Robust surface doping of Bi2Se3 by rubidium intercalation.
Rubidium adsorption on the surface of the topological insulator Bi(2)Se(3) is found to induce a strong downward band bending, leading to the appearance of a quantum-confined two-dimensional electron gas state (2DEG) in the conduction band. The 2DEG shows a strong Rashba-type spin-orbit splitting, and it has previously been pointed out that this has relevance to nanoscale spintronics devices. The adsorption of Rb atoms, on the other hand, renders the surface very reactive, and exposure to oxygen leads to a rapid degrading of the 2DEG. We show that intercalating the Rb atoms, presumably into the van der Waals gaps in the quintuple layer structure of Bi(2)Se(3), drastically reduces the surface reactivity while not affecting the promising electronic structure. The intercalation process is observed above room temperature and accelerated with increasing initial Rb coverage, an effect that is ascribed to the Coulomb interaction between the charged Rb ions. Coulomb repulsion is also thought to be responsible for a uniform distribution of Rb on the surface.


Discussion: Targeting is making trade-offs.
The previous articles presented different aspects of targeting: the implicit political implications, the trade-offs in giving power to different stakeholders to decide and to implement targeting, perceptions of frontline workers in implementing a program, and a technical article about selecting a scale for targeting, which we review in greater detail. It is well recognized that targeting results in a trade-off between not serving those who should be served and including those who should not be served. Less well recognized are the trade-offs that are the consequences of deciding between using indicators of risk vs. using indicators that predict benefit.


Ocular adnexal follicular lymphoma: a multicenter international study.
The clinical features of the follicular subtype of ocular adnexal lymphoma (OAL) have not been previously evaluated in a large cohort. To characterize the clinical features of follicular OAL. We performed a retrospective multicenter study that involved 6 eye cancer centers from January 1, 1980, through December 31, 2010. A total of 105 patients with follicular OAL were identified, of which 7 patients were excluded because of missing clinical data. The median follow-up time was 52 months (range, 13-118 months). Overall survival, disease-specific, and progression-free survivals were the primary end points. Ninety-eight eligible patients with follicular OAL were included; 60 (61%) were women. The median patient age was 63 years (range, 32-96 years). Sixty-nine patients (70%) had primary OAL, 19 (19%) had OAL in conjunction with a concurrent systemic lymphoma, and 10 (10%) presented with an ocular adnexal relapse. The lacrimal gland (28%), conjunctiva (28%), and orbit (28%) were the most frequently involved sites. Of the 69 patients with primary follicular lymphoma, 38 (55%) presented with Ann Arbor stage IE lymphoma, and 31 (45%) had stage IIE lymphoma. Patients with disseminated lymphoma had stage IIIE (9 of 19 [47%]) and stage IV (10 of 19 [53%]) disease, whereas patients with a relapse of systemic lymphoma presented with stage IE (8 of 10 [80%]), stage IIE (1 of 10 [10%]), and stage IIIE (1 of 10 [10%]) disease. Patients with primary follicular lymphoma (n = 69) and those with isolated ocular relapse (n = 9) were treated with external beam radiation therapy (EBRT) (35 of 78 [45%]) or EBRT plus chemotherapy (22 of 78 [28%]). Patients presenting with stage IIIE-IV follicular lymphoma (n = 20) most frequently received chemotherapy (9 of 20 [45%]) or EBRT plus chemotherapy (4 of 20 [20%]). The 10-year overall survival for the entire study cohort was 60%. Primary patients treated with EBRT had a better disease-specific survival compared with patients receiving ERBT plus chemotherapy (10-year disease-specific survival, 94% vs 40%; P = .02 by log-rank test). Follicular OAL was more commonly found in elderly female patients. These tumors were equally noted to involve the conjunctiva, lacrimal gland, and orbit. Patients with ocular adnexal follicular lymphoma primarily treated with EBRT had a more favorable long-term disease-specific survival.


Active template rotaxane synthesis through the Ni-catalyzed cross-coupling of alkylzinc reagents with redox-active esters.
The synthesis of unsymmetrical axle [2]rotaxanes through a recently developed Ni-catalyzed C(sp3)-C(sp3) cross-coupling of redox-active esters (formed directly from carboxylic acids) and organozinc reagents (derived from alkyl bromides) is reported. The method also furnishes, as a minor product, the symmetrical axle [2]rotaxanes resulting from the homo-coupling of the organozinc half-thread. The rotaxanes are formed in up to 56% yield with the ratio of unsymmetrical rotaxane increasing with the cavity size of the macrocycle. In the absence of the redox-active ester neither rotaxane is formed, even though the homo-coupling rotaxane product does not incorporate the redox-active ester building block. A Ni(iii) intermediate is consistent with these observations, providing support for the previously postulated mechanism of the Ni-catalyzed cross-coupling reaction.


Intrinsic superoxide dismutase activity of MnO nanoparticles enhances the magnetic resonance imaging contrast.
Superoxide radicals are associated with the development of many severe diseases, such as cancer. Under nonpathogenic conditions, the natural enzyme superoxide dismutase (SOD) regulates the intracellular superoxide concentrations, but nearly all tumor tissues show reduced SOD levels. Selective imaging in early progression stages remains a key requirement for efficient cancer diagnosis and treatment. Magnetic resonance imaging (MRI) as a noninvasive tool with high spatial resolution may offer advantages here, but MRI contrast agents exhibiting a redox-triggered change in the image contrast towards superoxide radicals have not been reported so far. Here we show that manganese oxide (MnO) nanoparticles (NPs) exhibit an intrinsic SOD-like activity, which is higher than that of the native Mn-dependent SOD. In addition, MnO NPs significantly enhance the MRI contrast when exposed to superoxide radicals, making them responsive MRI contrast agents for the treatment and imaging of cancer cells with reduced SOD levels.


Knowledge of pregnant women on mother-to-child transmission of HIV in Meket District, Northeast Ethiopia.
Knowledge of pregnant women on the three periods of mother-to-child transmission (MTCT) of HIV has implication for child HIV acquisition. This study aims to assess the knowledge of pregnant women on mother-to-child transmission of HIV and to identify associated factors in Meket district, northeast Ethiopia. Logistic regression models were fitted to identify associated factors. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) were used to determine the presence and strength of association. About one-fifth (19%) of women were knowledgeable on mother-to-child transmission of HIV (95% CI: 15.5%, 22.4%). Being urban resident (AOR: 2.69, 95% CI: 1.48, 4.87), having primary education (AOR: 2.41, 95% CI: 1.03, 5.60), reporting receiving information on HIV from health care providers (AOR: 3.24, 95% CI: 1.53, 6.83), having discussion with partner about mother-to-child transmission of HIV (AOR: 2.64, 95% CI: 1.59, 4.39), and attending antenatal care (AOR: 5.80, 95% CI: 2.63, 12.77) were positively associated with increased maternal knowledge of mother-to-child transmission of HIV. Knowledge of mother-to-child transmission of HIV among pregnant women was low. Providing information, especially for rural women and their partners, is highly recommended.


Insurance Plan Adherence to Mandate for Long-Acting Reversible Contraceptives in a Large Pediatric Hospital Network.
Long-acting reversible contraceptives (LARCs) are the most effective form of pregnancy prevention for sexually active adolescents, yet usage rates are low. The Affordable Care Act (ACA) mandated insurers cover LARCs without cost-sharing. Compliance with this policy is not well documented. This study assessed LARC coverage by insurers in a large pediatric health system. Between June and August 2016, LARC coverage was assessed through content reviews of insurance Web sites, formularies, and summaries of benefits for all Pennsylvania Medicaid plans and the top 20 commercial insurers for a large pediatric health system. The primary outcome was adherence to the ACA mandate for LARC coverage without cost-sharing. Among the 37 plans (17 public, 20 private), 21 (56.8%) were adherent and 16 (43.2%) were nonadherent. Among nonadherent plans, 3 plans covered LARC services but required cost-sharing, whereas 13 did not cover LARC services at all. There was not a statistically significant difference in LARC coverage between public and private plans. Despite the landmark ACA mandate, insurance coverage of LARCs in pediatric hospitals is low for young women among private and public insurers. Insurer failure to adhere to the ACA among pediatric patients represents a barrier to LARC access for those at high risk of unintended pregnancy.


Users' guides to the medical literature: how to use an article about mortality in a humanitarian emergency.
The accurate interpretation of mortality surveys in humanitarian crises is useful for both public health responses and security responses. Recent examples suggest that few medical personnel and researchers can accurately interpret the validity of a mortality survey in these settings. Using an example of a mortality survey from the Democratic Republic of Congo (DRC), we demonstrate important methodological considerations that readers should keep in mind when reading a mortality survey to determine the validity of the study and the applicability of the findings to their settings.


Proteomics analysis of serum and urine identifies VCP and CTSA as potential biomarkers associated with multiple myeloma.
We analyzed the differentially expressed proteins (DEPs) in serum and urine in order to provide new potential biomarkers for MM. Data-Independent Acquisition-based proteomics of serum and urine was performed to identify potential biomarkers for MM patients. Then we performed Western Blotting (WB), ELISA along with their ROC curve analysis to confirm DEPs. A total of 1653 proteins in serum and 4519 proteins in urine were identified using Data-Dependent Acquisition method. VCP was the only protein that showed significant differences in different comparison groups in both serum and urine. Pathway analysis revealed that protein processing in the endoplasmic reticulum was the most relevant pathway associated with MM. Furthermore, the increased expression of HSP90B1, VCP, CTSA, HYOU1, PDIA4, and RAB7A was detected by WB. The results of ELISA indicated that a combination of VCP and CTSA provided a high area under curve (AUC) value of 0.883 (95 % CI, 0.769-0.997, p < 0.001) to diagnose NDMM. The combination of VCP, CTSA, ALB, and HGB exhibited better performance (AUC = 0.981), with 100 % specificity and 86.7 % sensitivity. These findings suggest VCP and CTSA exhibit potential as biomarkers for MM, which may be helpful in the molecular mechanisms and pathogenesis upon further investigation.


