week later for a surprise incidental recognition memory task. Women with a history of MDD had worse recognition than women without a history of MDD for negative, but not positive images; this effect was independent of sCORT and sAA levels. Pregnancy did not affect emotional memory. Considering that several previous studies found enhanced memory bias for negative content during depressive states, our results suggest that clinical remission may be associated with an opposite cognitive processing of negative emotional content.


Community based needs assessment in an urban area: a participatory action research project.
Community assessment is a core function of public health. In such assessments, a commitment to community participation and empowerment is at the heart of the WHO European Healthy Cities Network, reflecting its origins in health for all and the Ottawa Charter for Health Promotion. This study employs a participation and empowerment plan in order to conduct community assessment. The method of participatory action research (PAR) was used. The study was carried out in an area of high socio-economic deprivation in Ardabil, a city in the northwest of Iran, which is currently served by a branch of the Social Development Center (SDC). The steering committee of the project was formed by some university faculty members, health officials and delegates form Farhikhteh non-governmental organization and representatives from twelve blocks or districts of the community. Then, the representatives were trained and then conducted focus groups in their block. The focus group findings informed the development of the questionnaire. About six hundred households were surveyed and study questionnaires were completed either during face-to-face interviews by the research team (in case of illiteracy) or via self-completion. The primary question for the residents was: 'what is the most important health problem in your community? Each health problem identified by the community was weighted based on the frequency it was selected on the survey, and steering committee perception of the problem's seriousness, urgency, solvability, and financial load. The main problems of the area appeared to be the asphalt problem, lack of easy access to medical centers, addiction among relatives and unemployment of youth. High participation rates of community members in the steering committee and survey suggest that the PAR approach was greatly appreciated by the community and that problems identified through this research truly reflect community opinion. Participatory action research is an effective method for community assessments. However, researchers must rigorously embrace principles of mutual cooperation, respect for public ideas, and a robust belief in community empowerment in order to pave the way for responsible and active citizen participation in the various stages of research.


The neuroprotective effects of ginsenosides on calcineurin activity and tau phosphorylation in SY5Y cells.
Calcineurin (CN) is a Ca(2+)/calmodulin-dependent protein phosphatase expressed at high levels in brain. Many findings have shown that calcineurin plays an important role in tau hyperphosphorylation, which is one of the neuropathologic features in the brains of Alzheimer's disease (AD). Based on the molecular screening model using p-nitrophenyl phosphate (p-NPP) as a substrate for preliminary screening and (32)P-labeled 19-residue phosphopeptide as a specific substrate for final determination, we found that the total ginsenoside extracts from stems and leaves of Panax ginseng (GSL) could enhance the phosphatase activity of purified CN. In the human neuroblastoma cells SY5Y, inhibition of CN by cyclosporine A (CsA) could induce hyperphosphorylation of tau at multiple sites, accompanied with oxidative stress. Pretreatment of the cells with GSL prior to CsA exposure could alleviate CsA-induced CN inhibition and tau hyperphosphorylation to some degree. Further oxidative parameters demonstrated that GSL caused increased SOD activity and content of SH significantly. It is speculated that GSL weakens CsA-induced CN inhibition through the antioxidant mechanisms. Although our results indicate that GSL may have neuroprotective effects on some characteristic features of AD, the chemical compositions of GSL and their potential for affecting the disease mechanism need to be further studied.


Partitioning of tetra- and pentabromo diphenyl ether and benzo[a]pyrene among water and dissolved and particulate organic carbon along a salinity gradient in coastal waters.
This study assessed the partitioning of 2,2',4,4'-tetrabromo diphenyl ether (BDE-47), 2,2',4,4',5-pentabromo diphenyl ether (BDE-99) and benzo[a]pyrene (BaP) among water, dissolved organic carbon (DOC: 4.93-8.72 mg/L), and particulate organic carbon (POC: 191-462 µg/L) along the salinity gradient (0-5.5‰) of the Baltic Sea off the coast of Finland. Equilibrium dialysis and two solid-phase extraction techniques using polyoxymethylene polymer (POM) were used to determine partitioning coefficients. Experiments using artificial coastal water (ACW) with Nordic fulvic (FAs) and humic acids (HAs) were used to assess the effect of salinity (0 and 5.5‰) on the DOC-water partitioning of the model compounds. All three compounds bound more (2.2-3.8-fold) to the HAs than to the FAs. Increasing salinity from 0 to 5.5‰ decreased sorption to dissolved humic substances in the ACW and Baltic Sea water samples. Along the salinity gradient, the sorption of compounds to organic material decreased when the salinity increased. Particulate organic matter sorbed model compounds per unit of carbon more than dissolved organic matter. Along the studied salinity gradient, the freely dissolved portion increased from 10 to 29% to 52 to 80% in the coastal water samples, mainly because of the increasing salinity and changes in DOC and quality of POC.


Health, economic, and social implications of COVID-19 for China's rural population.
This study examines the effects of local and nationwide COVID-19 disease control measures on the health and economy of China's rural population. We conducted phone surveys with 726 randomly selected village informants across seven rural Chinese provinces in February 2020. Four villages (0.55%) reported infections, and none reported deaths. Disease control measures had been universally implemented in all sample villages. About 74% of informants reported that villagers with wage-earning jobs outside the village had stopped working due to workplace closures. A higher percentage of rural individuals could not work due to transportation, housing, and other constraints. Local governments had taken measures to reduce the impact of COVID-19. Although schools in all surveyed villages were closed, 71% of village informants reported that students were attending classes online. Overall, measures to control COVID-19 appear to have been successful in limiting disease transmission in rural communities outside the main epidemic area. Rural Chinese citizens, however, have experienced significant economic consequences from the disease control measures.


Isobaric gas counterdiffusion in rabbit eye.
The superficial isobaric gas counterdiffusion phenomenon, which produces dermal lesions and lethal gas embolism, was investigated at sea level and 2 ATA for effects on the eye of the New Zealand White rabbit. The animals breathed an N2O-O2 mixture by mask and were surrounded by a He environment. There was no gas lesion formation in the conjunctiva or cornea and no gas bubble formation in the anterior compartment of the eye in any of the experimental animals, even at the maximal 8-h exposure. In contrast to the eye, the skin of these animals showed progressive gas-filled lesions after 3 h at 1 ATA. Reasons for the relative insensitivity of the structures of the eye to the counter-diffusion process are discussed.


Molecular analysis of hprt mutations generated in Chinese hamster ovary EM9 cells by uranyl acetate, by hydrogen peroxide, and spontaneously.
Naturally occurring uranium and depleted uranium (DU) are believed to be health hazards by virtue of both their chemical and radiological properties. The mechanism(s) behind uranium's chemotoxic effects has yet to be elucidated. Previous work has shown that DU, as uranyl acetate (UA), was mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus in XRCC1-deficient CHO EM9 cells. The purpose of the current study was to characterize the mutations induced by UA at the hprt locus of CHO EM9 cells and compare the mutation spectrum of UA with those of hydrogen peroxide and spontaneous mutations in the same line. The hypothesis being tested was that if DU as UA is chemically genotoxic then the mutation spectrum induced by the heavy metal should be distinct from that produced spontaneously or by H2O2. A total of 59 UA-induced, 38 spontaneous, and 45 H2O2-induced mutations were identified. Base substitutions comprised 29%, 42%, and 16% of UA, spontaneous, and H2O2 mutants, respectively. The frequency of G --> T or C --> A substitutions was not significantly different in spontaneous or H2O2-induced mutants than in UA-induced mutants, suggesting a possible role for 8-oxodG damage in UA mutagenesis. However, the observation that UA produced significantly more major genomic rearrangements (multiexon insertions and deletions) than occurred spontaneously suggests the possibility that DNA strand breaks or crosslinks could also be UA-induced mutagenic lesions. The unique mutation spectrum elicited by exposure to UA suggests that UA generates mutations in ways that are different from spontaneous and free radical as well as radiological mechanisms.


