Compositional Persistence in a Multicyclic Network of Synthetic Replicators.
The emergence of collections of simple chemical entities that create self-sustaining reaction networks, embedding replication and catalysis, is cited as a potential mechanism for the appearance on the early Earth of systems that satisfy minimal definitions of life. In this work, a functional reaction network that creates and maintains a set of privileged replicator structures through auto- and cross-catalyzed reaction cycles is created from the pairwise combinations of four reagents. We show that the addition of individual preformed templates to this network, representing instructions to synthesize a specific replicator, induces changes in the output composition of the system that represent a network-level response. Further, we establish through sets of serial transfer experiments that the catalytic connections that exist between the four replicators in this network and the system-level behavior thereby encoded impose limits on the compositional variability that can be induced by repeated exposure to instructional inputs, in the form of preformed templates, to the system. The origin of this persistence is traced through kinetic simulations to the properties and inter-relationships between the critical ternary complexes formed by the auto- and crosscatalytic templates. These results demonstrate that in an environment where there is no continuous selection pressure the network connectivity, described by the catalytic relationships and system-level interactions between the replicators, is persistent, thereby limiting the ability of this network to adapt and evolve.


Complex Interactions Between Weather, and Microbial and Physicochemical Water Quality Impact the Likelihood of Detecting Foodborne Pathogens in Agricultural Water.
Agricultural water is an important source of foodborne pathogens on produce farms. Managing water-associated risks does not lend itself to one-size-fits-all approaches due to the heterogeneous nature of freshwater environments. To improve our ability to develop location-specific risk management practices, a study was conducted in two produce-growing regions to (i) characterize the relationship between Escherichia coli levels and pathogen presence in agricultural water, and (ii) identify environmental factors associated with pathogen detection. Three AZ and six NY waterways were sampled longitudinally using 10-L grab samples (GS) and 24-h Moore swabs (MS). Regression showed that the likelihood of Salmonella detection (Odds Ratio [OR] = 2.18), and eaeA-stx codetection (OR = 6.49) was significantly greater for MS compared to GS, while the likelihood of detecting L. monocytogenes was not. Regression also showed that eaeA-stx codetection in AZ (OR = 50.2) and NY (OR = 18.4), and Salmonella detection in AZ (OR = 4.4) were significantly associated with E. coli levels, while Salmonella detection in NY was not. Random forest analysis indicated that interactions between environmental factors (e.g., rainfall, temperature, turbidity) (i) were associated with likelihood of pathogen detection and (ii) mediated the relationship between E. coli levels and likelihood of pathogen detection. Our findings suggest that (i) environmental heterogeneity, including interactions between factors, affects microbial water quality, and (ii) E. coli levels alone may not be a suitable indicator of food safety risks. Instead, targeted methods that utilize environmental and microbial data (e.g., models that use turbidity and E. coli levels to predict when there is a high or low risk of surface water being contaminated by pathogens) are needed to assess and mitigate the food safety risks associated with preharvest water use. By identifying environmental factors associated with an increased likelihood of detecting pathogens in agricultural water, this study provides information that (i) can be used to assess when pathogen contamination of agricultural water is likely to occur, and (ii) facilitate development of targeted interventions for individual water sources, providing an alternative to existing one-size-fits-all approaches.


Active tuberculosis among homeless persons, Toronto, Ontario, Canada, 1998-2007.
While tuberculosis (TB) in Canadian cities is increasingly affecting foreign-born persons, homeless persons remain at high risk. To assess trends in TB, we studied all homeless persons in Toronto who had a diagnosis of active TB during 1998-2007. We compared Canada-born and foreign-born homeless persons and assessed changes over time. We identified 91 homeless persons with active TB; they typically had highly contagious, advanced disease, and 19% died within 12 months of diagnosis. The proportion of homeless persons who were foreign-born increased from 24% in 1998-2002 to 39% in 2003-2007. Among foreign-born homeless persons with TB, 56% of infections were caused by strains not known to circulate among homeless persons in Toronto. Only 2% of infections were resistant to first-line TB medications. The rise in foreign-born homeless persons with TB strains likely acquired overseas suggests that the risk for drug-resistant strains entering the homeless shelter system may be escalating.


Self-compassion and psychological well-being of radiographers at work.
The aim of this study was to assess how self-compassion affects the psychological well-being of radiographers at work. An online survey was sent to radiology and radiotherapy departments in Rhône-Alpes, a region of France (from October 2021 to February 2022). The study is mixed: quantitative data, with closed questions and two validated scales, and qualitative data, with open questions aimed at assessing perceptions among radiologists as regards self-compassion. A total of 253 radiographers (mean age 32.9 years), took part in this survey. Radiographers reported a poor level of well-being and a moderate level of self-compassion. We found a link between well-being at work and self-compassion. Gender, age, number of years of experience and the desire to receive training on well-being appear to have an impact on the level of self-compassion. The perception of self-compassion by radiologists is essentially positive. Particular attention should be paid to radiologists who are female, young, and with only a few years of experience. Self-compassion is a protective factor for radiologists and may help them take care of themselves to continue caring for others. Training related to self-compassion should be promoted in medical imaging departments.


Clinical Relevance of Single-Voxel (1)H MRS Metabolites in Discriminating Suprasellar Tumors.
Spatially resolved metabolic data obtained from Proton Magnetic Resonance Spectroscopy ((1)H MRS) provides information which increases the diagnostic accuracy of imaging sequences in predicting the histology of suprasellar tumors. To evaluate the role of (1)H MRS in the diagnosis of various suprasellar tumors. Sixty cases of various suprasellar, hypothalamic and third ventricular neoplasms were investigated with long-echo single voxel (1)H -MRS using 1.5 Tesla clinical imager. Single-voxel spectroscopic examinations were guided by T1-weighted or T2-weighted images. Statistical analysis was carried out using IBM SPSS software version 19. We observed that whenever brain tissue was damaged or replaced by any process, NAA was markedly reduced. Extra-axial lesions which do not infiltrate brain or contain neuroglial tissue, didn't demonstrate any NAA resonances. Cr was used as an internal standard for semi-quantitative evaluation of metabolic changes of other brain metabolites. Increased Cho was seen in processes with elevated cell-membrane turnover. Spectra obtained from different tumors exhibit reproducible differences while histologically similar tumors yield characteristic spectra with only minor differences. Pituitary tumors were typically characterized by significant reduction of NAA, Cr peak and moderate elevation of Cho peak. Gliomas were typically characterized by decrease of NAA and Cr peaks and increase of Cho peak. Craniopharyngiomas were typically characterized by significant decrease of all metabolites.


Effector mechanisms of nonsuppurative destructive cholangitis in graft-versus-host disease and allograft rejection.
The biliary epithelium provides a physical barrier to ascending infection from the gastrointestinal tract and is also involved in actively regulating the immune response to invading pathogens. Cholangiocytes secrete chemokines and express adhesion molecules that attract effector leukocytes and promote the clearance of infected cells. However in the context of transplantation these properties make cholangiocytes targets for allogeneic cytotoxic T cells, and both graft-versus-host disease and liver allograft rejection are characterized by destruction of intrahepatic bile ducts by infiltrating lymphocytes. The mechanisms of cholangiocyte killing are complex but involve activation of apoptosis by the granzyme/perforin pathway and by activation of death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, most notably Fas. Fas-dependent apoptosis is carefully regulated by cooperative interactions with other TNF receptors, particularly CD40, that act to amplify autocrine and paracrine expression of Fas ligand and Fas-mediated killing. A better understanding of the molecular control of these processes may explain why bile duct loss continues despite conventional immunosuppression in the vanishing bile duct syndromes, and lead to novel therapies aimed at switching off the chronic inflammatory response and protecting cholangiocytes from apoptosis.


Recovery of herpes simplex virus from the corneas of experimentally infected rabbits.
Rabbits were inoculated in the left cornea with one of three strains of herpes simplex virus (HSV) i.e. HSV-1 strain 17, HSV-1 strain McKrae, HSV-2 strain HG52, or with and HSV-1 McKrae/HSV-2 HG52 recombinant R40/2. Fifty-nine to 67 days after inoculation trigeminal ganglia and corneas were explanted and screened for release of infectious virus. Virus was isolated from all left trigeminal ganglia after organ culture irrespective of viral strain. Virus was isolated from three of 16 corneas of animals inoculated with HSV-1 strain McKrae and from one of four corneas from animals inoculated with the HSV-1/HSV-2 recombinant. The isolation of HSV from explanted corneas, after between 15 and 35 days in organ culture suggests that the cornea may be a site additional to dorsal root ganglia where latent HSV can reside in rabbits.


Accumulation of plasma cells in inflamed sites: effects of antigen, nonspecific microbial activators, and chronic inflammation.
Plasma cells are common in chronically inflamed sites, including periodontal lesions. The aim of this study was to determine which factors contribute to this local accumulation of plasma cells. Specifically, we sought to evaluate the effects of specific antigen and nonspecific activators from an infectious agent associated with chronic inflammation (Fusobacterium nucleatum, an organism prominent in chronic periodontal lesions) and the effect of the chronic inflammation itself. Chronic inflammation (14 to 17 days) was induced in horseradish peroxidase (HRP)-immune rabbits by subcutaneous injection of 50 microliters of sterile alum in several sites in their backs. Controls included sites injected with saline or more acute sites examined after 3 days of alum inflammation. Sites were challenged with HRP (the antigen), sonicated F. nucleatum (the nonspecific activator), or both together to see whether F. nucleatum has an adjuvant effect. Three days after challenge, HRP-specific antibody-forming cells (AFC) were enumerated after peroxidase histochemistry. In noninflamed sites or sites with acute inflammation, virtually no HRP-specific AFC were evident. In contrast, chronic inflammation alone was sufficient to elicit a specific AFC response (congruent to 10 cells per mm2). Addition of either F. nucleatum or HRP to the chronic lesion about doubled the number of HRP-specific AFC. However, a dramatic 8- to 15-fold (80 to 150/mm2) increase was seen in chronically inflamed sites challenged with antigen and activator together. Interestingly, the activator did not have this adjuvant effect in the acute sites or in normal skin. In short, accumulation of plasma cells in inflamed sites is promoted by chronic inflammation, activators of microbial origin, and specific antigen. This milieu can be expected to develop in some periodontal lesions and could help explain why gingival crevicular fluid from some sites may contain extraordinary levels of locally produced specific antibodies for certain antigens.