The novel insecticides flupyradifurone and sulfoxaflor do not act synergistically with viral pathogens in reducing honey bee (Apis mellifera) survival but sulfoxaflor modulates host immunocompetence.
The decline of insect pollinators threatens global food security. A major potential cause of decline is considered to be the interaction between environmental stressors, particularly between exposure to pesticides and pathogens. To explore pesticide-pathogen interactions in an important pollinator insect, the honey bee, we used two new nicotinic acetylcholine receptor agonist insecticides (nACHRs), flupyradifurone (FPF) and sulfoxaflor (SULF), at sublethal and field-realistic doses in a fully crossed experimental design with three common viral honey bee pathogens, Black queen cell virus (BQCV) and Deformed wing virus (DWV) genotypes A and B. Through laboratory experiments in which treatments were administered singly or in combination to individual insects, we recorded harmful effects of FPF and pathogens on honey bee survival and immune gene expression. Though we found no evidence of synergistic interactions among stressors on either honey bee survival or viral load, the combined treatment SULF and DWV-B led to a synergistic upregulation of dicer-like gene expression. We conclude that common viral pathogens pose a major threat to honey bees, while co-exposure to these novel nACHR insecticides does not significantly exacerbate viral impacts on host survival in the laboratory.


Understanding Haemophilus parasuis infection in porcine spleen through a transcriptomics approach.
Haemophilus parasuis (HPS) is an important swine pathogen that causes Glässer's disease, which is characterized by fibrinous polyserositis, meningitis and arthritis. The molecular mechanisms that underlie the pathogenesis of the disease remain poorly understood, particularly the resistance of porcine immune system to HPS invasion. In this study, we investigated the global changes in gene expression in the spleen following HPS infection using the Affymetrix Porcine Genechip. A total of 931 differentially expressed (DE) transcripts were identified in the porcine spleen 7 days after HPS infection; of these, 92 unique genes showed differential expression patterns based on analysis using BLASTX and Gene Ontology. The DE genes involved in the immune response included genes for inflammasomes (RETN, S100A8, S100A9, S100A12), adhesion molecules (CLDN3, CSPG2, CD44, LGALS8), transcription factors (ZBTB16, SLC39A14, CEBPD, CEBPB), acute-phase proteins and complement (SAA1, LTF, HP, C3), differentiation genes for epithelial cells and keratinocytes (TGM1, MS4A8B, CSTA), and genes related to antigen processing and presentation (HLA-B, HLA-DRB1). Further immunostimulation analyses indicated that mRNA levels of S100A8, S100A9, and S100A12 in porcine PK-15 cells increased within 48 h and were sustained after administration of lipopolysaccharide (LPS) and Poly(I:C) respectively. In addition, mapping of DE genes to porcine health traits QTL regions showed that 70 genes were distributed in 7 different known porcine QTL regions. Finally, 10 DE genes were validated by quantitative PCR. Our findings demonstrate previously unrecognized changes in gene transcription that are associated with HPS infection in vivo, and many potential cascades identified in the study clearly merit further investigation. Our data provide new clues to the nature of the immune response in mammals, and we have identified candidate genes that are related to resistance to HPS.


The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis.
Generation of an immunosuppressive microenvironment may enable a persistent human papillomavirus infection in the setting of an otherwise normal immune system. We hypothesized that expression of the T-lymphocyte co-inhibitory receptor programmed death 1 (PD-1) and its ligand PD-L1 would be increased in the recurrent respiratory papillomatosis (RRP) microenvironment compared to normal controls. Case-control study. Formalin-fixed paraffin-embedded respiratory papilloma and normal controls were obtained under institutional review board approval, stained for CD4, CD8, FoxP3, and PD-1, and scored by automated cell count. PD-L1 staining was scored by a blinded pathologist using an adjusted inflammation score that accounted for epithelial and immune infiltrate. Thirty-nine RRP cases and seven controls were studied. All immunologic markers demonstrated significantly increased staining in RRP specimens compared to normal controls (all P < .01). PD-1 correlated with both CD4 (P < .0001) and CD8 (P < .001) cell counts. Epithelial staining for PD-L1 (68%) and PD-L1+ infiltrating immune cells (76%) were observed in the majority of papilloma samples. The strongest staining for PD-L1 was usually observed in the basal papilloma layer adjacent to the immunologic infiltrate in the vascular core. Disease severity inversely correlated with CD8 cell counts (P = .01). A correlation between disease severity and other immunologic markers was not observed. Most RRP specimens demonstrate PD-1 T-lymphocyte infiltration and PD-L1 expression on both papilloma and infiltrating immune cells. This study suggests that this checkpoint pathway may be contributing to local immunosuppression in RRP, and opens the door for clinical trials utilizing PD-blocking monoclonal antibodies. NA Laryngoscope, 128:E27-E32, 2018.


Puerto Rican families caring for an adult with mental retardation: role of familism.
The role of familism (a cultural value including interdependence among nuclear and extended family members for support, loyalty, and solidarity) in caregiving was explored for Puerto Rican mothers with children with mental retardation living at home. Familism--defined here as direct caregiving provided by family members to the person with mental retardation, mothers' social support networks, and mothers' obligations to other family members--was hypothesized to account for variation in maternal well-being. Better maternal well-being was predicted by larger social support networks, greater satisfaction with social support, and more minor children living in the household. A troubling but not unexpected finding is that these mothers faced many socioeconomic challenges and were in poor health in addition to the challenges of parenting a child with mental retardation.


[Repair osteogenesis during limb elongation using transosseous distraction osteosynthesis].
The objective of this study was the investigation of morho-functional peculiarities of repair osteogenesis during the surgical extremity elongation using transosseous distraction osteosynthesis. In experiment performed in dogs it was found that the extremity elongation using Ilizarov apparatus the distraction changed the spatial organization of osseous regenerates which acquired the characteristic zonal structure. Spheroidal bony trabeculae were transformed in the distraction regenerates into cylindrical primary osteons, which were formed along vertically oriented vascular loops. The osteogenic cells demonstrate intracellular markers--mitochondrial crystalline mineral inclusions.


Bilateral epididymal metastases from primary adenocarcinoma of the prostate.
A 65-year-old man diagnosed with adenocarcinoma of the prostate gland opted for hormonal manipulation and had bilateral orchiectomy. Histological evaluation showed tumour deposits in both epididymides. Despite the relatively common occurrence of adenocarcinoma of the prostate, epididymal metastasis is a rare occurrence. This case highlights the need for proper evaluation of the testes and para-testicular structures so that accurate staging of these tumours can be made.


Chordomas with malignant spindle cell components. A DNA flow cytometric and immunohistochemical study with histogenetic implications.
The authors studied four chordomas with malignant spindle cell components (SCs) and 12 conventional chordomas (CCs) by DNA flow cytometry using paraffin-embedded tissue. In addition, immunohistochemical stains for a variety of epithelial and mesenchymal markers were performed. The four SCs contained areas histologically identical to conventional chordomas, as well as a high-grade malignant spindle cell component. All four (100%) SCs had an aneuploid-multiploid DNA content. Of interest, the conventional chordoma areas in these tumors had DNA contents different from those containing the high-grade malignant spindle cells. In contrast, only three (27%) of the 11 conventional chordomas with analyzable histograms had an aneuploid-multiploid DNA content. Immunohistochemical studies performed on the four SCs showed the high-grade malignant spindle cells to stain strongly for vimentin and weakly for cytokeratin, S-100 protein, and epithelial membrane antigen (EMA), whereas the areas of conventional chordoma in these same neoplasms stained moderately for vimentin and S-100 protein, and strongly for cytokeratin and EMA. In two cases, the staining for EMA and cytokeratin highlighted a gradual transition between the areas of conventional chordoma and the spindle cell areas. The immunohistochemical staining pattern of the 12 conventional chordomas was similar to that seen in the conventional chordoma components of the four chordomas with malignant spindle cell components. These results suggest that: 1) aneuploidy is more common in SCs than in CCs, and 2) some SCs are multipotential neoplasms in which the neoplastic cells are capable of differentiation along both epithelial and mesenchymal pathways.


Increasing Motor Noise Impairs Reinforcement Learning in Healthy Individuals.
Motor variability from exploration is crucial for reinforcement learning as it allows the nervous system to find new task solutions. However, motor variability from noise can be detrimental to learning and may underlie slowed reinforcement learning performance observed in individuals with cerebellar damage. Here we examine whether artificially increasing noise in healthy individuals slows reinforcement learning in a manner similar to that seen in patients with cerebellar damage. Participants used binary reinforcement to learn to rotate their reach angle in a series of directions. By comparing task performance between conditions with different levels of added noise, we show that adding a high level of noise-matched to a group of patients with cerebellar damage-slows learning. In additional experiments, we show that the detrimental effect of noise may lie in reinforcing incorrect behavior, rather than not reinforcing correct behavior. By comparing performance between healthy participants with added noise and a group of patients with cerebellar damage, we found that added noise does not slow the learning of the control group to the same degree observed in the patient group. Using a mechanistic model, we show that added noise in the present study matched patients' motor noise and total learning. However, increased exploration in the control group relative to the group with cerebellar damage supports faster learning. Our results suggest that motor noise slows reinforcement learning by impairing the mapping of reward to the correct action and that this may underlie deficits induced by cerebellar damage.