The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.
Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.


MOZ fusion proteins in acute myeloid leukaemia.
MOZ (monocytic leukaemia zinc finger protein; also known as ZNF220 or MYST3) is a member of the MYST family of protein acetyltransferases. Chromosomal translocations involving the MOZ gene are associated with AML (acute myeloid leukaemia), suggesting that it has a role in haematopoiesis. Recurrent reciprocal translocations fuse the MOZ gene [or the gene encoding MORF (MOZ-related factor); also known as MYST4] to genes encoding the nuclear receptor co-activators CBP [CREB (cAMP response element-binding protein)-binding protein], p300 or the p160 protein TIF2 (transcription intermediary factor 2). The resulting fusion proteins can transform haematopoietic progenitors in vitro, and induce myeloproliferative disease in mice. Recent insights into the molecular mechanisms underlying these effects indicate that MOZ fusion proteins interfere with the activities of transcription factors such as nuclear receptors, p53 and Runx proteins. Our studies suggest that subverting the function of cellular CBP and p300 proteins may play a key role in this process. Here we review the recent progress in understanding the role of MOZ fusion proteins in the aetiology of AML.


Metabolic Phenotypes of Response to Vaccination in Humans.
Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.


Self-induced thermal distortion effects on target image quality.
Experimental results are reported that show the effects of the self-induced thermal lens due to a high power laser beam on imaging or tracking systems viewing along the same propagation path. The thermal distortion effects of a wind are simulated with a low power ( less, similar 3-W) CO(2) laser beam propagating through a cell of liquid CS(2) moving across the beam. The resulting image distortion includes a warping effect analogous to the deflection of the CO(2) beam, together with a pronounced demagnification of the central portion of the object. An active optical tracker is simulated with a He-Ne laser beam propagating collinearly with the CO(2) beam. The He-Ne beam pattern returned from a specular target is distorted and sharply confined to the outline of the crescent shaped CO(2) beam. Simple ray optics models are used to provide qualitative explanations for the experimental results.


Comparative genomics and functional analysis of rhamnose catabolic pathways and regulons in bacteria.
L-rhamnose (L-Rha) is a deoxy-hexose sugar commonly found in nature. L-Rha catabolic pathways were previously characterized in various bacteria including Escherichia coli. Nevertheless, homology searches failed to recognize all the genes for the complete L-Rha utilization pathways in diverse microbial species involved in biomass decomposition. Moreover, the regulatory mechanisms of L-Rha catabolism have remained unclear in most species. A comparative genomics approach was used to reconstruct the L-Rha catabolic pathways and transcriptional regulons in the phyla Actinobacteria, Bacteroidetes, Chloroflexi, Firmicutes, Proteobacteria, and Thermotogae. The reconstructed pathways include multiple novel enzymes and transporters involved in the utilization of L-Rha and L-Rha-containing polymers. Large-scale regulon inference using bioinformatics revealed remarkable variations in transcriptional regulators for L-Rha utilization genes among bacteria. A novel bifunctional enzyme, L-rhamnulose-phosphate aldolase (RhaE) fused to L-lactaldehyde dehydrogenase (RhaW), which is not homologous to previously characterized L-Rha catabolic enzymes, was identified in diverse bacteria including Chloroflexi, Bacilli, and Alphaproteobacteria. By using in vitro biochemical assays we validated both enzymatic activities of the purified recombinant RhaEW proteins from Chloroflexus aurantiacus and Bacillus subtilis. Another novel enzyme of the L-Rha catabolism, L-lactaldehyde reductase (RhaZ), was identified in Gammaproteobacteria and experimentally validated by in vitro enzymatic assays using the recombinant protein from Salmonella typhimurium. C. aurantiacus induced transcription of the predicted L-Rha utilization genes when L-Rha was present in the growth medium and consumed L-Rha from the medium. This study provided comprehensive insights to L-Rha catabolism and its regulation in diverse Bacteria.


Characterization of haptoglobin in the blood plasma of harbor seals (Phoca vitulina).
Haptoglobin (Hp) is one of the acute phase proteins (APP) in the blood of vertebrates that is involved in immune responses. Hp concentrations are found to vary under conditions of, for example, infection, trauma or cancer. These variations and the changes in its constitution are frequently used to assess the health status of mammals. In this work, Hp from the blood plasma of diseased and healthy harbor seals was isolated and structurally characterized. The process developed for the isolation of Hp is based on glycoprotein enrichment from crude plasma samples by means of ConA lectin affinity separation. Structural features of the protein backbone and the N-glycans were determined using MALDI-TOF/TOF-MS. De novo sequencing of seal Hp revealed an alpha-chain composed of 84 amino acids and a beta-chain comprising 245 amino acids. Comparison with Hp of the phylogenically related dog and human Hp 1-1 reveals the conserved and variable regions. All cysteine residues responsible for disulfide bonds and one glycosylation site have identical positions in the primary structures. Altogether, four possible glycosylation sites were identified. The glycoprofile is dominated by disialylated biantennary complex-type glycans.


Iron-Catalyzed α-C-H Cyanation of Simple and Complex Tertiary Amines.
This manuscript details the development of a general and mild protocol for the α-C-H cyanation of tertiary amines and its application in late-stage functionalization. Suitable substrates include tertiary aliphatic, benzylic, and aniline-type substrates and complex substrates. Functional groups tolerated under the reaction conditions include various heterocycles and ketones, amides, olefins, and alkynes. This broad substrate scope is remarkable, as comparable reaction protocols for α-C-H cyanation frequently occur via free radical mechanisms and are thus fundamentally limited in their functional group tolerance. In contrast, the presented catalyst system tolerates functional groups that typically react with free radicals, suggesting an alternative reaction pathway. All components of the described catalyst system are readily available, allowing implementation of the presented methodology without the need for lengthy catalyst synthesis.


Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes.
Mantle cell lymphoma (MCL) is an incurable, typically aggressive subtype of non-Hodgkin lymphoma, accounting for 4%-7% of newly diagnosed non-Hodgkin lymphoma cases. Chemoresistance commonly ensues in MCL, and patients with this heterogeneous disease invariably relapse, underscoring the unmet need for better therapies. Over the past few years, several novel agents with promising activity and unique mechanisms of action have been deemed effective in MCL. Bortezomib is a reversible proteasome inhibitor, approved as a single agent for patients with relapsed/refractory MCL who have received at least one prior line of therapy. Addition of bortezomib to chemoimmunotherapies has demonstrated good tolerability and superior efficacy, both in the upfront and salvage settings, and recently one such combination of bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone was approved as a frontline regimen in untreated patients with MCL. This review examines the role of bortezomib in a multitude of clinical settings and ongoing clinical trials designed to optimize its integration in the current treatment paradigms of MCL.


