Evolution and stability of ring species.
Neutral models, in which genetic change arises through random variation without fitness differences, have proven remarkably successful in describing observed patterns of biodiversity, despite the manifest role of selection in evolution. Here we investigate the effect of barriers on biodiversity by simulating the expansion of a population around a barrier to form a ring species, in which the two ends of the population are reproductively isolated despite ongoing gene flow around the ring. We compare the spatial and genetic properties of a neutral agent-based population model to the greenish warblers' complex, a well-documented example of an actual ring species in nature. Our results match the distribution of subspecies, the principal components of genetic diversity, and the linear spatial-genetic correlation of the observed data, even though selection is expected to be important for traits of this species. We find that ring species are often unstable to speciation or mixing but can persist for extended times depending on species and landscape features. For the greenish warblers, our analysis implies that the expanded area near the point of secondary contact is important for extending the duration of the ring, and thus, for the opportunity to observe this ring species. Nevertheless it also suggests the ring will break up into multiple species in 10,000 to 50,000 y. These results imply that simulations can be used to accurately describe empirical data for complex spatial-genetic traits of an individual species.


Facial Venous Malformations Are Associated with Cerebral Developmental Venous Anomalies.
A number of studies have demonstrated the existence of segmental vascular disorders affecting soft tissues of the head and neck along with the intracranial vasculature. The purpose of this study was to determine whether there is an association between cerebral developmental venous anomalies and venous malformations of the face, head, and neck. A consecutive series of patients with head and neck venous malformations who underwent MR imaging of the brain with postcontrast T1- or T2*-weighted imaging were included. Developmental venous anomaly prevalence in this patient population was compared with an age- and sex-matched control group without venous malformations at a ratio of 1:2. All images were interpreted by 2 neuroradiologists. Data were collected on venous malformation location, developmental venous anomaly location, developmental venous anomaly drainage pattern, and metameric location of venous malformations and developmental venous anomalies. Categoric variables were compared using χ2 tests. Forty-two patients with venous malformations were included. The mean age was 38.1 ± 11.1 years, and 78.6% of patients were female. The prevalence of developmental venous anomalies in this patient population was 28.6%. The control population of 84 patients had a mean age of 40.0 ± 5.9 years, and 78.6% of patients were female. The prevalence of developmental venous anomalies in this patient population was 9.5% (P = .01). In 83.3% of cases, developmental venous anomalies were ipsilateral to the venous malformation, and in 75% of cases, they involved the same metamere. Our case-control study demonstrated a significant association between brain developmental venous anomalies and superficial venous malformations. These findings suggest that there may be a similar pathophysiologic origin for these 2 entities.


Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis.
Delays in wound healing often result in infection, chronic ulceration, and possible amputation of extremities. Impaired wound healing is a major complication of the 23 million people in the USA with diabetes, and financial and medical burdens are demanding new treatments for wound healing. Previous studies have demonstrated that topical application of the opioid antagonist naltrexone (NTX) dissolved in moisturizing cream reverses delays in wound closure in rats with streptozotocin-induced type 1 diabetes. A target of NTX's action is DNA synthesis and cell proliferation. In this study, granulation tissue was evaluated to ascertain the specific cellular targets that were impaired in diabetic wounds, as well as those that were enhanced following NTX application. Mast cell number as well as the number of new blood vessels immunoreactive to fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), and alpha smooth muscle actin (α-SMA) antibodies were recorded at 3, 5, 8, 10, 15, and 20 days following creation of full-thickness dorsal cutaneous wounds in normal and type 1 diabetic rats. Diabetic rats displayed delays in wound closure as well as a reduction in the number of mast cells responding to the injury, and delays in the spatial and temporal expression of FGF-2, VEGF, and α-SMA in capillaries. Topical NTX accelerated the rate of wound closure and stimulated expression of angiogenic factors within granulation tissue of diabetic rats relative to control animals receiving saline in moisturizing cream. These data support observations that a novel biological pathway is impaired under diabetic conditions and can be modulated by topical NTX to enhance proliferative events in wound healing.


Efficacy of adjuvant chemotherapy for completely resected stage IB non-small cell lung cancer: a retrospective study.
Lung cancer is being increasingly detected in the early stages, highlighting the importance of lung cancer screening. However, there is no consensus on the post-operative management of stage IB non-small cell lung cancer (NSCLC). Therefore, this study aimed to identify the predictive factors for prognosis of stage IB NSCLC and determine the efficacy of adjuvant chemotherapy on recurrence and survival. We enrolled 89 patients with stage IB NSCLC who underwent complete resection surgery at Gangnam Severance Hospital from Jan 2008 to Dec 2014. As per the National Comprehensive Cancer Network guidelines, patients were considered to be at high risk when they showed poorly differentiated tumors, lymphovascular invasion, tumor size >4 cm, and visceral pleural invasion (VPI). Among the 89 patients, 27 underwent adjuvant chemotherapy. Young patients or patients with squamous cell lung cancer received adjuvant chemotherapy frequently. Adjuvant chemotherapy was not a significant factor for disease-free survival and overall survival. Adjuvant chemotherapy did not show a significant protective effect for survival, even for high-risk patients. However, VPI was a significant risk factor for disease-free survival [hazard ratio (HR): 7.051; 95% confidence interval (CI): 1.570-31.659; P=0.011] and overall survival (HR: 8.289; 95% CI: 1.036-66.307; P=0.046), even after adjustment for various factors. Adjuvant chemotherapy does not affect the prognosis of stage IB NSCLC, even in high-risk patients. Additionally, VPI is a strong prognostic factor of stage IB NSCLC.


Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts.
Tumor infiltration of immune cells (polymorphonuclear cells [PMNs] and macrophages) was initially thought to be an attempt by the host organism to combat malignancy. It appears, however, that certain subsets of chronically activated immune cells likely promote tumor growth, facilitate tumor cell survival and aid in metastasis. The association between tumor cells and tumor-associated PMNs has been demonstrated in several types of cancer, but the presence of tumor-associated PMNs in pancreatic cancer has not been well studied in vivo. Intercellular adhesion molecule-1 (ICAM-1) functions in cell-cell and cell-extracellular matrix adhesion and has a physiological role in PMN tight adhesion of leukocytes via interaction with the ligands LFA-1 and Mac-1. Increased ICAM-1 expression correlates with poor prognosis in pancreatic cancer. Therefore, the aim of this study was to investigate the function of ICAM-1 and tumor-associated PMNs in pancreatic cancer progression using ICAM-1-null (ICAM-1(-/-)) mice. We hypothesize that ICAM-1 null mice have decreased pancreatic cancer progression. Surprisingly, there is no significant difference in pancreatic cancer progression in wild-type versus ICAM-1 null mice. Interestingly, we found that tumor-derived ICAM-1 co-localizes with host PMNs at the leading edge of the tumor in ICAM-1 null mice. These results suggest that tumor-derived ICAM-1 is a sufficient ligand for tumor-associated PMNs and may play a role in subsequent tumor growth and metastasis.


Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals.
Invariant NK T (iNKT) cells influence the response to viral infections, although the mechanisms are poorly defined. In this study we show that these innate-like lymphocytes secrete IFN-gamma upon culture with CpG oligodeoxynucleotide-stimulated dendritic cells (DCs) from mouse bone marrow. This requires TLR9 signaling and IL-12 secretion by the activated DCs, but it does not require CD1d expression. iNKT cells also produce IFN-gamma in response to mouse CMV infection. Their mechanism of mouse CMV detection is quite similar to that of CpG, requiring both TLR9 signaling and IL-12 secretion, while the need for CD1d expression is relatively minor. Consequently, iNKT cells have the ability to respond to a variety of microbes, including viruses, in an Ag-independent manner, suggesting they may play a broad role in antipathogen defenses despite their limited TCR repertoire.


Prevalence of childhood disintegrative disorder.
The prevalence of childhood disintegrative disorder (CDD) is unknown. In this study, 32 epidemiological surveys of autism and pervasive developmental disorders published in English language journals since 1966 were reviewed. Four surveys yielded estimates for CDD ranging from 1.1 to 6.4 per 100,000 subjects. A pooled estimate across these four surveys is 1.7 per 100,000 (95 percent Confidence Interval: 0.6-3.8 per 100,000). The conclusion is that CDD is very rare and its prevalence is 60 times less than that for autistic disorder, assuming a prevalence of 10 per 10,000 for autism. If a rate of 30 per 10,000 is taken for all PDDs, only one child out of 175 children with a PDD diagnosis would, on average, meet criteria for CDD.


A 2.5-Mb physical map within 3p21.1 spans the breakpoint associated with Greig cephalopolysyndactyly syndrome.
Numerous investigations suggest that one or more genes residing in the p14 to p21 region of human chromosome 3 are critical to the development of neoplastic diseases such as renal cell carcinoma and small-cell lung cancer (SCLC). This region is additionally involved in several interchromosomal translocations, one of which is associated with the developmental disorder Greig cephalopolysyndactyly syndrome. A series of five loci that map in close proximity to the Greig syndrome breakpoint [t(3;7)(p21.1;p13)] at 3p21.1 have been physically linked by pulsed-field gel analysis over a 2.5-Mb region. The probes include ACY1, cA84 (D3S92), cA199 (D3S93), pHF12-32 (D3S2), and MW-Not153 (D3S332). The Greig 3;7 translocation breakpoint was discovered between clones cA199 and MW-Not153, separated by 825 kb. Further analysis revealed comigration of a rearranged fragment detected by MW-Not153 and a chromosome 7 probe previously shown to be in close proximity to the breakpoint (CRI-R944). This latter probe also detects a rearrangement in a second Greig-associated translocation, (6;7)(q27;p13). The physical map resulting from this analysis orders the markers along the chromosome and identifies several locations for CpG islands, likely associated with genes. Although probe pEFD145.1 (D3S32) has been genetically linked to D3S2 (2 cM), physical linkage to the other five loci could not be demonstrated. One of the linked loci, D3S2, has been widely utilized in the analysis of chromosome 3p loss in several malignant diseases. Since expression of ACY1, a housekeeping gene, is specifically reduced in many cases of SCLC, knowledge of its precise chromosomal position and identification of neighboring putative gene loci should facilitate investigation into the mechanism of this reduction.