Validation of PCR Assay for Identification of Sarcoptes scabiei var. hominis.
Infestation of the skin by the "itch mite" Sarcoptes scabiei var. hominis results in a contagious skin infection in humans called "scabies". By resolving morphology issues, the present study was designed to be acquainted with itch mite by molecular markers. The mite samples were collected from scabies patients by visiting government hospitals of twin City, Pakistan. For successful molecular detection approach, preparation of Sarcoptes mite DNA by commercial DNA extraction kit method. Furthermore, two primers i.e. Sarms 15 F/R and 16S D1/D2 were used to amplify target sequence by using PCR. The amplified products were then separated by agarose gel, electrophoresis and analyzed after staining and visualizing in UV transilluminator. Analysis of PCR product showed one specific band of 178 bp with primer Sarms 15 F/R, while, with primer 16S D1/D2 bands of 460 bp and 600 bp were observed on 2% agarose gel. The appearance of different band of 600 bp revealed that it might be due to heteroplasmy state present in the Pakistani Sarcoptes mites population. Current study adds validity to the claim that PCR is more accurate, specific and sensitive in the detection of the ectoparasites even in smallest amount.


Tunable doping of graphene nanoribbon arrays by chemical functionalization.
We demonstrate the controlled tuning of the electronic band structure of large-arrays of graphene nanoribbons (GNRs) by chemical functionalization. The GNR arrays are synthesized by substrate-controlled metal-assisted etching of graphene in H2 at high temperature, and functionalized with different molecules. From Raman spectroscopy and carrier transport measurements, we found that 4-nitrobenzenediazonium (4-NBD) and diethylene triamine (DETA) molecules can tune the doping level of the GNR arrays to p- and n-type, respectively. In both cases, the doping effects induced in the GNRs were found to be higher than for a pristine graphene sheet, due to the presence of a large quantity of edges. Effects of chemical doping on the Raman spectrum of sp(2) carbon materials are also discussed. Our findings offer an effective way to control the electronic structure of GNRs by chemical functionalization, and are expected to facilitate the production of nanoribbon-based p-n junctions for future implementation into electronic circuits.


Incentives for organ donation: some ethical issues.
Objections to commerce in organs has not stopped the spread of such practice around the world. In most countries the gap between supply and demand for organs continues to increase. Kidneys from living donors are considered a valuable addition to the donor pool, and in a more acquisitive world, donor incentives are becoming thinkable, even acceptable. Current incentives for cadaver and living organ donation are reviewed from ethical and legal perspectives. A new principle of reimbursement for the living donor's risk and pain is defined and presented for debate.


Histopathologic and immunohistochemical findings in gelatinous drop-like corneal dystrophy.
A cornea with gelatinous drop-like corneal dystrophy was examined by histochemical and immunohistochemical techniques. Pretreatment of the sections with potassium permanganate did not decrease the staining with Congo red dye. Immunohistochemically, amyloid deposits in the cornea with this disease almost did not stain with antibodies to amyloid protein AA and AA-3. However, the corneal epithelium reacted distinctly with antibodies to amyloid protein AA and AA-3. Cross-reactivity with antibodies to protein AA and serum precursor of protein AA has been reported and protein AA-3 is the synthesized peptide corresponding to the amino acid sequence 37-47 of the human amyloid protein AA molecule. The present study suggests at least that corneal epithelial cells with gelatinous drop-like corneal dystrophy may produce a precursor of amyloid related to protein AA-3.


Visual impairment and socioeconomic factors.
Information about socioeconomic factors associated with visual impairment can assist in the design of intervention programmes. Such information was collected by the Melbourne Visual Impairment Project (Melbourne VIP). The Melbourne VIP was a population based study of non-institutionalised permanent residents in nine suburbs of the Melbourne metropolitan area aged 40 years of age and older. A standardised eye examination was provided to eligible residents which included a structured interview. Variables of interest for this analysis were age, sex, country of birth, language spoken at home, education level, use of private health insurance, employment status, and living arrangements. Visual impairment was defined as a best corrected visual acuity < 6/18 and/or visual field constriction to within 20 degrees of fixation. A total of 3271 (83%) residents participated. Participants ranged in age from 40 to 98 years; 54% were female. Forty four (1.34%) were classified as visually impaired due to visual acuity and/or visual field loss. To evaluate the independent association of the significant sociodemographic variables with visual impairment, a regression model was constructed that included age, retirement status, use of private health insurance, and household arrangement. The results showed that age was the significant predictor of visual impairment (OR: 3.19; CI: 2.29-4.43), with the mean age of people with visual impairment significantly older (75.0 years) compared with people without visual impairment (58.2 years) (t test = 9.71; p = 0.0001). Of the 44 visually impaired people, 39 (87%) were aged 60 years of age and older. The results indicate that age is the most significant factor associated with visual impairment. Of some importance was the finding that people with visual impairment were less likely to have private health insurance. With the aging of the population, the number of people affected by visual impairment will increase significantly. Intervention programmes need to be established before the onset of middle age to offset the escalation of visual impairment in the older population.


Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells.
A key feature of type 2 diabetes is impairment in the stimulation of glycogen synthesis in skeletal muscle by insulin. Glycogen synthesis and the activity of the enzyme glycogen synthase (GS) have been studied in human myoblasts in culture under a variety of experimental conditions. Incubation in the absence of glucose for up to 6 h caused an approximately 50% decrease in glycogen content, which was associated with a small decrease in the fractional activity of GS. Subsequent reincubation with physiological concentrations of glucose led to a dramatic increase in the rate of glycogen synthesis and in the fractional activity of GS, an effect which was both time- and glucose concentration-dependent and essentially additive with the effects of insulin. This effect was seen only after glycogen depletion. Inhibitors of signaling pathways involved in the stimulation of glycogen synthesis by insulin were without significant effect on the stimulatory action of glucose. These results indicate that at least two distinct mechanisms exist to stimulate glycogen synthesis in human muscle: one acting in response to insulin and the other acting in response to glucose after glycogen depletion, such as that which results from exercise or starvation.


Detection and characterization of ESBL-producing Enterobacteriaceae from the gut of subsistence farmers, their livestock, and the surrounding environment in rural Nepal.
The increasing trend of gut colonization by extended-spectrum β-lactamase (ESBL) producing Enterobacterales has been observed in conventional farm animals and their owners. Still, such colonization among domesticated organically fed livestock has not been well studied. This study aimed to determine the gut colonization rate of ESBL-producing Enterobacteriaceae and carbapenemase-producing Enterobacteriaceae (CPE) among rural subsistence farming communities of the Kaski district in Nepal. Rectal swabs collected by systematic random sampling from 128 households of subsistence farming communities were screened for ESBL-producing Enterobacteriaceae and CPE by phenotypic and molecular methods. A total of 357 (57%) ESBL-producing Enterobacteriaceae isolates were obtained from 626 specimens, which included 97 ESBL-producing Enterobacteriaceae (75.8%) from 128 adult humans, 101 (79.5%) from 127 of their children, 51 (47.7%) from 107 cattle, 26 (51%) from 51 goats, 30 (34.9%) from 86 poultry and 52 (42%) from 127 environmental samples. No CPE was isolated from any of the samples. blaCTX-M-15 was the most predominant gene found in animal (86.8%) and human (80.5%) isolates. Out of 308 Escherichia coli isolates, 16 human and two poultry isolates were positive for ST131 and were of clade C. Among non-cephalosporin antibiotics, the resistance rates were observed slightly higher in tetracycline and ciprofloxacin among all study subjects. This is the first one-health study in Nepal, demonstrating the high rate of CTX-M-15 type ESBL-producing Enterobacteriaceae among gut flora of subsistence-based farming communities. Gut colonization by E. coli ST131 clade C among healthy farmers and poultry birds is a consequential public health concern.


Evaluation of a rubella hemagglutination inhibition test system.
Two systems for measurement of rubella hemagglutination inhibition antibodies were compared. One had chick erythrocytes as indicator and the other, which is available in kit form ("Rubindex," Ortho-Diagnostics), uses human group O erythrocytes. Correlation to within one dilution of each other was noted in 92% of the tests. The Rubindex system has the advantage of longer shelf life of reagents and also does not require one of the absorption steps necessary for the other method, thus saving technologist's time.


Magnoflorine and phenolic derivatives from the leaves of Croton xalapensis L. (Euphorbiaceae).
The alkaloid magnoflorine 1, has been isolated for the first time from Croton xalapensis (Euphorbiaceae), in addition two phenylpropenols derivates, 3,4-dimethoxy-(E)-cinnamyl alcohol 2 and 3,4-dimethoxy-5-hydroxy-(E)-cinnamyl alcohol 3, 3,4,5-trimethoxycinnamic acid 4, gallic acid 5, methyl gallate 6 and 3,4-dihydroxybenzoic acid 7 have been also found; these compounds were identified by spectroscopic analysis particularly, 2D NMR and ESI-MS/MS techniques. The high concentration of magnoflorine, calculated with quantitative HPLC, of the aqueous extract, probably contributes to the remarkable medicinal properties of this plant. In addition this is the first phytochemical study on Croton xalapensis to be reported.


[Clinicopathological aspects of and survival in patients with clinical stage I bronchioloalveolar carcinoma].
To analyze the clinicopathological aspects of bronchioloalveolar carcinoma (BAC) and the survival in a sample of patients at clinical stage I. A retrospective study involving 26 patients diagnosed with clinical stage I BAC and undergoing surgery at the Thoracic Diseases Institute of the Federal University of Rio de Janeiro, in the city of Rio de Janeiro, Brazil, between 1987 and 2007. We analyzed clinicopathological and radiological aspects, as well as mortality and survival. The data, which were collected from the medical charts of the patients, were statistically analyzed. Females predominated (n = 16). The mean age at diagnosis was 68.5 years. Most patients were active smokers (69.2%). The most common forms of presentation of BAC were the asymptomatic form (84.6%) and the nodular form (88.5%). Involvement of the upper lobes predominated (57.7%). Stage IB was the most common pathological stage, followed by stages IA and IIB (46.2%, 38.4% and 15.4%, respectively). There was no in-hospital mortality. Four patients died during the postoperative follow-up, with a mean disease-free survival time of 21.3 months. The overall five-year survival rate was 83%. The probability of survival for the patients diagnosed after 1999 showed a trend toward an increase when compared with that for those diagnosed up through 1999 (three-year survival rate: 92% vs. 68%; p = 0.07). The clinicopathological aspects of this study sample were similar to those of patients with BAC evaluated in previous studies.