A Randomized Comparative Effectiveness Trial for Preventing Type 2 Diabetes.
We evaluated the weight loss effectiveness of a YMCA model for the Diabetes Prevention Program (DPP) lifestyle intervention. Between July 2008 and November 2010, we individually randomized 509 overweight or obese, low-income, nondiabetic adults with elevated blood glucose in Indianapolis, Indiana, to receive standard care plus brief lifestyle counseling or be offered a group-based YMCA adaptation of the DPP (YDPP). Primary outcome was mean weight loss difference at 12 months. In our intention-to-treat analyses, we used longitudinal linear or logistic regression, multiply imputing missing observations. We used instrumental variables regression to estimate weight loss effectiveness among participants completing 9 or more intervention lessons. In the YDPP arm, 161 (62.6%) participants attended ≥ 1 lesson and 103 (40.0%) completed 9 or more lessons. In intention-to-treat analysis, mean 12-month weight loss was 2.3 kilograms (95% confidence interval [CI] = 1.1, 3.4 kg) more for the YDPP arm than for standard care participants. In instrumental variable analyses, persons attending 9 or more lessons had a 5.3-kilogram (95% CI = 2.8, 7.9 kg) greater weight loss than did those with standard care alone. The YMCA model for DPP delivery achieves meaningful weight loss at 12 months among low-income adults.


Cromoglycate drugs suppress eicosanoid generation in U937 cells by promoting the release of Anx-A1.
Using biochemical, epifluorescence and electron microscopic techniques in a U937 model system, we investigated the effect of anti-allergic drugs di-sodium cromoglycate and sodium nedocromil on the trafficking and release of the anti-inflammatory protein Annexin-A1 (Anx-A1) when this was triggered by glucocorticoid (GC) treatment. GCs alone produced a rapid (within 5min) concentration-dependent activation of PKCalpha/beta (Protein Kinase C; EC 188.8.131.52) and phosphorylation of Anx-A1 on Ser(27). Both phosphoproteins accumulated at the plasma membrane and Anx-A1 was subsequently externalised thereby inhibiting thromboxane (Tx) B(2) generation. When administered alone, cromoglycate or nedocromil had little effect on this pathway however, in the presence of a fixed sub-maximal concentration of GCs, increasing amounts of the cromoglycate-like drugs caused a striking concentration-dependent enhancement of Anx-A1 and PKCalpha/beta phosphorylation, membrane recruitment and Anx-A1 release from cells resulting in greatly enhanced inhibition of TxB(2) generation. GCs also stimulated phosphatase accumulation at the plasma membrane of U937 cells. Both cromoglycate and nedocromil inhibited this enzymatic activity as well as that of a highly purified PP2A phosphatase preparation. We conclude that stimulation by the cromoglycate-like drugs of intracellular Anx-A1 trafficking and release (hence inhibition of eicosanoid release) is secondary to inhibition of a phosphatase PP2A (phosphoprotein phosphatase; EC 188.8.131.52), which probably forms part of a control loop to limit Anx-A1 release. These experiments provide a basis for a novel mechanism of action for the cromolyns, a group of drugs that have long puzzled investigators.


Responses of soil nutrient concentrations and stoichiometry to different human land uses in a subtropical tidal wetland.
We studied the impacts of anthropogenic changes in land use on the stoichiometric imbalance of soil carbon (C), nitrogen (N), phosphorus (P) and potassium (K) in Phragmites australis wetlands in the Minjiang River estuary. We compared five areas with different land uses: P. australis wetland (control), grassland, a mudskipper breeding flat, pond aquaculture and rice cropland. Human activity has affected the elemental and stoichiometric compositions of soils through changes in land use. In general, soil C and N concentrations were lower and total soil K concentrations were higher at the sites under human land uses relative to the control site, and total soil P concentrations were generally not significantly different. The close relationship between total soil C and N concentrations in all cases, including fertilization with N, suggested that N was the most limiting nutrient in these wetlands. Lower soil N concentrations and similar soil P concentrations and higher soil K concentrations under human land-use activities suggest that human activity has increased the role of N limitation in these wetlands. Only grassland use increases soil N contents (only in the 0-10 cm of soil). Despite N fertilization, lower soil N concentrations were also observed in the rice cropland, indicating the difficulty of avoiding N limitation in these wetlands. The observed lower soil N:P ratio, together with higher soil P and K availabilities in rice croplands, is consistent with the tendency of human activity to change the competitive relationships of plants, in this case favoring species adapted to high rates of growth (low N:P ratio) and/or favoring plants with high demands for P and K. Both, soil C storage and respiration were higher in grasslands, likely due to the introduction of grasses, which led to a high density of plants, increased grazing activity and soil compaction. Soil C storage and respiration were lower under human land uses, except in the rice cropland, with respect to natural wetland. Using overall data, soil C storage and respiration were correlated, indicating that soil respiration was correlated with plant productivity. In this wetland area the impacts of different human land-uses on soil stoichiometry and C-cycle can be very different depending on the activity. Further regeneration of natural communities can be determined by the previous type of land-use.


Pemphigus.
Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell-cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.


Current status and trends in oral health in community dwelling older adults: a global perspective.
To record the available current national and regional data on the oral health of community-dwelling (living in their own homes, not institutionalised) older people globally and discuss the future trends considering existing dangers and opportunities. A literature search on tooth loss, dental decay and periodontal disease in the elderly was performed using available databases and electronic sources. The findings revealed that the updated national data are scarce in many parts of the world, particularly in Africa, Asia and South America, and direct comparisons are not always possible due to methodological variations. The available information may indicate that dental disease in older adults worldwide is more prevalent compared to younger age groups, with significant variation between countries and regions. Tooth loss is currently more common in the developed countries, while dental decay and periodontal disease are more widespread globally. There are important threats for further deterioration of the oral status among older adults in many developed and less developed areas due to existing sociodemographic and economic risk factors. National studies should be undertaken to record the specific oral problems of the elderly in each area. It is also necessary to develop gerodontology study programmes globally at the undergraduate, postgraduate and continuing education levels which will enhance dentists' knowledge, skills and attitudes towards oral care in the older population, and will promote opportunities for further research and development of relevant policies.


Review on City-Level Carbon Accounting.
Carbon accounting results for the same city can differ due to differences in protocols, methods, and data sources. A critical review of these differences and the connection among them can help to bridge our knowledge between university-based researchers and protocol practitioners in accounting and taking further mitigation actions. The purpose of this study is to provide a review of published research and protocols related to city carbon accounting, paying attention to both their science and practical actions. To begin with, the most cited articles in this field are identified and analyzed by employing a citation network analysis to illustrate the development of city-level carbon accounting from three perspectives. We also reveal the relationship between research methods and accounting protocols. Furthermore, a timeline of relevant organizations, protocols, and projects is provided to demonstrate the applications of city carbon accounting in practice. The citation networks indicate that the field is dominated by pure-geographic production-based and community infrastructure-based accounting; however, emerging models that combine economic system analysis from a consumption-based perspective are leading to new trends in the field. The emissions accounted for by various research methods consist essentially of the scope 1-3, as defined in accounting protocols. The latest accounting protocols include consumption-based accounting, but most cities still limit their accounting and reporting from pure-geographic production-based and community infrastructure-based perspectives. In conclusion, we argue that protocol practitioners require support in conducting carbon accounting, so as to explore the potential in mitigation and adaptation from a number of perspectives. This should also be a priority for future studies.


Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018.
The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy. This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months old were monitored for 42 days. The primary outcomes of the study were uncorrected and PCR-corrected efficacies to day 28 for AL and 42 for DP. Molecular markers of resistance to artemisinin derivatives and partner drugs were also analysed. Of 720 children enrolled, 672 reached study endpoints at day 28, 333 in the AL arm and 339 in the DP arm. PCR-corrected 28-day per protocol efficacy in the AL arm was 74% (64-83%) in Nanoro, 76% (66-83%) in Gourcy, and 92% (84-96%) in Niangoloko. The PCR-corrected 42-day per protocol efficacy in the DP arm was 84% (75-89%) in Gourcy, 89% (81-94%) in Nanoro, and 97% (92-99%) in Niangoloko. No Pfk13 mutation previously associated with artemisinin-resistance was observed. No statistically significant association was found between treatment outcome and presence of the 86Y mutation in the Pfmdr1 gene. There was also no association observed between treatment outcome and Pfpm2 or Pfmdr1 copy number variation. The results of this study indicate evidence of inadequate efficacy of AL at day 28 and DP at day 42 in the same two sites. A change of first-line ACT may be warranted in Burkina Faso. Trial Registry Pan African Clinical Trial Registry Identifier: PACTR201708002499311. Date of registration: 8/3/2017 https://pactr.samrc.ac.za/Search.aspx.


Adaptation to sustained high plasma vasopressin in water and electrolyte homeostasis in the rat transgenic for the metallothionein-vasopressin fusion gene.
Prolonged exposure of tissues to a receptor agonist often leads to adaptive changes that limit the subsequent responsiveness of the tissue to the same agonist. Recently, we have generated rats transgenic for the metallothionein I-human arginine vasopressin (AVP) fusion gene (Tg), which produced high plasma AVP with relatively preserved renal water excretion, suggesting that there might be adaptive mechanism(s) for maintaining water and electrolyte homeostasis against chronic AVP oversecretion from the earliest stage of life. In this study, to investigate whether down-regulation of AVP V2 receptor (V2R), which could possibly be caused by long-standing high plasma AVP, participates in this adaptive mechanism(s), non-peptidic V2R antagonist OPC31260 was administered to reverse the down-regulation, and water loading was performed after V2R antagonist treatment had been withdrawn. Additionally, to confirm the down-regulation, Northern blotting analysis for V2R mRNA was carried out. Tg rats showed slightly decreased urine volume and water intake with an equivalent plasma [Na(+)] level (Tg 140.4 +/- 0.6 mEq/l; control 139.3 +/- 0.6 mEq/l) under basal conditions. After water loading using a liquid diet containing zinc, which stimulates the promoter region in the transgene, the urine increase showed only limited suppression with a dramatically increased plasma AVP level and mild hyponatremia (135.8 +/- 1.8 mEq/l) in Tg rats. When diet containing OPC31260 had been provided for 4 days until the day before the start of water loading, antidiuresis and hyponatremia (125.4 +/- 1.mEq/l) were significantly potentiated. V2R mRNA expression in kidney was significantly less in Tg rats than in control rats under basal conditions, and this suppression was restored by OPC31260 treatment to levels comparable with those of control rats. These results suggest that long-standing high plasma AVP causes V2R down-regulation, and it may play an important role in the adaptive mechanism(s) for maintaining water and electrolyte homeostasis in chronically AVP-overexpressing rats.


Inadequate use of asthma medication in the United States: results of the asthma in America national population survey.
Studies of the use of anti-inflammatory asthma therapy have been limited to selected populations or have been unable to assess the appropriateness of therapy for individuals. We sought to describe the current use of asthma medication in the United States population and to examine the influence of symptoms and sociodemographics on medication use. This study was based on a cross-sectional, national, random-digit-dial household telephone survey in 1998 designed to identify adult patients and parents of children with current asthma. Respondents were classified as having current asthma if they had a physician's diagnosis of asthma and were either taking medication for asthma or had asthma symptoms during the past year. One or more persons met the study criteria for current asthma in 3273 (7.8%) households in which a screening questionnaire was completed. Of these, 2509 persons (721 children <16 years) with current asthma were interviewed. Current use of anti-inflammatory medication was reported by 507 (20.1%). Of these, most were using inhaled corticosteroids (72.5%), with use of antileukotrienes reported by 11.4% and use of cromolyn-nedocromil reported by 18.6%. Of persons with persistent asthma symptoms in the past month, 26.2% reported current use of some form of anti-inflammatory medication. In bivariate analysis persons reporting lower income, less education, and present unemployment, as well as smokers, were significantly (P <.001) less likely to report current anti-inflammatory use than were other populations. In a multiple regression model nonsmokers and those of white, non-Hispanic ethnicity, as well as persons reporting less asthma control, were more likely to report current anti-inflammatory medication use. In the United States use of appropriate asthma therapy remains inadequate. Strategies to increase use of anti-inflammatory therapy among patients with asthma are needed. These might include methods to increase access to asthma care for minorities and the socioeconomically disadvantaged.


Phenotypic and Functional Changes of Peripheral Ly6C+ T Regulatory Cells Driven by Conventional Effector T Cells.
A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence. We also demonstrate that Ly6C expression on Treg in a steady state is either up- or downregulated depending on relative amounts of tonic TCR signals derived from its contacts with self-ligands. Interestingly, peripheral appearance and maintenance of these Ly6C-expressing Treg cells largely differed in an age-dependent manner, with their proportion being continuously increased from perinatal to young adult period but then being gradually declined with age. The reduction of Ly6C+ Treg in the aged mice was not due to their augmented cell death but rather resulted from downregulation of Ly6C expression. The Ly6C downregulation was accompanied by proliferation of Ly6C+ Treg cells and subsequent change into Ly6C- effector Treg with concomitant restoration of immune-suppressive activity. Importantly, we found that this phenotypic and functional change of Ly6C+ Treg is largely driven by conventional effector T cell population. Collectively, these findings suggest a potential cross-talk between peripheral Treg subsets and effector T cells and provides better understanding for Treg homeostasis and function on maintaining self-tolerance.


Disinfectant Efficacy: Understanding the Expectations and How to Design Effective Studies That Include Leveraging Multi-Site Data to Drive an Efficient Program.
For manufacturers of both sterile and nonsterile pharmaceuticals, there is an expectation that the manufacturing process is performed in a manner that prevents extraneous contamination so that the products are provided in a safe, integral, pure, and unadulterated form. As part of that process, cleaning and disinfection are an absolute necessity. Although cleaning and disinfection support control of microbial contamination through preventive and corrective action, specific compendia methods do not currently exist. The intent of this paper is to provide a general guidance on how to perform disinfectant efficacy validation and implementation. This includes how to make sure the concepts are understood, how to interpret facility data and utilize it to demonstrate control awareness for your facilities, and how to leverage the data to reduce redundancies in validation or verification. This paper represents the thoughts and best practices of the authoring team and their respective companies and provides an efficient way to qualify disinfectants without impacting the quality of the study. If you choose to follow the recommendations in this paper, you must ensure that the appropriate rationale is sound and the scientific data is documented. It is the belief of the authoring team that only then will this approach meet regulatory requirements.