New phylogenetic perspectives on the Cervidae (Artiodactyla) are provided by the mitochondrial cytochrome b gene.
The entire mitochondrial cytochrome b (cyt b) gene was compared for 11 species of the artiodactyl family Cervidae, representing all living subfamilies, i.e., the antlered Cervinae (Cervus elaphus, C. nippon, Dama dama), Muntiacinae (Muntiacus reevesi), and Odocoileinae (Odocoileus hemionus, Mazama sp., Capreolus capreolus, C. pygargus, Rangifer tarandus, Alces alces); and the antlerless Hydropotinae (Hydropotes inermis). Phylogenetic analyses using Tragulidae, Antilocapridae, Giraffidae and Bovidae as outgroups provide evidence for three multifurcating principal clades within the monophyletic family Cervidae. First, Cervinae and Muntiacus are joined in a moderately-to-strongly supported clade of Eurasian species. Second, Old World Odocoileinae (Capreolus and Hydropotes) associate with the Holarctic Alces. Third, New World Odocoileinae (Mazama and Odocoileus) cluster with the Holarctic Rangifer. The combination of mitochondrial cyt b and nuclear k-casein sequences increases the robustness of these three clades. The Odocoileini + Rangiferini clade is unambiguously supported by a unique derived cranial feature, the expansion of the vomer which divides the choana. Contrasting with current taxonomy, Hydropotes is not the sister group of all the antlered deers, but it is nested within the Odocoileinae. Therefore, Hydropotes lost the antlers secondarily. Thus, the mitochondrial cyt b phylogeny splits Cervidae according to plesiometacarpal (Cervinae + Muntiacinae) versus telemetacarpal (Odocoileinae + Hydropotinae) conditions, and suggests paraphyly of antlered deer.


The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Organization, Objectives, and Activities.
BACKGROUND: Despite advances in neuro-imaging, neurosurgery, radiation therapy, and chemotherapy, limited progress has been made in the treatment of patients with high-grade astrocytomas. The National Cancer Institute has attempted to speed advances in this field by funding CNS consortia to conduct innovative clinical trials in this patient population since 1994. METHODS: The NABTT CNS Consortium is composed of a consortium headquarters and nine member institutions with outstanding multidisciplinary expertise, clinical and laboratory research capabilities, and access to large numbers of patients with brain tumors. RESULTS: The objectives of the NABTT Consortium are to improve the therapeutic outcome for adults with primary brain tumors, to conduct basic science and clinical research, and to improve the care and quality of life of adults with primary brain tumors. NABTT's clinical studies have discovered important drug interactions between anticonvulsant and antineoplastic agents, defined the activity of paclitaxel and 9-aminocamptothecin in glioblastoma multiforme, tested a novel dose escalation strategy for brain tumor trials, and established new protocol "classes" to expedite and standardize clinical research in this field. CONCLUSIONS: Significant progress in the care of patients with primary brain tumors is likely to result from the highly focused and multidisciplinary efforts of the NIH-funded CNS consortia.


Bufalin targeting CAMKK2 inhibits the occurrence and development of intrahepatic cholangiocarcinoma through Wnt/β-catenin signal pathway.
Intrahepatic cholangiocarcinoma (ICC) accounts for about 15% of primary liver cancer, and the incidence rate has been rising in recent years. Surgical resection is the best treatment for ICC, but the 5-year survival rate is less than 30%. ICC signature genes are crucial for the early diagnosis of ICC, so it is especially important to find its signature genes and therapeutic drug. Here, we studied that bufalin targeting CAMKK2 promotes mitochondrial dysfunction and inhibits the occurrence and metastasis of intrahepatic cholangiocarcinoma through Wnt/β-catenin signal pathway. IC50 of bufalin in ICC cells was determined by CCK8 and invasive and migratory abilities were verified by wound healing, cell cloning, transwell and Western blot. IF and IHC verified the expression of CAMKK2 between ICC patients and normal subjects. BLI and pull-down demonstrated the binding ability of bufalin and CAMKK2. Bioinformatics predicted whether CAMKK2 was related to the Wnt/β-catenin pathway. SKL2001, an activator of β-catenin, verified whether bufalin acted through this pathway. In vitro and in vivo experiments verified whether overexpression of CAMKK2 affects the proliferative and migratory effects of ICC. Transmission electron microscopy verified mitochondrial integrity. Associated Ca2+ levels verified the biological effects of ANXA2 on ICC. It was found that bufalin inhibited the proliferation and migration of ICC, and CAMKK2 was highly expressed in ICC, and its high expression was positively correlated with poor prognosis.CAMKK2 is a direct target of bufalin, and is associated with the Wnt/β-catenin signaling pathway, which was dose-dependently decreased after bufalin treatment. In vitro and in vivo experiments verified that CAMKK2 overexpression promoted ICC proliferation and migration, and bufalin reversed this effect. CAMKK2 was associated with Ca2+, and changes in Ca2+ content induced changes in the protein content of ANXA2, which was dose-dependently decreasing in cytoplasmic ANXA2 and dose-dependently increasing in mitochondrial ANXA2 after bufalin treatment. In CAMKK2 overexpressing cells, ANXA2 was knocked down, and we found that reversal of CAMKK2 overexpression-induced enhancement of ICC proliferation and migration after siANXA2. Our results suggest that bufalin targeting CAMKK2 promotes mitochondrial dysfunction and inhibits the proliferation and migration of intrahepatic cholangiocarcinoma through Wnt/β-catenin signal pathway. Thus, bufalin, as a drug, may also be used for cancer therapy in ICC in the future.


Australian dermatologists' prescribing behaviours for male androgenetic alopecia.
Androgenetic alopecia (AGA) is highly prevalent among Australian men and can have significant psychological impacts. Despite its prevalence, treatment options have traditionally been limited. In this study, we examined the current prescribing patterns of Australian dermatologists for male AGA.


Purkinje cell-specific ablation of Cav2.1 channels is sufficient to cause cerebellar ataxia in mice.
The Cacna1a gene encodes the α(1A) subunit of voltage-gated Ca(V)2.1 Ca(2+) channels that are involved in neurotransmission at central synapses. Ca(V)2.1-α(1)-knockout (α1KO) mice, which lack Ca(V)2.1 channels in all neurons, have a very severe phenotype of cerebellar ataxia and dystonia, and usually die around postnatal day 20. This early lethality, combined with the wide expression of Ca(V)2.1 channels throughout the cerebellar cortex and nuclei, prohibited determination of the contribution of particular cerebellar cell types to the development of the severe neurobiological phenotype in Cacna1a mutant mice. Here, we crossed conditional Cacna1a mice with transgenic mice expressing Cre recombinase, driven by the Purkinje cell-specific Pcp2 promoter, to specifically ablate the Ca(V)2.1-α(1A) subunit and thereby Ca(V)2.1 channels in Purkinje cells. Purkinje cell Ca(V)2.1-α(1A)-knockout (PCα1KO) mice aged without difficulties, rescuing the lethal phenotype seen in α1KO mice. PCα1KO mice exhibited cerebellar ataxia starting around P12, much earlier than the first signs of progressive Purkinje cell loss, which appears in these mice between P30 and P45. Secondary cell loss was observed in the granular and molecular layers of the cerebellum and the volume of all individual cerebellar nuclei was reduced. In this mouse model with a cell type-specific ablation of Ca(V)2.1 channels, we show that ablation of Ca(V)2.1 channels restricted to Purkinje cells is sufficient to cause cerebellar ataxia. We demonstrate that spatial ablation of Ca(V)2.1 channels may help in unraveling mechanisms of human disease.


Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin.
Particulate pollution is suspected to contribute to obstructive lung diseases characterized by chronic inflammation, mucus hypersecretion and bronchial remodeling. Our aim was to study the effect of real-world particulate matter (PM) on the expression of a mucin, MUC5AC, focusing on the role of the epidermal growth factor receptor (EGFR) pathway. MUC5AC induction was studied in vivo in mice trachea and in vitro in human bronchial epithelial cells (HBEC) exposed to urban fine PM. Fine PM were able to induce MUC5AC mRNA in mice trachea after 48 h of exposure (50 μg PM/mouse), and MUC5AC mRNA and protein in HBEC after 24 h of exposure (from 5 μg PM/cm(2)). It was associated with the increased expression of amphiregulin (AREG), an EGFR ligand. Experiments with conditioned media (media from PM-treated cells) demonstrated the involvement of AREG on MUC5AC induction as MUC5AC induction by media from PM-treated cells was prevented in the presence of either EGFR- or AREG-neutralizing antibodies. The effect of an inhibitor of a metalloprotease involved in the AREG shedding confirmed the autocrine loop made by AREG leading to MUC5AC induction by fine PM. We also demonstrated that IL-8 pro-inflammatory cytokine induction was dependent on the same autocrine mechanisms. We demonstrate for the first time that MUC5AC expression and production is increased by short-term exposure to fine PM through an autocrine effect of AREG. Our study provides mechanistic explanations to the exacerbation of obstructive lung diseases induced by particulate pollution characterized by mucus hypersecretion and chronic inflammation.