Limbic-cortical dysregulation: a proposed model of depression.
A working model of depression implicating failure of the coordinated interactions of a distributed network of limbic-cortical pathways is proposed. Resting state patterns of regional glucose metabolism in idiopathic depressed patients, changes in metabolism with antidepressant treatment, and blood flow changes with induced sadness in healthy subjects were used to test and refine this hypothesis. Dorsal neocortical decreases and ventral paralimbic increases characterize both healthy sadness and depressive illness; concurrent inhibition of overactive paralimbic regions and normalization of hypofunctioning dorsal cortical sites characterize disease remission. Normal functioning of the rostral anterior cingulate, with its direct connections to these dorsal and ventral areas, is postulated to be additionally required for the observed reciprocal compensatory changes, since pretreatment metabolism in this region uniquely predicts antidepressant treatment response. This model is offered as an adaptable framework to facilitate continued integration of clinical imaging findings with complementary neuroanatomical, neurochemical, and electrophysiological studies in the investigation of the pathogenesis of affective disorders.


DNA methylase activity of normal liver, regenerating liver, and a transplantable hepatocellular carcinoma.
DNA from transplantable hepatocellular carcinoma (THC) 252 has recently been found to have a lower 5-methylcytosine content than DNA from normal or regenerating rat liver. We have determined that DNA methylase, purified 200-fold from nuclei of regenerating rat liver, can add more methyl groups to THC 252 DNA than to DNA from normal or regenerating rat liver. Furthermore, a similarly purified DNA methylase from THC 252 was found to methylate THC 252 DNA at a higher rate than it methylated DNA from normal or regenerating liver. The larger number of unmethylated sites in THC 252 DNA was not due to a deficiency of DNA methylase since the level of methylase activity of nuclear extracts from THC 252 was 2.7 times that of normal liver and 1.5 times that of regenerating liver. Methylases from these three sources had similar rats of reaction with different DNA substrates. These findings suggest that the hypomethylation of THC 252 DNA is not due to decreased methylase activity or to altered enzyme specificity.


Frictional characteristics of graphene layers with embedded nanopores.
Graphite possessing extraordinary frictional properties has been widely used as solid lubricants. Interesting frictional characteristics have been observed for pristine graphene layers, for defective graphene, the frictional signal shows richer behaviors such as those found in topological defective graphene and graphene step edges. Recently discovered nanoporous graphene represents a new category of defect in graphene and its impact on graphene frictional properties has not yet been explored. In this work, we perform molecular dynamics simulations on the frictional responses of nanoporous graphene layers when slid using a silicon tip. We show that the buried nanopore raises maximum friction signal amplitude while preserving the stick-slip character, the size of the nanopore plays a key role in determining the maximum frictional force. Negative friction is observed when the silicon tip scanned towards the center of the nanopore, this phenomenon originates from the asymmetrical variation of the in-plane strain and the out-of-plane deformation when indented by the silicon tip. Moreover, the layer dependent frictional character is examined for the buried graphene nanopores, showing that increasing graphene layers weakens the effect of nanopore on the frictional signal.


Role of upper gastrointestinal investigations in a screening study for colorectal neoplasia.
Should patients with positive faecal occult blood screening tests who are free of colorectal neoplasia undergo upper gastrointestinal investigation? Altogether 16,985 faecal occult blood tests were completed in a group of 18,818 asymptomatic patients (45-75 years) offered screening at two yearly intervals. A total of 447 (2.6%) were positive and underwent large bowel investigations. No neoplastic disease was identified in 283 (63%) of them. Fourteen (5%) also underwent gastroscopy for upper gastrointestinal symptoms, benign conditions were identified in five and a gastric carcinoma in one. No further investigations were instituted in the remaining 269 subjects who have now been followed up for a median period of 5 years (2-8 years). Five have been referred for benign upper gastrointestinal conditions, but none for upper gastrointestinal malignancy. Thirty one subjects have died - one from gastric cancer (a patient who had undergone a previous partial gastrectomy for a duodenal ulcer and who had persistent upper gastrointestinal symptoms). The remaining deaths were unrelated to the upper gastrointestinal tract. Nineteen people who have left the trial area have been monitored for the development of malignant disease; none have presented with upper gastrointestinal malignancy. These data support the view that upper gastrointestinal investigations need not be performed routinely in this group of subjects, but may be reserved for those with relevant symptoms.


Ischaemia-reperfusion injury in liver transplantation--from bench to bedside.
Ischaemia-reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate-adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia-reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate-adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia-reperfusion inflammation and organ dysfunction.


Effect of Comorbidities Features in Machine Learning Models for Survival Analysis to Predict Prodromal Alzheimer's Disease.
Alzheimer's Disease (AD) is the most common form of dementia, specifically a progressive degenerative disorder affecting 47 million people worldwide and is only expected to grow in the elderly population. The detection of AD in its early stages is crucial to allow early intervention aiding in the prevention or slowing down of the disease. The effect of using comorbidity features in machine learning models to predict the time until a patient develops a prodrome was observed. In this study, we used Alzheimer's Disease Neuroimaging Initiative (ADNI) high-dimensional clinical data to compare the performance of six machine learning algorithms for survival analysis, combined with six feature selection methods trained on two settings: with and without comorbidities features. Our ridge model combined with permutation feature selection achieves maximum performance of 0.90 when using comorbidity features with the concordance index as a performance indicator. This demonstrated that incorporating comorbidities into the feature set enhances the performance of survival analysis for Alzheimer's disease. There is potential to identify risk factors (coronary artery disease) from comorbidities which could guide preventative care based on medical history.


Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets.
Blocking heat-shock protein 90 (Hsp90) induces death of malignant plasma cells by activation of the unfolded protein response, a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum. We hypothesized that nontransformed plasma cells are also hypersensitive to Hsp90 inhibition because of their high amount of protein biosynthesis. To investigate this hypothesis, 2 different Hsp90 inhibitors, the geldanamycin derivative 17-DMAG and the nontoxic peptide derivative TCBL-145, were applied to mice with experimental epidermolysis bullosa acquisita, an autoimmune bullous disease characterized by autoantibodies against type VII collagen of the dermal-epidermal junction. Both inhibitors ameliorated clinical disease of type VII collagen-immunized mice, suppressed auto-antibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cell numbers, type VII collagen-specific plasma cells, and germinal center B cells were unaffected by anti-Hsp90 treatment in vivo. However, T-cell proliferation was potently inhibited, as evidenced by the reduced response of isolated lymph node cells from immunized mice to in vitro restimulation with anti-CD3/CD28 antibody or autoantigen in the presence of Hsp90 inhibitors. Our results suggest that Hsp90 blockade has no impact on normal or autoreactive plasma cells in vivo and indentify T cells as targets of anti-Hsp90 treatment in autoimmunity to type VII collagen.


SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing.
The stratum corneum (SC), the outermost layer of the epidermis, acts as a barrier against the external environment. It is hydrated by endogenous humectants to avoid desiccation. However, the molecular mechanisms of SC hydration remain unclear. We report that skin-specific retroviral-like aspartic protease (SASPase) deficiency in hairless mice resulted in dry skin and a thicker and less hydrated SC with an accumulation of aberrantly processed profilaggrin, a marked decrease of filaggrin, but no alteration in free amino acid composition, compared with control hairless mice. We demonstrated that recombinant SASPase directly cleaved a linker peptide of recombinant profilaggrin. Furthermore, missense mutations were detected in 5 of 196 atopic dermatitis (AD) patients and 2 of 28 normal individuals. Among these, the V243A mutation induced complete absence of protease activity in vitro, while the V187I mutation induced a marked decrease in its activity. These findings indicate that SASPase activity is indispensable for processing profilaggrin and maintaining the texture and hydration of the SC. This provides a novel approach for elucidating the complex pathophysiology of atopic dry skin.


Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout.
Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9.


[A simplified method for the statistical evaluation of experimental data].
A simplified method excluding the use of special tables is proposed for rapid determination of the confidence interval values in biomedical or other experimental studies. The method is based on a simplified approximation of quantitative relation of experimental data with commonly employed standard methods. Approximation formula has been calculated to warrant rapid memorizing.


Three-Dimensional Stereophotogrammetry in the Evaluation of Craniosynostosis: Current and Potential Use Cases.
Three-dimensional (3D) stereophotogrammetry is a novel imaging technique that has gained popularity in the medical field as a reliable, non-invasive, and radiation-free imaging modality. It uses optical sensors to acquire multiple 2D images from different angles which are reconstructed into a 3D digital model of the subject's surface. The technique proved to be especially useful in craniofacial applications, where it serves as a tool to overcome the limitations imposed by conventional imaging modalities and subjective evaluation methods. The capability to acquire high-dimensional data in a quick and safe manner and archive them for retrospective longitudinal analyses, provides the field with a methodology to increase the understanding of the morphological development of the cranium, its growth patterns and the effect of different treatments over time.This review describes the role of 3D stereophotogrammetry in the evaluation of craniosynostosis, including reliability studies, current and potential clinical use cases, and practical challenges. Finally, developments within the research field are analyzed by means of bibliometric networks, depicting prominent research topics, authors, and institutions, to stimulate new ideas and collaborations in the field of craniofacial 3D stereophotogrammetry.We anticipate that utilization of this modality's full potential requires a global effort in terms of collaborations, data sharing, standardization, and harmonization. Such developments can facilitate larger studies and novel deep learning methods that can aid in reaching an objective consensus regarding the most effective treatments for patients with craniosynostosis and other craniofacial anomalies, and to increase our understanding of these complex dysmorphologies and associated phenotypes.