Object localization in the presence of a strong heterogeneous background in fluorescent tomography.
We propose a method for object localization in fluorescent tomography (FT) in the presence of a highly heterogeneous background. Existing approaches typically assume a homogeneous background distribution; thus, they are incapable of accurately accounting for the more general case of an unconstrained, possibly heterogeneous, background. The proposed method iteratively solves the inverse problem over a solution space partitioned into a background subspace and an object subspace to simultaneously estimate the background and localize the target fluorescent objects. Simulation results of this algorithm applied to continuous-wave FT demonstrate effective localization of target objects in the presence of highly heterogeneous background distributions.


Polyphenolic extract attenuates fatty acid-induced steatosis and oxidative stress in hepatic and endothelial cells.
Phenolic compounds (PC) of virgin olive oil exert several biochemical and pharmacological beneficial effects. Some dietary PC seem to prevent/improve obesity and metabolic-related disorders such as non-alcoholic fatty liver disease (NAFLD). We investigated the possible effects of PC extracted from olive pomace (PEOP) and of the main single molecules present in the extract (tyrosol, apigenin, oleuropein, p-coumaric and caffeic acid) in protecting hepatocytes and endothelial cells against triglyceride accumulation and oxidative stress. Rat hepatoma and human endothelial cells were exposed to a mixture of oleate/palmitate to mimic the condition of NAFLD and atherosclerosis, respectively. Then, cells were incubated for 24 h in the absence or in the presence of PC or PEOP. Different parameters were evaluated, such as lipid accumulation and oxidative stress-related markers. In hepatic cells, expression of peroxisome proliferator-activated receptors (PPARs) and of stearoyl-CoA desaturase 1 (SCD-1) were assessed as index of lipid metabolism. In endothelial cells, expression of intercellular adhesion molecule-1 (ICAM-1), activation of nuclear factor kappa-B (NF-kB), release of nitric oxide (NO), and wound-healing rate were assessed as index of inflammation. PEOP extract ameliorated hepatic lipid accumulation and lipid-dependent oxidative imbalance thus showing potential applications as therapeutic agent tuning down hepatosteatosis and atherosclerosis.


Experiences of Intimate Partner Violence and Subsequent Police Reporting Among Lesbian, Gay, Bisexual, Transgender, and Queer Adults in Colorado: Comparing Rates of Cisgender and Transgender Victimization.
Research indicates that lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals are at high risk of victimization by others and that transgender individuals may be at even higher risk than their cisgender LGBQ peers. In examining partner violence in particular, extant literature suggests that LGBTQ individuals are at equal or higher risk of partner violence victimization compared with their heterosexual peers. As opposed to sexual orientation, there is little research on gender identity and partner violence within the LGBTQ literature. In the current study, the authors investigated intimate partner violence (IPV) in a large sample of LGBTQ adults (N = 1,139) to determine lifetime prevalence and police reporting in both cisgender and transgender individuals. Results show that more than one fifth of all participants ever experienced partner violence, with transgender participants demonstrating significantly higher rates than their cisgender peers. Implications focus on the use of inclusive language as well as future research and practice with LGBTQ IPV victims.


Cobalt(2+) binding to human and tomato copper chaperone for superoxide dismutase: implications for the metal ion transfer mechanism.
The copper chaperone for superoxide dismutase (CCS) gene encodes a protein that is believed to deliver copper ions specifically to copper-zinc superoxide dismutase (CuZnSOD). CCS proteins from different organisms share high sequence homology and consist of three distinct domains; a CuZnSOD-like central domain 2 flanked by domains 1 and 3, which contain putative metal-binding motifs. We report deduced protein sequences from tomato and Arabidopsis, the first functional homologues of CCS identified in plants. We have purified recombinant human (hCCS) and tomato (tCCS) copper chaperone proteins, as well as a truncated version of tCCS containing only domains 2 and 3. Their cobalt(2+) binding properties in the presence and absence of mercury(2+) were characterized by UV-vis and circular dichroism spectroscopies and it was shown that hCCS has the ability to bind two spectroscopically distinct cobalt ions whereas tCCS binds only one. The cobalt binding site that is common to both hCCS and tCCS displayed spectroscopic characteristics of cobalt(2+) bound to four or three cysteine ligands. There are only four cysteine residues in tCCS, two in domain 1 and two in domain 3; all four are conserved in other CCS sequences including hCCS. Thus, an interaction between domain 1 and domain 3 is concluded, and it may be important in the copper chaperone mechanism of these proteins.


Insulation lead failure: is it a matter of insulation coating, venous approach, or both?
Lead insulation material and implant route have a major impact on lead reliability and durability. We compare the incidence of lead insulation failure resulting from both the venous approach and insulation type. Two hundred ninety consecutive leads were followed for a mean period of 57 +/- 30 months; leads with < 1 year follow-up were excluded. There were 116 Silicone Rubber insulated leads and 174 with polyurethane (151 Pellethane 80A and 23 Pellethane 55D) insulation; 279 leads were bipolar and 11 unipolar; 274 leads were implanted in the ventricle and 66 in the atrium. The venous route was the subclavian vein for 170 leads (58%) and the cephalic vein for 120 leads (42%). Insulation failure was diagnosed when a single sign of oversensing, undersensing, failure to capture, early pulse battery depletion, and lead impedance < 250 omega was present. Measurement of lead impedance was performed intraoperatively at implantation and during lead revision or pulse generator replacement. Lead failure caused by conductor coil fracture was not considered. There were 13 lead insulation failures, all among leads with polyurethane insulation (12 Pellethane 80A and 1 Pellethane 55D). Eleven failures (10%) occurred when the subclavian vein and 2 (3%) when the cephalic vein approach was used. The cumulative survival rate of polyurethane and silicone rubber insulated leads was 88.7% and 100%, respectively (P = 0.02); the cumulative survival rate of polyurethane insulated leads was 83.2% when the subclavian vein and 95.1% when the cephalic vein were used (P = 0.03). The mean time to polyurethane lead failure when the subclavian vein approach was used was 54 +/- 17 months and when the cephalic route was 73 +/- 4 months (P < 0.02). By multivariate analysis, the route of entry was found to be a significant variable related to polyurethane insulated lead failure (P < 0.05). At lead revision failure to capture was present in 7, oversensing in 4, and undersensing in 2 instances; impedance was < 250 omega in all cases. Pellethane 80A insulated leads are prone to insulation failure, but more when the subclavian vein is used, rather than the cephalic vein.


Cell biology of pathologic renal calcification: contribution of crystal transcytosis, cell-mediated calcification, and nanoparticles.
The earliest lesion in the kidneys of idiopathic calcium oxalate stone formers is deposition of calcium phosphate in the interstitium, termed a Randall's plaque. Yet the cellular and molecular factors leading to their formation are unknown. The influence of urinary proteins on adhesion of preformed calcium oxalate crystals to rat continuous inner medullary collecting duct (cIMCD) cells was studied in vitro, and cIMCD cells were also exposed to calcifying media containing beta-glycerophosphate for up to 28 days. Renal tissue was obtained from a stone-forming and non-stone-forming individual at the time of nephrectomy. These nanoparticles, isolated from renal stones obtained at the time of surgical resection, were analyzed and propagated in standard cell culture medium. Urinary proteins influence crystal adhesion to renal epithelial cells, and this activity is abnormal in the urine of stone-forming patients. cIMCD cells assumed an osteoblastic phenotype when exposed to the calcifying medium, expressing two bone matrix proteins (osteopontin and bone sialoprotein) that were also identified in the kidney of the stone-forming patient and associated with crystal deposition. Nanoparticles were propagated from the majority of renal stones. Isolates were susceptible to selected metabolic inhibitors and antibiotics and contained conserved bacterial proteins and deoxyribonucleic acid (DNA). These results suggest new paradigms for Randall's plaque formation and idiopathic calcium oxalate stone disease. It seems unlikely that these events are driven solely by physical chemistry; rather, they are critically influenced by specific proteins and cellular responses, and understanding these events will provide clues toward novel therapeutic targets.