Effect of length history on contractile behavior of canine tracheal smooth muscle.
The effects of shortening on force redevelopment were studied in canine tracheal smooth muscles that were tonically contracted with electrical stimulation or acetylcholine. Muscle strips were suspended in vitro so that muscle length, force, and rate of change of force could be continuously monitored. The strips were rapidly shortened from different initial lengths to the same final length, at which the effects of shortening distance on force redevelopment were evaluated. Both the rate and magnitude of force redevelopment declined as the shortening distance was increased. Decreasing the activation of the muscle or increasing the prerelease contraction time enhanced the depressive effect of shortening. The time course of the latter corresponded to a decline in the velocity of unloaded shortening. However, force redevelopment was also substantially decreased by releases performed before the onset of force development. The shortening process per se had a depressive effect on both the rate and magnitude of force redevelopment in contracted canine tracheal smooth muscle, and this effect was reduced as the activation of the muscle was increased.


Direct measurement of Lighthill's energetic efficiency of a minimal magnetic microswimmer.
The realization of artificial microscopic swimmers able to propel in viscous fluids is an emergent research field of fundamental interest and vast technological applications. For certain functionalities, the efficiency of the microswimmer in converting the input power provided through an external actuation into propulsive power output can be critical. Here we use a microswimmer composed by a self-assembled ferromagnetic rod and a paramagnetic sphere and directly determine its swimming efficiency when it is actuated by a swinging magnetic field. Using fast video recording and numerical simulations we fully characterize the dynamics of the propeller and identify the two independent degrees of freedom which allow its propulsion. We then obtain experimentally the Lighthill's energetic efficiency of the swimmer by measuring the power consumed during propulsion and the energy required to translate the propeller at the same speed. Finally, we discuss how the efficiency of our microswimmer could be increased upon suitable tuning of the different experimental parameters.


Porphyromonas gingivalis lipopolysaccharide stimulation in human periodontal ligament stem cells: role of epigenetic modifications to the inflammation.
Periodontitis is a chronic oral inflammatory disease produced by bacteria. Gingival retraction and bone and connective tissues resorption are the hallmarks of this disease. Chronic periodontitis may contribute to the risk of onset or progression of neuroinflammatory pathological conditions, such as Alzheimer's disease. The main goal of the present study was to investigate if the role of epigenetic modulations is involved in periodontitis using human periodontal ligament stem cells (hPDLSCs) as an in vitro model system. hPDLSCs were treated with lipopolysaccharide of Porphyromonas gingivalis and the expression of proteins associated with DNA methylation and histone acetylation, such as DNMT1 and p300, respectively, and inflammatory transcription factor NF-kB, were examined. Immunofluorescence, Western blot and next generation sequencing results demonstrated that P. gingivalis lipopolysaccharide significantly reduced DNA methylase DNMT1, while it markedly upregulated the level of histone acetyltransferase p300 and NF-kB in hPDLSCs. Our results showed that P. gingivalis lipopolysaccharide markedly regulate the genes involved in epigenetic mechanism, which may result in inflammation induction. We propose that P. gingivalis lipopolysaccharide-treated hPDLSCs could be a potential in vitro model system to study epigenetics modulations associated with periodontitis, which might be helpful to identify novel biomarkers linked to this oral inflammatory disease.


Fusion of PspA to detoxified pneumolysin enhances pneumococcal vaccine coverage.
Despite the implementation of conjugate vaccines in several countries, S. pneumoniae continues to pose a great burden worldwide, causing around 1 million annual deaths. Pneumococcal proteins have long been investigated as serotype-independent vaccines against this pathogen, with promising results. However, it is a consensus that one antigen alone will not be sufficient to provide long-term protection with wide coverage. Amongst the most well studied pneumococcal proteins are PspA and pneumolysin (Ply), two major virulence factors required by the bacterium for successful invasion of host tissues. PspA is highly immunogenic and protective, but it is structurally variable; pneumolysin is conserved among different pneumococci, but it is toxic to the host. To overcome these limitations, N-terminal PspA fragments have been genetically fused to non-toxic pneumolysin derivatives (PlD) to create PspA_PlD chimeras. Mouse immunization with these fusions confers protection against pneumococcal strains expressing heterologous PspAs, which correlates with antibody-induced complement C3 deposition on the surface of multiple pneumococcal strains. Analysis of mutant strains lacking PspA or Pneumolysin shows that both proteins contribute to the antibody-mediated enhancement in complement deposition induced by the fusion. These results expand previous data evaluating PspA_PlD and demonstrate that the fusion combines the protective traits of both proteins, inducing antibodies that efficiently promote complement deposition on multiple strains and cross-protection.


[Niemann-Pick disease--a rare disease in children's hepatology (a clinical case)].
The aim is to acquaint medical society with literature data and specific details of clinical incidents of Niemann-Pick disease among 14 year old children. The article gives a brief review of literature on the problem of diagnostics, symptoms and treatment of Niemann-Pick disease in children. A clinical case of a forteen-year-old girl with type C Niemann-Pick disease is presented, the peculiarity of which is a combination of symptoms typical of the disease with a low level of ceruloplasmin in serum.


Raphasatin is a more potent inducer of the detoxification enzymes than its degradation products.
The biological activity of cruciferous vegetables is hypothesized to be due to the metabolites of a class of phytochemicals called glucosinolates. The chemical properties of these metabolites, including isothiocyanates, determine the biological activity of these compounds and thus their effects on human health. The 2 primary radish (Raphanus sativus L.) glucosinolates, glucoraphasatin, and glucoraphenin, were isolated using solid phase extraction followed by preparative HPLC purification. In an aqueous environment, 77.6% of the maximum amount of sulforaphene produced by the metabolism of glucoraphenin was present after 24 h. Under the same conditions raphasatin, the isothiocyanate metabolite of glucoraphasatin and the oxidized counterpart of sulforaphene, was highly unstable with a half-life of less than 30 min and no raphasatin was detectable after 24 h. In HepG2 cells, raphasatin-induced quinone reductase activity and the RNA expression of several phase 1 and 2 detoxification enzymes by a significantly greater amount than the degradation products of raphasatin. Raphasatin, but not its degradation products, activated the antioxidant response element (ARE) in a stably-transfected reporter cell line. Mice fed a diet consisting of 20% freeze dried radishes for 2 wk had significantly higher liver expression of cytochrome P450 (CYP) 1A1, 1A2, quinone reductase, microsomal epoxide hydrolase, and glutathione S-transferase α2 than mice fed a nutritionally-matched control diet. Glucoraphasatin, the primary glucosinolate in radishes, is metabolized into an isothiocyanate (raphasatin) that has biological activity but is also unstable in an aqueous environment. Despite the instability of raphasatin, dietary exposure to radishes produced significant induction of detoxification enzymes. Understanding the chemical properties of raphasatin, both in terms of biological activity and instability, could help develop processing methods to retain the most activity from radishes, glucoraphasatin, and raphasatin.


Video-Based AAL and Intimate Pictures - Criminal Liability in European, Irish, and Polish Law.
Active and Assisted Living (AAL) technologies offer solutions for addressing healthcare challenges associated with ageing societies and a shortage of care personnel. At the same time, these technologies raise significant privacy issues, which may constitute a barrier to the sustainable adoption and acceptance of AAL. In particular, concerns arise from the presence of cameras in intimate situations, including nudity, and the potential production and dissemination of intimate pictures, which constitutes a risk for AAL users. The paper compares the regimes of criminal liability for making and disseminating intimate pictures under EU, Irish, and Polish law. The study aims to help AAL users understand their legal protection, and give providers and developers more insight into their legal responsibilities. The paper first presents different understandings of an intimate picture in each jurisdiction, followed by a discussion of what the crime entails and who may be liable for it. The conclusion includes a checklist of rules concerning criminal liability, which may be useful for AAL users and providers, and conclusions de lege ferenda.


Antimicrobial susceptibility and fluctuations in clonal complexes of serogroup 6 Streptococcus pneumoniae isolates collected from children in Beijing, China, between 1997 and 2016.
This study examined the antimicrobial susceptibility patterns and clonal complex (CC) characteristics of serogroup 6 Streptococcus pneumoniae isolates collected from children in Beijing, China, between 1997 and 2016. Serotypes were determined using the Quellung reaction, and the antimicrobial susceptibility profiles of the isolates were determined using the disc-diffusion method or by E-test. Sequence types (STs) were assigned based on multilocus sequence typing. A total of 250 isolates were examined, with 55.2%, 30.0%, 12.8%, and 2.0% of isolates identified as serotypes 6A, 6B, 6C, and 6D, respectively. All of the isolates were susceptible to levofloxacin and vancomycin, and the non-suceptibitility rate to penicillin was 41.6%. Eighty-two distinct STs, assigned to 13 CCs and 28 singletons, were identified. CC982 was the most prevalent CC amongst serotype 6A isolates (34%), followed by CC9789 and CC3173. Amongst serotype 6B isolates, CC90 and CC4542 were the most common, accounting for 25.3% and 14.7% of isolates respectively. Over the study period, the prevalence of CC982, CC4542, and CC4536 isolates showing susceptibility to penicillin and cefuroxime decreased, and the proportion of CC3173, CC9789, CC855, and CC902 isolates showing non-susceptibility to these two antibiotics increased.