A rare case of scurvy in an otherwise healthy child: diagnosis through oral signs.
The purpose of this paper was to report the case of a 2-year-old Caucasian female who was referred with a presumed diagnosis of pediatric rheumatoid arthritis. The patient presented widespread gingival swelling with bleeding, sharp pain, and halitosis. The patient also presented pain and swelling of the right knee joint, and psychomotor restlessness associated with muscular frailty. Little compliance on the part of both the patient and parents was also noted. Oral manifestations, together with an accurate medical history, led to the diagnosis of infantile scurvy, caused by an inadequate dietary supply of vitamin C. Administering 250 mg of ascorbic acid orally twice a day led to the remission of gingival swelling and of the other symptoms. The parents were advised to feed the child appropriate foods. Nutritional problems are traditionally linked to an insufficient availability of food, but can also be associated with child- or family-related psychological problems.


Mindcontrol: A web application for brain segmentation quality control.
Tissue classification plays a crucial role in the investigation of normal neural development, brain-behavior relationships, and the disease mechanisms of many psychiatric and neurological illnesses. Ensuring the accuracy of tissue classification is important for quality research and, in particular, the translation of imaging biomarkers to clinical practice. Assessment with the human eye is vital to correct various errors inherent to all currently available segmentation algorithms. Manual quality assurance becomes methodologically difficult at a large scale - a problem of increasing importance as the number of data sets is on the rise. To make this process more efficient, we have developed Mindcontrol, an open-source web application for the collaborative quality control of neuroimaging processing outputs. The Mindcontrol platform consists of a dashboard to organize data, descriptive visualizations to explore the data, an imaging viewer, and an in-browser annotation and editing toolbox for data curation and quality control. Mindcontrol is flexible and can be configured for the outputs of any software package in any data organization structure. Example configurations for three large, open-source datasets are presented: the 1000 Functional Connectomes Project (FCP), the Consortium for Reliability and Reproducibility (CoRR), and the Autism Brain Imaging Data Exchange (ABIDE) Collection. These demo applications link descriptive quality control metrics, regional brain volumes, and thickness scalars to a 3D imaging viewer and editing module, resulting in an easy-to-implement quality control protocol that can be scaled for any size and complexity of study.


Bioactive phytoconstituents as potent inhibitors of casein kinase-2: dual implications in cancer and COVID-19 therapeutics.
Casein kinase 2 (CK2) is a conserved serine/threonine-protein kinase involved in hematopoietic cell survival, cell cycle control, DNA repair, and other cellular processes. It plays a significant role in cancer progression and viral infection. CK2 is considered a potential drug target in cancers and COVID-19 therapy. In this study, we have performed a virtual screening of phytoconstituents from the IMPPAT database to identify some potential inhibitors of CK2. The initial filter was the physicochemical properties of the molecules following the Lipinski rule of five. Then binding affinity calculation, PAINS filter, ADMET, and PASS analyses followed by interaction analysis were carried out to discover nontoxic and better hits. Finally, two compounds, stylopine and dehydroevodiamines with appreciable affinity and specific interaction towards CK2, were identified. Their time-evolution analyses were carried out using all-atom molecular dynamics simulation, principal component analysis and free energy landscape. Altogether, we propose that stylopine and dehydroevodiamines can be further explored in in vitro and in vivo settings to develop anticancer and antiviral therapeutics.


Comparative effectiveness of natural and synthetic bone grafts in oral and maxillofacial surgery prior to insertion of dental implants: Systematic review and network meta-analysis of parallel and cluster randomized controlled trials.
Bone grafts are often used to enhance bone volume/quality prior to implantation insertion. This systematic review compares the histomorphometric effectiveness of bone grafts in an evidence-based manner. Randomized clinical trials comparing histomorphometrically the % of newly-formed bone between two grafts were included. Risk of bias within and across studies was assessed with the Cochrane tool and the GRADE approach, respectively. Random-effects pairwise meta-analyses were conducted, followed by network meta-analysis, network meta-regression and sensitivity analyses. Four electronic databases were searched from inception to June 2015 without limitations. A total of 12 trials (5 parallel; 7 cluster) with a total of 231 patients (302 grafted sites) were included. No statistically significant differences were found in the % of new bone from pairwise comparisons between any two bone grafts. Treatment ranking based on the evidence network indicated that autografts presented the highest percentage of new bone, followed by synthetic grafts, xenografts, and allografts. No differences according to patient age, sex, healing time, membrane used or kind of surgical graft use were identified. Our confidence on pairwise comparisons was moderate to very low due to study limitations, inconsistency, and imprecision; our confidence on graft ranking was moderate due to study limitations. No significant differences were found in the percentage of new bone between any two grafts. Synthetic bone substitutes or xenologous bone grafts can be used as an alternative to autologous graft in order to overcome problems of additional surgeries or limited graft availability.


Monocyte activation in patients with non-seminomatous germ cell tumour of the testis before and after tumour eradication.
To investigate the kinetics of normalisation of monocyte oxidative activity following tumour eradication. Whole blood lucigenin enhanced chemiluminescence was studied in patients with non-seminomatous germ cell tumours. Group 1 comprised 14 patients who had been "cured" of their cancer (the term "cured" as used in this report denotes a relapse free period of at least three years). Group 2 comprised 15 patients who were followed from diagnosis to up to two years after the start of treatment. Lucigenin enhanced chemiluminescence of whole blood in the "cured" patients was similar to that of controls and lower than that in patients who had not yet received chemotherapy (group 2). After treatment, chemiluminescence decreased slowly and did not normalise until 18 months after the start of treatment. Tumour necrosis factor alpha (TNF alpha) concentrations were normal in "cured" patients but were raised in those who had not yet received treatment. TNF alpha was normalised 12 months after start of treatment. Alpha-fetoprotein concentrations were raised in most patients but normalised rapidly after tumour eradication. The activity of blood monocytes, as measured by whole blood lucigenin enhanced chemiluminescence, is increased in cancer. This activity may be a consequence of the presence of tumour cells. Immunocompetent cells remain active for over a year after eradication of the tumour.


Thoracoscopic-assisted placement of azygos vein central venous catheter in a child.
Loss of central venous access in intestinal failure patients is a potentially fatal complication, and an indication for intestinal transplantation. Thrombosis of the superior vena cava (SVC) has historically been considered a contraindication to small bowel transplantation; however, unconventional central venous access can facilitate survival and eventual transplant procedure in patients with end-stage central venous access. We describe a technique for azygos vein central catheter insertion utilizing thoracoscopic guidance in a 14-year-old girl with thrombosis of the SVC and chronic idiopathic pseudo-obstruction syndrome awaiting multivisceral transplantation. The technique is simplified by utilizing carbon dioxide (CO(2)) insufflation of the thoracic cavity to collapse the lung instead of double-lumen endotracheal tube placement, and no postoperative chest tube drainage of the pleural space is required. Thoracoscopic-assisted central access can also be used in children requiring chronic hemodialysis with limited venous sites due to thrombosis or small size of vessels.


fMRI of intrasubject variability in ADHD: anomalous premotor activity with prefrontal compensation.
Children with attention-deficit/hyperactivity disorder (ADHD) consistently display increased intrasubject variability (ISV) in response time across varying tasks, signifying inefficiency of response preparation compared to typically developing (TD) children. Children with ADHD also demonstrate impaired response inhibition; inhibitory deficits correlate with ISV, suggesting that similar brain circuits may underlie both processes. To better understand the neural mechanisms underlying increased ISV and inhibitory deficits in children with ADHD, functional magnetic resonance imaging was used to examine the neural correlates of ISV during Go/No-go task performance. Event-related functional magnetic resonance imaging was used to study 25 children with ADHD and 25 TD children ages 8 to 13 years performing a simplified Go/No-go task. Brain-behavior correlations were examined between functional magnetic resonance imaging activation and ISV within and between groups. For TD children, increased rostral supplementary motor area (pre-supplementary motor area) activation during No-go events was associated with less ISV, whereas the reverse was true for children with ADHD for whom increased pre-supplementary motor area activation was associated with more ISV. In contrast, children with ADHD with less ISV showed greater prefrontal activation, whereas TD children with more prefrontal activation demonstrated more ISV. These findings add to evidence that dysfunction of premotor systems may contribute to increased variability and impaired response inhibition in children with ADHD and that compensatory strategies eliciting increased cognitive control may improve function. However, recruitment of prefrontal resources as a compensatory mechanism for motor task performance may preclude the use of those prefrontal resources for higher order, more novel executive functions with which children with ADHD often struggle.


An Approach to Some Aspects of Strabismus from Ocular and Orbital Trauma.
Strabismus caused by ocular or orbital trauma can be the result of localized acute soft tissue swelling or may follow orbital fractures, partial or complete loss of extraocular muscle (EOM) and/or cranial nerve function, or damage to surrounding tissues causing mechanical restriction. The strabismus is frequently incomitant and can be difficult, if not impossible to completely correct. The resulting diplopia can affect the individual's ability to function at work, in sports and in common tasks of daily living like driving. The preoperative evaluation should include an assessment of the degree of limitation, muscle function and the condition of the surrounding tissue. In most cases, high resolution computed tomography and/or surface coil dynamic magnetic resonance imaging are required to determine the extent and nature of suspected bony or EOM injury, as well as muscle contractility. If the scan reveals an intact but paretic muscle or only minor muscle injury, surgical intervention is based on the degree of muscle recovery 6 months after the initial insult. If a rectus muscle has been lacerated, and the proximal stump is functional, retrieval should be attempted, either by a direct conjunctival approach if located anteriorly, or by an anterior medial orbitotomy if located deep in the orbit. If a damaged muscle cannot be found, recovered or repaired at any time, then muscle transposition should be considered. If multiple muscles are damaged or scar tissue is excessive, a tether procedure may be indicated. This paper will present an approach to some aspects of strabismus in this setting.


