Consumption of alcohol and binge drinking among pregnant women in Addis Ababa, Ethiopia: Prevalence and determinant factors.
People in Ethiopia, including pregnant women, highly consume both home-made and manufactured alcohol beverages due to lack of awareness about the harmful effect of risky alcohol use, and cultural acceptance of alcohol consumption. Alcohol consumption and other hazardous patterns of use like binge drinking have tremendous adverse effects on fetus and mothers. Therefore, this study aimed to assess the magnitude of alcohol consumption, binge drinking and its determinants among pregnant women residing in Kolfe sub-city, Addis Ababa, Ethiopia. Institutional based cross-sectional study was conducted among a total of 367 pregnant women. The participants were selected using a systematic random sampling method. Data were collected through a structured questionnaire. A binary logistic regression was conducted using SPSS version 20 software to identify determinants of alcohol consumption and binge drinking. A p-value < 0.05 was used to declare a statistical significance in multiple logistic regression. The results were described using adjusted odds ratio with a 95% confidence interval. This study revealed that the prevalence of alcohol consumption, binge drinking, and weekly alcohol consumption of four or more units among pregnant women was 39.78%, 3.54% and 4.9%, respectively. Not having formal education [AOR 95% CI = 8.47 (2.42, 29.62), having primary education [AOR 95% CI = 4.26 (1.23, 14.74), being a housewife [AOR 95% CI = 4.18 (2.13, 8.22), having an unplanned pregnancy [AOR 95% CI = 2.47(1.33, 4.60), having a history of abortion [AOR 95% CI = 3.33 (1.33, 6.05)], not having awareness about the harmful effect of alcohol consumption [AOR 95% CI = 4.66 (2.53, 8.61)], and not having family social support [AOR 95% CI = 2(1.14,3.53) were determinants of alcohol consumption among pregnant women. This study found a high level of alcohol consumption among pregnant women. Interventions to create awareness on the harmful effects of alcohol are needed. Moreover, strengthening social support during pregnancy and family planning services to reduce unplanned pregnancy and abortion should be considered.


Morphogen gradients, in theory.
The idea that morphogen gradients are established by a process of repeated cycles of exocytosis and endocytosis-so-called planar transcytosis-has been gaining acceptance. This is now challenged by a theoretical approach that experimental biologists should not dismiss; diffusive mechanisms of gradient formation may be correct after all.


A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation.
Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in two genes, KCNQ2 and KCNQ3, encoding for potassium channel subunits underlying the M-current. This current limits neuronal hyperexcitability by causing spike-frequency adaptation. The authors describe a BFNC family with four affected members: two of them exhibit BFNC only while the other two, in addition to BFNC, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation. All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tri-dimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression. The KCNQ2 K526N mutation may affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus. Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family.


Monodisperse and LPS-free Aggregatibacter actinomycetemcomitans leukotoxin: interactions with human β2 integrins and erythrocytes.
Aggregatibacter actinomycetemcomitans is a gram-negative, facultatively anaerobic cocco-bacillus and a frequent member of the human oral flora. It produces a leukotoxin, LtxA, belonging to the repeats-in-toxin (RTX) family of bacterial cytotoxins. LtxA efficiently kills neutrophils and mononuclear phagocytes. The known receptor for LtxA on leukocytes is integrin α(L)β(2) (LFA-1 or CD11a/CD18). However, the molecular mechanisms involved in LtxA-mediated cytotoxicity are poorly understood, partly because LtxA has proven difficult to prepare for experiments as free of contaminants and with its native structure. Here, we describe a protocol for the purification of LtxA from bacterial culture supernatant, which does not involve denaturing procedures. The purified LtxA was monodisperse, well folded as judged by the combined use of synchrotron radiation circular dichroism spectroscopy (SRCD) and in silico prediction of the secondary structure content, and free of bacterial lipopolysaccharide. The analysis by SRCD and similarity to a lipase from Pseudomonas with a known three dimensional structure supports the presence of a so-called beta-ladder domain in the C-terminal part of LtxA. LtxA rapidly killed K562 target cells transfected to express β(2) integrin. Cells expressing α(M)β(2) (CD11b/CD18) or α(X)β(2) (CD11c/CD18) were killed as efficiently as cells expressing α(L)β(2). Erythrocytes, which do not express β(2) integrins, were lysed more slowly. In ligand blotting experiments, LtxA bound only to the β(2) chain (CD18). These data support a previous suggestion that CD18 harbors the major binding site for LtxA as well as identifies integrins α(M)β(2) and α(X)β(2) as novel receptors for LtxA.


Associations Among Individuals' Perceptions of Future Time, Individual Resources, and Subjective Well-Being in Old Age.
Perceptions of future time are of key interest to aging research because of their implications for subjective well-being. Interestingly, perceptions about future time are only moderately associated with age when looking at the second half of life, pointing to a vast heterogeneity in future time perceptions among older adults. We examine associations between future time perceptions, age, and subjective well-being across two studies, including moderations by individual resources. Using data from the Berlin Aging Study (N = 516; Mage = 85 years), we link one operationalization (subjective nearness to death) and age to subjective well-being. Using Health and Retirement Study data (N = 2,596; Mage = 77 years), we examine associations of another future time perception indicator (subjective future life expectancy) and age with subjective well-being. Consistent across studies, perceptions of limited time left were associated with poorer subjective well-being (lower life satisfaction and positive affect; more negative affect and depressive symptoms). Importantly, individual resources moderated future time perception-subjective well-being associations with those of better health exhibiting reduced future time perception-subjective well-being associations. We discuss our findings in the context of the Model of Strength and Vulnerability Integration.


Role of NAD in regulating the adhE gene of Escherichia coli.
The fermentative alcohol dehydrogenase of Escherichia coli is encoded by the adhE gene, which is induced under anaerobic conditions but repressed in air. Previous work suggested that induction of adhE might depend on NADH levels. We therefore directly measured the NAD+ and NADH levels for cultures growing aerobically and anaerobically on a series of carbon sources whose metabolism generates different relative amounts of NADH. Expression of adhE was monitored both by assay of alcohol dehydrogenase activity and by expression of phi(adhE'-lacZ) gene fusions. The expression of the adhE gene correlated with the ratio of NADH to NAD+. The role of NADH in eliciting adhE induction was supported by a variety of treatments known to change the ratio of NADH to NAD+ or alter the total NAD+-plus-NADH pool. Blocking the electron transport chain, either by mutation or by chemical inhibitors, resulted in the artificial induction of the adhE gene under aerobic conditions. Conversely, limiting NAD synthesis, by introducing mutational blocks into the biosynthetic pathway for nicotinic acid, decreased the expression of adhE under anaerobic conditions. This, in turn, was reversed by supplementation with exogenous NAD or nicotinic acid. In merodiploid strains carrying deletion or insertion mutations abolishing the synthesis of AdhE protein, an adhE-lacZ fusion was expressed at nearly 10-fold the level observed in an adhE+ background. Introduction of mutant adhE alleles producing high levels of inactive AdhE protein gave results equivalent to those seen in absence of the AdhE protein. This finding implies that it is the buildup of NADH due to lack of enzyme activity, rather than the absence of the AdhE protein per se, which causes increased induction of the phi(adhE'-lacZ) fusion. Moreover, mutations giving elevated levels of active AdhE protein decreased the induction of the phi(adhE'-lacZ) fusion. This finding suggests that the enzymatic activity of the AdhE protein modulates the level of NADH under anaerobic conditions, thus indirectly regulating its own expression.


A multispecies probiotic reduces oral Candida colonization in denture wearers.
The prevalence of Candida infections has been rising with an increasingly aging population and a larger population of immunocompromised individuals. The use of probiotics may be an alternative approach to antifungal agents in the prevention and treatment of oral candidiasis. This study aimed to evaluate the short-term effect of probiotics in reducing the infection level of oral Candida in candidiasis-asymptomatic elderly denture wearers. In a double-blind randomized study, 59 denture wearers harboring Candida spp. in the oral cavity with no clinical symptoms were allocated into two groups: probiotic and placebo. All patients were instructed to clean the denture daily. The probiotic group poured a capsule containing lyophilized Lactobacillus rhamnosus HS111, Lactobacillus acidophillus HS101, and Bifidobacterium bifidum daily on the palatal surface of the maxillary denture, whereas the placebo group was submitted to the same regimen using placebo capsules. Candida spp. infection levels were evaluated in palate mucosa samples obtained before and after a 5-week experimental period. All patients harbored Candida in the palate mucosa at baseline. Fifty-five individuals completed the experimental period. The detection rate of Candida spp. was 92.0% in the placebo group after the experimental period, whereas it was reduced to 16.7% in the probiotic group. The reduction promoted by the probiotic regimen was independent of baseline characteristics such as Candida infection level and colonizing species, age of denture, and other variables. The probiotic product was effective in reducing the colonization of the oral cavity with Candida in candidiasis-asymptomatic elderly denture wearers, suggesting that this multispecies probiotic could be used to prevent oral candidiasis. Colonization of oral surfaces by Candida is considered a risk factor for invasive fungal infections. The use of a product with L. rhamnosus, L. acidophilus, and B. bifidum may represent an alternative treatment for reduction of Candida infections in elderly denture wearers.


Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs.
Angiogenesis, the formation of new blood vessels from preexisting one, represents a critical process for oxygen and nutrient supply to proliferating cells, therefore promoting tumor growth and metastasis. The Vascular Endothelial Growth Factor (VEGF) pathway is one of the key mediators of angiogenesis in cancer. Therefore, several therapies including monoclonal antibodies or tyrosine kinase inhibitors target this axis. Although preclinical studies demonstrated strong antitumor activity, clinical studies were disappointing. Antiangiogenic drugs, used to treat metastatic patients suffering of different types of cancers, prolonged survival to different extents but are not curative. In this review, we focused on different mechanisms involved in resistance to antiangiogenic therapies from early stage resistance involving mainly tumor cells to late stages related to the adaptation of the microenvironment.


Acute Muscle Trauma due to Overexercise in an Otherwise Healthy Patient with Cystic Fibrosis.
Cystic fibrosis (CF) is one of the most common inherited diseases and is caused by mutations in the CFTR gene. Although the pulmonary and gastrointestinal manifestations of the disease remain in the focus of treatment, recent studies have shown expression of the CFTR gene product in skeletal muscle cells and observed altered intramuscular Ca(2+) release dynamics in CFTR-deficient animal models. Physical exercise is beneficial for maintaining fitness and well-being in CF patients and constitutes one aspect of modern multimodal treatment, which has considerably increased life span and reduced morbidity. We report on a case of acute muscle trauma resulting from excessive dumbbell exercise in a young adult with cystic fibrosis and describe clinical, laboratory and imaging characteristics of acute exercise-induced muscle injury.


Modification of the Penn State forage and total mixed ration particle separator and the effects of moisture content on its measurements.
The Penn State Particle Separator has led to widespread measurement of forage and total mixed ration (TMR) particle size. However, a large proportion of small particles may pass through both sieves when a TMR is analyzed, and field research has suggested that both shaking frequency and sample dry matter may affect the results. The objectives of this project were to test the effects of an additional sieve with a smaller aperture size, shaking frequency, and sample moisture content on results obtained. A sieve was constructed out of wire with a nominal size aperture of 1.18 mm. Samples of alfalfa haylage, corn silage, and a TMR were shaken at frequencies of 0.9, 1.1, and 1.6 Hz with a 17-cm stroke length. Reducing shaking frequency to 0.9 Hz resulted in more material being retained on the 19.0-mm sieve for all sample types, increasing the geometric mean. Increasing frequency to 1.6 Hz did not affect the geometric mean, but did result in a greater amount of corn silage falling through the 1.18-mm sieve. For alfalfa haylage, moisture content between 57.4 and 35.6% did not affect results; however, for corn silage, less moisture increased the percentage of particles less than 1.18 mm and decreased the geometric mean. For both sample types, further drying caused a greater proportion of small particles and a smaller geometric mean. We suggest using a third sieve and shaking at 1.1 Hz or greater with a stroke length of 17 cm when using the Penn State Particle Separator to analyze forage particle size.


Efficient colonization and therapy of human hepatocellular carcinoma (HCC) using the oncolytic vaccinia virus strain GLV-1h68.
Virotherapy using oncolytic vaccinia virus strains is one of the most promising new strategies for cancer therapy. In this study, we analyzed for the first time the therapeutic efficacy of the oncolytic vaccinia virus GLV-1h68 in two human hepatocellular carcinoma cell lines HuH7 and PLC/PRF/5 (PLC) in cell culture and in tumor xenograft models. By viral proliferation assays and cell survival tests, we demonstrated that GLV-1h68 efficiently colonized, replicated in, and did lyse these cancer cells in culture. Experiments with HuH7 and PLC xenografts have revealed that a single intravenous injection (i.v.) of mice with GLV-1h68 resulted in a significant reduction of primary tumor sizes compared to uninjected controls. In addition, replication of GLV-1h68 in tumor cells led to strong inflammatory and oncolytic effects resulting in intense infiltration of MHC class II-positive cells like neutrophils, macrophages, B cells and dendritic cells and in up-regulation of 13 pro-inflammatory cytokines. Furthermore, GLV-1h68 infection of PLC tumors inhibited the formation of hemorrhagic structures which occur naturally in PLC tumors. Interestingly, we found a strongly reduced vascular density in infected PLC tumors only, but not in the non-hemorrhagic HuH7 tumor model. These data demonstrate that the GLV-1h68 vaccinia virus may have an enormous potential for treatment of human hepatocellular carcinoma in man.


Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.
Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.


Generation of heart and vascular system in rodents by blastocyst complementation.
Generating organs from stem cells through blastocyst complementation is a promising approach to meet the clinical need for transplants. In order to generate rejection-free organs, complementation of both parenchymal and vascular cells must be achieved, as endothelial cells play a key role in graft rejection. Here, we used a lineage-specific cell ablation system to produce mouse embryos unable to form both the cardiac and vascular systems. By mouse intraspecies blastocyst complementation, we rescued heart and vascular system development separately and in combination, obtaining complemented hearts with cardiomyocytes and endothelial cells of exogenous origin. Complemented chimeras were viable and reached adult stage, showing normal cardiac function and no signs of histopathological defects in the heart. Furthermore, we implemented the cell ablation system for rat-to-mouse blastocyst complementation, obtaining xenogeneic hearts whose cardiomyocytes were completely of rat origin. These results represent an advance in the experimentation towards the in vivo generation of transplantable organs.


The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4.
1. The novel tri-aryl ethane CDP840, is a potent and selective inhibitor of cyclic AMP phosphodiesterase type 4 (PDE 4) extracted from tissues or recombinant PDE 4 isoforms expressed in yeast (IC50S: 4-45 nM). CDP840 is stereo-selective since its S enantiomer (CT 1731) is 10-50 times less active against all forms of PDE 4 tested while both enantiomers are inactive (IC50S: > 100 microM) against PDE types 1, 2, 3 and 5. 2. Oral administration of CDP840 caused a dose-dependent reduction of interleukin-5 (IL-5)-induced pleural eosinophilia in rats (ED50 = 0.03 mg kg-1). The eosinophils in pleural exudates from CDP840-treated animals contained higher levels of eosinophil peroxidase (EPO) than cells from control animals, suggesting a stabilizing effect on eosinophil degranulation. CDP840 was approximately equi-active with the steroid dexamethasone in this model and was 10-100 times more potent than the known PDE 4-selective inhibitors rolipram and RP73401. The activity of CDP840 was not influenced by adrenalectomy, beta-sympathomimetics or beta-sympatholytics. 3. Antigen-induced pulmonary eosinophilia in sensitized guinea-pigs was reduced dose-dependently by CDP840 (0.01-1 mg kg-1, i.p.) and intracellular EPO levels were significantly higher. CDP840 was more potent in these activities than CT1731 or rolipram and comparable in potency to RP73401. 4. Rolipram or CDP840 were less active than dexamethasone in preventing neutrophil accumulation, or exudate formation in carrageenan-induced pleurisy in rats and thus do not exhibit general anti-inflammatory activity. 5. In sensitized guinea-pigs, aerosols of the antigen ovalbumin caused a dose-dependent bronchoconstriction demonstrated by an increase in pulmonary inflation pressure. Administration of CDP840 (0.001-1.0 mg kg-1, i.p.), 1 h before antigen challenge, resulted in dose-dependent reduction in response to antigen. This activity was not due to bronchodilatation since higher doses of CDP840 (3 mg kg-1) did not significantly change the bronchoconstrictor response to histamine. Rolipram was approximately 10 times less active than CDP840 in preventing antigen-induced bronchoconstriction. 6. These results confirm the observations that selective PDE 4 inhibitors reduce antigen-induced bronchoconstriction and pulmonary eosinophilic inflammation. CDP840 is more potent than rolipram in inhibiting native or recombinant PDE 4. Unlike the recently described potent PDE 4 inhibitor RP73401, CDP840 is more active than rolipram in the rat IL-5 model following oral administration. The novel series of tri-aryl ethanes, of which CDP840 is the lead compound, could be the basis of an orally active prophylactic treatment for human asthma.