S100A8/A9 as a risk factor for breast cancer negatively regulated by DACH1.
S100A8 and S100A9 are members of Ca2+-binding EF-hand superfamily, mainly expressed by macrophages and neutrophils. Limited by the poor stability of homodimers, they commonly exist as heterodimers. Beyond acting as antibacterial cytokines, S100A8/A9 is also associated with metabolic and autoimmune diseases such as obesity, diabetes, and rheumatoid arthritis. While the involvement of S100A8/A9 in breast cancer development has been documented, its prognostic significance and the precise regulatory mechanisms remain unclear. S100A8/A9 protein in breast cancer samples was evaluated by immunohistochemistry staining with tumor tissue microarrays. The serum S100A8 concentration in patients was measured by enzyme-linked immunosorbent assay (ELISA). The S100A8 secreted by breast cancer cells was detected by ELISA as well. Pooled analyses were conducted to explore the relationships between S100A8/A9 mRNA level and clinicopathological features of breast cancer patients. Besides, the effects of S100A8/A9 and DACH1 on patient outcomes were analyzed by tissue assays. Finally, xenograft tumor assays were adopted to validate the effects of DACH1 on tumor growth and S100A8/A9 expression. The level of S100A8/A9 was higher in breast cancer, relative to normal tissue. Increased S100A8/A9 was related to poor differentiation grade, loss of hormone receptors, and Her2 positive. Moreover, elevated S100A8/A9 predicted a worse prognosis for breast cancer patients. Meanwhile, serum S100A8 concentration was upregulated in Grade 3, basal-like, and Her2-overexpressed subtypes. Additionally, the results of public databases showed S100A8/A9 mRNA level was negatively correlated to DACH1. Stable overexpressing DACH1 in breast cancer cells significantly decreased the generation of S100A8. The survival analysis demonstrated that patients with high S100A8/A9 and low DACH1 achieved the shortest overall survival. The xenograft models indicated that DACH1 expression significantly retarded tumor growth and downregulated S100A8/A9 protein abundance. S100A8/A9 is remarkedly increased in basal-like and Her2-overexpressed subtypes, predicting poor prognosis of breast cancer patients. Tumor suppressor DACH1 inhibits S100A8/A9 expression. The combination of S100A8/A9 and DACH1 predicted the overall survival of breast cancer patients more preciously.


Exercise and recovery metabolism in the Pacific spiny dogfish (Squalus acanthias).
We examined the effects of exhaustive exercise and post-exercise recovery on white muscle substrate depletion and metabolite distribution between white muscle and blood plasma in the Pacific spiny dogfish, both in vivo and in an electrically stimulated perfused tail-trunk preparation. Measurements of arterial-venous lactate, total ammonia, beta-hydroxybutyrate, glucose, and L-alanine concentrations in the perfused tail-trunk assessed white muscle metabolite fluxes. Exhaustive exercise was fuelled primarily by creatine phosphate hydrolysis and glycolysis as indicated by 62, 71, and 85% decreases in ATP, creatine phosphate, and glycogen, respectively. White muscle lactate production during exercise caused a sustained increase (approximately 12 h post-exercise) in plasma lactate load and a short-lived increase (approximately 4 h post-exercise) in plasma metabolic acid load during recovery. Exhaustive exercise and recovery did not affect arterial PO2, PCO2, or PNH3 but the metabolic acidosis caused a decrease in arterial HCO3- immediately after exercise and during the first 8 h recovery. During recovery, lactate was retained in the white muscle at higher concentrations than in the plasma despite increased lactate efflux from the muscle. Pyruvate dehydrogenase activity was very low in dogfish white muscle at rest and during recovery (0.53 +/- 0.15 nmol g wet tissue(-1) min(-1); n=40) indicating that lactate oxidation is not the major fate of lactate during post-exercise recovery. The lack of change in white muscle free-carnitine and variable changes in short-chain fatty acyl-carnitine suggest that dogfish white muscle does not rely on lipid oxidation to fuel exhaustive exercise or recovery. These findings support the notion that extrahepatic tissues cannot utilize fatty acids as an oxidative fuel. Furthermore, our data strongly suggest that ketone body oxidation is important in fuelling recovery metabolism in dogfish white muscle and at least 20% of the ATP required for recovery could be supplied by uptake and oxidation of beta-hydroxybutyrate from the plasma.


Increasing walking in college students using a pedometer intervention: differences according to body mass index.
The researchers assessed the effectiveness of a pedometer intervention and differences in walking behaviors according to body mass index (BMI). Two hundred ninety college students completed the intervention from January to February 2005. Participants wore pedometers 5 days per week for 12 weeks and completed questionnaires assessing demographic information. The authors calculated daily step averages for weeks 1, 6, and 12. They then classified students as underweight (UW), normal weight (NW), or overweight/obese, by BMI. The authors analyzed data using repeated-measures analysis of variance. The average number of daily steps increased from week 1 to week 6 (p < .001) and week 12 (p = .002). UW participants reported the fewest steps at each time point, but the difference was significant only when compared with NW participants (p = .03). These results support the effectiveness of a pedometer intervention to increase walking in college students. Health benefits other than weight management should be emphasized to maximize the effects for all students.


Dual-responsive probe and DNA interstrand crosslink precursor target the unique redox status of cancer cells.
Elevated GSH and H2O2 in cancer cells is sometimes doubted due to their contrary reactivities. Here, we construct a dual-responsive fluorescent probe to confirm the conclusion, and employ this to exploit a redox-inducible DNA interstrand crosslink (ICL) precursor. It crosslinks DNA upon activation by GSH and H2O2, affording an alternative dual-responsive strategy.


Nocturnality and species survival.
Surveys of butterfly and moth diversity in tropical forest fragments suggest that nocturnality confers a dispersal, and possibly a survival, advantage. The butterfly faunas of smaller fragments were depauperate; in contrast, the species richness of nocturnal moths was similar in all fragments and even in pasture. The lack of correlation between butterfly and moth species richness among fragments (r2 = 0.005) is best explained by movements of moths at night when ambient conditions in forest and pasture are most similar; butterflies face substantial daytime temperature, humidity, and solar radiation barriers. This interpretation is supported by information on birds, beetles, and bats.


A cellular framework for gut-looping morphogenesis in zebrafish.
Many vertebrate organs adopt asymmetric positions with respect to the midline, but little is known about the cellular changes and tissue movements that occur downstream of left-right gene expression to produce this asymmetry. Here, we provide evidence that the looping of the zebrafish gut results from the asymmetric migration of the neighboring lateral plate mesoderm (LPM). Mutations that disrupt the epithelial structure of the LPM perturb this asymmetric migration and inhibit gut looping. Asymmetric LPM migration still occurs when the endoderm is ablated from the gut-looping region, suggesting that the LPM can autonomously provide a motive force for gut displacement. Finally, reducing left-sided Nodal activity randomizes the pattern of LPM migration and gut looping. These results reveal a cellular framework for the regulation of organ laterality by asymmetrically expressed genes.


Loss of control over the ethanol consumption: differential transcriptional regulation in prefrontal cortex.
Alcohol use disorder (AUD) is a complex multifactorial disease with heritability of ∼50% and corresponds to the state in which the body triggers a reinforcement or reward compulsive behavior due to ethanol consumption, even when faced with negative consequences. Although several studies have shown the impact of high ethanol intake on the prefrontal cortex (PFC) gene expression, few have addressed the relationship between the patterns of gene expression underlying the compulsive behaviour associated with relapsing. In this study, we used a chronic three-bottle free-choice mouse model to investigate the PFC transcriptome in three different groups of mice drinkers: 'Light drinkers' (preference for water throughout the experiment); 'Heavy drinkers' (preference for ethanol with a non-compulsive intake), and 'Inflexible drinkers' (preference for ethanol with a compulsive drinking component). Our aim was to correlate the intake patterns observed in this model with gene expression changes in the PFC, a brain region critical for the development and maintenance of alcohol addiction. We found that the Camk2a gene showed a downregulated profile only in the Inflexible when compared to the Light drinkers group, the Camk2n1 and Pkp2 genes showed an upregulated profile only in the Inflexible drinkers when compared to the Control group, and the Gja1 gene showed an upregulated profile in the Light and Inflexible drinkers when compared to the Control group. These different transcription patterns have been associated to the presence of alcohol, in the Camk2n1 and Gja1 genes; to the amount of ethanol consumed, in the Camk2a gene; and to the loss of control in the alcohol consumption, in the Pkp2 gene. Here, we provide, for the first time, the potential involvement of the Pkp2 gene in the compulsivity and loss of control over the voluntary ethanol consumption.


Peroxidase content in cell subpopulations of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats.
Peroxidase has been investigated as a potential marker protein for the prediction of response to hormonal therapy in tumors of steroid-sensitive tissues, but the cellular origin of the enzyme has been questioned. To localize the observed peroxidase activity, in this study cell subpopulations were isolated from mammary tumors induced by 7,12-dimethylbenz(a)anthracene and from mammary tissue of virgin and lactating female rats. Cells from each of the four cell bands, regularly obtained by isopyknic velocity sedimentation after mechanical and enzymatic dispersion of these tissues, were assayed biochemically and histochemically for peroxidase activity. In addition, cells from each subpopulation were examined at both the light and electron microscopic levels. Elevated enzyme levels were observed in each of the cell subpopulations of 7,12-dimethylbenz(a)anthracene-induced tumors when these were compared with tissue in either of the physiological states assayed. In each tissue type, the levels of peroxidase increased from the lighter cell bands to the heavier cell bands. Light and electron microscopic examination revealed the highest proportion of epithelial cells in the lighter bands and an increase in granulocytes and fibroblasts in the heavier bands, suggesting a nonepithelial contribution. Histochemical examination of intact tissue revealed most peroxidase activity in the stromal compartment with limited activity in parenchymal cells.


Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.
Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.


Guanosine triphosphate cyclohydrolase I deficiency: a rare cause of hyperphenylalaninemia.
Tetrahydrobiopterin (BH4) deficiencies are a heterogeneous group of disorders caused by a defect in two of the three enzymes involved in its biosynthesis or in the two recycling enzymes. Except for the deficiency of dehydratase, an enzyme catalyzing a reaction in the recycling pathway, all other variants of BH4 deficiency are characterized by developmental delay, progressive neurological deterioration, hypokinesis, drooling, swallowing difficulty, truncal hypotonia, increased limb tone, myoclonus and brisk deep tendon reflexes. A deficiency of guanosine triphosphate cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway of BH4, is described in a 14-month-old male infant with hyperphenylalaninemia, developmental delay, hypertonia of the extremities, seizures, feeding difficulties, and vomiting. Urinary pteridine screening revealed very low levels of neopterin and biopterin which was highly suggestive of GTPCH deficiency. Low cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid concentrations, together with no detectable neopterin and decreased concentrations of biopterin and folate, agreed with the diagnosis of GTPCH deficiency. Subsequently measured neopterin and biopterin synthesis in cytokine-stimulated skin fibroblasts confirmed GTPCH deficiency, albeit indirectly. The patient showed marked improvement on a low-protein low-phenylalanine diet with neurotransmitter precursor administration. The favorable outcome in this patient clearly shows that not only newborns with elevated phenylalanine levels but also older children with neurological signs and symptoms should be screened for a BH4 deficiency in order to have maximum benefit of the treatment.


E-cadherin nuclear staining is useful for the diagnosis of ovarian adult granulosa cell tumor.
We recently have demonstrated nuclear localization of E-cadherin in ovarian adult granulosa cell tumors (Histopathology 2011;58:423). The purpose of the present study is to investigate the diagnostic utility of E-cadherin nuclear staining for the differential diagnosis between ovarian adult granulosa cell tumor and its morphological mimics. Tissue samples taken from 81 ovarian tumors and 20 extraovarian tumors were immunohistochemically stained using monoclonal anti-E-cadherin antibody recognizing cytoplasmic domain (clone 36 supplied by BD Biosciences, San Jose, CA). The ovarian tumors consisted of 30 adult granulosa cell tumors, 3 Sertoli-stromal cell tumors, 14 fibrothecomas, 5 carcinoid tumors, 1 large cell neuroendocrine carcinoma, 18 endometrioid adenocarcinomas, and 10 poorly differentiated serous adenocarcinomas. Extraovarian tumors consisted of 16 uterine endometrial stromal neoplasms and 4 pulmonary small cell carcinomas. Only tumor cells with nuclear staining were considered positive in this study. Ninety percent of adult granulosa cell tumors, 67% of Sertoli-stromal cell tumors, 64% of fibrothecomas, 75% of endometrial stromal neoplasms, 75% of small cell carcinomas, and the one large cell neuroendocrine carcinoma showed E-cadherin nuclear expression, whereas all the ovarian carcinoid tumors, endometrioid adenocarcinomas, and poorly differentiated serous adenocarcinomas were negative. E-cadherin nuclear staining is useful in distinguishing between adult granulosa cell tumors and ovarian adenocarcinomas or carcinoid tumors. However, it is of limited use for distinguishing between adult granulosa cell tumors and endometrial stromal neoplasms or small cell carcinomas. E-cadherin should be included in the immunohistochemical panel for an accurate diagnosis of ovarian adult granulosa cell tumors.


Multiplicity of stem cell memories of inflammation and tissue repair in epithelia.
Adaptation enables cells to change their behavior in response to transient stimuli. While adaptive programs of immune cells have been widely described, it has recently emerged that epithelial cells also acquire memories in vivo. Here, we discuss and classify the adaptations identified in epithelia and describe the associated long-term consequences.


The significance of low-grade prostate cancer on needle biopsy. A radical prostatectomy study of tumor grade, volume, and stage of the biopsied and multifocal tumor.
Twenty-one cases showing only low Gleason grade prostate carcinoma on needle biopsy were identified. In 15 cases radical prostatectomy was performed with the entire prostate embedded for thorough evaluation of grade, volume, and stage of tumor at the needle biopsy site as well as of multifocal tumor. Eight specimens had solitary low grade and low volume tumor, with only one of these cases showing minimal capsular penetration and the others confined to the prostate. Four cases had low-grade tumor at the biopsy site, yet multifocal higher grade tumor. All of these tumor nodules were low volume and confined to the prostate. In three cases there was both low-grade and high-grade tumor in the nodule sampled by needle biopsy. In two of these cases the tumor was large and in the third it was small but mostly higher grade, with two of these cases showing capsular penetration. Although transrectal ultrasound and repeat needle biopsy would most likely have identified either the tumors' large size or high-grade component in these latter three cases, it is unlikely that these techniques would have identified the cases of multifocal higher grade tumor because of their relatively small size. Furthermore, preoperative serum prostate specific antigen levels and clinical stage failed to distinguish those cases with higher grade tumor. Because of the difficulty in identifying these areas of high-grade tumor preoperatively, it is uncertain whether expectant therapy could be recommended even for patients with very low-grade cancer on needle biopsy.


Rank truncated product of P-values, with application to genomewide association scans.
Large exploratory studies are often characterized by a preponderance of true null hypotheses, with a small though multiple number of false hypotheses. Traditional multiple-test adjustments consider either each hypothesis separately, or all hypotheses simultaneously, but it may be more desirable to consider the combined evidence for subsets of hypotheses, in order to reduce the number of hypotheses to a manageable size. Previously, Zaykin et al. ([2002] Genet. Epidemiol. 22:170-185) proposed forming the product of all P-values at less than a preset threshold, in order to combine evidence from all significant tests. Here we consider a complementary strategy: form the product of the K most significant P-values. This has certain advantages for genomewide association scans: K can be chosen on the basis of a hypothesised disease model, and is independent of sample size. Furthermore, the alternative hypothesis corresponds more closely to the experimental situation where all loci have fixed effects. We give the distribution of the rank truncated product and suggest some methods to account for correlated tests in genomewide scans. We show that, under realistic scenarios, it provides increased power to detect genomewide association, while identifying a candidate set of good quality and fixed size for follow-up studies.


Food safety knowledge and behaviors of women, infant, and children (WIC) program participants in the United States.
Although the incidence of foodborne illnesses has declined, thousands of cases are still reported in the United States. In conjunction with industry efforts to reduce foodborne pathogens, consumers play an important role in decreasing foodborne illnesses. To assess food safety knowledge and food handling behaviors of low-income, high-risk populations, a study was conducted with participants of the Special Supplemental Food Program for Women, Infants, and Children (WIC). A survey was conducted with 1,598 clients from 87 WIC agencies nationwide. Descriptive statistics, chi-square analyses, t tests, and analyses of variance were calculated. A majority of respondents received food safety information from WIC (78.7%), family (63.1%), and television (60.7%). Most respondents recognized the necessity for washing and sanitizing cutting boards and utensils (94.3%), but only 66.1% knew the correct ways to sanitize. Using a thermometer to ensure doneness of meat was least recognized (23.7%) and used by even fewer respondents (7.7%). The majority (77.4%) used color of meat and/or juices when checking the doneness of ground beef items. Over half of the respondents (58.4%) used acceptable thawing methods, but many thawed frozen meats on the counter (21.0%) or in a sink filled with water (20.6%). There were significant differences in thawing methods, overall knowledge scores, and overall behavior scores among different racial and ethnic groups. White respondents had higher knowledge scores than did Hispanics, and blacks had lower behavior scores than did individuals in the other racial and ethnic groups. Results of the study suggested the need for food safety education for low-income consumers and different messages to be delivered to specific demographic groups.


Neurotensin receptor 1 gene (NTSR1) polymorphism is associated with working memory.
Recent molecular genetics studies showed significant associations between dopamine-related genes (including genes for dopamine receptors, transporters, and degradation) and working memory, but little is known about the role of genes for dopamine modulation, such as those related to neurotensin (NT), in working memory. A recent animal study has suggested that NT antagonist administration impaired working memory in a learning task. The current study examined associations between NT genes and working memory among humans. Four hundred and sixty healthy undergraduate students were assessed with a 2-back working memory paradigm. 5 SNPs in the NTSR1 gene were genotyped. 5 ANOVA tests were conducted to examine whether and how working memory differed by NTSR1 genotype, with each SNP variant as the independent variable and the average accuracy on the working memory task as the dependent variable. ANOVA results suggested that two SNPs in the NTSR1 gene (rs4334545 and rs6090453) were significantly associated with working memory. These results survived corrections for multiple comparisons. Our results demonstrated that NTSR1 SNP polymorphisms were significantly associated with variance in working memory performance among healthy adults. This result extended previous rodent studies showing that the NT deficiency impairs the working memory function. Future research should replicate our findings and extend to an examination of other dopamine modulators.