Diagnostic yield and therapeutic impact of transthoracic echocardiography in patients with potential cardiac sources of cerebral embolism.
To explore the diagnostic yield of transthoracic echocardiography (TTE), and assess the effect of echocardiographic findings on subsequent therapy. In this retrospective study, we reviewed TTE reports and hospital records of patients diagnosed with a stroke or transient ischemic attack (TIA), screening for potential cardiac sources of embolism (CSE) from January 2006 to December 2008 at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia by considering at least 15 predefined TTE criteria. The therapeutic interventions employed as a consequence of the TTE findings were sought. We analyzed 240 patients (mean patient age 58.514) out of 10563 TTEs. While only one patient exhibited a definite CSE on TTE, potential CSEs were found in 35 patients (14.6%), most commonly caused by left ventricular (LV) systolic dysfunction (31.4%), followed by LV regional wall motion abnormalities (25.7%). Multivariate analysis revealed 2 independent predictors for identifying a CSE on TTE: history of coronary artery disease (odds ratio [OR] 6.2, 95% confidence interval [CI]:2.6-14.8, p=0.0001), and nationality (OR 0.16, 95% CI: 0.3-0.7, p=0.019). The TTE findings affected therapy in only 3 patients (1.2%). The TTE performed to exclude a CSE in patients with stroke or TIA resulted in low diagnostic yield, and had little impact on therapeutic decisions. Future refinement of clinical strategies to predict a CSE is needed to improve diagnosis, and possibly cost-effectiveness, of TTE.


Validation of an enzyme-linked immunosorbent assay (ELISA) for quantification of endostatin levels in mice as a biomarker of developing glomerulonephritis.
Endostatin, the C-terminal fragment of type XVIII collagen, was shown to be one of the most potent endothelial cell-specific inhibitors of angiogenesis. As altered circulating endostatin concentration is associated with impaired kidney function, new tools for measuring endostatin in rodents may be helpful to further investigate and understand its role within kidney disease progression. A novel and commercially available ELISA for the quantification of mouse and rat endostatin was developed and validated according to international quality guidelines including the parameters specificity, robustness, accuracy, dilution linearity, precision, limit of detection (LOD) and lower limit of quantification (LLOQ). Endostatin and blood urea nitrogen (BUN) concentration were measured in mice with a glomerulonephritis phenotype. The validation revealed that within the range of 0.5-32 nmol/L the immunoassay is robust and highly specific for the measurement of rodent endostatin with high sensitivity (LOD 0.24 nmol/L, LLOQ 0.5 nmol/L) and good reproducibility (intra- and inter-assay CV <10%). Also accuracy and dilution linearity were within the range of acceptance. BCL2 transgenic and ETV6/RUNX1;BCL2 double transgenic mice develop a glomerulonephritis phenotype over time, which was displayed by staining of kidney sections. Even before full manifestation of disease serum endostatin concentration rises significantly, whereas BUN levels just slightly increase. This newly developed and commercially available ELISA provides a reliable and accurate tool for the quantification of mouse and rat endostatin and may give new perspectives in the investigation of the role of endostatin as an important and early biomarker for reduced kidney function. Measurement of endostatin concentration is recommended to be used as a superior biomarker for chronic kidney disease compared to BUN.


Effects of resistance training on blood pressure in the elderly.
The aging process drastically reduces muscle mass, strength and power, decreasing the capacity to perform the activities of daily living. The practice of resistance exercises can reverse this picture, helping to maintain the muscular mass and improving muscular strength and resistance. However, the aging process causes cardiovascular alterations, which can result in increased blood pressure levels at rest and it is important to analyze the effects of resistance exercises on the blood pressure of elderly individuals. The objective of this study is to evaluate the current scientific knowledge on the responses of the blood pressure to resistance exercises and their mechanisms in elderly individuals. In order to do that, we carried out a literature review related to the theme, in both Portuguese and English. Based on the studies found, the current corpus, although scarce and controversial, suggests that, chronically, resistance exercises can have a hypotensive effect on elderly individuals. However, this effect occurs mainly in normotensive elderly individuals submitted to low-intensity training. The mechanisms involved in the hypotensive response still need to be clarified. Although the resistance training is recommended for elderly individuals and there is some evidence that it can have a chronic hypotensive effect, there is still lack of scientific data and much debate on the subject, which demonstrates that this field is still open to investigation.


30 years of preventive studies of uterine cervical cancer 1982-2012.
The studies for the prevention of uterine cervical cancer in Panama City began in a private institute, impelled by the high incidence of cancer. The preventive programs were initiated with the support of the Obstetrics and Gynecology Institute of the University of Padua in Italy. In these studies, we applied the methodological diagnostics of this Institute with certain modifications adapted to our needs. The diagnosis, treatment, and follow-up were carried out under the protocol of the University of Padua. We achieved a diagnosis of oncogenic risk (OR) in 6,411 patients which corresponded to 5,498 cases of human papillomavirus (HPV), 1,150 cases of dysplasia, 210 cases of cancer, and 794 cases of OR. From 2011, polymerase chain reaction (PCR) was also applied with the aim to improve the accuracy of the diagnosis. With this method the prevalence of pathologies were HPV infections both in healthy patients or in patients cured from HPV. Patients were treated by means of local destructive treatments (LDT), basically with cryotherapy and cauterization. We can consider these results as successful prevention and suggest to extend a preventive program to all the population.


Risk of cutaneous malignant melanoma in relation to use of sunbeds: further evidence for UV-A carcinogenicity.
In a population-based, matched, case-control study from southern Sweden of 571 patients with a first diagnosis of cutaneous malignant melanoma and 913 healthy controls aged 16-80 years, the association between sunbed use and malignant melanoma was evaluated. A total of 250 (44%) cases and 372 (41%) controls reported ever having used sunbeds. A significantly elevated odds ratio for developing malignant melanoma after regular exposure to sunbeds was found, adjusted for hair colour, raised naevi, skin type and number of sunburns (odds ratio (OR) 1.8, 95% confidence interval (CI) 1.2-2.7). A dose-response relationship between total number of sunbed uses and melanoma risk was only found up to the level of 250 times. The OR was higher in individuals younger than age 36 years (adjusted OR 8.1, 95% CI 1.3-49.5 for regular vs. never use). The association seemed to be true only for subjects with black/dark brown or light brown hair and among females. Lesions of the extremities showed the strongest association of increased risk with sunbed use. An increased risk was related to commercial exposure and to exposure during the winter. The results substantiate the hypothesis that exposure to sunbeds might increase the risk of developing malignant melanoma.


[Primary Kaposi's sarcoma of the penis].
Kaposi's sarcoma is a vascular tumor involving the wall of lymphatic vessels. There are four types: classic, endemic, iatrogenic and HIV-associated. It is a systemic, malignant and multifactorial disease and has a variable course. The primary presentation on the penis is uncommon and is mainly observed in HIV-positive patients. In HIV-negative individuals, asymptomatic papules, nodules, plaques and verrucous lesions are found. The treatment for the classic form involves surgery, cryotherapy, electrosurgery, laser and radiation therapy. The authors present a rare case of a patient with the classic form on the penis, who was successfully treated by radiation therapy.


An Integrated Multi-Omics Analysis Defines Key Pathway Alterations in a Diet-Induced Obesity Mouse Model.
Obesity is a multifactorial disease with many complications and related diseases and has become a global epidemic. To thoroughly understand the impact of obesity on whole organism homeostasis, it is helpful to utilize a systems biological approach combining gene expression and metabolomics across tissues and biofluids together with metagenomics of gut microbial diversity. Here, we present a multi-omics study on liver, muscle, adipose tissue, urine, plasma, and feces on mice fed a high-fat diet (HFD). Gene expression analyses showed alterations in genes related to lipid and energy metabolism and inflammation in liver and adipose tissue. The integration of metabolomics data across tissues and biofluids identified major differences in liver TCA cycle, where malate, succinate and oxaloacetate were found to be increased in HFD mice. This finding was supported by gene expression analysis of TCA-related enzymes in liver, where expression of malate dehydrogenase was found to be decreased. Investigations of the microbiome showed enrichment of Lachnospiraceae, Ruminococcaceae, Streptococcaceae and Lactobacillaceae in the HFD group. Our findings help elucidate how the whole organism metabolome and transcriptome are integrated and regulated during obesity.


[Cardiac failure following sting of yellow scorpion in an adult].
3 men, aged 18, 29, and 47 had severe cardiovascular disturbances following the sting of the yellow scorpion (Leiurus quinquestriatus hebraeus), which is considered the most dangerous scorpion in Israel. Cardiovascular complications are common in children after scorpion sting, but are rare in adults. Pulmonary edema developed in 1 of those being reported and hypertension and arrhythmias in the other 2. Severe deterioration in left ventricle function was confirmed by echocardiographic measurement of diminished ejection fraction. All patients recovered completely. This is the first report of severe cardiac involvement in adults following scorpion sting. We therefore recommend that even adults who develop cardiac symptoms after scorpion sting, particularly those with chronic cardiac disease, be monitored and treated in an intensive care unit.