Discrimination of extended-spectrum beta-lactamases by a novel nitrocefin competition assay.
We describe a nitrocefin competition assay for determining inhibition profiles as a useful adjunct to existing biochemical methods for the discrimination of beta-lactamases. The hydrolysis rate of nitrocefin was measured with a plate photometer as the change in A480 over 45 min in the presence of 17 inhibitors. Fourteen well-established beta-lactamases and 13 extended-spectrum beta-lactamases were tested. Correlations with data from isoelectric focusing and amino acid sequencing suggested that the inhibition profile reflects alterations in the active-site configuration of beta-lactamases. The method was especially useful in measuring the relative affinities of beta-lactamases against poorly hydrolyzed substrates and in screening large numbers of isolates for the detection of new beta-lactamase types.


A New Electrospray Aerosol Generator with High Particle Transmission Efficiency.
A new single-capillary electrospray (ES) aerosol generator has been developed for monodisperse particle production with maximal transmission efficiency. The new generator consists of both a spray chamber in a point-to-orifice-plate configuration and a charge reduction chamber that can hold up to 4 Nuclespot ionizers (Model P-2042, NRD Inc.). The 2 chambers are partitioned by an orifice plate. To optimize the particle transmission efficiency of the prototype, a systematic study was performed on the generator by varying the system setup and operation. Two key dimensions of the generator setup, the orifice diameter and the distance from the capillary tip to the orifice plate, were varied. Fluorescence analysis was applied to characterize the loss of ES-generated particles at different locations of the prototype. It was found that particle loss in the generator could be reduced by either increasing the orifice diameter or decreasing the distance between the capillary tip and the orifice plate. Increasing either the total radioactivity of the ionizers or the flowrate of the particle carrier gas also further decreased the particle loss in the system. The maximum particle transmission efficiency of 88.0% was obtained with the spray chamber fully opened to the charge reduction chamber, the capillary tip at the same level as the orifice plate, and 4 bipolar ionizers installed.


Isotype switching increases efficacy of antibody protection against staphylococcal enterotoxin B-induced lethal shock and Staphylococcus aureus sepsis in mice.
Staphylococcal enterotoxin B (SEB) is a potent toxin that is produced by Staphylococcus aureus strains and is classified as a category B select agent. We have previously shown that monoclonal antibody (MAb) 20B1, a murine anti-SEB IgG1, successfully treats SEB-induced lethal shock (SEBILS) and bacteremia that is caused by SEB-producing S. aureus. In this study, we have generated two isotype switch variants of the original IgG1 MAb 20B1, an IgG2a and IgG2b, both bearing the same variable region sequence, and compared their neutralizing and protective activity in in vitro and in vivo assays, respectively. All 3 isotypes demonstrated comparable affinity to SEB and comparable 50% inhibitory concentrations (IC50s) in T cell proliferation assays. In vivo, however, the IgG2a isotype variant of 20B1 exhibited significantly greater protection than IgG1 or IgG2b in murine SEB intoxication and S. aureus sepsis models. Protection was associated with downmodulation of inflammatory host response. Our data demonstrate that changing the isotype of already protective MAbs, without affecting their antigen specificity or sensitivity, can result in an enhancement of their protective ability. Isotype selection, therefore, should be carefully considered in the development of toxin-neutralizing MAbs and the design of antibody therapeutics. The purpose of this study was to enhance the protective efficacy of an existing, protective monoclonal antibody against staphylococcal enterotoxin B. Using two in vivo mouse models, our study demonstrates that the protective efficacy of a monoclonal antibody may be improved by inducing an isotype switch at the Fc region of an antibody, without altering the antigen specificity or sensitivity of the antibody. The development of therapeutic MAbs with higher efficacy may allow for the achievement of equal therapeutic benefit with a lower dosage. In turn, the use of lower doses may reduce the cost of these therapies, while reducing the potential for adverse side effects.


A randomized controlled trial of an adapted Illness Management and Recovery program for people with schizophrenia awaiting discharge from a psychiatric hospital.
Most research on the Illness Management and Recovery (IMR) program for people with severe mental illnesses has focused on individuals with stable symptoms living in the community, with less attention to persons being treated in an inpatient setting. We evaluated the feasibility and effects of an IMR program adapted for individuals with schizophrenia who were awaiting discharge into the community. A randomized controlled trial was conducted at 2 hospitals in Taiwan to compare the adapted IMR program with treatment as usual (TAU). Ninety-seven individuals with schizophrenia were randomized to the adapted IMR program or TAU. Four outcome indicators including illness-management knowledge, attitudes toward medication, insight, and symptoms were assessed at baseline, posttreatment, and at a 1-month follow-up following discharge from the hospital. Participants in the adapted IMR group showed significantly greater improvements at posttreatment and 1-month follow-up in illness-management knowledge, attitudes toward medication, insight, and negative symptoms on the Brief Psychiatric Rating Scale (BPRS) than individuals in the TAU group. There were no significant differences between the 2 groups on other subscales of the BPRS. This is the first controlled evaluation of a version of the IMR program in an East Asian culture, and the first to evaluate it in an acute care inpatient setting. Our findings support the feasibility and potential benefits of implementing an adapted IMR program, focused on the prevention of relapses and rehospitalizations, during the discharge period of an inpatient treatment stay to prepare individuals to reenter the community.


Chronic mucocutaneous candidiasis - an immunological mystery.
Chronic mucocutaneous candidiasis (CMC) refers to a group of disorders which have in common recurrent and persistent infections of the skin, nails and mucous membranes by Candida albicans and occasionally other candida species. A proportion of these patients show an associated endocrinopathy as part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. Many cases, however, are not associated with endocrinopathy and demonstrate a variety of T-cell or antigen-presenting cell defects leading to abnormal cell-mediated responses to C. albicans.


Modeling timelines for translational science in cancer; the impact of technological maturation.
This work examines translational science in cancer based on theories of innovation that posit a relationship between the maturation of technologies and their capacity to generate successful products. We examined the growth of technologies associated with 138 anticancer drugs using an analytical model that identifies the point of initiation of exponential growth and the point at which growth slows as the technology becomes established. Approval of targeted and biological products corresponded with technological maturation, with first approval averaging 14 years after the established point and 44 years after initiation of associated technologies. The lag in cancer drug approvals after the increases in cancer funding and dramatic scientific advances of the 1970s thus reflects predictable timelines of technology maturation. Analytical models of technological maturation may be used for technological forecasting to guide more efficient translation of scientific discoveries into cures.


Her versus his migraine: multiple sex differences in brain function and structure.
Migraine is twice as common in females as in males, but the mechanisms behind this difference are still poorly understood. We used high-field magnetic resonance imaging in male and female age-matched interictal (migraine free) migraineurs and matched healthy controls to determine alterations in brain structure. Female migraineurs had thicker posterior insula and precuneus cortices compared with male migraineurs and healthy controls of both sexes. Furthermore, evaluation of functional responses to heat within the migraine groups indicated concurrent functional differences in male and female migraineurs and a sex-specific pattern of functional connectivity of these two regions with the rest of the brain. The results support the notion of a 'sex phenotype' in migraine and indicate that brains are differentially affected by migraine in females compared with males. Furthermore, the results also support the notion that sex differences involve both brain structure as well as functional circuits, in that emotional circuitry compared with sensory processing appears involved to a greater degree in female than male migraineurs.


Continuous-scale physical functional performance in healthy older adults: a validation study.
The continuous-scale physical functional performance test (CS-PFP) is an original instrument designed to provide a comprehensive, in-depth measure of physical function that reflects abilities in several separate physical domains. It is based on a concept of physical function as the integration of physiological capacity, physical performance, and psychosocial factors. The test was administered under standard conditions in a hospital facility with a neighborhood setting. The CS-PFP consists of a battery of 15 everyday tasks, ranging from easy to demanding, that sample the physical domains of upper and lower body strength, upper body flexibility, balance and coordination, and endurance. Participants are told to work safely but at maximal effort, and physical functional performance was measured as weight, time, or distance. Scores were standardized and scaled 0 to 12. The test yields a total score and separate physical domain scores. The CS-PFP was evaluated using 148 older adults-78 community dwellers, 31 long-term care facility residents living independently, and 39 residents with some dependence. Maximal physical performance assessment included measures of maximal oxygen consumption (VO2max), isokinetic strength, range of motion, gait, and balance. Psychosocial factors were measured as self-defined health status using the Sickness Impact Profile (SIP), self-perceived function using the Health Survey (SF36), and Instrumental Activities of Daily Living (IADL). IADL scores were not significantly different among the groups. Test-retest correlations ranged from .84 to .97 and inter-rater reliability from .92 to .99 for the CS-PFP total and 5 domains. Internal consistency was high (Cronbach's alpha, .74 to .97). Both total and individual domain CS-PFP scores were significantly different for the three groups of study participants, increasing with higher levels of independence, supporting construct validity. CS-PFP domain scores were significantly correlated with measures of maximal physical performance (VO2max, strength, etc) and with physical but not emotional aspects of self-perceived function. The CS-PFP is a valid, reliable measure of physical function, applicable to a wide range of functional levels, and having minimal floor and ceiling effect. The total and physical domains may be used to evaluate, discriminate, and predict physical functional performance for both research and clinical purposes.


Somatotype of elite Italian gymnasts.
The somatotyping method is especially helpful in sports in which the body could directly influence the biomechanics of movements and the performance's results. The purpose of this study was to determine the somatotype of elite Italian gymnasts and to compare it in terms of competition levels. The sample comprised 64 elite gymnasts (42 females (F), somatotype 1.4-4.4-3.2; and 22 males (M), somatotype 1.6-6.3-2.1) belonging to the Italian National Artistic Gymnastic Team (2007) at different competition levels: Allieve, Junior, and Senior. Mean whole somatotypes, by competition levels, were not significantly different in both sexes (Female gymnasts: Allieve, 1.3-4.6-3.3; Junior, 1.3-4.2-3.6; Senior, 1.7-4.2-2.7; Male gymnasts: Junior, 1.5-6.3-2.5; Senior, 1.7-6.3-1.6). Male Junior gymnasts exhibited greater ectomorphy than Senior athletes (F1,20 = 7.75, p < 0.01). Compared to other elite athletes male and female gymnasts tend to be less endomorphic and more mesomorphic. This study highlighted the peculiarities of the somatotype of Italian elite gymnasts and their strong homogeneity, evident also from the low values of somatotype attitudinal mean (SAM). The results emphasize the need for a specific somatotype to reach an elite level in sport and the need to integrate the somatotype analysis between the scientific instruments for selecting talent also in artistic gymnastics.