Impact of adding a limitations section to abstracts of systematic reviews on readers' interpretation: a randomized controlled trial.
To allow an accurate evaluation of abstracts of systematic reviews, the PRISMA Statement recommends that the limitations of the evidence (e.g., risk of bias, publication bias, inconsistency, imprecision) should be described in the abstract. We aimed to evaluate the impact of adding such limitations sections on reader's interpretation. We performed a two-arm parallel group randomized controlled trial (RCT) using a sample of 30 abstracts of systematic reviews evaluating the effects of healthcare intervention with conclusions favoring the beneficial effect of the experimental treatments. Two formats of these abstracts were derived: one reported without and one with a standardized limitations section written according to the PRISMA statement for abstracts. The primary outcome was readers' confidence in the results of the systematic review as stated in the abstract assessed by a Likert scale from 0, not at all confident, to 10, very confident. In total, 300 participants (corresponding authors of RCT reports indexed in PubMed) were randomized by a web-based randomization procedure to interpret one abstract with a limitations section (n = 150) or without a limitations section (n = 150). Participants were blinded to the study hypothesis. Adding a limitations section did not modify readers' interpretation of findings in terms of confidence in the results (mean difference [95% confidence interval] 0.19 [-0.37-0.74], p = 0.50), confidence in the validity of the conclusions (0.07 [-0.49-0.62], p = 0.80), or benefit of the experimental intervention (0.12 [-0.42-0.44], p = 0.65).This study is limited because the participants were expert-readers and are not representative of all systematic review readers. Adding a limitations section to abstracts of systematic reviews did not affect readers' interpretation of the abstract results. Other studies are needed to confirm the results and explore the impact of a limitations section on a less expert panel of participants. ClinicalTrial.gov (NCT01848782).


Studies on the reactivity of organometallic Ru-, Rh- and Os-pta complexes with DNA model compounds.
The reactions of arene-metal complexes (arene=p-cymene, benzene or pentamethylcyclopentadienyl, metal=Ru, Rh or Os), including 1,3,5-triaza-7-phosphatricyclo-[22.214.171.124]decanephosphine (pta) and chloro co-ligands, with 9-methylguanine, adenine, and a series of nucleosides were studied in water to ascertain the binding modes. The products were characterized by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Tandem mass spectrometry was found to provide excellent information on preferential binding sites. In general, the N7 position on guanine (the most basic site) was found to be the preferred donor atom for coordination to the metal complexes. The X-ray structures of the precursor complexes, [(eta5-C10H15)RhCl(pta-Me)2]Cl2, [(eta6-C10H14)OsCl(pta)2]Cl, and [(eta6-C6H6)OsCl2(CH3CN)], are also reported.


A single-round selection of selective DNA aptamers for mammalian cells by polymer-enhanced capillary transient isotachophoresis.
A single-round DNA aptamer selection for mammalian cells was successfully achieved for the first time using a capillary electrophoresis (CE)-based methodology called polymer-enhanced capillary transient isotachophoresis (PectI). The PectI separation yielded a single peak for the human lung cancer cell line (PC-9) complexed with DNA aptamer candidates, which was effectively separated from a free randomized DNA library peak, ensuring no contamination from free DNA in the PC-9-DNA aptamer complex fraction. The DNA aptamer candidates obtained after a single-round selection employing counter selection with HL-60 were proven to bind selectively and form kinetically stable complexes with PC-9 cells. Interestingly, most aptamer candidates showed high binding ability (Kd = 70-350 nM) with different extents of binding on the cell surface. These facts proved that a single-round selection for mammalian cells by PectI is feasible to obtain various types of aptamer candidates, which have high-affinity even for non-overexpressed but unique targets on the cell surface in addition to overexpressed targets.


Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults.
The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas. Our results show a remarkably low mutation frequency, with only a single somatic point mutation, a K277E mutation in the STK10 gene, being identified in a total of more than 15 megabases of sequence analyzed. Sequencing of STK10 in an additional 40 TGCTs revealed no further mutations. Comparative genomic hybridization and LOH analysis using SNP arrays demonstrated that the 13 TGCTs mutationally screened through the 518 protein kinase genes were uniformly aneuploid with consistent chromosomal gains on 12p, 8q, 7, and X and losses on 13q, 18q, 11q, and 4q. Our results do not provide evidence for a mutated protein kinase implicated in the development of TGCT other than KIT. Moreover, they demonstrate that the general prevalence of point mutations in TGCT is low, in contrast to the high frequency of copy number changes.


Effect of heat, cold, and pressure on the transverse carpal ligament and median nerve: a pilot study.
This study quantified the effects of heat, cold, and pressure on the median nerve and transverse carpal ligament in subjects without carpal tunnel syndrome. Subjects were individuals ages 20-50 who had no symptoms of carpal tunnel disease. Imaging ultrasound was used to measure the clearance around the median nerve, transverse ligament elasticity, nerve conduction velocity, thickness of the carpal ligament, and area of the median nerve. Pressure was applied to the carpal ligament to assess the effects of increasing pressure on these structures. On 3 separate days, 10 subjects had ThermaCare heat or cold packs applied, for either 60 or 120 minutes for heat or 20 minutes for cold, to the palmer surface of the hand. Tissue changes were recorded as a response to pressure applied at 0, 5, 10, and 20 N. The size of the nerve and ligaments were not significantly altered by pressure with the hand at room temperature and after cold exposure. After heat, the nerve, ligaments, and tendons showed significantly more elasticity. Application of cold to the hand may reduce compression of the carpal ligament and nerve.


Current concepts of cerebrospinal fluid dynamics and the translaminar cribrosa pressure gradient: a paradigm of optic disk disease.
Modern advances in measuring and studying cerebrospinal fluid dynamics have furthered our understanding of intracranial pressure and its pathophysiological effects on the eye. In particular, the cerebrospinal fluid pressure and composition within the optic nerve subarachnoid space are key factors in diseases of the optic disk. Intracranial pressure and intraocular pressure establish a pressure gradient across the lamina cribrosa. Alterations in this translaminar cribrosa pressure difference induce structural deformations in the lamina cribrosa manifested clinically by the appearance of optic disk edema or optic disk cupping. Much has been learned about papilledema (i.e., optic disk edema due to elevated intracranial pressure) from clinical observations and studies on patients with idiopathic intracranial hypertension. Furthermore, optic nerve subarachnoid space hydrodynamics and translaminar cribrosa pressure difference are postulated to contribute to the pathogenesis of optic disk edema observed in spaceflight-associated neuroocular syndrome. Recently, a substantial body of literature has accumulated suggesting low intracranial pressure may be a risk factor for the development of glaucomatous optic disk cupping within the context of the translaminar cribrosa pressure difference and posterior scleral biomechanics.


Analysis of dispersion effects for white-light interferometric fiber-optic sensors.
We derived the transfer function for a white-light interferometric sensor based on highly birefringent (HB) fiber, assuming that both sensing and receiving interferometers are dispersive. This transfer function indicates that different responses to changes in the measurand may be observed depending on whether displacement of the contrast function or the interference fringes is detected. In the first case the sensitivity of the sensor is determined by the influence of the measurand on modal polarization dispersion while in the second case it depends on the influence of the measurand on modal birefringence of the HB fiber. This sensitivity difference limits the operation range of recently proposed zero-order fringe-tracking methods within which the unambiguous measurement is possible. The dispersion effects for a white-light interferometric strain sensor composed of York HB or Andrew E-type fiber as a sensing element and a quartz Wollaston prism as a receiving interferometer were studied experimentally. Sensites of modal polarization dispersion, modal birefringence, and chromatic dispersion of modal birefringence to the strain were determined for both types of sensing fiber. For these specific combinations of sensing/receiving interferometers we also determined the unambiguous measurement range for zero-order fringe-tracking techniques.


Behavioral mechanisms and morphological symptoms of zombie ants dying from fungal infection.
Parasites that manipulate host behavior can provide prominent examples of extended phenotypes: parasite genomes controlling host behavior. Here we focus on one of the most dramatic examples of behavioral manipulation, the death grip of ants infected by Ophiocordyceps fungi. We studied the interaction between O. unilateralis s.l. and its host ant Camponotus leonardi in a Thai rainforest, where infected ants descend from their canopy nests down to understory vegetation to bite into abaxial leaf veins before dying. Host mortality is concentrated in patches (graveyards) where ants die on sapling leaves ca. 25 cm above the soil surface where conditions for parasite development are optimal. Here we address whether the sequence of ant behaviors leading to the final death grip can also be interpreted as parasite adaptations and describe some of the morphological changes inside the heads of infected workers that mediate the expression of the death grip phenotype. We found that infected ants behave as zombies and display predictable stereotypical behaviors of random rather than directional walking, and of repeated convulsions that make them fall down and thus precludes returning to the canopy. Transitions from erratic wandering to death grips on a leaf vein were abrupt and synchronized around solar noon. We show that the mandibles of ants penetrate deeply into vein tissue and that this is accompanied by extensive atrophy of the mandibular muscles. This lock-jaw means the ant will remain attached to the leaf after death. We further present histological data to show that a high density of single celled stages of the parasite within the head capsule of dying ants are likely to be responsible for this muscular atrophy. Extended phenotypes in ants induced by fungal infections are a complex example of behavioral manipulation requiring coordinated changes of host behavior and morphology. Future work should address the genetic basis of such extended phenotypes.