Interventions for treating proximal humeral fractures in adults.
Proximal humeral fractures are common yet management varies widely. In particular, the role and timing of any surgical intervention have not been clearly defined. To collate and evaluate the scientific evidence supporting the various methods used for treating proximal humeral fractures. We searched the Cochrane Musculoskeletal Injuries Group specialised register, MEDLINE, EMBASE, the Cochrane Controlled Trials Register, CINAHL, the National Research Register (UK), AMED, PEDro and bibliographies of trial reports. The search was completed in November 2001. All randomised studies pertinent to the treatment of proximal humeral fractures were selected. Independent quality assessment and data extraction were performed by two reviewers. Although quantitative data from trials are presented, trial heterogeneity prevented pooling of results. Ten randomised trials were included. All were small trials; the largest study involved only 85 patients. Bias in these trials could not be ruled out. Six trials evaluated conservative treatment, three compared surgery with conservative treatment and one compared two surgical techniques. In the 'conservative' group there was very limited evidence indicating that the type of bandage used made any difference in terms of time to fracture union and the functional end result. However, an arm sling was generally more comfortable than a body bandage. There was some evidence that mobilisation at one week instead of three weeks alleviated pain in the short term without compromising long term outcome. Two trials provided some evidence that patients, when given sufficient instruction to pursue an adequate physiotherapy programme, could generally achieve a satisfactory outcome if allowed to exercise without supervision. Operative reduction improved fracture alignment in two trials. However, in one trial, surgery was associated with a greater risk of complication, and did not result in improved shoulder function. In one trial, hemi-arthroplasty resulted in better short-term function with less pain and less need for help with activities of daily living when compared with conservative treatment for severe injuries. Fracture fixation of severe injuries was associated with a high rate of re-operation in one trial, comparing tension-band wiring fixation with hemi-arthroplasty. Only tentative conclusions can be drawn from the available randomised trials, which do not provide robust evidence for many of the decisions that need to be made in contemporary fracture management. It is unclear whether operative intervention, even for specific fracture types, will produce consistently better long term outcomes. There is a need for good quality evidence for the management of these fractures.


A rapid and efficient method for region- and strand-specific mutagenesis of cloned DNA.
The single-stranded viral DNA of an M13 phage recombinant containing the early promoter region of SV40 was hybridized with linear, double-stranded replicative form DNA of a related M13 phage containing a short deletion in the cloned SV40 sequence. The heteroduplexes formed between these DNA molecules contained a short, defined single-stranded region in an otherwise duplex molecule. These heteroduplexes were treated with sodium bisulphite to deaminate exposed unpaired cytosines to uracil residues. The single-stranded region was filled in with DNA polymerase I, which incorporates adenine opposite the mutated uracils, and the DNA then transfected into the M13 host JM103 . Viral DNA from the resultant plaques was used for the rapid dideoxy-DNA sequencing procedure; all of the plaques studied contained point mutations within the desired area. This method allows the very rapid and efficient generation of region-directed point mutants which can be quickly sequenced.


Dynamic programming approach for newborn's incubator humidity control.
The anatomy, physiology, and biochemistry of the human skin have been studied for a long time. A special interest has been shown in the water permeability of the premature infant's skin, which is known to be an important factor in the maintenance of a controlled water and heat balance. The rate of evaporative heat exchange between the skin surface of a very premature infant and the surrounding incubator air may be so high that evaporative heat loss alone may exceed the infant's total metabolic heat production. However, it has been demonstrated in several investigations published in recent years that basal evaporative water loss can be consistently reduced by increasing the ambient humidity. Nevertheless, the passive humidification system (water reservoir) used in most incubators cannot achieve high and steady humidity levels. In this paper, we propose an active humidification system. The algorithm is based on a combination of optimal control theory and dynamic programming approach. The relative-humidity (R.H.) regulation is performed in range of 35-90% at 33 degrees C with small oscillations (+/- 0.5% R.H.) around the reference value (i.e., prescribed R.H.).


An integrated approach for structural characterization of Gui Ling Ji by traveling wave ion mobility mass spectrometry and molecular network.
Gui Ling Ji (GLJ), an ancient reputable traditional Chinese medicine (TCM) formula prescription, has been applied for the treatment of oligospermia and asthenospermia in clinical practice. However, its inherent compounds have not yet been systematically elucidated, which hampers developing standards or guidelines for quality evaluation and even the understanding of pharmacological effects. In this study, an integrated approach has been established for comprehensive structural characterization of GLJ. Mass spectrometry datasets of GLJ and each of the single herb medicines in this prescription have been developed by dynamic exclusion fast data-dependent acquisition and high-definition data-independent acquisition modes on ultra-high-performance liquid chromatography coupled with travelling wave ion mobility quadrupole time-of-flight mass spectrometry (UPLC-TWIMS-QTOF-MS). A global natural product social molecular networking (GNPS) platform was then applied for the visualization of chemical space of GLJ and further for the high throughput identification of the targeted or untargeted compounds due to the support of data-transmitting from each single herbal medicine to the formula GLJ. Moreover, drift time, predicted CCS, and diagnostic fragment ions were induced for annotating isomer compounds. Consequently, based on molecular network and library hits, a total of 257 compounds from GLJ, which were classified into 4 structural types, were positively or tentatively characterized. Among them, 20 potential new compounds were detected and 30 pairs of isomers were comprehensively distinguished. The established strategy was effective for attribution, classification, recognition of various constituents, and also was valuable for integrating large amounts of disordered MS/MS data and mining trace compounds in other complex chemical or biochemical systems.


Developing and Validating Risk Scores for Predicting Major Cardiovascular Events Using Population Surveys Linked with Electronic Health Insurance Records.
A risk prediction model for major cardiovascular events was developed using population survey data linked to National Health Insurance (NHI) claim data and the death registry. Another set of population survey data were used to validate the model. The model was built using the Nutrition and Health Survey in Taiwan (NAHSIT) collected from 1993-1996 and linked with 10 years of events from NHI data. Major adverse cardiovascular events (MACEs) were identified based on hospital admission or death from coronary heart disease or stroke. The Taiwanese Survey on Hypertension, Hyperglycemia, and Hyperlipidemia (TwSHHH), conducted in 2002 was used for external validation. The NAHSIT data consisted of 1658 men and 1652 women aged 35-70 years. The incidence rates for MACE per 1000 person-years were 13.77 for men and 7.76 for women. These incidence rates for the TwSHHH were 7.27 for men and 3.58 for women. The model had reasonable discrimination (C-indexes: 0.76 for men; 0.75 for women), thus can be used to predict MACE risks in the general population. NHI data can be used to identify disease statuses if the definition and algorithm are clearly defined. Precise preventive health services in Taiwan can be based on this model.


Mycorrhizal and non-mycorrhizal Lactuca sativa plants exhibit contrasting responses to exogenous ABA during drought stress and recovery.
The arbuscular mycorrhizal (AM) symbiosis enhances plant tolerance to water deficit through the alteration of plant physiology and the expression of plant genes. These changes have been postulated to be caused (among others) by different contents of abscisic acid (ABA) between AM and non-AM plants. However, there are no studies dealing with the effects of exogenous ABA on the expression of stress-related genes and on the physiology of AM plants. The aim of the present study was to evaluate the influence of AM symbiosis and exogenous ABA application on plant development, physiology, and expression of several stress-related genes after both drought and a recovery period. Results show that the application of exogenous ABA had contrasting effects on AM and non-AM plants. Only AM plants fed with exogenous ABA maintained shoot biomass production unaltered by drought stress. The addition of exogenous ABA enhanced considerably the ABA content in shoots of non-AM plants, concomitantly with the expression of the stress marker genes Lsp5cs and Lslea and the gene Lsnced. By contrast, the addition of exogenous ABA decreased the content of ABA in shoots of AM plants and did not produce any further enhancement of the expression of these three genes. AM plants always exhibited higher values of root hydraulic conductivity and reduced transpiration rate under drought stress. From plants subjected to drought, only the AM plants recovered their root hydraulic conductivity completely after the 3 d recovery period. As a whole, the results indicate that AM plants regulate their ABA levels better and faster than non-AM plants, allowing a more adequate balance between leaf transpiration and root water movement during drought and recovery.


Systemic levels of anti-PAD4 autoantibodies correlate with airway obstruction in cystic fibrosis.
Cystic fibrosis (CF) airway disease is characterized by the long-term presence of neutrophil granulocytes. Formation of neutrophil extracellular traps (NETs) and/or autoantibodies directed against extracellular components of NETs are possible contributors to neutrophil-mediated lung damage in CF. The goal of this study was to measure their levels in CF adults compared to healthy controls and subjects with rheumatologic diseases known to develop NET-related autoantibodies and pathologies, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Sera were analyzed from the following number of subjects: 37 CF, 23 healthy controls (HC), 20 RA, and 21 SLE. CF had elevated serum myeloperoxidase (MPO) concentrations (347.5±56.1 ng/ml, mean+/-S.E.M., p = .0132) compared to HC (144.5±14.6 ng/ml) but not of neutrophil elastase (NE) complexed with alpha-1-antitrypsin, cell-free DNA or NE-DNA complexes. The peptidylarginine deiminase 4 (PAD4) enzyme is required for NET formation and associated DNA release in neutrophils. Serum levels of anti-PAD4 antibodies (Ab) were elevated in CF (p = .0147) compared to HC and showed an inverse correlation with a measure of lung function, FEV1% predicted (r = -0.5020, p = .015), as did MPO levels (r = -0.4801, p = .0026). Anti-PAD4 Ab levels in CF sera associated with lung infection by P. aeruginosa, but not that by S. aureus, age, sex, CF-related diabetes or the presence of musculoskeletal pain. Serum levels of anti-citrullinated protein Abs (ACPAs) and anti-nucleosome Abs were not elevated in CF compared to HC (p = .7498, p = .0678). In summary, adult CF subjects develop an autoimmune response against NET components that correlates with worsening lung disease.


Drug Interactions with Gender-Affirming Hormone Therapy: Focus on Antiretrovirals and Direct Acting Antivirals.
Gender-affirming care may include hormonal therapy to attain desired health outcomes in transgender (trans) individuals. To provide safe, affirming medical care for trans patients, health care providers must identify and manage drug-drug interactions (DDIs) between gender affirming hormonal therapy (GAHT) and other medication therapies. This review summarizes available data on DDIs between GAHT and antiretrovirals (ARVs) or hepatitis C direct acting antivirals (DAAs). Potential pharmacokinetic and pharmacodynamic DDIs are predicted based on GAHT, ARV, and DAA pharmacology and adverse event profiles. Clinical management strategies are discussed. GAHT may be involved in pharmacokinetic and/or pharmacodynamic DDIs. Certain ARV classes (non-nucleoside reverse transcriptase inhibitors, protease inhibitors) may alter GAHT disposition, whereas selected ARVs (unboosted integrase inhibitors, doravirine, or rilpivirine) may have less impact on GAHT. DAAs may interact with GAHT, but the clinical relevance is unclear. ARV- and/or DAA-associated side effects (including depression, cardiovascular disease, hyperlipidemia) are important to consider in the clinical management of trans patients. Clinicians must evaluate potential DDIs and overlapping side effects between ARVs, DAAs and GAHT when providing care for trans patients.