Delving below the surface. Understanding how race and ethnicity influence relationships in health care.
There is increasing evidence that racial and ethnic minority patients receive lower quality interpersonal care than white patients. Therapeutic relationships constitute the interpersonal milieu in which patients are diagnosed, given treatment recommendations, and referred for tests, procedures, or care by consultants in the health care system. This paper provides a review and perspective on the literature that explores the role of relationships and social interactions across racial and ethnic differences in health care. First, we examine the social and historical context for examining differences in interpersonal treatment in health care along racial and ethnic lines. Second, we discuss selected studies that examine how race and ethnicity influence clinician-patient relationships. While less is known about how race and ethnicity influence clinician-community, clinician-clinician, and clinician-self relationships, we briefly examine the potential roles of these relationships in overcoming disparities in health care. Finally, we suggest directions for future research on racial and ethnic health care disparities that uses a relationship-centered paradigm.


Genetic association analysis of functional polymorphisms in neuronal nitric oxide synthase 1 gene (NOS1) and mood disorders and fluvoxamine response in major depressive disorder in the Japanese population.
Nitric oxide has been reported to play a role in neural transmitter release and N-methyl-D-aspartate receptor activation, as well as to be related to oxidative stress. Abnormalities in both of these mechanisms are thought to be involved in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BP). In addition, several lines of evidence support an association between abnormalities in neuronal nitric oxide synthases (nNOS) and mood disorders. Therefore, we studied the association of nNOS gene (NOS1) and mood disorders and the efficacy of fluvoxamine treatment in Japanese MDD patients. Using a single nucleotide polymorphism (SNP; rs41279104, also called ex1c), we conducted a genetic association analysis of case-control samples (325 MDD patients, 154 BP patients and 807 controls) in the Japanese population. In addition, we performed an association analysis between NOS1 and the efficacy of fluvoxamine treatment in 117 MDD patients. We defined a clinical response as a decrease of more than 50% in baseline SIGH-D (Structured Interview Guide for the Hamilton Rating Scale for Depression) score within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. We did not detect a significant association between NOS1 and MDD, BP or the fluvoxamine therapeutic response in MDD in allele/genotype-wise analysis. We did not detect an association between only one marker (rs41279104) in NOS1 and Japanese mood disorder patients and fluvoxamine response, but sample sizes were probably too small to allow a meaningful test. Moreover, because we did not perform an association analysis based on linkage disequilibrium and a mutation scan of NOS1, a replication of the study using a larger sample and based on linkage disequilibrium may be required for conclusive results.


Implementation and evaluation of an incentivized Internet-mediated walking program for obese adults.
In response to rising health care costs associated with obesity rates, some health care insurers are adopting incentivized technology-enhanced wellness programs. The purpose of this study is to evaluate the large-scale implementation of an incentivized Internet-mediated walking program for obese adults and to examine program acceptance, adherence, and impact. A mixed-methods evaluation was conducted to investigate program implementation, acceptance, and adherence rates, and physical activity rates among program participants. Program implementation was shaped by national and state policies, data security concerns, and challenges related to incentivizing participation. Among 15,397 eligible individuals, 6,548 (43 %) elected to participate in the walking program, achieving an average of 6,523 steps/day (SD 2,610 steps). Participants who uploaded step counts for 75 % of days for a full year (n = 2,885) achieved an average of 7,500 steps (SD 3,093). Acceptance and participation rates in this incentivized Internet-mediated walking program suggest that such interventions hold promise for engaging obese adults in physical activity.


In Vivo Biomolecule Corona around Blood-Circulating, Clinically Used and Antibody-Targeted Lipid Bilayer Nanoscale Vesicles.
The adsorption of proteins and their layering onto nanoparticle surfaces has been called the "protein corona". This dynamic process of protein adsorption has been extensively studied following in vitro incubation of many different nanoparticles with plasma proteins. However, the formation of protein corona under dynamic, in vivo conditions remains largely unexplored. Extrapolation of in vitro formed protein coronas to predict the fate and possible toxicological burden from nanoparticles in vivo is of great interest. However, complete lack of such direct comparisons for clinically used nanoparticles makes the study of in vitro and in vivo formed protein coronas of great importance. Our aim was to study the in vivo protein corona formed onto intravenously injected, clinically used liposomes, based on the composition of the PEGylated liposomal formulation that constitutes the anticancer agent Doxil. The formation of in vivo protein corona was determined after the recovery of the liposomes from the blood circulation of CD-1 mice 10 min postinjection. In comparison, in vitro protein corona was formed by the incubation of liposomes in CD-1 mouse plasma. In vivo and in vitro formed protein coronas were compared in terms of morphology, composition and cellular internalization. The protein coronas on bare (non-PEGylated) and monoclonal antibody (IgG) targeted liposomes of the same lipid composition were also comparatively investigated. A network of linear fibrillary structures constituted the in vitro formed protein corona, whereas the in vivo corona had a different morphology but did not appear to coat the liposome surface entirely. Even though the total amount of protein attached on circulating liposomes correlated with that observed from in vitro incubations, the variety of molecular species in the in vivo corona were considerably wider. Both in vitro and in vivo formed protein coronas were found to significantly reduce receptor binding and cellular internalization of antibody-conjugated liposomes; however, the in vivo corona formation did not lead to complete ablation of their targeting capability.


Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (me-can): analysis of six prospective cohorts.
Prospective studies have indicated that elevated blood glucose levels may be linked with increased cancer risk, but the strength of the association is unclear. We examined the association between blood glucose and cancer risk in a prospective study of six European cohorts. The Metabolic syndrome and Cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included 274,126 men and 275,818 women. Mean age at baseline was 44.8 years and mean follow-up time was 10.4 years. Excluding the first year of follow-up, 18,621 men and 11,664 women were diagnosed with cancer, and 6,973 men and 3,088 women died of cancer. We used Cox regression models to calculate relative risk (RR) for glucose levels, and included adjustment for body mass index (BMI) and smoking status in the analyses. RRs were corrected for regression dilution ratio of glucose. RR (95% confidence interval) per 1 mmol/l increment of glucose for overall incident cancer was 1.05 (1.01-1.10) in men and 1.11 (1.05-1.16) in women, and corresponding RRs for fatal cancer were 1.15 (1.07-1.22) and 1.21 (1.11-1.33), respectively. Significant increases in risk among men were found for incident and fatal cancer of the liver, gallbladder, and respiratory tract, for incident thyroid cancer and multiple myeloma, and for fatal rectal cancer. In women, significant associations were found for incident and fatal cancer of the pancreas, for incident urinary bladder cancer, and for fatal cancer of the uterine corpus, cervix uteri, and stomach. Data from our study indicate that abnormal glucose metabolism, independent of BMI, is associated with an increased risk of cancer overall and at several cancer sites. Our data showed stronger associations among women than among men, and for fatal cancer compared to incident cancer. Please see later in the article for the Editors' Summary.