Evaluating statistical methods using plasmode data sets in the age of massive public databases: an illustration using false discovery rates.
Plasmode is a term coined several years ago to describe data sets that are derived from real data but for which some truth is known. Omic techniques, most especially microarray and genomewide association studies, have catalyzed a new zeitgeist of data sharing that is making data and data sets publicly available on an unprecedented scale. Coupling such data resources with a science of plasmode use would allow statistical methodologists to vet proposed techniques empirically (as opposed to only theoretically) and with data that are by definition realistic and representative. We illustrate the technique of empirical statistics by consideration of a common task when analyzing high dimensional data: the simultaneous testing of hundreds or thousands of hypotheses to determine which, if any, show statistical significance warranting follow-on research. The now-common practice of multiple testing in high dimensional experiment (HDE) settings has generated new methods for detecting statistically significant results. Although such methods have heretofore been subject to comparative performance analysis using simulated data, simulating data that realistically reflect data from an actual HDE remains a challenge. We describe a simulation procedure using actual data from an HDE where some truth regarding parameters of interest is known. We use the procedure to compare estimates for the proportion of true null hypotheses, the false discovery rate (FDR), and a local version of FDR obtained from 15 different statistical methods.


Consumption of chokeberry (Aronia mitschurinii) products modestly lowered blood pressure and reduced low-grade inflammation in patients with mildly elevated blood pressure.
Previous studies suggest that consumption of chokeberries may improve cardiovascular disease risk factor profiles. We hypothesized that chokeberries (Aronia mitschurinii) have beneficial effects on blood pressure, low-grade inflammation, serum lipids, serum glucose, and platelet aggregation in patients with untreated mild hypertension. A total of 38 participants were enrolled into a 16-week single blinded crossover trial. The participants were randomized to use cold-pressed 100% chokeberry juice (300 mL/d) and oven-dried chokeberry powder (3 g/d), or matched placebo products in random order for 8 weeks each with no washout period. The daily portion of chokeberry products was prepared from approximately 336 g of fresh chokeberries. Urinary excretion of various polyphenols and their metabolites increased during the chokeberry period, indicating good compliance. Chokeberries decreased daytime blood pressure and low-grade inflammation. The daytime ambulatory diastolic blood pressure decreased (-1.64 mm Hg, P = .02), and the true awake ambulatory systolic (-2.71 mm Hg, P = .077) and diastolic (-1.62 mm Hg, P = .057) blood pressure tended to decrease. The concentrations of interleukin (IL) 10 and tumor necrosis factor α decreased (-1.9 pg/mL [P = .008] and -0.67 pg/mL [P = .007], respectively) and tended to decrease for IL-4 and IL-5 (-4.5 pg/mL [P = .084] and -0.06 pg/mL [P = .059], respectively). No changes in serum lipids, lipoproteins, glucose, and in vitro platelet aggregation were noted with the chokeberry intervention. These findings suggest that inclusion of chokeberry products in the diet of participants with mildly elevated blood pressure has minor beneficial effects on cardiovascular health.


Education predicts cervical cancer survival: a Lithuanian cohort study.
: We examined inequalities in cervical cancer survival in Lithuania by education and place of residence. : The study is based on the linked dataset that includes all records of the 2001 population Census, all records from Lithuanian Cancer Registry (cancer incidence) and all death and emigration records from Statistics Lithuania for the period between 6 April 2001 and 31 December 2009. The study group includes cervical cancers registered in the Cancer Registry from 1 January 2002 to 31 December 2006. Analysis was restricted to women who were 25-64 years old at the Census date (in total 1 866 cases). : During the study period there were 671 deaths corresponding to an overall 5-year survival proportion 64.13% (95% CI 61.86-66.31). Place of residence and education of cervical cancer patients had strong impact on survival; 5-year survival was higher in women living in urban areas than in rural (68.61 and 55.93%) and survival decreased with decreasing education: from 79.77% in highest education group to 64.85 and 50.48% in groups with secondary and lower than secondary education. The effect of place of residence declined when stage of disease was included in the model and became not significant in final model with education adjustment. The effect of education declined after inclusion of stage and other variables, however, remained significant. : We found that women with higher education experienced higher survival following a cervical cancer diagnosis, and stage of disease at the time of diagnosis explains only the part of observed differences.


Clinical prediction of acute aortic dissection.
Clinical criteria for aortic dissection are poorly defined. Thus, 35% of aortic dissections remain unsuspected in vivo, and 99% of suspected cases can be refuted. To identify independent predictors of acute aortic dissection and create a prediction model for facilitated estimation of the individual risk of dissection. Two hundred fifty patients with acute chest pain, back pain, or both; absence of an established differential diagnosis of the pain syndrome; and clinical suspicion of acute aortic dissection were evaluated for the presence of 26 clinical variables in a prospective, observational study. Multivariate analysis was performed to create a prediction model of aortic dissection. Aortic pain with immediate onset, a tearing or ripping character, or both; mediastinal widening, aortic widening, or both on chest radiography; and pulse differentials, blood pressure differentials, or both (P<.001 for all) were identified as independent predictors of acute aortic dissection. Probability of dissection was low with absence of all 3 variables (7%), intermediate with isolated findings of aortic pain or mediastinal widening (31% and 39%, respectively), and high with isolated pulse or blood pressure differentials or any combination of the 3 variables (> or = 83%). Accordingly, 4% of all dissections were assigned to the low-probability group, 19% to the intermediate-probability group, and 77% to the high-probability group of aortic dissection. Assessment of 3 clinical variables permitted identification of 96% of the acute aortic dissections and stratification into high-, intermediate-, and low-probability groupings of disease. With better selection for prompt diagnostic imaging, this prediction model can be used as an aid to improve patient care in aortic dissection. Arch Intern Med. 2000;160:2977-2982


First Principles Calculations on the Stoichiometric and Defective (101) Anatase Surface and Upon Hydrogen and H2Pc Adsorption: The Influence of Electronic Exchange and Correlation and of Basis Set Approximations.
Anatase TiO2 provides photoactivity with high chemical stability at a reasonable cost. Different methods have been used to enhance its photocatalytic activity by creating band gap states through the introduction of oxygen vacancies, hydrogen impurities, or the adorption of phthalocyanines, which are usually employed as organic dyes in dye-sensitized solar cells. Predicting how these interactions affect the electronic structure of anatase requires an efficient and robust theory. In order to document the efficiency and accuracy of commonly used approaches we have considered two widely used implementations of density functional theory (DFT), namely the all-electron linear combination of atomic orbitals (AE-LCAO) and the pseudo-potential plane waves (PP-PW) approaches, to calculate the properties of the stoichiometric and defective anatase TiO2 (101) surface. Hybrid functionals, and in particular HSE, lead to a computed band gap in agreement with that measured by using UV adsorption spectroscopy. When using PBE+U, the gap is underestimated by 20 % but the computed position of defect induced gap states relative to the conduction band minimum (CBM) are found to be in good agreement with those calculated using hybrid functionals. These results allow us to conclude that hybrid functionals based on the use of AE-LCAO provide an efficient and robust approach for predicting trends in the band gap and the position of gap states in large model systems. We extend this analysis to surface adsorption and use the AE-LCAO approach with the hybrid functional HSED3 to study the adsorption of the phthalocyanine H2Pc on anatase (101). Our results suggest that H2Pc prefers to be adsorbed on the surface Ti5c rows of anatase (101), in agreement with that seen in recent STM experiments on rutile (110).


The ITALK project: a developmental robotics approach to the study of individual, social, and linguistic learning.
This article presents results from a multidisciplinary research project on the integration and transfer of language knowledge into robots as an empirical paradigm for the study of language development in both humans and humanoid robots. Within the framework of human linguistic and cognitive development, we focus on how three central types of learning interact and co-develop: individual learning about one's own embodiment and the environment, social learning (learning from others), and learning of linguistic capability. Our primary concern is how these capabilities can scaffold each other's development in a continuous feedback cycle as their interactions yield increasingly sophisticated competencies in the agent's capacity to interact with others and manipulate its world. Experimental results are summarized in relation to milestones in human linguistic and cognitive development and show that the mutual scaffolding of social learning, individual learning, and linguistic capabilities creates the context, conditions, and requisites for learning in each domain. Challenges and insights identified as a result of this research program are discussed with regard to possible and actual contributions to cognitive science and language ontogeny. In conclusion, directions for future work are suggested that continue to develop this approach toward an integrated framework for understanding these mutually scaffolding processes as a basis for language development in humans and robots.


Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study.
To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.


Hip kinematics and kinetics in persons with and without cam femoroacetabular impingement during a deep squat task.
Previous studies have indicated that hip and pelvis kinematics may be altered during functional tasks in persons with femoroacetabular impingement. The purpose of this study was to compare hip and pelvis kinematics and kinetics during a deep squat task between persons with cam femoroacetabular impingement and pain-free controls. Fifteen persons with cam femoroacetabular impingement and 15 persons without cam femoroacetabular impingement performed a deep squat task. Peak hip flexion, abduction, and internal rotation, and mean hip extensor, adductor, and external rotator moments were quantified. Independent t-tests (α<0.05) were used to evaluate between group differences. Compared to the control group, persons with cam femoroacetabular impingement demonstrated decreased peak hip internal rotation (15.2° (SD 9.5°) vs. 9.4° (SD 7.8°); P=0.041) and decreased mean hip extensor moments (0.56 (SD 0.12) Nm/kg vs. 0.45 (SD 0.15) Nm/kg; P=0.018). In addition persons in the cam femoroacetabular impingement group demonstrated decreased posterior pelvis tilt during squat descent compared to the control group, resulting in a more anteriorly tilted pelvis at the time peak hip flexion (12.5° (SD 17.1°) vs. 23.0° (SD 12.4°); P=0.024). The decreased hip internal rotation observed in persons with cam femoroacetabular impingement may be the result of bony impingement. Furthermore, the decrease in posterior pelvis tilt may contribute to impingement by further approximating the femoral head-neck junction with the acetabulum. Additionally, decreased hip extensor moments suggest that diminished hip extensor muscle activity may contribute to decreased posterior pelvis tilt.