Vulvovaginal candidiasis in children and adolescents with type 1 diabetes mellitus.
In this prospective study we investigated the frequency of vulvovaginal candidiasis, the results of yeast cultures and detection of ketoconazole resistance in female children and adolescents with type 1 diabetes mellitus (DM1). The study consisted of 35 patients with DM1 (age 1.7-20 years) and 22 controls (age 1.5-18 years). Age, duration of DM1 and evidence of genital symptoms were recorded initially. After a pelvic examination, two separate swabs and samples for blood glucose and hemoglobin A1c (HbA1c) were taken. One of the swabs was used for direct examination and the second was placed on Sabouraud's dextrose agar and incubated. In vitro susceptibility of Candida species to ketoconazole was established by using Etest (AB B1ODISC). Candida species were isolated in 32 of 61 (52.5%) swabs of patients with DM1 and five of 22 (18.2%) of the control group. The predominant Candida species isolated from patients with DM1 were C. albicans (72.7%), C. glabrata (22.7%), C. tropicalis (2.3%), and C. parapsilosis (2.3%). The mean HbA1c in diabetic patients from whom Candida species were isolated was significantly higher than that of patients without Candida infection (p = 0.002). Most of the C. glabrata isolates were significantly resistant to ketoconazole. During the follow-up of patients with DM1, genital candidiasis is generally overlooked. It should not be forgotten that species other than C. albicans might cause genital candidiasis.


[The influence of nutrition on age menarche].
The onset of menarche is later in Brazilian girls than in American and European girls. According to the Author one of the causes is the difference in nutritions due to different social-economical levels.


Moving Morality Beyond the In-Group: Liberals and Conservatives Show Differences on Group-Framed Moral Foundations and These Differences Mediate the Relationships to Perceived Bias and Threat.
Moral foundations research suggests that liberals care about moral values related to individual rights such as harm and fairness, while conservatives care about those foundations in addition to caring more about group rights such as loyalty, authority, and purity. However, the question remains about how conservatives and liberals differ in relation to group-level moral principles. We used two versions of the moral foundations questionnaire with the target group being either abstract or specific ingroups or outgroups. Across three studies, we observed that liberals showed more endorsement of Individualizing foundations (Harm and Fairness foundations) with an outgroup target, while conservatives showed more endorsement of Binding foundations (Loyalty, Authority, and Purity foundations) with an ingroup target. This general pattern was found when the framed, target-group was abstract (i.e., 'ingroups' and 'outgroups' in Study 1) and when target groups were specified about a general British-ingroup and an immigrant-outgroup (Studies 2 and 3). In Studies 2 and 3, both Individualizing-Ingroup Preference and Binding-Ingroup Preference scores predicted more Attitude Bias and more Negative Attitude Bias toward immigrants (Studies 2 and 3), more Implicit Bias (Study 3), and more Perceived Threat from immigrants (Studies 2 and 3). We also demonstrated that increasing liberalism was associated with less Attitude Bias and less Negative Bias toward immigrants (Studies 2 and 3), less Implicit Bias (Study 3), and less Perceived Threat from immigrants (Studies 2 and 3). Outgroup-individualizing foundations and Ingroup-Binding foundations showed different patterns of mediation of these effects.


Progesterone enhances target gene transcription by receptor free of heat shock proteins hsp90, hsp56, and hsp70.
Steroid receptors regulate transcription of target genes in vivo and in vitro in a steroid hormone-dependent manner. Unoccupied progesterone receptor exists in the low-salt homogenates of target cells as a functionally inactive 8 to 10S complex with several nonreceptor components such as two molecules of 90-kDa heat shock protein (hsp90), a 70-kDa heat shock protein (hsp70), and a 56-kDa heat shock protein (hsp56). Ligand-induced dissociation of receptor-associated proteins such as hsp90 has been proposed as the mechanism of receptor activation. Nevertheless, it has not been established whether, beyond release of heat shock proteins, the steroidal ligand plays a role in modulating receptor activity. To examine whether the release of these nonreceptor proteins from receptor complex results in a constitutively active receptor, we isolated an unliganded receptor form essentially free of hsp90, hsp70, and hsp56. Using a recently developed steroid hormone-responsive cell-free transcription system, we demonstrate for the first time that the dissociation of heat shock proteins is not sufficient to generate a functionally active receptor. This purified receptor still requires hormone for high-affinity binding to a progesterone response element and for efficient transcriptional activation of a target gene. When an antiprogestin, Ru486, is bound to the receptor, it fails to promote efficient transcription. We propose that in the cell, in addition to the release of receptor-associated inhibitory proteins, a distinct hormone-mediated activation event must precede efficient gene activation.


Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its effect on gametogenesis and early pregnancy.
SARS-CoV-2 infection and pregnancy has been the topic of hundreds of publications over the last several months; however, few studies have focused on the implications of infection in early pregnancy and reproductive tissues. Here, we analyzed available evidence pertaining to SARS-CoV-2 infection, in early pregnancy, and in reproductive tissues. We searched PubMed and Embase databases in accordance with guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for publications from inception to June 4, 2020. Four reviewers screened titles and abstracts and obtained full-text articles for analysis. Sixty-two studies were included in the review. Biological plausibility for infection with SARS-CoV-2 exists in testis, ovaries, and placenta as they express ACE2 receptor activity. In males, SARS-CoV-2 infection could lead to functional abnormalities leading to spermatogenic failure and male infertility. In females, an alteration of the ACE2 cascade via SARS-CoV-2 infection could lead to impairment in important follicular and luteal processes. There is also evidence of significant placental pathology in SARS-CoV-2 infection, but it is unclear what effects there may be for early pregnancy, though available data suggest less severe effects compared to other respiratory virus outbreaks. Further investigation is needed regarding SARS-CoV-2 in reproductive function and early pregnancy.


Employment and self-employment in the wake of Hurricane Katrina.
We use data from the monthly Current Population Survey to examine the short- and longer-term effects of Hurricane Katrina on the labor market outcomes of prime-age individuals in the most affected states--Alabama, Florida, Louisiana, and Mississippi--and for evacuees in any state. We focus on rates of labor force participation, employment, and unemployment, and we extend prior research by also examining rates of self-employment. With the exception of Mississippi, employment and unemployment one year after the hurricane were at similar rates as the end of 2003. This aggregate pattern of labor market shock and recovery has been observed for other disasters but masks important differences among subgroups. Those evacuated from their residences, even temporarily, were a harder-hit group, and evacuees who had yet to return to their pre-Katrina state up to one year later were hit especially hard; these findings hold even after controlling for differences in observable characteristics. We also find evidence of an important role for self-employment as part of post-disaster labor market recovery, especially for evacuees who did not return. This may result from poor job prospects in the wage and salary sector or new opportunities for starting businesses in the wake of Katrina.


Screening protein isoforms predictive for cancer using immunoaffinity capture and fast LC-MS in PRM mode.
We report an immunocapture strategy to extract proteins known to harbor driver mutations for a defined cancer type before the simultaneous assessment of their mutational status by MS. Such a method bypasses the sensitivity and selectivity issues encountered during the analysis of unfractionated complex biological samples. Fast LC separations using short nanobore columns hyphenated with a high-resolution quadrupole-orbitrap mass spectrometer have been devised to take advantage of fast MS cycle times in conjunction with sharp chromatographic peak widths to accelerate the sample analysis throughput. Such an analytical platform is well suited to analyze simple protein mixtures obtained after immunoaffinity enrichment. After establishing the technical performance of the platform, the method was applied to the quantitative profiling of cellular Ras and EGFR protein isoforms, as well as serum amyloid A isoforms in plasma. Immunoaffinity purification combined with fast LC-MS detection for the detection of driver mutations in tissue and tumor biomarkers in plasma samples can assist clinicians to select an optimal therapeutic intervention for patients.


Relative importance of infochemicals from first and second trophic level in long-range host location by the larval parasitoidCotesia glomerata.
Recently parasitoids were hypothesized to encounter a reliability-detectability problem relating to chemical stimuli from the first and second trophic level, when searching for hosts. The relative role of infochemicals originating from the host,Pieris brassicae (second trophic level), and its food plant, cabbage (first trophic level), have been investigated with respect to long-range host location by the larval parasitoidCotesia glomerata. Flight-chamber dual choice tests showed that uninfested cabbage plants are least attractive to female wasps. Host larvae and their feces were more attractive than clean plants but far less attractive than artificially damaged and herbivore-damaged plants. The plant-host complex, with host larvae actively feeding on the plant, was the most attractive odor source for the parasitoids. The data indicate that one of the solutionsC. glomerata uses to solve the reliability-detectability problem is to respond to infochemicals that are emitted from herbivore-damaged plants. Whether these infochemicals are herbivore-induced synomones that are produced by the plant remains to be demonstrated. Infochemicals emitted by the herbivore or its by-products are of little importance in the foraging behavior ofC. glomerata.


A comparison of in situ methods for measuring net nitrogen mineralization rates of organic soil amendments.
In situ incubation methods may help provide site-specific estimates of N mineralization from land-applied wastes. However, there are concerns about the reliability of the data generated by the various methods due to containment artifacts. We amended a sandy soil with either poultry manure, biosolids, or yard-waste compost and incubated the mixtures using four in situ methods (buried bags, covered cylinders, standard resin traps, and "new" soil-resin traps) and a conventional laboratory technique in plastic bags. Each incubation device was destructively sampled at 45-d intervals for 180 d and net N mineralization was determined by measuring the amount of inorganic N that accumulated in the soil or soil plus resin traps. Containment effects were evaluated by comparing water content of the containerized soil to a field-reference soil column. In situ incubation methods provided reasonable estimates of short-term (< 45 d) N mineralization, but long-term (> 45 d) mineralization data were not accurate due to a variety of problems specific to each technique. Buried bags and covered cylinders did not retain mineralized N due to water movement into and out of the containers. Neither resin method captured all of the mineralized N that leached through the soil columns, but the new soil-resin trap method tracked field soil water content better than all other in situ methods evaluated. With further refinement and validation, the new soil-resin trap method may be a useful in situ incubation technique for measuring net N mineralization rates of organic soil amendments.


Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome.
To evaluate the effect of continued cigarette smoking among patients undergoing radiation therapy for head-and-neck cancer by comparing the clinical outcomes among active smokers and quitters. A review of medical records identified 101 patients with newly diagnosed squamous cell carcinoma of the head and neck who continued to smoke during radiation therapy. Each active smoker was matched to a control patient who had quit smoking before initiation of radiation therapy. Matching was based on tobacco history (pack-years), primary site, age, sex, Karnofsky Performance Status, disease stage, radiation dose, chemotherapy use, year of treatment, and whether surgical resection was performed. Outcomes were compared by use of Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer toxicity criteria. With a median follow-up of 49 months, active smokers had significantly inferior 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and disease-free survival (42% vs. 65%) compared with the former smokers who had quit before radiation therapy (p < 0.05 for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of Grade 3 or greater late complications was also significantly increased among active smokers compared with former smokers (49% vs. 31%, p = 0.01). Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcomes. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.


Adolescent and adult rats differ in the amnesic effects of acute ethanol in two hippocampus-dependent tasks: Trace and contextual fear conditioning.
Experience-produced deficits in trace conditioning and context conditioning have been useful tools for examining the role of the hippocampus in learning. It has also been suggested that learning in these tasks is especially vulnerable to neurotoxic effects of alcohol during key developmental periods such as adolescence. In five experiments we systematically examined the presence and source of age-dependent vulnerability to the memory-disrupting effects of acute ethanol in trace conditioning and contextual fear conditioning. In Experiment 1a pre-training ethanol disrupted trace conditioning more strongly in adolescent (postnatal day, PD30-35) than adult rats (PD65-75). In Experiment 1b when pre-training ethanol was accompanied by pre-test ethanol no deficit in trace conditioning was observed in adolescents, suggesting that state-dependent retrieval failure mediated ethanol's disruption of trace conditioning at this age. Experiment 2a and b examined the effect of ethanol pretreatment on context conditioning. Here, adult but not adolescent rats were impaired in conditioned freezing to context cues. Experiment 2c explored state-dependency of this effect. Pre-training ethanol continued to disrupt context conditioning in adults even when ethanol was also administered prior to test. Collectively these findings reveal clear age-dependent and task-dependent vulnerabilities in ethanol's disruptive effects on hippocampus-dependent memory. Adolescents were more disrupted by ethanol in trace conditioning than adults, and adults were more disrupted by ethanol in context conditioning than adolescents. We suggest that adolescents may be more susceptible to changes in internal state (state-dependent retrieval failure) than adults and that ethanol disrupted performance in trace and context conditioning through different mechanisms. Relevance of these findings to theories of hippocampus function is discussed.


Resveratrol-Linoleate protects from exacerbated endothelial permeability via a drastic inhibition of the MMP-9 activity.
Gelatinolytic matrix metalloproteinases (MMP-2, -9) play a critical role not only in mammals physiology but also during inflammation and healing processes. The natural stilbenoid, resveratrol (RES), exhibits potent antioxidant effects, in a hormetic mode of action, and is known to inhibit MMP-9. However, RES administration exhibits major issues, including poor bioavailability and water solubility, hampering its potential therapeutic effect in vivo In the present study, we synthesized and evaluated five novel RES-lipid conjugates to increase their cell membrane penetration and improve their bioavailability. The best in vitro MMP-9 inhibitory activity of RES-lipids conjugates was observed with RES-linoleic acid (LA) (5 µM), when dissolved in a natural deep eutectic solvent (NADES), composed of an equimolar content of 1,2-propanediol:choline chloride (ChCl):water. The inhibition of MMP-9 expression by RES-LA in activated THP-1 monocytes, was, at least due to the deactivation of ERK1/2 and JNK1/2 MAP kinase signaling pathways. Moreover, RES-LA exhibited a strong effect protecting the TNF-α-induced exacerbated permeability in an HUVEC in vitro monolayer (by 81%) via the integrity protection of intercellular junction proteins from the MMP-9 activity. This effect was confirmed by using several complementary approaches including, the real-time monitoring of trans-endothelial electric resistance (TEER), the Transwell HUVEC permeability level, the microscopic examination of the platelet endothelial cell adhesion molecule-1 (CD31/PECAM-1) integrity as well as the fluorescence in intercellular spaces. Consequently, following this strong in vitro proof-of-concept, there is a need to test this promising RES-lipid derivative compound to control the pathological endothelial permeability in vivo.


[Tamoxifen adjuvant delays early breast cancer. Results of a cooperative randomized trial].
Adjuvant tamoxifen (TAM) has been proved to reduce recurrence and mortality in early breast cancer, nevertheless many patients did not receive TAM as adjuvant therapy after local treatment. In order to study the efficacy of delayed TAM therapy in patients who were not given immediate adjuvant hormonal treatment, a multicenter randomized trial has been conducted by the French National Cancer Centers (FNCLCC). According to eligibility criterias all women with breast cancer who received curative local treatment at least 2 years before (surgery +/- radiotherapy) with or without adjuvant chemotherapy but no hormonal treatment could have been included. Between September 1986 and October 1989, 494 women were randomized to receive either TAM 30 mg/day for 5 years or no treatment. Patients' characteristics such as age, tumoral stage, number of positive nodes, receptors status and time from local treatment were equally distributed in the 2 groups. An improvement in the disease free survival in the TAM treated patients can be observed with a significative difference (p = 0.05), nevertheless the overall survival is not improved in the TAM group. In the same way, in nodes positive patients although no significative improvement in the overall survival can be observed, a significative improvement in the disease free survival (p = 0.05) can be noted. In estradiol receptors positive patients tamoxifen gives a significative reduction in the odds of death (p = 0.04) and recurrence (p = 0.03). The disease free improvement seems to be limited to 50 and more years old patients. The first results of this trial lead to prescribe tamoxifen to all postmenopausal women previously treated for an early breast cancer without adjuvant tamoxifen treatment.


Cooperative transforming activities of ras, myc, and src viral oncogenes in nonestablished rat adrenocortical cells.
Early-passage rat adrenocortical cells were infected with Kirsten murine sarcoma virus and MMCV mouse myc virus, two retroviruses carrying the v-Ki-ras and v-myc oncogenes, respectively. Efficient morphological transformation required coinfection with the two viruses, was dependent on the presence of high serum concentrations, and was not immediately accompanied by growth in soft agar. The doubly infected cells coordinately acquired the capacity for anchorage- and serum-independent growth during passage in culture. The appearance of such highly transformed cells was correlated with the emergence of a dominant clone, as suggested by an analysis of retrovirus integration sites. These results indicate that the concerted expression of v-Ki-ras and v-myc could induce rapid morphological transformation of nonestablished adrenocortical cells but that an additional genetic or epigenetic event was required to permit full transformation by these two oncogenes. In contrast, v-src, introduced by retrovirus infection in conjunction with v-myc, rapidly induced serum- and anchorage-independent growth. Therefore, the p60v-src protein-tyrosine kinase, unlike p21v-ras, is apparently not restricted in the induction of a highly transformed phenotype in adrenocortical cells. This system provides an in vitro model for the progressive transformation of epithelial cells by dominantly acting oncogenes.


The application of selective neck dissection while preserving the cutaneous branches of cervical plexus in the surgical treatment of differentiated thyroid cancer-experiences from thousands of cases.
Differentiated thyroid cancer (DTC) is associated with the highest propensity for lymph node metastases, given the significant morbidity associated with sacrificing the spinal accessory nerve, surgeons increasingly looked to minimizing functional deficits while maintaining oncologic outcome. We have detailed the technique of a selective neck dissection with more attention to preserving the cervical sensory nerves since 1999 in Fudan University Shanghai Cancer Center. We found that the radical dissection with preservation of the cutaneous branches including the great auricular nerve, the less occipital nerve and the supraclavicular nerve can maximally decrease the complications of paresthesia and dysesthesia postoperatively in the lower neck, the shoulders and the area around the ear in DTC cases when indications were allowed. As long as the principles of cancer surgery are strictly followed, our approach guarantees radical tumor removal and exhibit more functional preservation.


Isolation of Tibet Orbivirus from Culicoides jacobsoni (Diptera, Ceratopogonidae) in China.
Tibet Orbivirus (TIBOV) is a recently discovered Orbivirus known to infect cattle, Asian buffalo and goats in south-western China. It was first isolated from mosquitoes and subsequently from biting midges (Culicoides spp.) in Yunnan, China, indicating that it is an arbovirus. Little is known of its potential to cause disease, but the economic importance of related viruses promoted an investigation of potential Culicoides spp. vectors of TIBOV. Biting midges were collected approximately once per week between May and December 2020, at a cattle farm in Wulong village, Shizong County, Yunnan Province, China. Approximately 3000 specimens of nine species were subsequently used in attempts to isolate virus, and a further 2000 specimens of six species were tested for the presence of bluetongue virus (BTV) and TIBOV using a RT-qPCR test. Virus isolation attempts resulted in the isolation of three viruses. One isolate from a pool of Culicoides jacobsoni was identified as TIBOV, while the other two viruses from C. orientalis and C. tainanus remain unidentified but are not BTV or TIBOV. RT-qPCR analysis did not detect BTV in any specimens, but a single pool containing five specimens of C. jacobsoni and another containing five specimens of C. tainanus produced PCR quantification cycle (Cq) values of around 28 that may indicate infection with TIBOV. The isolation of TIBOV from C. jacobsoni satisfies one criterion required to prove its status as a vector of this virus. This isolation is supported by a low Cq value produced from a different pool of this species in the RT-qPCR test. The low Cq value obtained from a pool of C. tainanus suggests that this species may also be able to satisfy this criterion. Both of these species are widespread throughout Asia, with C. jacobsoni extending into the Pacific region, which raises the possibility that TIBOV may be more widespread than is currently known.