[Parenteral nutrition in hematologic patients treated with hematopoietic stem cell transplantation].
The transplant of haematopoyetic parent cells is on common way of treating haematological neoplasias and other types of immunological and tumoural disorders. The aggressive nature of the treatment, leading to peculiar nutritional and metabolic conditions in these patients, as well as the notable incidence of complications, have meant that nutritional support is included in the therapeutic armoury. As in other clinical situations, we are currently able to go beyond merely ensuring the necessary nutritional support. We can also influence the progress of the illness by means of the provision of specific substrates which interfere in a positive manner with the disturbed intermediate metabolism. Even more, in some of these substrates we can find a nutrient drug action.


Hirschsprung's disease prevalence in Europe: a register based study.
Hirschsprung's disease is a congenital gut motility disorder, characterised by the absence of the enteric ganglion cells along the distal gut. The aim of this study was to describe the epidemiology of Hirschsprung's disease, including additional congenital anomalies, total prevalence, trends, and association with maternal age. Cases of Hirschsprung's disease delivered during 1980 to 2009 notified to 31 European Surveillance of Congenital Anomaly registers formed the population-based case-series. Prevalence rates and 95% confidence intervals were calculated as the number of cases per 10,000 births. Multilevel Poisson regression was performed to investigate trends in prevalence, geographical variation and the association with maternal age. There were 1,322 cases of Hirschsprung's disease among 12,146,210 births. The total prevalence was 1.09 (95% confidence interval, 1.03-1.15) per 10,000 births and there was a small but significant increase in prevalence over time (relative risk = 1.01; 95% credible interval, 1.00-1.02; p = 0.004). There was evidence of geographical heterogeneity in prevalence (p < 0.001). Excluding 146 (11.0%) cases with chromosomal anomalies or genetic syndromes, there were 1,176 cases (prevalence = 0.97; 95% confidence interval, 0.91-1.03 per 10,000 births), of which 137 (11.6%) had major structural anomalies. There was no evidence of a significant increased risk of Hirschsprung's disease in cases born to women aged ≥35 years compared with those aged 25 to 29 (relative risk = 1.09; 95% credible interval, 0.91-1.31; p = 0.355). This large population-based study found evidence of a small increasing trend in Hirschsprung's disease and differences in prevalence by geographic location. There was also no evidence of an association with maternal age.


Energy expenditure and exercise intensity of interactive video gaming in individuals poststroke.
Off-the-shelf activity-promoting video games (AVGs) are proposed as a tool for promoting regular physical activity among individuals poststroke. To characterize the energy expenditure (EE), exercise intensity, and energy metabolism of individuals poststroke, while playing AVGs in different positions, from different consoles, and to compare the performance with comfortable walking and with able-bodied individuals. Eleven poststroke and 8 able-bodied participants played in standing Wii-Boxing Xbox-Boxing, Wii-Run and Penguin, and also Wii-Boxing in sitting. EE (expressed as metabolic equivalents [METs]); exercise intensity (expressed as %predicted maximal heart rate [HR]), rate of perceived exertion (RPE), and respiratory exchange ratio (RER) were used to characterize the games. Participants' poststroke EE ranged from 1.81 ± 0.74 to 3.46 ± 1.3 METs and was lower compared with able-bodied participants for Xbox-Boxing (P = .001), Wii-Boxing in standing (P = .01), Run (P < .001), and Penguin (P = .001). Participants' poststroke exercise intensity ranged from 49.8 ± 9.3 to 64.7 ± 9.3 %predicted maximal HR and was lower compared with able-bodied participants for Xbox-Boxing (P = .007) and Run (P = .005). For participants poststroke, EE of walking at a comfortable did not differ from boxing games in standing or Run. For able-bodied participants only, the EE for Xbox-Boxing was higher than Wii-Boxing (6.5 ± 2.6 vs 4.4 ± 1.1, P = .02). EE was higher in standing versus sitting for poststroke (P = .04) and able-bodied (P = .03) participants. There were no significant group differences for RPEs. RER of playing in sitting approached anaerobic metabolism. Playing upper extremity (ie, Boxing) or mobility (ie, Run) AVGs in standing resulted in moderate EE and intensity for participants poststroke. EE was lower for poststroke than for able-bodied participants.


Influence of thermal balance on cold-induced vasodilation.
We examined the effect of thermal balance perturbation on cold-induced vasodilation through a dynamic A-B-A-B design applying heat (condition A) and cold (condition B) to the body's core, while the hand is exposed to a stable cold stimulus. Fifteen healthy adults (8 men, 7 women) volunteered. Applications of heat and cold were achieved through water immersions in two tanks maintained at 42 and 12 degrees C water temperature, respectively, in an A-B-A-B fashion. Throughout the experiment, the participants' right hand up to the ulnar styloid process was placed inside a temperature-controlled box set at 0 degrees C air temperature. Results demonstrated that cold-induced vasodilation occurred only during condition B and at times when body heat content was decreasing but rectal temperature had not yet dropped to baseline levels. Following the occurrence of all cold-induced vasodilation events, rectal temperature was reduced, and the phenomenon ceased when rectal temperature fell below baseline. Heart rate variability data obtained before and during cold-induced vasodilation demonstrated a shift of autonomic interaction toward parasympathetic dominance, which, however, was attributed to a sympathetic withdrawal. Receiver operating characteristics curve analyses demonstrated that the cold-induced vasodilation onset cutoff points for rectal temperature change and finger temperature were 0.62 and 16.76 degrees C, respectively. It is concluded that cold-induced vasodilation is a centrally originating phenomenon caused by sympathetic vasoconstrictor withdrawal. It is dependent on excess heat, and it may be triggered by excess heat with the purpose of preserving thermal balance.


Dynamic and cellular interactions of nanoparticles in vascular-targeted drug delivery (review).
Vascular-targeted drug delivery systems could provide more efficient and effective pharmaceutical interventions for treating a variety of diseases including cardiovascular, pulmonary, inflammatory, and malignant disorders. However, several factors must be taken into account when designing these systems. The diverse blood hemodynamics and rheology, and the natural clearance process that tend to decrease the circulation time of foreign particles all lessen the probability of successful carrier interaction with the vascular wall. An effective vascular-targeted drug delivery system must be able to navigate through the bloodstream while avoiding immune clearance, attach to the vascular wall, and release its therapeutic cargo at the intended location. This review will summarize and analyze current literature reporting on (1) nanocarrier fabrication methods and materials that allow for optimum therapeutic encapsulation, protection, and release; (2) localization and binding dynamics of nanocarriers as influenced by hemodynamics and blood rheology in medium-to-large vessels; (3) blood cells' responses to various types of nanocarrier compositions and its effects on particle circulation time; and (4) properties that affect nanocarrier internalization at the target site.


Induction with sevoflurane-remifentanil is comparable to propofol-fentanyl-rocuronium in PONV after laparoscopic surgery.
To compare sevoflurane-remifentanil induction and propofol-fentanyl-rocuronium induction with regards to the frequency of moderate to severe postoperative nausea and vomiting (PONV) in the first 24 hr after laparoscopic day surgery. After informed consent, 156 ASA physical status class I to III patients undergoing laparoscopic cholecystectomy or tubal ligation were randomized to either induction with sevoflurane 8%, N(2)O 67% and iv remifentanil 1 to 1.5 microg.kg(-1) or induction with iv fentanyl 2 to 3 microg.kg(-1), propofol 2 mg.kg(-1), and rocuronium 0.3 to 0.5 mg.kg(-1). All patients received iv ketorolac 0.5 mg.kg(-1) at induction and sevoflurane-N(2)O maintenance anesthesia with rocuronium as needed. PONV was treated with iv ondansetron, droperidol, or dimenhydrinate; postoperative pain was treated with opioid analgesics. Patients were followed for 24 hr with regards to PONV and pain. Intubating conditions, induction and emergence times, time to achieve fast-track discharge criteria, and drug costs were measured. No differences were seen between the two groups in their frequencies of 24-hr moderate to severe PONV and postoperative pain, or in their intubating conditions, induction and emergence times, and time to achieve fast-track discharge criteria. Patients undergoing sevoflurane-remifentanil induction received more morphine (11 mg vs 8 mg; P < 0.001) in the postanesthetic care unit. Sevoflurane-remifentanil induction resulted in similar anesthetic and total drug costs for both procedures. We did not demonstrate any difference in PONV, pain, or anesthetic/recovery times or costs between the sevoflurane and propofol groups. Sevoflurane-remifentanil induction is a feasible technique for anesthetic induction.


[Some microcirculatory and metabolic changes of rat myocardium following coronary artery occlusion].
The experiments conducted on 50 albino male rats have shown that the increase of capillary metabolic surface area and capillary bed capacity detected 1-15 days after the coronary artery occlusion in the zones distant from necrotic focus, and resulting mainly from capillary dilation, correlated with the progressive reduction of lipid peroxidation intensity, decline in the necrotic focus area and in the activity of necrotic marker enzymes in blood serum. These changes were accompanied by a gradual increase in the activity of some enzymes and substrate content that characterize the myocardial energy supply. The changes detected could be regarded as a result of improvement of microcirculatory blood supply to the myocardium. while a prolonged (lasting for 15 days) increase of myocardial lipid peroxide content could reflect the natural reoxygenation arising from a collateral circulation development.