Transmission dynamics of re-emerging rabies in domestic dogs of rural China.
Despite ongoing efforts to control transmission, rabies prevention remains a challenge in many developing countries, especially in rural areas of China where re-emerging rabies is under-reported due to a lack of sustained animal surveillance. By taking advantage of detailed genomic and epidemiological data for the re-emerging rabies outbreak in Yunnan Province, China, collected between 1999 and 2015, we reconstruct the demographic and dispersal history of domestic dog rabies virus (RABV) as well as the dynamics of dog-to-dog and dog-to-human transmission. Phylogeographic analyses reveal a lower diffusion coefficient than previously estimated for dog RABV dissemination in northern Africa. Furthermore, epidemiological analyses reveal transmission rates between dogs, as well as between dogs and humans, lower than estimates for Africa. Finally, we show that reconstructed epidemic history of RABV among dogs and the dynamics of rabid dogs are consistent with the recorded human rabies cases. This work illustrates the benefits of combining phylogeographic and epidemic modelling approaches for uncovering the spatiotemporal dynamics of zoonotic diseases, with both approaches providing estimates of key epidemiological parameters.


Energetic, Topological and Electric Field Analyses of Cation-Cation Nucleic Acid Interactions in Watson-Crick Disposition.
A theoretical study of the effect of the diprotonation on the nucleic acid bases (A : U, A : T and G : C) in Watson-Crick conformation has been carried out by means of DFT computational methods in vacuum. In addition, the corresponding neutral and monoprotonated binary complexes have been considered. Most of the diprotonated species studied are stable, even though the binding energy is positive due to the overall repulsive electrostatic term. Local electrostatic attractive forces in the regions of hydrogen bonds (HBs) are responsible for equilibrium geometries, as shown by the electric field lines connecting the electrophilic and nucleophilic sites involved in the HB interactions. Secondary electrostatic effects also affect the assembling of the nucleic acid complexes in either neutral or cationic form. In particular, the electric field lines flowing from electrophilic sites in one base to nucleophilic sites in the other reinforce the linking between them. Hence, when the nucleophilic site concerns the free lone pair of the heteroatom involved in the HB interaction as acceptor, the HB distance shortens. However, if the free lone pair of the HB acceptor interacts with an electrophilic site in the same molecule, the HB distance elongates, weakening the HB interaction. The topological analysis of the electron density distribution in HB regions indicates that neutral, monoprotonated and diprotonated complexes show no differences in the nature of their HB's.


Harlequin ichthyosis unmasked: a defect of lipid transport.
Harlequin ichthyosis (HI)--the most severe form of keratinizing disorders, often lethal in the neonatal period--is characterized by a profound thickening of the keratin skin layer, a dense "armor"-like scale that covers the body, and contraction abnormalities of the eyes, ears, and mouth. In this issue of the JCI, Akiyama et al. report that mutations in ABCA12 caused defective lipid transport that significantly impacted normal development of the skin barrier. Lipid secretion was recovered after corrective ABCA12 gene transfer into patient keratinocytes. These results should allow for early prenatal diagnosis of HI and lend hope to the possibility of a specific treatment for this devastating disorder.


Social learning spreads knowledge about dangerous humans among American crows.
Individuals face evolutionary trade-offs between the acquisition of costly but accurate information gained firsthand and the use of inexpensive but possibly less reliable social information. American crows (Corvus brachyrhynchos) use both sources of information to learn the facial features of a dangerous person. We exposed wild crows to a novel 'dangerous face' by wearing a unique mask as we trapped, banded and released 7-15 birds at five study sites near Seattle, WA, USA. An immediate scolding response to the dangerous mask after trapping by previously captured crows demonstrates individual learning, while an immediate response by crows that were not captured probably represents conditioning to the trapping scene by the mob of birds that assembled during the capture. Later recognition of dangerous masks by lone crows that were never captured is consistent with horizontal social learning. Independent scolding by young crows, whose parents had conditioned them to scold the dangerous mask, demonstrates vertical social learning. Crows that directly experienced trapping later discriminated among dangerous and neutral masks more precisely than did crows that learned through social means. Learning enabled scolding to double in frequency and spread at least 1.2 km from the place of origin over a 5 year period at one site.


A community computational challenge to predict the activity of pairs of compounds.
Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing. We highlight similarities between the methods. Although the accuracy of predictions was not optimal, we find that computational prediction of compound-pair activity is possible, and that community challenges can be useful to advance the field of in silico compound-synergy prediction.


Ethnomedicine in healthcare systems of the world: a Semester at Sea pilot survey in 11 countries.
An understanding and appreciation for the varied healthcare systems in use throughout the world are increasingly vital for medical personnel as patient populations are now composed of ethnically diverse people with wide-ranging belief systems. While not a statistically valid survey, this pilot study gives a global overview of healthcare differences around the world. A pilot study of 459 individuals from 11 different countries around the world was administered by 33 students in the upper division course, People, Pathology, and World Medicine from Semester at Sea, Fall 2007, to ascertain trends in healthcare therapies. Open-ended surveys were conducted in English, through an interpreter, or in the native language. Western hospital use ranked highly for all countries, while ethnomedical therapies were utilized to a lesser degree. Among the findings, mainland China exhibited the greatest overall percentage of ethnomedical therapies, while the island of Hong Kong, the largest use of Western hospitals. The figures and trends from the surveys suggest the importance of understanding diverse cultural healthcare beliefs when treating individuals of different ethnic backgrounds. The study also revealed the increasingly complex and multisystem-based medical treatments being used internationally.


Walk-off and pattern selection in optical parametric oscillators.
The effect of walk-off in pattern selection in optical parametric oscillators is theoretically examined. We show that a dynamic mechanism also allows us to observe the formation of structures for positive signal detunings. In this regime the pattern that is generated is a periodic array of kinks that separate regions in which one of two stable steady states is alternately selected. This structure can be regarded as a train of dark soliton stripes because the two solutions have opposite signs. The wavelength of the selected pattern is theoretically predicted, and the prediction agrees with the results of the numerical solutions of the equations governing the device.


Epizootic situation and risk of rabies exposure in Polish population in 2000, with special attention to Lublin province.
In Poland in 2000 a total of 2,221 cases of animal rabies were reported, including 1,874 (84.4%) of wild animals. The evaluation of epizootic situation in 2000 has shown a few cases of animal rabies in western provinces of Poland, so in regions where a programme aimed at oral vaccination of foxes was introduced. Most cases of animal rabies were identified in the northeastern region, as well as in eastern and central Poland. In October 2000 in Warminsko-Mazurskie province (northeastern region of Poland) rabies was responsible for the death of 59-year-old woman, bitten by a rabid cat, and refused post-exposure specific antirabies prophylaxis. Among domestic animals, the highest incidence of rabies occurred in cattle--167 cases (7.5%), cats--113 (5.1%) and dogs--61 (2.7%). In the group of wild animals, red foxes accounted for 1,587 (71.5%) cases, raccoon dogs for 210 (9.5%) and martens for 36 (1.6%). People have been vaccinated against rabies in all provinces of Poland. The number of people vaccinated against rabies in regions adjoining the western border was much smaller compared to other provinces of Poland. The highest rates of using post-exposure prophylaxis occurred in northeastern regions of Poland (Warminsko-Mazurskie province) and eastern and central parts of Poland. On the basis of analysis of cases consulted in the dispensary of rabies prophylaxis in the Department of Infectious Diseases in Lublin, it can be concluded that the number of people with exposure to rabid animals is rather small. Most vaccinations are carried out when animals suspected of being rabid bite patients. These are primarily domestic animals--dogs and cats.


Malnutrition in infants receiving cult diets: a form of child abuse.
Severe nutritional disorders, including kwashiorkor, marasmus, and rickets, were seen in four children and were due to parental food faddism, which should perhaps be regarded as a form of child abuse. All disorders were corrected with more normal diets and vitamin supplements. In view of the potentially serious consequences of restricted diets being fed to children, families at risk should be identified and acceptable nutritional advice given. When children are found to be suffering from undernutrition due to parental food faddism a court order will normally be a necessary step in providing adequate treatment and supervision.


Complete Genome Sequence of Streptococcus iniae 89353, a Virulent Strain Isolated from Diseased Tilapia in Taiwan.
Streptococcus iniae 89353 is a virulent strain isolated from diseased tilapia in Taiwan. The full-genome sequence of S. iniae 89353 is 2,098,647 bp. The revealed genome information will be beneficial for identification and understanding of potential virulence genes of Streptococcus iniae and possible immunogens for vaccine development against streptococcosis.