[Krukenberg tumor of the ovary].
Light microscopic, ultrastructural and histochemical observation of 46 cases of ovarian Krukenberg tumors are described. The clinical material is also analysed. The histologic classification of this tumor is suggested to be four types: 1. classical Krukenberg tumor (CKT), 27 cases; 2. tubular Krukenberg tumor (TKT), 9 cases; 3. sclerosing Krukenberg tumor (SKT), 5 cases; and 4. mixed Krukenberg tumor (MKT), 5 cases. In CKT, single signet ring cells predominated over lumen-forming cells and contained ultrastructural and histochemical characteristics similar to cylindral cells of colonic and ovarian mucinous adenocarcinomas. The stroma contained extracellular mucin. In TKT, the lumen was formed by non-secretory and secretory cylindral cells. Some rare argentaffin cells were observed. Steroidgenic stromal lutein cells were identified in one case by electron microscope. Cells in both CKT and TKT produced neutral and sialomucins. Hypertrophic stromal fibroblasts were extremely rich in five SKT with signet ring cells occasionally located inside. It is easy to be misdiagnosed as fibroma or sclerosing stromal tumor. Five cases of MKT showed the mixed features of the above two or three types. Krukenberg tumors are almost always made up of intestinal type cells basing on cell differentiation. The TKT is better differentiated than CKT and SKT. Hypertrophy and hyperplasia of ovarian stromal cells may occur in response to malignant growth or the extracellular mucinous products of malignant cells. They may play a role in the control of tumor invasion.


Trends and predictors of HIV-positive community attachment among PLWHA.
Communities most affected by HIV/AIDS have been instrumental in shaping Australia's responses to the threat of the epidemic. There are recent signs that levels of engagement in communities based around HIV-positivity have changed: a diminished sense of an AIDS crisis, the relative success of highly active antiretroviral therapy (HAART), and an increasing individualization of the HIV experience may be contributing to changes in the way HIV-community is experienced. In this paper, we explore levels of engagement in HIV-positive community among a cohort of people living with HIV/AIDS (PLWHA) and seek to explain why some PLWHA engage in an HIV-positive community while others do not. Using multivariate logistic regression, we found that three factors were independently related to feeling part of an HIV-positive community: having been diagnosed with HIV prior to the advent of HAART; having more recently taken Bactrim or Septrin for PCP; and finding it easier to take 'pills' on time. Taken together, these results suggest that both historical effects, such as the introduction of HAART, and effects related to living with HIV, such as the experience of an AIDS-related illness, help explain HIV-positive community engagement among PLWHA.


Exploring assistive technology as a potential beneficial intervention tool for people with Alzheimer's disease - a systematic review.
Nowadays, due to the increase in the number of aging population groups, there is also a growth of aging diseases such as Alzheimer's disease (AD), which is a progressive brain disorder that eventually results in death. At the moment, it cannot be cured, only its symptoms can be alleviated both by using pharmacological and non-pharmacological approaches in order to maintain and in some cases even enhance quality of life of people living with AD, as well as their caregivers. One of such non-pharmacological approaches is the use of assistive technology (AT), which can contribute to the improvement and maintenance of the quality of life of both patients and their caregivers. The purpose of this study was to explore what types of AT are mostly used by patients with AD and how these devices can help their caregivers. This was done by conducting a literature review of available sources found in the Web of Science, Scopus, and PubMed. The findings, apart from one study, reveal that AT may have the potential to maintain the quality of life of people with AD, especially in the early stages of the disease, as well as to mitigate the mental and physical burden of their caregivers. The most common types of AT for patients with AD are devices of daily living and safety devices. The less frequent are still telecare devices and devices to support engagement, social participation, and leisure. Future research should focus on the effectiveness of AT on the improvement of patients' symptoms, as well as on the development and use of AT for social interactions, which can be used in patients with AD of different degree of severity and have a positive impact on their behavioral and psychological symptoms.


Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs.
Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.


Hemolysis associated with 25% human albumin diluted with sterile water--United States, 1994-1998.
Since 1994, a shortage of 5% human albumin, a product used off-label during therapeutic plasma exchange (TPE), has existed in the United States. Because of this shortage, hospital pharmacists may prepare 5% solution of human albumin by diluting 25% human albumin with 0.9% NaCl or, when sodium load is a concern, 5% dextrose. However, if sterile water alone is used as the diluent, the osmolarity (tonicity) of the albumin solution is reduced and may cause hemolysis in recipients. This report describes two of 10 episodes of hemolysis (one fatal) among persons who received 25% human albumin diluted with sterile water and emphasizes that sterile water alone should not be used to dilute albumin.


Proposing a Core Outcome Set for Physical Activity and Exercise Interventions in People With Rare Neurological Conditions.
Rare neurological conditions (RNCs) encompass a variety of diseases that differ in progression and symptoms but typically include muscle weakness, sensory and balance impairment and difficulty with coordinating voluntary movement. This can limit overall physical activity, so interventions to address this are recommended. The aim of this study was to agree a core outcome measurement set for physical activity interventions in people living with RNCs. We followed established guidelines to develop core outcome sets. Broad ranging discussions in a series of stakeholder workshops led to the consensus that (1) physical well-being; (2) psychological well-being and (3) participation in day-to-day activities should be evaluated in interventions. Recommendations were further informed by a scoping review of physical activity interventions for people living with RNCs. Nearly 200 outcome measures were identified from the review with a specific focus on activities or functions (e.g, on lower limb function, ability to perform daily tasks) but limited consideration of participation based outcomes (e.g., social interaction, work and leisure). Follow on searches identified two instruments that matched the priority areas: the Oxford Participation and Activities Questionnaire and the Sources of Self-Efficacy for Physical Activity. We propose these scales as measures to assess outcomes that are particularly relevant to assess when evaluating physical activity interventions mong people with RNCs. Validation work across rare neurological conditions is now required to inform application of this core outcome set in future clinical trials to facilitate syntheses of results and meta-analyses.


Estrogen receptor, progesterone receptor, interleukin-6 and interleukin-8 are variable in breast cancer and benign stem/progenitor cell populations.
Estrogen receptor positive breast cancers have high recurrence rates despite tamoxifen therapy. Breast cancer stem/progenitor cells (BCSCs) initiate tumors, but expression of estrogen (ER) or progesterone receptors (PR) and response to tamoxifen is unknown. Interleukin-6 (IL-6) and interleukin-8 (IL-8) may influence tumor response to therapy but expression in BCSCs is also unknown. BCSCs were isolated from breast cancer and benign surgical specimens based on CD49f/CD24 markers. CD44 was measured. Gene and protein expression of ER alpha, ER beta, PR, IL-6 and IL-8 were measured by proximity ligation assay and qRT-PCR. Gene expression was highly variable between patients. On average, BCSCs expressed 10-106 fold less ERα mRNA and 10-103 fold more ERβ than tumors or benign stem/progenitor cells (SC). BCSC lin-CD49f-CD24-cells were the exception and expressed higher ERα mRNA. PR mRNA in BCSCs averaged 10-104 fold less than in tumors or benign tissue, but was similar to benign SCs. ERα and PR protein detection in BCSCs was lower than ER positive and similar to ER negative tumors. IL-8 mRNA was 10-104 higher than tumor and 102 fold higher than benign tissue. IL-6 mRNA levels were equivalent to benign and only higher than tumor in lin-CD49f-CD24-cells. IL-6 and IL-8 proteins showed overlapping levels of expressions among various tissues and cell populations. BCSCs and SCs demonstrate patient-specific variability of gene/protein expression. BCSC gene/protein expression may vary from that of other tumor cells, suggesting a mechanism by which hormone refractory disease may occur.


A CNN-based method to reconstruct 3-D spine surfaces from US images in vivo.
Three-dimensional (3-D) reconstruction of the spine surface is of strong clinical relevance for the diagnosis and prognosis of spine disorders and intra-operative image guidance. In this paper, we report a new technique to reconstruct lumbar spine surfaces in 3-D from non-invasive ultrasound (US) images acquired in free-hand mode. US images randomly sampled from in vivo scans of 9 rabbits were used to train a U-net convolutional neural network (CNN). More specifically, a late fusion (LF)-based U-net trained jointly on B-mode and shadow-enhanced B-mode images was generated by fusing two individual U-nets and expanding the set of trainable parameters to around twice the capacity of a basic U-net. This U-net was then applied to predict spine surface labels in in vivo images obtained from another rabbit, which were then used for 3-D spine surface reconstruction. The underlying pose of the transducer during the scan was estimated by registering stacks of US images to a geometrical model derived from corresponding CT data and used to align detected surface points. Final performance of the reconstruction method was assessed by computing the mean absolute error (MAE) between pairs of spine surface points detected from US and CT and by counting the total number of surface points detected from US. Comparison was made between the LF-based U-net and a previously developed phase symmetry (PS)-based method. Using the LF-based U-net, the averaged number of US surface points across the lumbar region increased by 21.61% and MAE reduced by 26.28% relative to the PS-based method. The overall MAE (in mm) was 0.24±0.29. Based on these results, we conclude that: 1) the proposed U-net can detect the spine posterior arch with low MAE and large number of US surface points and 2) the newly proposed reconstruction framework may complement and, under certain circumstances, be used without the aid of an external tracking system in intra-operative spine applications.