Glutamate transport and renal function.
Brush border gamma-glutamyltransferase-glutaminase activity and the high-affinity glutamate transporter EAAC1 function as a unit in generating and transporting extracellular glutamate into proximal tubules as a signal that modulates intracellular glutamine/glutamate metabolism, paracellular permeability, and urinary acidification. The reported presence of a second glutamate transporter, GLT1, on the antiluminal tubule surface points to specific functional roles for each subtype in physiological and pathophysiological processes.


Meningiomas may be a component tumor of multiple endocrine neoplasia type 1.
Recently, an increased incidence of some nonendocrine tumors are reported in patients with multiple endocrine neoplasia type 1 (MEN 1). There are rare reports of meningiomas and other central nervous system tumors in these patients, but it is unknown if they are more frequent or if allelic loss of the MEN1 gene is important in their pathogenesis. The aim of this study was to address these two latter questions. Results from a prospective study of 74 MEN 1 patients with suspected/proven pancreatic endocrine tumors (PETs) were analyzed, as well as molecular studies performed on a resected meningioma. All patients had serial brain imaging studies (computed tomography, magnetic resonance imaging, and octreoscanning since 1994) and yearly studies evaluating MEN 1 involvement with a mean follow-up of 7.2 years. Results were compared with 185 patients with sporadic Zollinger-Ellison syndrome. Six patients (8%) had meningiomas. Meningiomas were single and found late in the MEN 1 course (mean age = 51 years). Magnetic resonance imaging/computed tomography were more sensitive than octreoscanning. Their diagnosis averaged 18 years after the onset of hyperparathyroidism, 10-15 years after pituitary disease or PETs. Meningiomas were 11 times more frequent in patients with PETs with MEN 1 than without MEN 1 (P = 0.017). No clinical, laboratory, or MEN 1 feature distinguished patients with meningiomas. Meningiomas were asymptomatic and 60% showed no growth. A resected meningioma showed loss of heterozygosity at 11q13 and 1p, including at p73 and ARHI/NOEY2 locus, but not at the neurofibromatosis 2 gene locus. These results show meningiomas are not an infrequent occurrence in MEN 1, and loss of the function of the MEN1 gene product plays a role in their pathogenesis in these patients.


Nintendo wii sports and wii fit game analysis, validation, and application to stroke rehabilitation.
Interactive video gaming has become ubiquitous in the practice of rehabilitation. The Nintendo Wii is one such system. Interactive gaming can promote intensive task-based therapy in a manner that is motivating for the user. Widespread enthusiasm for consoles and their games prompted us to analyze the games for their rehabilitation elements related to improving balance and mobility for individuals poststroke. The purpose of this article is to provide a game analysis for clinical application and evaluation of the game elements for research on interactive video gaming. Using a team of game players and raters, 5 tables (1 for the Wii Sports and 4 for the Wii Fit) were developed and validated. The tables consist of 3 categories: game description, impairments targeted (strength, endurance, balance, and coordination), and feedback provided (knowledge of performance [KP] and knowledge of results [KR]). Two domain content experts established face validity. Construct validity was performed by 2 therapist-raters who had more than 15 years' clinical experience and postgraduate training in motor learning. Observations about the games including the fidelity of the interfaces, the nature of the feedback, and some of the challenges to adapting the games for rehabilitation are presented. An 80% agreement between raters set as the criterion for establishing the construct validity was met for feedback evaluation. There was 100% agreement on impairment ratings. Games provide a greater amount of KR compared with KP. Given the preponderance of KR, therapists will need to monitor motor performance. Adaptation of interactive video consoles for rehabilitation requires careful evaluation of the games' attributes using relevant rehabilitation construits.


Radiative and Nonradiative Recombination in CuInS2 Nanocrystals and CuInS2-Based Core/Shell Nanocrystals.
Luminescent copper indium sulfide (CIS) nanocrystals are a potential solution to the toxicity issues associated with Cd- and Pb-based nanocrystals. However, the development of high-quality CIS nanocrystals has been complicated by insufficient knowledge of the electronic structure and of the factors that lead to luminescence quenching. Here we investigate the exciton decay pathways in CIS nanocrystals using time-resolved photoluminescence and transient absorption spectroscopy. Core-only CIS nanocrystals with low quantum yield are compared to core/shell nanocrystals (CIS/ZnS and CIS/CdS) with higher quantum yield. Our measurements support the model of photoluminescence by radiative recombination of a conduction band electron with a localized hole. Moreover, we find that photoluminescence quenching in low-quantum-yield nanocrystals involves initially uncoupled decay pathways for the electron and hole. The electron decay pathway determines whether the exciton recombines radiatively or nonradiatively. The development of high-quality CIS nanocrystals should therefore focus on the elimination of electron traps.


Effects of Selected Resveratrol Analogues on Activation and Polarization of Lipopolysaccharide-Stimulated BV-2 Microglial Cells.
Increasing health-promoting effects of resveratrol and its molecular structural analogues have been discovered, and the acting mechanism has been explored. However, the activity comparison of such compounds in targeting macrophage-related inflammation associated with neurodegenerative diseases remains untouched. In this study, we evaluated the activation and polarization transition of lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial macrophages exposed to resveratrol (RES) and its analogues pterostilbene (PTE), oxyresveratrol (ORES), acetyl-trans-resveratrol (ARES), and trans-2,3,5,4'-tetrahydroxystilbene-2-O-glucopyranoside (TSG). At 10 μM, all of the five stilbene compounds have effectively suppressed the LPS-stimulated BV-2 cell release of proinflammatory mediators such as NO, TNF-α, iNOS, IL-1β, and IL-6. Mechanism study elucidated that they exert anti-inflammatory effects through MAPKs (ERK1/2, JNK, and p38) and NF-κB signaling pathways. Further investigation in treating BV-2 cells with resveratrol and its analogues revealed the reversal of LPS-induced phenotype molecules from M1 (iNOS, IL-1β, IL-6, and CD86) to M2 (Arg1, CD163, and IL-10) subtypes, manifesting that these five stilbenes suppressed inflammation through modulating the polarized phenotypes of BV-2 microglia. Most importantly, PTE demonstrated the most potent inhibitory activity among these five stilbene compounds. Therefore, this study not only highlights microglia-induced inflammatory responses as a potential therapeutic target but also suggests future insights in considering the options of nutraceutical development for resveratrol and its analogues.


Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis.
Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment. Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage. Previous studies have confirmed that tumor necrosis factor-stimulated gene-6 (TSG-6) can exert a neuroprotective effect by suppressing oxidative stress and apoptosis. However, no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage. In this study, a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method. Our results indicated that TSG-6 expression was predominantly detected in astrocytes, along with NLRC4 and gasdermin-D (GSDMD). The expression of NLRC4, GSDMD and its N-terminal domain (GSDMD-N), and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment. To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage, recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles. Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits. Moreover, TSG-6 knockdown further increased the expression of NLRC4, which was accompanied by more severe astrocyte pyroptosis. In summary, our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.


CATALYST trial protocol: a multicentre, open-label, phase II, multiarm trial for an early and accelerated evaluation of the potential treatments for COVID-19 in hospitalised adults.
Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. EudraCT2020-001684-89, ISRCTN40580903.


[A case of relapsing iridocyclitis in tropical malaria].
An African student developed bilateral relapsing iridocyclitis with increased intraocular pressure. General examinations and parasitological studies revealed tropical malaria. Etiotropic and local therapy normalized intraocular pressure and improved vision acuity of both eyes. This case should be borne in mind by general practitioners as a possibility of transportation of various tropical diseases.


Segregation of fluorescent membrane lipids into distinct micrometric domains: evidence for phase compartmentation of natural lipids?
We recently reported that sphingomyelin (SM) analogs substituted on the alkyl chain by various fluorophores (e.g. BODIPY) readily inserted at trace levels into the plasma membrane of living erythrocytes or CHO cells and spontaneously concentrated into micrometric domains. Despite sharing the same fluorescent ceramide backbone, BODIPY-SM domains segregated from similar domains labelled by BODIPY-D-e-lactosylceramide (D-e-LacCer) and depended on endogenous SM. We show here that BODIPY-SM further differed from BODIPY-D-e-LacCer or -glucosylceramide (GlcCer) domains in temperature dependence, propensity to excimer formation, association with a glycosylphosphatidylinositol (GPI)-anchored fluorescent protein reporter, and lateral diffusion by FRAP, thus demonstrating different lipid phases and boundaries. Whereas BODIPY-D-e-LacCer behaved like BODIPY-GlcCer, its artificial stereoisomer, BODIPY-L-t-LacCer, behaved like BODIPY- and NBD-phosphatidylcholine (PC). Surprisingly, these two PC analogs also formed micrometric patches yet preferably at low temperature, did not show excimer, never associated with the GPI reporter and showed major restriction to lateral diffusion when photobleached in large fields. This functional comparison supported a three-phase micrometric compartmentation, of decreasing order: BODIPY-GSLs > -SM > -PC (or artificial L-t-LacCer). Co-existence of three segregated compartments was further supported by double labelling experiments and was confirmed by additive occupancy, up to ∼70% cell surface coverage. Specific alterations of BODIPY-analogs domains by manipulation of corresponding endogenous sphingolipids suggested that distinct fluorescent lipid partition might reflect differential intrinsic propensity of endogenous membrane lipids to form large assemblies. We conclude that fluorescent membrane lipids spontaneously concentrate into distinct micrometric assemblies. We hypothesize that these might reflect preexisting compartmentation of endogenous PM lipids into non-overlapping domains of differential order: GSLs > SM > PC, resulting into differential self-adhesion of the two former, with exclusion of the latter.