Leptin enhances human beta-defensin-2 production in human keratinocytes.
Leptin, an adipocyte-derived cytokine/hormone, modulates innate and adaptive immunity. Human beta-defensin-2 (hBD-2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense, inflammation, and wound repair. We examined the in vitro effects of leptin on hBD-2 production in human keratinocytes. hBD-2 secretion and mRNA expression were analyzed by ELISA and RT-PCR, respectively. Although leptin alone was ineffective, it enhanced IL-1beta-induced hBD-2 secretion and mRNA expression in keratinocytes. IL-1beta- and IL-1beta plus leptin-induced hBD-2 production both were suppressed by antisense oligonucleotides against nuclear factor-kappaB (NF-kappaB) p50 and p65; the latter was also suppressed by antisense signal transducer and activator of transcription (STAT)1 and STAT3. IL-1beta enhanced the transcriptional activity of NF-kappaB, whereas leptin enhanced STAT1 and STAT3 activity. The p38 MAPK inhibitor SB202190 suppressed IL-1beta- and IL-1beta plus leptin-induced hBD-2 production, IL-1beta-induced NF-kappaB activity, and leptin-induced STAT1 and STAT3 activity; contrastingly, the Janus kinase (JAK) 2 inhibitor AG490 suppressed IL-1beta plus leptin-induced hBD-2 production and leptin-induced STAT1 and STAT3 activity. IL-1beta induced serine phosphorylation of inhibitory kappaBalpha, STAT1, and STAT3. Leptin induced tyrosine and serine phosphorylation of STAT1 and STAT3, both of which were suppressed by AG490, and serine phosphorylation was also suppressed by SB202190. IL-1beta or leptin individually induced threonine/tyrosine phosphorylation of p38 MAPK, whereas only leptin induced tyrosine phosphorylation of JAK2, suggesting that leptin may enhance hBD-2 production in keratinocytes by activating STAT1 and STAT3 via JAK2 and p38 MAPK in cooperation with NF-kappaB, which is activated by IL-1beta. Leptin may promote cutaneous antimicrobial defense, inflammation, and wound repair via hBD-2.


Rotenone and paraquat perturb dopamine metabolism: A computational analysis of pesticide toxicity.
Pesticides, such as rotenone and paraquat, are suspected in the pathogenesis of Parkinson's disease (PD), whose hallmark is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Thus, compounds expected to play a role in the pathogenesis of PD will likely impact the function of dopaminergic neurons. To explore the relationship between pesticide exposure and dopaminergic toxicity, we developed a custom-tailored mathematical model of dopamine metabolism and utilized it to infer potential mechanisms underlying the toxicity of rotenone and paraquat, asking how these pesticides perturb specific processes. We performed two types of analyses, which are conceptually different and complement each other. The first analysis, a purely algebraic reverse engineering approach, analytically and deterministically computes the altered profile of enzyme activities that characterize the effects of a pesticide. The second method consists of large-scale Monte Carlo simulations that statistically reveal possible mechanisms of pesticides. The results from the reverse engineering approach show that rotenone and paraquat exposures lead to distinctly different flux perturbations. Rotenone seems to affect all fluxes associated with dopamine compartmentalization, whereas paraquat exposure perturbs fluxes associated with dopamine and its breakdown metabolites. The statistical results of the Monte-Carlo analysis suggest several specific mechanisms. The findings are interesting, because no a priori assumptions are made regarding specific pesticide actions, and all parameters characterizing the processes in the dopamine model are treated in an unbiased manner. Our results show how approaches from computational systems biology can help identify mechanisms underlying the toxicity of pesticide exposure.


Racial differences and the role of neighborhood in the sequencing of marijuana and tobacco initiation among urban youth.
With patterns of initiation of tobacco and marijuana changing, there is increasing evidence that marijuana use may serve as an antecedent to tobacco use among adolescents. However, studies have not fully characterized the prevalence of these patterns among vulnerable youth and have rarely examined the factors that predict the sequencing of onset of tobacco and marijuana use. Utilizing longitudinal data from a sample of urban youth followed from age 6 to age 18, the authors identify the sequencing of initiation of tobacco and marijuana and test whether race and 5 neighborhood factors (i.e., perceived disorder, drug activity, drug access, exposure to violence, and exposure to violent victimization) predict onset sequencing. Various sequencing patterns were observed, with 12.4% of the sample initiating marijuana use before tobacco use was initiated. In adjusted logistic regression models, black youth were 2.66 times as likely as whites to initiate marijuana before tobacco compared with initiating tobacco before marijuana (P = .032). Youth with greater exposure to violent victimization were 3.89 times as likely to initiate marijuana first than initiate tobacco first (P = .002). Other neighborhood factors were not statistically significantly associated with sequencing. Black youth and youth with greater exposure to victimization had an increased risk of initiating marijuana before tobacco, which suggests that this pattern may be rooted in specific risk factors. Substance use prevention efforts should consider taking into account that marijuana use may put certain youth at risk of initiating tobacco. Future research needs to monitor sequencing, as well as risk factors for and consequences of the various patterns, particularly since marijuana use and the mixing of tobacco and marijuana use are gaining acceptability in general populations.


Dairy cattle serum and milk factors contributing to the risk of colon and breast cancers.
The analysis of published epidemiological data on colon and breast cancer reveals a remarkable concordance for most regions of the world. A low incidence for both cancers has been recorded in Mongolia and Bolivia. Discrepant data, however, have been reported for India, Japan and Korea. In India, the incidence of breast cancer is significantly higher than for colon cancer, in Japan and Korea colon cancer exceeds by far the rate of breast cancer. Here, studies are summarized pointing to a species-specific risk for colon cancer after consumption of beef originating from dairy cattle. Uptake of dairy products of Bos taurus-derived milk cattle, particularly consumed at early age, is suggested to represent one of the main risk factors for the development of breast cancer. A recent demonstration of reduced breast cancer rates in individuals with lactose intolerance (Ji et al., Br J Cancer 2014; 112:149-52) seems to be in line with this interpretation. Species-specific risk factors for these cancers are compatible with the transmission of different infectious factors transferred via meat or dairy products. Countries with discordant rates of colon and breast cancer reveal a similar discordance between meat and milk product consumption of dairy cattle. The recent isolation of a larger number of novel presumably viral DNAs from serum, meat and dairy products of healthy dairy cows, at least part of them infectious for human cells, deserves further investigation. Systemic infections early in life, resulting in latency and prevention of subsequent infections with the same agent by neutralizing antibodies, would require reconsideration of ongoing prospective studies conducted in the adult population.


The failure of anxiolytic therapies in early clinical trials: what needs to be done.
Anxiety spectrum disorders (ASDs) are highly prevalent psychiatric illnesses that affect millions of people worldwide. Strongly associated with stress, common ASDs include generalized anxiety disorder, panic, social anxiety, phobias and drug-abuse-related anxiety. In addition to ASDs, several other prevalent psychiatric illnesses represent trauma/stressor-related disorders, such as post-traumatic stress disorder and acute stress disorder. Anxiolytic drugs, commonly prescribed to treat ASDs and trauma/stressor-related disorders, form a highly heterogenous group, modulating multiple neurotransmitters and physiological mechanisms. However, overt individual differences in efficacy and the potential for serious side-effects (including addiction and drug interaction) indicate a need for further drug development. Yet, over the past 50 years, there has been relatively little progress in the development of novel anxiolytic medications, especially when promising candidate drugs often fail in early clinical trials. Herein, the authors present recommendations of the Task Force on Anxiolytic Drugs of the International Stress and Behavior Society on how to improve anxiolytic drug discovery. These recommendations cover a wide spectrum of aspects, ranging from methodological improvements to conceptual insights and innovation. In order to improve the success of anxiolytic drugs in early clinical trials, the goals of preclinical trials may need to be adjusted from a clinical perspective and better synchronized with those of clinical studies. Indeed, it is important to realize that the strategic goals and approaches must be similar if we want to have a smoother transition between phases.


Cell therapy: a safe and efficacious therapeutic treatment for Alzheimer's disease in APP+PS1 mice.
Previously, our lab was the first to report the use of antigen-sensitized dendritic cells as a vaccine against Alzheimer's disease (AD). In preparation of this vaccine, we sensitized the isolated dendritic cells ex vivo with Aβ peptide, and administered these sensitized dendritic cells as a therapeutic agent. This form of cell therapy has had success in preventing and/or slowing the rate of cognitive decline when administered prior to the appearance of Aβ plaques in PDAPP mice, but has not been tested in 2 × Tg models. Herein, we test the efficacy and safety of this vaccine in halting and reversing Alzheimer's pathology in 9-month-old APP + PS1 mice. The results showed that administration of this vaccine elicits a long-lasting antibody titer, which correlated well with a reduction of Aβ burden upon histological analysis. Cognitive function in transgenic responders to the vaccine was rescued to levels similar to those found in non-transgenic mice, indicating that the vaccine is capable of providing therapeutic benefit in APP+PS1 mice when administered after the onset of AD pathology. The vaccine also shows indications of circumventing past safety problems observed in AD immunotherapy, as Th1 pro-inflammatory cytokines were not elevated after long-term vaccine administration. Moreover, microhemorrhaging and T-cell infiltration into the brain are not observed in any of the treated subjects. All in all, this vaccine has many advantages over contemporary vaccines against Alzheimer's disease, and may lead to a viable treatment for the disease in the future.