Promoting Quality Face-to-Face Communication during Ophthalmology Encounters in the Electronic Health Record Era.
To evaluate informatics-enabled quality improvement (QI) strategies for promoting time spent on face-to-face communication between ophthalmologists and patients. This prospective study involved deploying QI strategies during implementation of an enterprise-wide vendor electronic health record (EHR) in an outpatient academic ophthalmology department. Strategies included developing single sign-on capabilities, activating mobile- and tablet-based applications, EHR personalization training, creating novel workflows for team-based orders, and promoting problem-based charting to reduce documentation burden. Timing data were collected during 648 outpatient encounters. Outcomes included total time spent by the attending ophthalmologist on the patient, time spent on documentation, time spent on examination, and time spent talking with the patient. Metrics related to documentation efficiency, use of personalization features, use of team-based orders, and note length were also measured from the EHR efficiency portal and compared with averages for ophthalmologists nationwide using the same EHR. Time spent on exclusive face-to-face communication with patients initially decreased with EHR implementation (2.9 to 2.3 minutes, p = 0.005) but returned to the paper baseline by 6 months (2.8 minutes, p = 0.99). Observed participants outperformed national averages of ophthalmologists using the same vendor system on documentation time per appointment, number of customized note templates, number of customized order lists, utilization of team-based orders, note length, and time spent after-hours on EHR use. Informatics-enabled QI interventions can promote patient-centeredness and face-to-face communication in high-volume outpatient ophthalmology encounters. By employing an array of interventions, time spent exclusively talking with the patient returned to levels equivalent to paper charts by 6 months after EHR implementation. This was achieved without requiring EHR redesign, use of scribes, or excessive after-hours work. Documentation efficiency can be achieved using interventions promoting personalization and team-based workflows. Given their efficacy in preserving face-to-face physician-patient interactions, these strategies may help alleviate risk of physician burnout.


SPECT/CT imaging in breast cancer - current status and challenges.
The increasing incidence of breast cancer worldwide raises the importance of improving imaging techniques for disease stratification after early lesion detection. SPECT/CT imaging is now widely available but its diagnostic potential is not fully utilized for more specific purposes including breast cancer patient stratification. A Pubmed search for both original and review articles related to the value of SPECT/CT in breast cancer patients and comparison to other diagnostic methods. 62 articles were found using the key words SPECT/CT, Fusion Image and Breast Cancer. Development of a new generation of SPECT/CT systems and their introduction into practice has changed the old diagnostic algorithm. The increasing importance of SPECT/CT in the detection of bone metastases is confirmed. The diagnostic accuracy of new SPECT/CT instruments in the diagnostics of bone metastases is nearly comparable to PET/CT scans. SPECT/CT is more widely available and costs less than PET. It is able not only to identify a sentinel lymph nodes in atypical localizations but also to detect sentinel lymph nodes non visualized on previous planar scans. SPECT/CT offers precise anatomic localization of sentinel lymph nodes, thereby facilitating surgery. Knowledge of precise sentinel lymph node localization can also be applied in radiotherapy. The role of hybrid SPECT/CT imaging in breast cancer patients is changing. It is a powerful modality for skeletal and nodal staging in breast cancer patients with important impact on therapy.


Strength training effects in prepubescent boys.
Possible changes in muscle size and function due to resistance training were examined in prepubertal boys. Thirteen boys (9-11 yr) volunteered for each of the training and control groups. Progressive resistance training was performed three times weekly for 20 wk. Measurements consisted of the following: 1 repetition maximum (RM) bench press and leg press; maximal voluntary isometric and isokinetic elbow flexion and knee extension strength; evoked isometric contractile properties of the right elbow flexors and knee extensors; muscle cross-sectional area (CSA) by computerized tomography at the mid-right upper arm and thigh; and motor unit activation (MUA) by the interpolated twitch procedure. Training significantly increased 1 RM bench press (35%) and leg press (22%), isometric elbow flexion (37%) and knee extension strength (25% and 13% at 90 degrees and 120 degrees, respectively), isokinetic elbow flexion (26%) and knee extension (21%) strength, and evoked twitch torque of the elbow flexors (30%) and knee extensors (30%). There were no significant effects of training on the time-related contractile properties (time to peak torque, half-relaxation time), CSA, or %MUA of the elbow flexors or knee extensors. There was, however, a trend toward increased MUA for the elbow flexors and knee extensors in the trained group. Strength gains were independent of changes in muscle CSA, and the increases in twitch torque suggest possible adaptations in muscle excitation-contraction coupling. Improved motor skill coordination (especially during the early phase of training), a tendency toward increased MUA, and other undetermined neurological adaptations, including better coordination of the involved muscle groups, are likely the major determinants of the strength gains in this study.


Concurrent antipsychotic use in older adults treated with antidepressants in Asia.
Depressive disorders are common in old age. Antipsychotics (APs) are often used as an adjunctive treatment with antidepressants (ADs) in this population but its patterns of use in Asia are not known. This study explored the rate of combination of APs and ADs in older adult psychiatric patients in Asia. This is a secondary analysis of the database of a multicentre study which recorded participants' basic demographical and clinical data in standardised format in 10 Asian countries and territories. The data were analysed using univariate and multivariate logistic regression analyses. A total of 955 older adult psychiatric in- and outpatients were included in this study. The proportion of concurrent AP and AD use was 32.0%, ranging from 23.3% in Korea to 44.0% in Taiwan. Multivariate logistic regression analysis found that younger age, inpatient status and diagnosis of schizophrenia, anxiety and other mental disorders were significantly related to a higher proportion of concurrent use of APs and ADs. Around a third of older adult psychiatric patients had concurrent AP and AD use in the Asian countries/regions surveyed. Considering the uncertain effectiveness and questionable safety of the AP and AD combination in this patient population, such should be cautiously used.


Evaluating the effect of unbalanced data in biomedical document classification.
Nowadays, document classification has become an interesting research field. Partly, this is due to the increasing availability of biomedical information in digital form which is necessary to catalogue and organize. In this context, machine learning techniques are usually applied to text classification by using a general inductive process that automatically builds a text classifier from a set of pre-classified documents. Related with this domain, imbalanced data is a well-known problem in many practical applications of knowledge discovery and its effects on the performance of standard classifiers are remarkable. In this paper, we investigate the application of a Bayesian Network (BN) model for the triage of documents, which are represented by the association of different MeSH terms. Our results show that BNs are adequate for describing conditional independencies between MeSH terms and that MeSH ontology is a valuable resource for representing Medline documents at different abstraction levels. Moreover, we perform an extensive experimental evaluation to investigate if the classification of Medline documents using a BN classifier poses additional challenges when dealing with class-imbalanced prediction. The evaluation involves two methods, under-sampling and cost-sensitive learning. We conclude that BN classifier is sensitive to both balancing strategies and existing techniques can improve its overall performance.