Parasite-host ecology: the limited impacts of an intimate enemy on host microbiomes.
Impacts of biotic stressors, such as consumers, on coral microbiomes have gained attention as corals decline worldwide. Corallivore feeding can alter coral microbiomes in ways that contribute to dysbiosis, but feeding strategies are diverse - complicating generalizations about the nature of consumer impacts on coral microbiomes. In field experiments, feeding by Coralliophila violacea, a parasitic snail that suppresses coral growth, altered the microbiome of its host, Porites cylindrica, but these impacts were spatially constrained. Alterations in microbial community composition and variability were largely restricted to snail feeding scars; basal or distal areas ~ 1.5 cm or 6-8 cm away, respectively, were largely unaltered. Feeding scars were enriched in taxa common to stressed corals (e.g. Flavobacteriaceae, Rhodobacteraceae) and depauperate in putative beneficial symbionts (e.g. Endozoicomonadaceae) compared to locations that lacked feeding. Previous studies that assessed consumer impacts on coral microbiomes suggested that feeding disrupts microbial communities, potentially leading to dysbiosis, but those studies involved mobile corallivores that move across and among numerous individual hosts. Sedentary parasites like C. violacea that spend long intervals with individual hosts and are dependent on hosts for food and shelter may minimize damage to host microbiomes to assure continued host health and thus exploitation. More mobile consumers that forage across numerous hosts should not experience these constraints. Thus, stability or disruption of microbiomes on attacked corals may vary based on the foraging strategy of coral consumers.


Novel and emerging diabetes mellitus drug therapies for the type 2 diabetes patient.
Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of < 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucose cotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.


Evolution of the vertebrate DNMT3 gene family: a possible link between existence of DNMT3L and genomic imprinting.
DNA methylation plays an essential role in genomic imprinting observed in eutherian mammals and marsupials. In mouse, one of the two de novo DNA methyltransferases, Dnmt3a, and a related protein, Dnmt3L have been shown to be essential for imprint establishment in the parental germline. To gain insights into the evolution of imprinting mechanisms, we have identified and characterized the DNMT3 family genes in other vertebrate species. We cloned cDNAs for chicken DNMT3A and DNMT3B, whose putative protein products shared 81.5% and 48.6% amino acid sequence identity with their mouse orthologues. Using computer-assisted database searches, we also identified DNMT3A and DNMT3B orthologues in fish (fugu and zebrafish) and marsupials (opossum). We found that, while opossums had an orthologue for DNMT3L, chickens and fish did not have this gene. Thus, unlike the other DNMT3 members, DNMT3L was restricted to the species in which imprinting occurs. The acquisition of DNMT3L by a common ancestor of eutherians and marsupials might have been closely related to the evolution of imprinting.


Correlated responses to selection for postweaning gain in the rat.
Evidence for correlated responses to selection was investigated in lines of rats selected for 13 generations for high (U line) and low (D line) 3-9-week gain in comparison with random-bred control lines (R and C lines). The increase in 3-9-week gain in the U lines was shown to be due largely to an increase in 9-week weight, although 3-week weight also increased in these lines. In the D lines, where a marked decrease in 3-9-week gain was observed, this was found to be due to a large decrease in 9-week weight and no detectable change in 3-week weight. The average 2-week litter weight, a measure of the lactational performance of the dam, was significanly greater in the U lines than in the D lines. Selection for 3-9-week gain in these lines of rats led to changes of litter size at birth in the same direction as that of selection. This resulted in a significantly higher litter size in the U lines than in the D lines. The number of rats alive 2 and 9 weeks of age and the percentage of mated females pupping were similar in the U and D lines but lower in these lines than the random bred C lines, providing evidence for a reduction of "fitness" in the selected lines. Carcass composition was studied for all lines at the 11th generation of selection. Carcass composition, in terms of water, fat, ash and protein, was similar in the R and C lines. The U lines had more water and lesss fat than the R or C line. The D lines had similar carcass composition to the R and C lines. It is suggested that these selected and random-bred lines of rats are potentially useful animals to investigate further the developmental and physiological mechanisms which control growth.


Management practices to support donor transition: lessons from Avahan, the India AIDS Initiative.
During 2009-2012, Avahan, a large donor funded HIV/AIDS prevention program in India was transferred from donor support and operation to government. This transition of approximately 200 targeted interventions (TIs), occurred in three tranches in 2009, 2011 and 2012. This paper reports on the management practices pursued in support of a smooth transition of the program, and addresses the extent to which standard change management practices were employed, and were useful in supporting transition. We conducted structured surveys of a sample of 80 TIs from the 2011 and 2012 rounds of transition. One survey was administered directly before transition and the second survey 12 month after transition. These surveys assessed readiness for transition and practices post-transition. We also conducted 15 case studies of transitioning TIs from all three rounds, and re-visited 4 of these 1-3 years later. Considerable evolution in the nature of relationships between key actors was observed between transition rounds, moving from considerable mistrust and lack of collaboration in 2009 toward a shared vision of transition and mutually respectful relationships between Avahan and government in later transition rounds. Management practices also evolved with the gradual development of clear implementation plans, establishment of the post of "transition manager" at state and national levels, identified budgets to support transition, and a common minimum programme for transition. Staff engagement was important, and was carried out relatively effectively in later rounds. While the change management literature suggests short-term wins are important, this did not appear to be the case for Avahan, instead a difficult first round of transition seemed to signal the seriousness of intentions regarding transition. In the Avahan case a number of management practices supported a smooth transition these included: an extended and sequenced time frame for transition; co-ownership and planning of transition by both donor and government; detailed transition planning and close attention to program alignment, capacity development and communication; engagement of staff in the transition process; engagement of multiple stakeholders post transition to promote program accountability and provide financial support; signaling by actors in charge of transition that they were committed to specified time frames.


Characterization of wet-heat inactivation of single spores of bacillus species by dual-trap Raman spectroscopy and elastic light scattering.
Dual-trap laser tweezers Raman spectroscopy (LTRS) and elastic light scattering (ELS) were used to investigate dynamic processes during high-temperature treatment of individual spores of Bacillus cereus, Bacillus megaterium, and Bacillus subtilis in water. Major conclusions from these studies included the following. (i) After spores of all three species were added to water at 80 to 90 degrees C, the level of the 1:1 complex of Ca(2+) and dipicolinic acid (CaDPA; approximately 25% of the dry weight of the spore core) in individual spores remained relatively constant during a highly variable lag time (T(lag)), and then CaDPA was released within 1 to 2 min. (ii) The T(lag) values prior to rapid CaDPA release and thus the times for wet-heat killing of individual spores of all three species were very heterogeneous. (iii) The heterogeneity in kinetics of wet-heat killing of individual spores was not due to differences in the microscopic physical environments during heat treatment. (iv) During the wet-heat treatment of spores of all three species, spore protein denaturation largely but not completely accompanied rapid CaDPA release, as some changes in protein structure preceded rapid CaDPA release. (v) Changes in the ELS from individual spores of all three species were strongly correlated with the release of CaDPA. The ELS intensities of B. cereus and B. megaterium spores decreased gradually and reached minima at T(1) when approximately 80% of spore CaDPA was released, then increased rapidly until T(2) when full CaDPA release was complete, and then remained nearly constant. The ELS intensity of B. subtilis spores showed similar features, although the intensity changed minimally, if at all, prior to T(1). (vi) Carotenoids in B. megaterium spores' inner membranes exhibited two changes during heat treatment. First, the carotenoid's two Raman bands at 1,155 and 1,516 cm(-1) decreased rapidly to a low value and to zero, respectively, well before T(lag), and then the residual 1,155-cm(-1) band disappeared, in parallel with the rapid CaDPA release beginning at T(lag).


Biological membranes as bilayer couples. III. Compensatory shape changes induced in membranes.
We have previously proposed the hypothesis that asymmetric membranes behave like bilayer couples: the two layers of the bilayer membrane can respond differently to a particular perturbation. Such a perturbation, for example, can result in the expansion of one layer relative to the other, thereby producing a curvature of that membrane. In experiments with erythrocytes and lymphocytes, we now demonstrate that different membrane perturbations which have opposite effects on membrane curvature can compensate and neutralize one another, as expected from the bilayer couple hypothesis. This provides a rational basis, for example, for understanding the effects of amphipathic drugs on a variety of cellular phenomena which involve shape changes of membranes.


Visual and auditory cortical evoked potentials in interictal episodic migraine: An audit on 624 patients from three centres.
Background Many studies report a habituation deficit of visual evoked potentials (VEP) and/or increased intensity dependence of auditory evoked cortical potentials (IDAP) in episodic migraine patients between attacks. These findings have a pathophysiological interest, but their diagnostic utility is not known. Aims To perform an audit on a large database of interictal VEP and IDAP recordings in episodic migraine patients and evaluate their diagnostic accuracy. Methods We pooled data for VEP habituation and IDAP measured in 624 episodic migraineurs (EM) and 360 healthy volunteers (HV) from three centers. Thresholds were calculated by Receiver Operating Curve analysis and used to calculate sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and the accuracy of each test, using ICHD diagnostic criteria as the gold standard. Results In EM, VEP habituation was significantly lower than in HV, and IDAP slopes were significantly steeper. VEP (five blocks of 50 responses), VEP (six blocks of 100 responses) and IDAP had respectively 61.0%, 61.4% and 45.7% sensitivity, and 77.9%, 77.9% and 87.2% specificity. Their positive (LR+) and negative (LR-) likelihood ratios were respectively 2.760, 2.778, 3.570 and 0.500, 0.495, 0.623, with diagnostic accuracies of 65.3%, 69.0% and 54.3%. In combined VEP + IDAP recordings, an abnormality of at least one test had 83.4% sensitivity, 66.7% specificity, 2.504 LR+, 0.249 LR- and 81.1% accuracy. Conclusions In this large database, VEP habituation is significantly reduced and IDAP increased in episodic migraine patients between attacks. Taken alone, neither VEP nor IDAP has sufficient diagnostic accuracy. However, when both tests are performed in the same patient, an abnormality of at least one of them is highly predictive of interictal episodic migraine.