Un ménage à quatre: the molecular biology of chromosome segregation in meiosis.
Sexually reproducing organisms rely on the precise reduction of chromosome number during a specialized cell division called meiosis. Whereas mitosis produces diploid daughter cells from diploid cells, meiosis generates haploid gametes from diploid precursors. The molecular mechanisms controlling chromosome transmission during both divisions have started to be delineated. This review focuses on the four fundamental differences between mitotic and meiotic chromosome segregation that allow the ordered reduction of chromosome number in meiosis: (1) reciprocal recombination and formation of chiasmata between homologous chromosomes, (2) suppression of sister kinetochore biorientation, (3) protection of centromeric cohesion, and (4) inhibition of DNA replication between the two meiotic divisions.


Ulnar neuropathy in surgical patients.
The goal of this project was to study the frequency and natural history of perioperative ulnar neuropathy. A prospective evaluation of ulnar neuropathy in 1,502 adult patients undergoing noncardiac surgical procedures was performed. Patients were assessed with a standard questionnaire and neurologic examination before surgery, daily during hospitalization in the first week after surgery, and by telephone if they were discharged before 1 postoperative week. Patients in whom ulnar neuropathy developed were followed for 2 yr. Ulnar neuropathy developed in seven patients (0.5%; 95% confidence interval, 0.2% to 1.0%). Six of the seven patients were men. Symptoms of ulnar neuropathy began 2-7 days after surgery. Manifestations were mild and confined to sensory deficits in six patients. Symptoms resolved in four patients within 6 weeks. The remaining three patients had residual symptoms 2 yr later. In this surgical population, ulnar neuropathy was an infrequent complication. It occurred primarily in men who were 50-75 yr old and was not symptomatic until several days after surgery. Gender-dependent differences in the anatomy of the ulnar nerve and related structures at the elbow may serve as risk factors for ulnar neuropathy in patients having surgery.


Inter-prescriber variability in the decision to prescribe antibiotics to febrile patients attending primary care in Myanmar.
Most antibiotic prescribing occurs in primary care. Even within the same health facility, there may be differences between prescribers in their tendency to prescribe antibiotics, which may be masked by summary data. We aimed to quantify prescriber variability in antibiotic prescription to patients with acute fever in primary care clinics in Myanmar. We conducted a secondary analysis of prescribing data from 1090 patient consultations with 40 prescribing doctors from a trial investigating the effect of point-of-care C-reactive protein (CRP) tests on antibiotic prescription for acute fever. We used multilevel logistic regression models to assess inter-prescriber variability in the decision to prescribe antibiotics. The median odds ratio (MOR) in the unadjusted model was 1.82 (95% CI: 1.47-2.56) indicating that when two prescribers from this population are randomly selected then in half of these pairs the odds of prescription will be greater than 1.82-fold higher in one prescriber than the other. The estimated variability from this sample of prescribers corresponds to a population of prescribers where the top 25% of prescribers will prescribe antibiotics to over 41% of patients while the bottom 25% will prescribe antibiotics to less than 23% of patients. Inter-prescriber variation in antibiotic prescribing remained after adjustment for patient characteristics and CRP information (P < 0.001). Despite sharing the same management guidelines, there was substantial inter-prescriber variation in antibiotic prescription to patients with acute fever. This variation should be considered when designing trials and stewardship programmes aiming to reduce inappropriate antibiotic prescribing.


Dual role of nitric oxide in pancreatic β-cells.
An involvement of inducible nitric oxide (NO) synthase (NOS) in pancreatic β-cell degeneration during the process of type 1 diabetes has been well discussed. Recently, there is growing evidence for pivotal roles of constitutive NOS (cNOS) in β-cells; the presence of NOS1 and NOS3 in pancreatic β-cells and the effects of low-concentration NO, which is assumed to be derived from cNOS, on β-cell functions have been reported. However, the roles of cNOS-derived NO in β-cells are still under debate. One of the reasons seems to be that NO has multiple biological activities, which are dependent on its concentration. In β-cells, NO has been shown to exert positive and negative regulation of insulin secretion and anti- and pro-apoptotic activities, which is likely to be dependent on concentrations. In this review article, we will describe the current understanding of the roles of NO in pancreatic β-cells, especially focusing on cNOS-derived NO and its differential roles depending on concentrations.


Application of digital speckle photography to flash X-ray studies of internal deformation fields in impact experiments.
A technique to measure two-dimensional deformation fields of a layer inside materials during dynamic events such as impact experiments is presented. Even optically opaque materials like cement can be evaluated when flash x rays are used. Blocks of polyester and cement were prepared with a layer of x-ray-absorbing lead particles. The specimens were then hit by a 9-mm-diameter steel sphere (ball bearing) fired from a 9-mm-bore gas gun at a velocity of 373.5 +/- 3.0 ms(-1). A 30-ns-long x-ray pulse exposed one radiograph before impact; another radiograph was exposed a short time after the impact on the specimen. The two-dimensional displacement field was obtained when the x-ray radiographs were digitized by a conventional flatbed scanner, and a digital speckle photography algorithm was used to calculate the displacements. The flash x-ray technique allowed examination of the deformation at the layer inside the material during failure, thus giving interesting data about the material flow field around the impactor.


Perceived risk of cancer and patient reports of participation in decisions about screening: the DECISIONS study.
Health behavior theories suggest that high perceived risk for cancer will be associated with screening, but few studies have examined how perceived risk relates to the screening decision process. To examine relationships between perceived risk of cancer and behaviors during decision making for 3 screening tests. Cross-sectional survey conducted between November 2006 and May 2007. Nationwide random-digit dial telephone survey. A total of 1729 English-speaking US adults aged 40 y and older who reported making a cancer screening decision (about breast, colon, or prostate tests) in the previous 2 y. Participants completed measures of perceived risk, information seeking, and shared decision-making tendencies. As perceived risk for cancer increased, patients were more likely to seek information about screening on their own (e.g., 35% of participants who perceived a high risk of cancer searched the Internet compared with 18% for those who perceived a low risk, P < 0.001) and in interactions with their physicians. As perceived risk increased, patients were also more likely to consult with more than 1 provider. Gender moderated the shared decision-making preference such that men with high perceived risks were more likely than women with high perceived risks to report they would have preferred more involvement in the decision (35% v. 9%, P = 0.001). Cross-sectional data limit causal inferences. Higher perceived risk was associated with greater patient participation, as shown by more information seeking and greater desire for decisional involvement (moderated by gender). The results suggest that perceived risk of cancer could influence patient behavior when deciding about screening.


The Association between Obstructive Sleep Apnea on Diabetic Kidney Disease: A Systematic Review and Meta-Analysis.
This systematic review aims to investigate the association between obstructive sleep apnea (OSA) and diabetic kidney disease (DKD). MeSH terms and free text searches were performed on MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception to April 2015. Zetoc and OpenGrey databases were queried for grey literature, and lastly, hand searches were carried out. Study selection and quality assessment were conducted by two authors. One author carried out data extraction, which was checked by other authors. The relationships between apneahypopnea index (AHI), oxygen desaturation index (ODI), time spent under 90% oxygen saturation (%TST < 90), and minimum and mean oxygen saturation (O2) on DKD were examined. Two longitudinal and ten cross-sectional studies were included for our narrative synthesis, and seven studies for meta-analysis. Studies that performed multi-variable analysis demonstrated significant associations between OSA (assessed using either apnea-hypopnea index or ODI) and DKD in type 2 diabetes mellitus (T2DM). This was confirmed by meta-analysis (pooled OR 1.73, 95% CI: 1.13-2.64). There was some evidence to suggest that %TST < 90 may have an association with DKD. There was insufficient evidence to conclude on the relationship between minimum and mean oxygen saturation on DKD. There was no evidence available on the associations between OSA and other respiratory parameters in type 1 diabetes mellitus populations. There is moderate evidence that OSA is associated with DKD in patients with T2DM. Large prospective studies with long-term follow up are needed to assess the possible bi-directional mechanisms between OSA and DKD.


Characterization and lymphocyte proliferation activity of an oligosaccharide degraded from Astragalus polysaccharide.
An Astragalus oligosaccharide (AOS) degraded from Astragalus polysaccharide (APS) and purified by membrane dialysis and silicon gel chromatography is studied in this paper. The structural features of AOS were investigated by a combination of chemical and instrumental analysis, such as monosaccharide analysis, periodate oxidation-Smith degradation, methylation analysis, electrospray ionization mass spectrometry (ESI-MS), Fourier transform infrared (FT-IR) spectrometry and nuclear magnetic resonance (NMR). The results indicated that AOS is an octasaccharide that consists of (3→)-linked-Rha, (1→3)-linked-Rha, (1→3,4)-linked-Araf, (1→3)-linked-Gal, terminal-linked-Gal and terminal-linked-Glc. The effects of AOS on cyclophosphamide-induced immunosuppression were determined by various studies, such as the proliferation of nucleated marrow, red blood cell (RBC) and white blood cell (WBC) populations, growth of the spleen and thymus, and increases in hemoglobin (HGB) concentration and granulocyte-macrophage colony stimulating factor (GM-CSF) level. The results indicated that AOS can restore cyclophosphamide-induced immunosuppression by stimulating the secretion of GM-CSF, which promoted the differentiation of progenitor cells after proliferation.