Antidiabetic and Neuroprotective Effect of the N-Butanol Extract of Fragaria nilgerrensis Schlecht. in STZ-Induced Diabetic Mice.
Diabetes has been associated with neurodegenerative disorders that are accompanied by memory loss and cognitive impairments, but there is no effective treatment for it at present. Fragaria nilgerrensis Schlecht. (FNS), a well-known Chinese materia medica, has been traditionally used for the folkloric treatment of diabetes and other diseases. However, its effects are poorly documented. Here, we investigated the antidiabetic and neuroprotective effect of FNS in diabetic mice. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) evaluations of N-butanol extract of Fragaria nilgerrensis Schlecht. (N-FNS) showed the presence of flavonoid and its structure is similar to scutellarin. For the first time, we show the potential neuroprotective and antidiabetic effects of FNS. After 4 weeks of FNS intervention, a significant decrease in blood glucose, increase in body weight, and amelioration in glucose tolerance were observed in FNS treated diabetic mice. In the acute study, FNS enhanced motor activity in the open field task and significantly prevented spatial-learning deficits in Morris water maze tests. Besides, synapse ultrastructure of the hippocampus showed that the mitochondrial morphology was basically restored and all the synaptic structural parameters were gradually normalized after treatment with FNS. Importantly, we found that the activities of SOD and CAT in liver and hippocampus of diabetic mice significantly increased after FNS administration. In vitro, FNS and scutellarin showed high DPPH radical scavenging activity. The study suggests that FNS exerted significant antidiabetic and neuroprotective effects which may be attributed to its antioxidant property.


Novel gene acquisition on carnivore Y chromosomes.
Despite its importance in harboring genes critical for spermatogenesis and male-specific functions, the Y chromosome has been largely excluded as a priority in recent mammalian genome sequencing projects. Only the human and chimpanzee Y chromosomes have been well characterized at the sequence level. This is primarily due to the presumed low overall gene content and highly repetitive nature of the Y chromosome and the ensuing difficulties using a shotgun sequence approach for assembly. Here we used direct cDNA selection to isolate and evaluate the extent of novel Y chromosome gene acquisition in the genome of the domestic cat, a species from a different mammalian superorder than human, chimpanzee, and mouse (currently being sequenced). We discovered four novel Y chromosome genes that do not have functional copies in the finished human male-specific region of the Y or on other mammalian Y chromosomes explored thus far. Two genes are derived from putative autosomal progenitors, and the other two have X chromosome homologs from different evolutionary strata. All four genes were shown to be multicopy and expressed predominantly or exclusively in testes, suggesting that their duplication and specialization for testis function were selected for because they enhance spermatogenesis. Two of these genes have testis-expressed, Y-borne copies in the dog genome as well. The absence of the four newly described genes on other characterized mammalian Y chromosomes demonstrates the gene novelty on this chromosome between mammalian orders, suggesting it harbors many lineage-specific genes that may go undetected by traditional comparative genomic approaches. Specific plans to identify the male-specific genes encoded in the Y chromosome of mammals should be a priority.


Population dynamics of the rubber plantation litter beetle Luprops tristis, in relation to annual cycle of foliage phenology of its host, the para rubber tree, Hevea brasiliensis.
The population dynamics of the rubber plantation litter beetle, Luprops tristis Fabricius 1801 (Coleoptera: Tenebrionidae) was assessed in relation to the phenology of leaf shedding and defoliation pattern of para rubber trees, Hevea brasiliensis Müll. Arg (Malpighiales: Euphorbiaceae), during a two year study period. The abundance of adults, larvae and pupae per 1m(2) of litter sample was recorded. Post dormancy beetles appeared in leaf litter following annual leaf shedding, whereas larvae, pupae and teneral adults were present after leaf flush. No stages were recorded from plantations following the summer rains until the annual litter fall in the next season. Parental adults peaked at the time of leaf sprouting and tender leaf fall. Larvae and teneral adults peaked at the time of premature fall of green leaves and flowers. Teneral adults of six age classes were recorded and all entered dormancy irrespective of the feeding time available to each age class. Females outnumbered males in the parent generation, while the sex ratio of new generation adults was not biased towards either sex. The phenological stages of rubber trees included leaf fall in late December and early January, leaf sprouting and new leaf production in January and flowering in February. All feeding stages of L. tristis peaked in abundance when premature leaves are most abundant in the leaf litter. Prediction of the timing of appearance of various developmental stages of L. tristis in plantations, invasion into buildings and intensity of population build up in rubber belts is possible by tracking the phenology of leaf fall in rubber plantations, time of return of post dormancy adults and the onset of summer rainfall. Perfect synchrony was recorded between the field return of parental adults with annual leaf shedding, the oviposition phase of parental adults with tender leaf fall at the time of leaf sprouting, and larval and teneral adult stages with premature fall of leaves. Premature leaf availability is suggested as contributing to the reproductive efficiency of parental adults, the survival of early developmental stages and of new generation adults during dormancy.


Thrombotic risk factors in pulmonary hypertension.
Thrombotic lesions are consistently observed in chronic thromboembolic pulmonary hypertension (CTEPH) and frequently found in primary pulmonary hypertension (PPH). It remains unknown, however, whether thrombosis is related to defects of the antithrombotic pathway or to previous vascular injury. This study therefore analysed the frequency of both hereditary and acquired thrombotic risk factors in CTEPH and PPH. One hundred and forty-seven consecutive patients with CTEPH investigated in the author's institution were compared to 99 consecutive patients with PPH. In 116 CTEPH patients and 83 PPH patients, phospholipid-dependent antibodies (antiphospholipid antibodies and lupus anticoagulant) were analysed by both immunological and clotting assays. In patients enrolled since 1994 (46 CTEPH and 64 PPH), hereditary thrombotic risk factors were also determined. Antithrombin, protein C and protein S activities were measured by functional assays. Mutations of factor V and factor II were identified by polymerase chain reaction. The prevalence of hereditary thrombotic risk factors was not increased in patients with either PPH or CTEPH. In contrast, a high frequency of phospholipid-dependent antibodies was observed in PPH (10%) and more notably in CTEPH (20%). Moreover, in PPH, antibodies were present only in low titre whereas in CTEPH, half of the patients with antiphospholipid antibodies had high titres. In addition, in CTEPH all but one of the patients with lupus anticoagulant also had antiphospholipid antibodies. The most striking finding of this study was the high prevalence of phospholipid-dependent antibodies but their clinical relevance appears to be different in primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension. In primary pulmonary hypertension, these antibodies in low titre probably reflect endothelial dysfunction. In contrast, in chronic thromboembolic pulmonary hypertension the presence of antibodies in high titre associated with lupus anticoagulant, underlines the role of thrombosis in the pathogenesis of this condition.


Stimulation of bone formation in vivo by phosphate supplementation.
The effect of phosphate supplementation on bone remodeling was assessed in six mature, healthy beagle dogs. The phosphate supplement was given in divided doses orally, daily for 12 weeks in the form of a neutral potassium phosphate preparation. The dose averaged 108 mg P/kg per day, which is double the normal canine phosphorus intake. Bone remodeling was assessed by measurement, at sacrifice, of areas of cortical bone containing different color-coded tetracyclines which had been continuously administered during 12-week control and treatment periods; remodeling was assessed kinetically during the control and treatment periods by replicate studies employing 47Ca intravenously. Both techniques demonstrated that the principal effect of phosphate supplementation was a significant stimulation of bone formation. Within cortical bone, formation was doubled, from an average of 2.7% to 5.3% per year. The major location of new bone deposits was endosteal. Whole skeletal mineral accretion, measured kinetically, increased 45% above an average control value of 0.154 g/day. These studies suggest that, in the adult dog, "normal" plasma phosphate levels are suboptimal for new bone formation. Even with this short duration of administration, phosphate produced microscopic calcification of the renal parenchyma. However, there was no biochemical evidence of renal functional impairment.