VvSUN may act in the auxin pathway to regulate fruit shape in grape.
Fruit shape is an essential agronomic feature in many crops. We identified and functionally characterized an auxin pathway-related gene, VvSUN. VvSUN, which belongs to the SUN/IQ67-DOMAIN (IQD) family, localizes to the plasma membrane and chloroplast and may be involved in controlling fruit shape through auxin. It is highly expressed in the ovary, and the expression level 1 week before the anthesis stage is positively correlated with the fruit shape index. Functional analyses illustrated that VvSUN gene overexpression in tomato and tobacco plants changed fruit/pod shape. The VvSUN promoter directly bound to VvARF6 in yeast and activated ß-glucuronidase (GUS) activity by indole-3-acetic acid (IAA) treatments in grapevine leaves, indicating that VvSUN functions are in coordination with auxin. Further analysis of 35S::VvSUN transgenic tomato ovaries showed that the fruit shape changes caused by VvSUN were predominantly caused by variations in cell number in longitudinal directions by regulating endogenous auxin levels via polar transport and/or auxin signal transduction process variations. Moreover, enrichment of the 35S::VvSUN transgenic tomato differentially expressed genes was found in a variety of biological processes, including primary metabolic process, transmembrane transport, calcium ion binding, cytoskeletal protein binding, tubulin binding, and microtubule-based movement. Using weighted gene co-expression network analysis (WGCNA), we confirmed that this plant hormone signal transduction may play a crucial role in controlling fruit shape. As a consequence, it is possible that VvSUN acts as a hub gene, altering cellular auxin levels and the plant hormone signal transduction pathway, which plays a role in cell division patterns, leading to anisotropic growth of the ovary and, ultimately, an elongated fruit shape.


Bacillus subtilis phage phi29. Characterization of gene products and functions.
A total of 22 phi29-induced proteins have been resolved by slab gel electrophoresis; two of these proteins are the precursor and product fragment, respectively, in the synthesis of the neck appendage protein of the phage. The protein products of 10 out of the 17 cistrons detected in the genome of phage phi29 have been identified. Mutants in two other cistrons fail to synthesize two proteins. Mutants in six genes do not synthesize phage DNA. A cistron, probably involved in the final lysis of the infected bacteria, has been found. Mutants in this gene give place, under restrictive conditions, to delayed lysis and produce, after artificial lysis, a burst size similar or higher than that obtained after wild-type phage infection.


Competency assessment for infection control in the undergraduate dental curriculum.
This study aimed at investigating the introduction of an infection control competency assessment on undergraduate dental student's awareness and knowledge of infection control. A short course, including an introductory lecture and a three component competency based assessment exercise testing student's knowledge and ability in infection control measures was incorporated into the previously established training programme. The assessment exercises included a written test of students' knowledge of the Infection Control Policy, a unit management exercise and a hand hygiene assessment. The infection control competency was initially incorporated into the final term of the second year in 2004 and is now an established part of the 5-year dental undergraduate degree programme. Re-assessments were scheduled (at the start of third year) for students failing to meet the required standard as successful completion of this course was compulsory prior to students being allowed to treat their first patients. Student performance over the last 2 years on this course and during their first year on clinic were analysed to determine potential improvements in student knowledge and application in infection control. Examination results from the year 3, infection control spot test were compared with those of earlier years. In addition, the opinions, as assessed by questionnaire analysis, of dental staff and students on the infection control competency were obtained. All students successfully completed the infection control competency (either at first or second attempt) and were subsequently allowed to enter clinical training in year 3. Significant improvements were seen in students passing the course at their initial attempt, 42% and 78%, in the 2004 and 2005 academic years, respectively. Also subsequent testing of these students during their first year on clinic showed marked increases in awareness and knowledge of the infection control protocols. Staff and student feedback on this course was also found to be highly supportive of the introduction of the infection control competency. Incorporation of additional formal pre-clinical teaching and introduction of an infection competency potentially provides enduring knowledge and clinical application benefits.


Does in-brace correction affect coronal spinal and thoracic cage parameters in individuals with idiopathic scoliosis? A retrospective cohort study.
The aim of the study is to identify the effects of in-brace correction on coronal spinal and thoracic cage parameters in individuals with idiopathic scoliosis (IS). The coronal spinal parameters [Cobb angle, apical vertebral rotation (AVR), lateral trunk shift, coronal alignment, biacromial slope and pelvic asymmetry] and the thoracic cage parameters [T1- 12 height, T1-S1 height, thoracic transverse diameter, and apical vertebral body-rib ratio (AVB-R)] of 89 child and adolescent patients were measured on posterior-anterior full-spine radiographs at pre-brace and in-brace conditions using Surgimap software. The initial in-brace correction (IBC) was calculated as a percentage decrease in the Cobb angle on the in-brace radiographs. The mean IBC rate for the primary curve was 37% (range = 10-100%). In the in- brace condition, the Cobb angle (p<0.001), AVR (p<0.001) and lateral trunk shift (p<0.001) decreased significantly; no statistically significant difference was found in the biacromial slope (p=0.713) and the coronal alignment (p=0.074). The T1-12 height and the T1-S1 height increased significantly (p<0.001) whereas the thoracic transverse diameter and the AVB-R decreased significantly (p<0.001). Unlike IBC rate was below 30% as IBC rate was above 30%, the T1-12 height (p<0.001) increased and the AVB-R decreased (p<0.001). The bracing improved the lateral trunk shift, the AVB-R, the thoracic and spine heights, but decreased the thoracic transverse diameter. The thoracic cage parameters may be better when the IBC rate is above 30%.


Learning Inverse Rig Mappings by Nonlinear Regression.
We present a framework to design inverse rig-functions-functions that map low level representations of a character's pose such as joint positions or surface geometry to the representation used by animators called the animation rig. Animators design scenes using an animation rig, a framework widely adopted in animation production which allows animators to design character poses and geometry via intuitive parameters and interfaces. Yet most state-of-the-art computer animation techniques control characters through raw, low level representations such as joint angles, joint positions, or vertex coordinates. This difference often stops the adoption of state-of-the-art techniques in animation production. Our framework solves this issue by learning a mapping between the low level representations of the pose and the animation rig. We use nonlinear regression techniques, learning from example animation sequences designed by the animators. When new motions are provided in the skeleton space, the learned mapping is used to estimate the rig controls that reproduce such a motion. We introduce two nonlinear functions for producing such a mapping: Gaussian process regression and feedforward neural networks. The appropriate solution depends on the nature of the rig and the amount of data available for training. We show our framework applied to various examples including articulated biped characters, quadruped characters, facial animation rigs, and deformable characters. With our system, animators have the freedom to apply any motion synthesis algorithm to arbitrary rigging and animation pipelines for immediate editing. This greatly improves the productivity of 3D animation, while retaining the flexibility and creativity of artistic input.


Ripple phases induced by alpha-tocopherol in saturated diacylphosphatidylcholines.
The effect of alpha-tocopherol on the structure and phase behavior of dilauroyl-, dimyristoyl-, dipalmitoyl-, and distearoyl-phosphatidylcholines was examined using X-ray diffraction and freeze-fracture electron microscopic methods. A ripple phase was observed in all of the mixtures at temperatures well below the pretransition temperature of the corresponding pure phospholipid. Freeze-fracture studies indicated that with proportion of alpha-tocopherol less than 5 mol% a ripple phase with large periodicity (50-150 nm) predominated and with about 10 mol% alpha-tocopherol a ripple phase of periodicity about 16 nm was formed. With more than 10 mol% alpha-tocopherol planar bilayers tended to be formed. Partial phase diagrams of mixed aqueous dispersions of saturated phosphatidylcholines and alpha-tocopherol over temperature ranges about the gel to liquid-crystal phase boundary have been constructed. Alpha-tocopherol-enriched domains form ripple phases that coexist with regions of lamellar gel phase of the pure phospholipid in mixtures containing less than 10 mol% alpha-tocopherol. The presence of increasing amounts of alpha-tocopherol in the phospholipid causes an increase in the proportion of ripple phase at the expense of pure phospholipid bilayer indicating that the alpha-tocopherol-enriched domains might possess a defined stoichiometry of the two constituents.


A Vietnamese man with selective mutism: the relevance of multiple interacting 'cultures' in clinical psychiatry.
Multiple cultural variables have effects on the psychobiology and behavioral manifestations of illness, as do patient and physician perceptions of illness. The interaction among these variables is at the heart of clinical psychiatry. This case of a Vietnamese man with selective mutism underscores the relevance of the 'cultures' of medicine, psychiatry, and war and trauma on the manifestations of illness and illness perceptions by patient and physician. The discussion focuses on how these cultures interact and play a crucial role in formulating diagnosis and treatment planning. Suggestions are given for shifts in medical education that will encourage relevant cultural paradigms to make their way into educational and clinical systems, which in turn should improve cultural competence in clinical psychiatry.