The Concept of Biosimilars: From Characterization to Evolution-A Narrative Review.
Biologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small-molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords "biosimilars," "market," and "regulatory." In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the "pharmerging" economies. This article highlights the importance of biosimilars, as a cost-cutting strategy, in the delivery of state-of-the-art health care in developing countries, at a fraction of what a reference biological agent would cost.


Isolated liver gap junctions: gating of transjunctional currents is similar to that in intact pairs of rat hepatocytes.
We have shown previously that conductance of rat liver gap junctions is blocked by an affinity-purified polyclonal antibody generated against rat liver junctional membranes, is not affected by moderate transjunctional or transmembrane potentials, and is reversibly decreased by cytoplasmic acidification and perfusion with octanol. We have now recorded currents from isolated liver gap junctions using patch electrodes dipped through a layer of mixed lipids whose concentrations match those of isolated liver appositional membranes. These currents are blocked by the same polyclonal antibody, are insensitive to moderate voltages imposed across the pipette tip, and are reversibly blocked by similar concentrations of H ions and octanol as are junctions in situ. The currents are likely to be gap junctional in origin; their block by low pH and other agents indicates that the gating mechanisms are intrinsic to the gap junctions themselves and presumably result from conformational change in the channel-forming protein.


APPLYING INSIGHTS FROM BEHAVIORAL ECONOMICS TO POLICY DESIGN.
The premise of this article is that an understanding of psychology and other social science disciplines can inform the effectiveness of the economic tools traditionally deployed in carrying out the functions of government, which include remedying market failures, redistributing income, and collecting tax revenue. An understanding of psychology can also lead to the development of different policy tools that better motivate desired behavior change or that are more cost-effective than traditional policy tools. The article outlines a framework for thinking about the psychology of behavior change in the context of market failures. It then describes the research on the effects of a variety of interventions rooted in an understanding of psychology that have policy-relevant applications. The article concludes by discussing how an understanding of psychology can also inform the use and design of traditional policy tools for behavior change, such as financial incentives.


CFU-M-derived human megakaryocytes synthesize glycoproteins IIb and IIIa.
Human megakaryocytes have been shown by immunofluorescent techniques to express platelet glycoprotein IIb/IIIa antigen. We report evidence that megakaryocytes derived from human committed megakaryocytic progenitor cells in vitro (CFU-M) synthesize glycoproteins IIb and IIIa. Nonadherent light-density human bone marrow cells were cultured in human plasma and methylcellulose using conditions that promote large megakaryocytic colonies. On day 13 the megakaryocytic colonies were picked, pooled, and pulsed with 35S-methionine in methionine-free media. Populations of approximately 100,000 cells with greater than or equal to 95% viability and containing 70% to 90% megakaryocytes were obtained reliably for study. After the radioactive pulse, the cell suspension was solubilized with nonionic detergent. To reduce nonspecific binding of 35S-labeled proteins to agarose, the lysate was chromatographed sequentially on glycine-quenched Affi-gel and antihuman factor X-Sepharose. The unbound material from these resins was then chromatographed on an antiglycoprotein IIb/IIIa monoclonal antibody resin (HP1-1D-Sepharose) or on a control monoclonal antibody resin. Bound fractions were eluted and analyzed by polyacrylamide gel electrophoresis and autoradiography. Autoradiograms of diethylamine eluates from HP1-1D-Sepharose revealed two labeled proteins with electrophoretic mobilities identical with those of human platelet membrane glycoproteins IIb and IIIa, isolated using similar conditions. Autoradiograms of material synthesized by control macrophages from the same donors revealed no significant labeling of proteins in the glycoprotein IIb/IIIa molecular weight range, nor were such proteins bound by HP1-1D-Sepharose. Our observations show that protein synthesis by CFU-M-derived human megakaryocytes can be readily studied using a small amount of bone marrow aspirate as starting material. This approach will allow the study of protein synthesis by megakaryocytes from normal subjects or from subjects with clinical disorders, and it will circumvent the need to obtain large amounts of bone marrow to prepare enriched populations of megakaryocytes.


Role of sleep disturbances in occupational accidents among women.
This population-based cohort study was performed to assess the association between sleep disturbances and the risk of occupational accidents among women. Data were collected by questionnaires on two different occasions (2000 and 2010) and data on work injuries were also collected from Swedish government records (ISA). Insomnia symptoms were defined as having severe or very severe problems with (i) difficulty initiating sleep, (ii) difficulty maintaining sleep, or (iii) early morning awakening. Symptom of obstructive sleep apnea syndrome (OSAS) was defined as reporting both snoring and daytime sleepiness. Working-age respondents (20-67 years of age) who responded to both baseline and follow-up questionnaires and had worked for part or all of the 10-year follow-up period (N=4320) were included in the study. Of the subjects responding to the questionnaire, 12.2% reported ≥1 accident and 6.3% reported an accident requiring sick leave in the government register. Blue-collar workers and night and shift work were more common in the group with occupational accidents. Subjects with insomnia symptoms both at baseline and follow-up (persistent insomnia symptoms) ran a higher risk of being involved in an self-reported occupational accident [adjusted OR (OR adj) 1.5, 95% confidence interval (95% CI) 1.2-2.0] after adjusting for age, body mass index, smoking, alcohol dependency, white- or blue-collar worker, years at work, night work, and physical activity. Persistent insomnia symptoms did not reach statistical significance as an independent predictor of register-reported occupational accident with sick leave (OR adj1.4, 95% CI 0.99-2.1). No significant association was found between symptoms of OSAS and self-reported or register-based occupational accidents. Persistent insomnia symptoms were associated with an increased risk of self-reported occupational accidents, while no significant association was found with occupational accidents with sick leave reported to government register.


Systematic comparison of non-invasive measures for the assessment of atrial fibrillation complexity: a step forward towards standardization of atrial fibrillation electrogram analysis.
To present a comparison of electrocardiogram-based non-invasive measures of atrial fibrillation (AF) substrate complexity computed on invasive animal recordings to discriminate between short-term and long-term AF. The final objective is the selection of an optimal sub-set of measures for AF complexity assessment. High-density epicardial direct contact mapping recordings (234 leads) were acquired from the right and the left atria of 17 goats in which AF was induced for 3 weeks (short-term AF group, N = 10) and 6 months (long-term AF group, N = 7). Several non-invasive measures of AF organization proposed in the literature in the last decade were investigated to assess their power in discriminating between the short-term and long-term group. The best performing measures were identified, which when combined attained a correct classification rate of 100%. Their ability to predict standard invasive AF complexity measures was also tested, showing an average R(2) of 0.73 ± 0.04. An optimal set of measures of the AF substrate complexity was identified out of the set of non-invasive measures analysed in this study. These measures may contribute to improve patient-tailored diagnosis and therapy of sustained AF.


Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes.
Bone marrow or hematopoietic stem cell transplantation is a potential treatment for autoimmune disease. The clinical application of this approach is, however, limited by the risks associated with allogeneic transplantation. In contrast, syngeneic transplantation would be safe and have wide clinical application. Because T cell tolerance can be induced by presenting antigen on resting antigen-presenting cells (APCs), we reasoned that hematopoietic stem cells engineered to express autoantigen in resting APCs could be used to prevent autoimmune disease. Proinsulin is a major autoantigen associated with pancreatic beta cell destruction in humans with type 1 diabetes (T1D) and in autoimmune NOD mice. Here, we demonstrate that syngeneic transplantation of hematopoietic stem cells encoding proinsulin transgenically targeted to APCs totally prevents the development of spontaneous autoimmune diabetes in NOD mice. This antigen-specific immunotherapeutic strategy could be applied to prevent T1D and other autoimmune diseases in humans.


Heberden Oration 1981: epidemiology and the arthritides.
The multifactorial control of serum uric acid levels is discussed from an epidemiological point of view and the principles at issue related to the epidemiology of osteoarthrosis. It is shown that in osteoarthrosis the clinical characteristics vary from one joint group to another. Association of x-ray changes with pain varies between joints and between sexes for the various joints. The disease tends to be commoner in females but not in all age groups. There is an association between obesity and osteoarthrosis in the hands and knees but not the hips or ankles. These differences raise questions about the homogeneity of generalised osteoarthrosis. Such questions might be answered by epidemiological studies which consider individual joint groups and are carefully directed towards specific hypotheses, the development of which could be facilitated by the use of iconic models.


Mifepristone as Bridge or Adjunct Therapy in the Management of Challenging Cushing Disease Cases.
Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.


HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4+ T Cell Responses.
Antigen-specific CD4(+) T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4(+) T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4(+) T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4(+) T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4(+) T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4(+) T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4(+) T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4(+) T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4(+) T cells and, to a lesser extent, gp41-specific CD4(+) T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies. One of the earliest discoveries related to CD4(+) T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4(+) T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4(+) T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4(+) T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4(+) T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4(+) T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.


UV screening by phenolics in berries of grapevine (Vitis vinifera).
The role of phenolics in UV-screening was investigated in berries of a white grape cultivar (Vitis vinifera L. cv. Bacchus). Fluorescence microscopy revealed accumulation of phenolics in the skin of berries and, by high performance liquid chromatography and mass spectrometry, flavonols and hydroxycinnamic acids were identified as the main groups of UV-absorbing phenolics. Relationships between natural radiation and the synthesis of phenolics were studied in plants that were cultivated in the absence of UV radiation in a greenhouse before outdoor exposure to three different light regimes: the entire solar spectrum, the solar spectrum minus UV-B radiation and only visible radiation. During six days of exposure, flavonol synthesis was significantly stimulated by natural UV, in particular UV-B, but concentrations of hydroxycinnamic acids decreased under all conditions. Direct comparison of fluorimetrically-determined skin absorbance with absorbance of extracted flavonols or hydroxycinnamic acids suggested that acclimation of UV screening depends almost exclusively on flavonol synthesis. While increased flavonol levels resulted in efficient UV-A shielding, UV-B shielding was incomplete, probably due to decreased levels of the UV-B-absorbing hydroxycinnamic acids during exposure.


Evidence of adaptive divergence in plasticity: density- and site-dependent selection on shade-avoidance responses in Impatiens capensis.
We investigated the conditions under which plastic responses to density are adaptive in natural populations of Impatiens capensis and determined whether plasticity has evolved differently in different selective environments. Previous studies showed that a population that evolved in a sunny site exhibited greater plasticity in response to density than did a population that evolved in a woodland site. Using replicate inbred lines in a reciprocal transplant that included a density manipulation, we asked whether such population differentiation was consistent with the hypothesis of adaptive divergence. We hypothesized that plasticity would be more strongly favored in the sunny site than in the woodland site; consequently, we predicted that selection would be more strongly density dependent in the sunny site, favoring the phenotype that was expressed at each density. Selection on internode length and flowering date was consistent with the hypothesis of adaptive divergence in plasticity. Few costs or benefits of plasticity were detected independently from the expressed phenotype, so plasticity was selected primarily through selection on the phenotype. Correlations between phenotypes and their plasticity varied with the environment and would cause indirect selection on plasticity to be environment dependent. We showed that an appropriate plastic response even to a rare environment can greatly increase genotypic fitness when that environment is favorable. Selection on the measured characters contributed to local adaptation and fully accounted for fitness differences between populations in all treatments except the woodland site at natural density.


Trends in the diagnosis and treatment of pediatric primary spinal cord tumors.
Pediatric primary spinal cord tumors (PSCTs) are rare, with limited comprehensive data regarding incidence and patterns of diagnosis and treatment. The authors evaluated trends in the diagnosis and treatment of PSCTs using a nationwide database. The Surveillance, Epidemiology, and End Results (SEER) registry was queried for the years 1975-2007, evaluating clinical patterns in 330 patients 19 years of age or younger in whom a pediatric PSCT had been diagnosed. Histological diagnoses were grouped into pilocytic astrocytoma, other low-grade astrocytoma, ependymoma, and high-grade glioma. Patient demographics, tumor pathology, use of external beam radiation (EBR), and overall survival were analyzed. The incidence of pediatric PSCT was 0.09 case per 100,000 person-years and did not change over time. Males were more commonly affected than females (58% vs 42%, respectively; p < 0.006). Over the last 3 decades, the specific diagnoses of pilocytic astrocytoma and ependymoma increased, whereas the use of EBR decreased (60.6% from 1975 to 1989 vs 31.3% from 1990 to 2007; p < 0.0001). The 5- and 10-year survival rates did not differ between these time periods. While the incidence of pediatric PSCT has not changed over time, the pattern of pathological diagnoses has shifted, and pilocytic astrocytoma and ependymoma have been increasingly diagnosed. The use of EBR over time has declined. Relative survival of patients with low-grade PSCT has remained high regardless of the pathological diagnosis.


Early production of IL-4 and induction of Th2 responses in the lymph node originate from an MHC class I-independent CD4+NK1.1- T cell population.
Splenic CD4+NK1.1+ T cells have been shown to secrete large and transient amounts of IL-4 mRNA 90 min after i.v. injection of anti-CD3 Ab, suggesting that this novel subset of T cells may induce Th2 responses in the spleen by quickly providing IL-4 at the onset of an immune response. beta2-microglobulin-deficient (beta2m(o/o)) mice have been shown to contain strongly reduced numbers of NK1.1+ T cells and to be severely impaired in their capacity for rapid induction of IL-4 mRNA in response to anti-CD3, demonstrating that these cells are MHC class I dependent. To address the role of CD4+NK1.1+ T cells in the induction of Th2 responses against Leishmania major, we have dissected the onset and the outcome of the immune response elicited against the parasite in BALB/c-beta2m(o/o) mice and in anti-NK1.1-treated congenic BALB/c mice expressing the NK1.1 marker (BALB/c-NK1.1+). Both BALB/c-beta2m(o/o) and NK1.1-depleted BALB/c-NK1.1+ mice developed a progressive, nonhealing disease that was indistinguishable from wild-type mice. Upon infection, early induction of IL-4 mRNA in the lymph node was not affected in BALB/c-beta2m(o/o) and in NK1.1-depleted BALB/c-NK1.1+ mice, but was abrogated by injection of a CD4-depleting Ab. These data suggest that, in the lymph node, MHC class I-dependent CD4+NK1.1+ T cells do not play a major role in the generation of Th2 responses against L. major. To investigate whether the inability of NK1.1+ T cells to induce IL-4 production in the lymph node was specific to L. major Ag, mice were challenged with low doses of anti-CD3 Ab s.c. in the footpad. In contrast to the spleen, normal levels of IL-4 mRNA were expressed in the lymph nodes of BALB/c-beta2m(o/o) mice. Thus, the MHC class I-dependent CD4+NK1.1+ cell population that gives a rapid IL-4 response in the spleen appears not to contribute significantly to early induced IL-4 responses in the popliteal lymph nodes.


The ecology of cancer from an evolutionary game theory perspective.
The accumulation of somatic mutations, to which the cellular genome is permanently exposed, often leads to cancer. Analysis of any tumour shows that, besides the malignant cells, one finds other 'supporting' cells such as fibroblasts, immune cells of various types and even blood vessels. Together, these cells generate the microenvironment that enables the malignant cell population to grow and ultimately lead to disease. Therefore, understanding the dynamics of tumour growth and response to therapy is incomplete unless the interactions between the malignant cells and normal cells are investigated in the environment in which they take place. The complex interactions between cells in such an ecosystem result from the exchange of information in the form of cytokines- and adhesion-dependent interactions. Such processes impose costs and benefits to the participating cells that may be conveniently recast in the form of a game pay-off matrix. As a result, tumour progression and dynamics can be described in terms of evolutionary game theory (EGT), which provides a convenient framework in which to capture the frequency-dependent nature of ecosystem dynamics. Here, we provide a tutorial review of the central aspects of EGT, establishing a relation with the problem of cancer. Along the way, we also digress on fitness and of ways to compute it. Subsequently, we show how EGT can be applied to the study of the various manifestations and dynamics of multiple myeloma bone disease and its preceding condition known as monoclonal gammopathy of undetermined significance. We translate the complex biochemical signals into costs and benefits of different cell types, thus defining a game pay-off matrix. Then we use the well-known properties of the EGT equations to reduce the number of core parameters that characterize disease evolution. Finally, we provide an interpretation of these core parameters in terms of what their function is in the ecosystem we are describing and generate predictions on the type and timing of interventions that can alter the natural history of these two conditions.


Mechanisms of vascular damage in obstructive sleep apnea.
Obstructive sleep apnea (OSA) is characterized by repetitive apnea-hypopnea cycles during sleep, which are associated with oxygen desaturation and sleep disruption. Up to 30% of the adult population in Western countries are thought to be affected by asymptomatic OSA and approximately 2-4% by symptomatic OSA (also known as obstructive sleep apnea syndrome, or OSAS). Controlled trials have demonstrated that OSAS causes hypertension and prospective epidemiological studies have indicated that OSAS might be an independent risk factor for stroke and myocardial ischemia. Three biological mechanisms are thought to underpin the association of OSA with endothelial dysfunction and arterial disease: intermittent hypoxia leading to increased oxidative stress, systemic inflammation, and sympathetic activity; intrathoracic pressure changes leading to excessive mechanical stress on the heart and large artery walls; and arousal-induced reflex sympathetic activation with resultant repetitive blood-pressure rises. More clinical interventional trials are needed to determine the magnitude of the effect OSA has on cardiovascular damage and to enable a comparison with conventional vascular risk factors.