A review of saliva: normal composition, flow, and function.
An adequate supply of saliva is critical to the preservation and maintenance of oral tissue. Clinicians often do not value the many benefits of saliva until quantities are decreased. Much is written on the subject of salivary hypofunction, but little attention is paid to normal salivary flow and function. This article is a brief, up-to-date overview of the literature on the basics of normal salivary composition, flow, and function. A review of the literature was conducted using MEDLINE and Healthstar (1944 through 1999); articles were selected for inclusion on the basis of relevance and significance to the clinician.


Segmentation by texture using correlation.
The correlation coefficients are used for segmentation according to texture. They are first evaluated on a set of square regions forming two levels of the quadratic picture tree (or pyramid). If the coefficients of a square and its four children in the tree are similar, then that region is considered to be of uniform texture. If not, it is replaced by its children. In this way, the split-and-merge algorithm is used to achieve a preliminary segmentation. It is followed by a grouping algorithm using the correlation coefficients and the region adjacency graph, plus a small region elimination step. The latter regions are grouped according to their gray level because texture cannot be defined reliably on very small regions. Examples of implementation on four pictures are included.


Risk factors for SARS infection within hospitals in Hanoi, Vietnam.
We investigated a nosocomial infection of severe acute respiratory syndrome (SARS) in Vietnam in 2003 and attempted to identify risk factors for SARS infection. Of the 146 subjects who came into contact with SARS patients at Hospital A, 43 (29.5%) developed SARS, and an additional 16 (11%) were asymptomatic but SARS-coronavirus (CoV) seropositive. The asymptomatic infection rate accounted for 15.5% of the total number of infected patients at Hospital A, which was higher than that of 6.5% observed at Hospital B, to where all patients from Hospital A were eventually transported (P<0.05). At Hospital A, the risk for developing SARS was 12.6 times higher in individuals not using a mask than in those using a mask. The SARS epidemic in Vietnam resulted in numerous secondary infections due to its unknown etiology and delayed recognition at the beginning of the epidemic. The consistent and proper use of a mask was shown to be crucial for constant protection against infection with SARS.


Influence of fiber inserts, type of composite, and gingival margin location on the microleakage in Class II resin composite restorations.
This study evaluated the influence of fiber inserts, type of composites, and location of the gingival seat on microleakage in Class II resin composite restorations. Fifty noncarious human third molars were selected for the study. Standardized Class II box type cavities were prepared on the mesial and distal side of 45 teeth. The gingival margin was placed above the cementoenamel junction (CEJ) on the mesial side and below the CEJ on the distal side. The remaining five teeth received no cavity preparations. The prepared samples were divided randomly on the basis of type of composite and presence or absence of fiber inserts, into four experimental groups of 10 teeth each and two control groups of five teeth each. The groups were defined as follows: group I (n=10) - Z350 XT; group II (n=10) - Z350 XT with fibers; group III (n=10) - P90; group IV (n=10) - P90 with fibers; and group V (n=5) - positive controls, cavities were not restored; group VI (n=5) - negative controls, no cavities were prepared. The samples were stored in distilled water in incubator at 37°C for 24 hours and then subjected to 500 cycles of thermocycling (5°C and 55°C) with a dwell time of 15 seconds. They were then placed in a 2% methylene blue dye solution for 24 hours at 37°C. Samples were sectioned longitudinally and evaluated for microleakage at the occlusal and gingival margin under a stereomicroscope at 20× magnification. Kruskal-Wallis and Mann-Whitney U-tests were used to compare the mean leakage scores. Restorations with gingival margins in enamel showed significantly less microleakage. Significant reduction in microleakage was observed in groups restored with P90 composite than those restored with Z350 XT. No improvement in microleakage was observed with the use of fiber inserts (p>0.05).


A single germline VH gene segment of normal A/J mice encodes autoantibodies characteristic of systemic lupus erythematosus.
These experiments tested the hypothesis that unmutated germline genes from normal mice can encode autoantibodies. We found that the unmutated VHIdCR gene segment, which encodes a large proportion of antiarsonate antibodies in A/J mice, also encodes antibodies with the ability to bind to DNA and cytoskeletal proteins. After Ars immunization, at a time when the VHIdCR gene segment mutates and antibody affinity for the hapten increases, reactivity with the autoantigens was lost. Six antibodies obtained after immunization with Ars bound both the Ars and DNA. Results of competitive inhibition assays suggested that the same variable region site in the antibodies bound to both Ars and DNA. The properties of the individual germline-encoded antibodies, which include reactivity to both DNA and cytoskeletal proteins, suggest that autoantibodies characteristic of SLE might be a subset of antibodies encoded by unmutated germline V genes.


Child and adolescent benzodiazepine exposure and overdose in the United States: 16 years of poison center data.
Background: Recently, there has been an increase in prescription drug abuse and related fatalities. Although opioid analgesics are commonly implicated, there have been significant increases in the prevalence of benzodiazepine exposures and overdoses.Objective: To describe national trends in pediatric benzodiazepine exposures from 2000 to 2015.Methods: A retrospective database analysis was conducted. Data regarding benzodiazepine exposures in children ages 0 to <18 years reported to participating United States poison centers from January 2000 through December 2015 were obtained from the National Poison Data System. Population data were obtained from the US Census Bureau to determine annual population estimates. Data were analyzed using chi-square tests.Results: A total of 296,838 pediatric benzodiazepine exposures were identified during the study period. The rate of pediatric benzodiazepine exposure increased 54% between 2000 and 2015. The severity of medical outcomes also increased, as did the prevalence of co-ingestion of multiple drugs, especially in children ages 12 to <18 years. Nearly half of all reported exposures in 2015 were documented as intentional abuse, misuse, or attempted suicide, reflecting a change from prior years. The most commonly identified pediatric benzodiazepines of exposures were alprazolam, clonazepam, and lorazepam.Conclusions: The rate and severity of reported pediatric benzodiazepine exposure is increasing over time. Adolescent exposures are of specific concern, as co-ingestion and intentional abuse were found to be more common in this group. Medical providers and caretakers should be cognizant of this growing epidemic to avoid preventable harm to adolescents, young children, and infants.


Prophylactic effect of cimetidine in duodenal ulcer disease.
Fifty-seven symptom-free patients with duodenal ulcer entered a double-blind trial to assess the prophylactic effect of cimetidine. Patients were randomly allocated to receive cimetidine 400 mg twice daily (29 patients) or placebo (28 patients). The trial was designed to imitate daily clinical practice, so duodenal ulcer disease was diagnosed by means of x-ray examination. Three patients from each group withdrew from the trial. All remaining patients continued to receive treatment for 12 months or until symptoms recurred. Three out of 26 patients suffered relapses during cimetidine treatment, compared with 20 out of 25 receiving placebo. No side effects were attributable to cimetidine. Long-term cimetidine treatment had no curative effect as relapses occurred soon after treatment was stopped. The estimated chance (cumulative remission rate +/- 2 SE) of remaining symptom-free 13 weeks after one year's cimetidine treatment had been completed was 47 +/- 21%. Maintenance treatment with cimetidine is a suitable alternative to elective in surgery in patients with duodenal ulcer subjects frequent relapses. Further study is needed to establish the optimal duration and safety of prolonged cimetidine treatment.


Valuing the Benefits of Rock Climbing and the Welfare Gains from Decreasing Injury Risk.
Rock climbing is an increasingly popular recreation activity worldwide, nevertheless there are only few studies that estimate the demand for it. In this article the Kuhn-Tucker approach is used to estimate the demand for rock climbing in Sicily, the recreation value of different climbing sites, and the welfare impact of reducing injury risk. In modeling the demand for climbing we account for the heterogeneity of preferences. We find that decreasing the level of injury risk generates remarkable welfare gains to climbers. This is the first study we know of that provides a welfare measure of risk reduction in rock climbing and one of a very few studies in environmental economics that uses a revealed preference approach to estimate a welfare measure associated with a reduction in risk.


Comparison of alternating pressure mattresses and overlays for prevention of pressure ulcers in ventilated intensive care patients: a quasi-experimental study.
To compare the effectiveness of alternating pressure air mattresses vs. overlays to prevent pressure ulcers in mechanically ventilated patients in intensive care units. Pressure ulcers prevention is an important issue in the nursing of critically ill patients. It is not clear whether alternating pressure air mattresses are more effective than overlays to prevent pressure ulcers. Prospective quasi-experimental study. A prospective quasi-experimental study was conducted among patients in the medical-surgery intensive care unit of a university hospital on mechanical ventilation ≥24 hours during two time periods (2001 and 2006). Overlays were used in 2001 and mattresses in 2006. Primary outcome was the incidence of pressure ulcers grade ≥II (according to the European Pressure Ulcer Advisory Panel) during intensive care unit stay. The study included 221 patients (116 in 2001 and 105 in 2006). Baseline characteristics were similar between groups except for a higher Acute Physiology and Chronic Health Evaluation III score, total and first-day respiratory Sequential Organ Failure Assessment Score on day 1 in overlay group. There was significantly lower incidence density in the mattress vs. overlay group (12·41 cases/1000 days vs. 18·67 cases/1000 days of stay). The multivariate analyses showed the use of the mattress to be a protective factor against pressure ulcer onset. This quasi-experiment study that alternative pressure air mattresses were more effective than alternating pressure air overlays in preventing pressure ulcers in mechanically ventilated critical care patients.


Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations.
Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations. Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here. T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences. T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.