S1P1 and VEGFR-2 form a signaling complex with extracellularly regulated kinase 1/2 and protein kinase C-alpha regulating ML-1 thyroid carcinoma cell migration.
Sphingosine 1-phosphate (S1P) and vascular endothelial growth factor receptor 2 (VEGFR-2) signaling have been shown to integrate in many biological processes. The follicular thyroid carcinoma cell line ML-1 expresses VEGFR-2 and secretes substantial amounts of both vascular endothelial growth factor (VEGF)-A and VEGF-C. ML-1 cells also express S1P-receptors (S1P(1-3,5)). S1P is able to phosphorylate VEGFR-2, and inhibiting VEGFR-2 attenuates S1P-induced migration and down-regulates S1P(1) expression in ML-1 cells. In the present study, we focused on the interactions between S1P(1) and VEGFR-2. We show that S1P receptors form complexes with VEGFR-2 and that the S1P(1)/VEGFR-2 complex associates with protein kinase C (PKC)-alpha and ERK1/2. Furthermore, the complex evokes bidirectional signaling since the S1P-induced ERK1/2 phosphorylation is sensitive to VEGFR-2 kinase inhibition and VEGF-A-induced ERK1/2 phosphorylation is sensitive to pertussis toxin treatment as well as S1P(1) small interfering RNA (siRNA) treatment. Both S1P- and VEGF-A-induced haptotaxis is sensitive to pertussis toxin treatment and S1P(1) siRNA treatment. Phosphorylation of ERK1/2 evoked by both VEGF-A and the S1P(1) agonist SEW-2871 is inhibited by PKC-alpha and PKC-betaI siRNA. We hypothesize that VEGFR-2 forms a signaling complex with S1P(1), evoking bidirectional signaling regulating both ERK1/2 phosphorylation and haptotaxis of ML-1 cells.


Factors associated with health-related quality of life (HRQoL) deterioration in glioma patients during the progression-free survival period.
Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8-5.4 months, and median time-to-deterioration between 8.2-11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients' functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled.


Mitochondrial epilepsy in pediatric and adult patients.
Few data are available about the difference between epilepsy in pediatric mitochondrial disorders (MIDs) and adult MIDs. This review focuses on the differences between pediatric and adult mitochondrial epilepsy with regard to seizure type, seizure frequency, and underlying MID. A literature search via Pubmed using the keywords 'mitochondrial', 'epilepsy', 'seizures', 'adult', 'pediatric', and all MID acronyms, was carried out. Frequency of mitochondrial epilepsy strongly depends on the type of MID included and is higher in pediatric compared to adult patients. In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. In pediatric patients, mitochondrial epilepsy is associated with a syndromic phenotype in half of the patients and in adults more frequently with a non-syndromic phenotype. In pediatric patients, focal seizures are more frequent than generalized seizures and vice versa in adults. Electro-clinical syndromes are more frequent in pediatric MIDs compared to adult MIDs. Differences between pediatric and adult mitochondrial epilepsy concern the onset of epilepsy, frequency of epilepsy, seizure type, type of electro-clinical syndrome, frequency of syndromic versus non-syndromic MIDs, and the outcome. To optimize management of mitochondrial epilepsy, it is essential to differentiate between early and late-onset forms.


Unhappy (and happy) in their own way: a developmental psychopathology perspective on quality of life for families living with developmental disability with and without autism.
Research on families living with developmental disability generally and autism specifically is dominated by a deficit view that elicits an elaborate representation of problems and risks without the benefit of considering families' potential for adaptation and resilience. A central tenet of developmental psychopathology is that the study of adaptive and maladaptive development is mutually informative. Specifically, one can examine resilience within the context of adversity and the multiple processes and pathways to adaptive and maladaptive developmental outcomes. We believe these concepts can also be extended to the study of families living with developmental disability as they transition through the family lifecycle. This paper provides an overview of the family quality of life (FQOL) construct, including its conceptualization and measurement, and a review of studies on FQOL among families of children with various developmental disabilities. Special attention is given to families of children with autism, as this is a circumstance characterized by unique adversity. We suggest benefits from adopting a developmental psychopathology perspective, and illustrate how relevant concepts can inform our methodologies as we move forward. We will demonstrate how such an integrated, systemic, and temporal approach will help generate more refined questions on FQOL among families caring for a child with developmental disability in order to provide the specific answers needed to directly inform policy and clinical practice.


[Biotyping and molecular phenotypic characterization of Bordetella bronchiseptica].
In the present study biochemical tests and outer membrane protein profile (OMP) capacity for typing Bordetella bronchiseptica field isolates were evaluated. The biochemical tests were performed by API 20NE system. OMP enriched fractions were obtained from cultures under virulent and modulated conditions and were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). We have identified five patterns by differences in the bands in the 85-95 kDa region (alpha, beta, gamma, delta and epsilon) from virulent cultures; and three different patterns by the flagellin expressed isotype from modulated cultures (A: 40 kDa, B: 45 kDa, and C: 40 and 45 kD simultaneously). Isotypes alpha, beta and gamma were linked to isotpye A, isotype delta to B and C, and isotypes epsilon to B. There is no evident correlation between characterized isotypes and the origin of the isolate. Nitrate reduction was the unique variable biochemical characteristic, only observed in rabbit isolates. It was possible to differentiate seven groups with the traits included in the study. The capacity of discrimination of the traits analyzed using the Hunter and Gaston index was 0.829.


Fatty acid biosynthesis in Pseudomonas aeruginosa: cloning and characterization of the fabAB operon encoding beta-hydroxyacyl-acyl carrier protein dehydratase (FabA) and beta-ketoacyl-acyl carrier protein synthase I (FabB).
The Pseudomonas aeruginosa fabA and fabB genes, encoding beta-hydroxyacyl-acyl carrier protein dehydratase and beta-ketoacyl-acyl carrier protein synthase I, respectively, were cloned, sequenced, and expressed in Escherichia coli. Northern analysis demonstrated that fabA and fabB are cotranscribed and most probably form a fabAB operon. The FabA and FabB proteins were similar in size and amino acid composition to their counterparts from Escherichia coli and to the putative homologs from Haemophilus influenzae. Chromosomal fabA and fabB mutants were isolated; the mutants were auxotrophic for unsaturated fatty acids. A temperature-sensitive fabA mutant was obtained by site-directed mutagenesis of a single base that induced a G101D change; this mutant grew normally at 30 degrees C but not at 42 degrees C, unless the growth medium was supplemented with oleate. By physical and genetic mapping, the fabAB genes were localized between 3.45 and 3.6 Mbp on the 5.9-Mbp chromosome, which corresponds to the 58- to 59.5-min region of the genetic map.


Affinity maturation of leukemia inhibitory factor and conversion to potent antagonists of signaling.
Leukemia inhibitory factor (LIF)-induced cell signaling occurs following sequential binding to the LIF receptor alpha-chain (LIFR), then to the gp130 co-receptor used by all members of the interleukin-6 family of cytokines. By monovalently displaying human LIF on the surface of M13 phage and randomizing clusters of residues in regions predicted to be important for human LIFR binding, we have identified mutations, which lead to significant increases in affinity for binding to LIFR. Six libraries were constructed in which regions of 4-6 amino acids were randomized then panned against LIFR. Mutations identified in three distinct clusters, residues 53-57, 102-103, and 150-155, gave rise to proteins with significantly increased affinity for binding to both human and mouse LIFR. Combining the mutations for each of these regions further increased the affinity, such that the best mutants bound to human LIFR with >1000-fold higher affinity than wild-type human LIF. NMR analysis indicated that the mutations did not alter the overall structure of the molecule relative to the native protein, although some local changes occurred in the vicinity of the substituted residues. Despite increases in LIFR binding affinity, these mutants did not show any increase in activity as agonists of LIF-induced proliferation of Ba/F3 cells expressing human LIFR and gp130 compared with wild-type LIF. Incorporation of two additional mutations (Q29A and G124R), which were found to abrogate cell signaling, led to the generation of highly potent antagonists of both human and murine LIF-induced bioactivity.


Evaluation of a novel virtual screening strategy using receptor decoy binding sites.
Virtual screening is used in biomedical research to predict the binding affinity of a large set of small organic molecules to protein receptor targets. This report shows the development and evaluation of a novel yet straightforward attempt to improve this ranking in receptor-based molecular docking using a receptor-decoy strategy. This strategy includes defining a decoy binding site on the receptor and adjusting the ranking of the true binding-site virtual screen based on the decoy-site screen. The results show that by docking against a receptor-decoy site with Autodock Vina, improved Receiver Operator Characteristic Enrichment (ROCE) was achieved for 5 out of fifteen receptor targets investigated, when up to 15 % of a decoy site rank list was considered. No improved enrichment was seen for 7 targets, while for 3 targets the ROCE was reduced. The extent to which this strategy can effectively improve ligand prediction is dependent on the target receptor investigated.


Beyond multidisciplinary care: a new conceptual model for spina bifida services.
Medical care for people who are born with spina bifida (myelodysplasia) is complex and challenging, but the goal of such care is to optimize health and function for people with this condition. Despite years of expert agreement that multidisciplinary care is the medical standard for individuals with spina bifida, this model does not seem to go far enough towards accomplishing the goal of improved function as well as health for all people with spina bifida. Advances in the medical and surgical management of people with spina bifida and society's increased desire to include those with disabilities in family and community life has heightened our expectations for functional/participatory improvement for people with this condition. Some large spina bifida programs have added a separate rehabilitation component to the comprehensive package of services offered to people with spina bifida. The problem with adding further services to the traditional multidisciplinary spina bifida program is the increased complexity and potential for fragmentation that it presents, particularly for the patient and family. We performed a MEDLINE literature search to find information on integrating these services. Although several articles address the importance of either the multidisciplinary spina bifida clinic or a rehabilitation approach, there is little information about integration of medical and rehabilitation services. We propose a new model for spina bifida services throughout the lifespan that integrates the medical and functional/rehabilitative perspectives. Our model for conceptualizing spina bifida services builds on the WHO framework for coding disability (ICIDH-2). This framework includes not only health and functional perspectives, but a participation dimension as well. Furthermore, our new model emphasizes the importance of anticipatory guidance and transitional planning as an integrating dimension applicable across the lifespan. The model is based on three main conceptual dimensions--comprehensiveness, coordination and longitudinality. We are using the model to create standards of care, integrate services and improve their efficiency, and to develop policies regarding spina bifida services. Through this effort we hope to provide better medical and rehabilitation services to those with spina bifida and meet the complex challenge the condition presents throughout the lifespan.