A comparison of community-based and hospital-based head and neck cancer screening campaigns: identifying high-risk individuals and early disease.
An enduring challenge in the care of patients with head and neck cancer is identifying disease earlier. Appropriately designed screening campaigns are one proposed strategy. To determine whether a hospital-based or a community-based head and neck cancer (HNC) screening strategy is more effective in identifying high-risk individuals, signs and symptoms, and findings consistent with head and neck neoplasia. In this retrospective cohort analysis, data from HNC screening efforts held at a tertiary care medical center and at a local motorsports event were compared. Participants completed a questionnaire, and a focused physical examination was performed. Identification rates of high-risk individuals, signs and symptoms, and findings consistent with head and neck neoplasia. The hospital-based and community-based efforts yielded 210 and 1380 individuals screened, respectively. The community-based screening events attracted a significantly greater proportion of participants with risk factors of HNC including male sex (P < .001), current tobacco use (P < .001), lifetime history of tobacco use (P = .03), smokeless tobacco use (P = .003), and current alcohol use (P = .04). The hospital-based screening events, however, attracted a statistically greater proportion of people reporting prior head and neck or otolaryngologic treatment (P < .001), history of cancer outside the head and neck (P < .001), and a greater median number of symptoms (P < .001) and examination findings (P < .001). These data suggest that the 2 screening models attract 2 fundamentally different types of participants, and those in both groups may benefit from screening, albeit for different reasons: one has a higher rate of risk factors, and early-stage HNC might be discovered while it is more readily treatable; the other has a higher rate of concerning signs, symptoms, and findings, and screening might be used to diagnose or rule out HNC.


Timing and origin of natural gas accumulation in the Siljan impact structure, Sweden.
Fractured rocks of impact craters may be suitable hosts for deep microbial communities on Earth and potentially other terrestrial planets, yet direct evidence remains elusive. Here, we present a study of the largest crater of Europe, the Devonian Siljan structure, showing that impact structures can be important unexplored hosts for long-term deep microbial activity. Secondary carbonate minerals dated to 80 ± 5 to 22 ± 3 million years, and thus postdating the impact by more than 300 million years, have isotopic signatures revealing both microbial methanogenesis and anaerobic oxidation of methane in the bedrock. Hydrocarbons mobilized from matured shale source rocks were utilized by subsurface microorganisms, leading to accumulation of microbial methane mixed with a thermogenic and possibly a minor abiotic gas fraction beneath a sedimentary cap rock at the crater rim. These new insights into crater hosted gas accumulation and microbial activity have implications for understanding the astrobiological consequences of impacts.


Immunoprofile of mesenchymal chondrosarcoma: aberrant desmin and EMA expression, retention of INI1, and negative estrogen receptor in 22 female-predominant central nervous system and musculoskeletal cases.
Mesenchymal chondrosarcoma is a rare malignant tumor in the differential diagnosis of other small, round blue cell tumors, including atypical teratoid tumor in the central nervous system (CNS) and rhabdomyosarcoma in the musculoskeletal (MSK) locations. We reviewed the morphology of CNS and MSK cases and applied a panel of immunostains. Archival cases were pulled from our files. Immunohistochemistry and follow-up were obtained. Twenty-two cases included 5 CNS (all female; mean age, 30.2) and 17 MSK (11 female and 6 male; mean age, 31.1). Both CNS and MSK examples had similar round cells, staghorn vascular pattern, increased mitotic activity, and centrally located hyaline cartilage islands. The CNS examples demonstrated more spindling and the MSK cases more necrosis. INI1 was retained in all tumors studied. Epithelial membrane antigen (EMA) and desmin were expressed focally in 35% and 50% of cases, respectively. The round cells of all cases were negative for MyoD1, myogenin, smooth muscle actin (SMA), glial fibrillary acid protein (GFAP), keratins, and estrogen receptor, as well as a panel of other antiobodies. Eighty percent of patients with follow-up had pulmonary metastases and/or died within a mean of 5 years. The CNS and MSK mesenchymal chondrosarcoma predominantly affects adult females with poor prognosis. There are only subtle morphologic differences between the CNS and MSK groups. By immunohistochemistry, mesenchymal chondrosarcoma occasionally expresses aberrant desmin and EMA but is negative for SMA, myogenin MyoD1, GFAP, and keratins, refuting true smooth or skeletal muscle, epithelial, or meningothelial phenotype. Retained INI1 separates these tumors from atypical teratoid tumor. Despite marked female predominance in our series, estrogen receptor is negative in mesenchymal chondrosarcoma.


Interindividual variation in the response by fibrinogen, C-reactive protein and interleukin-6 to yellow fever vaccination.
The acute phase reaction is important in many disease processes. Habitual levels of the acute phase proteins fibrinogen, C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with an increased risk of cardiovascular disease, but the dynamic variation of plasma levels of acute phase proteins may be of importance as well. The aim of this study was to document the variation in response by fibrinogen, CRP and IL-6 levels to a mild inflammatory stimulus (yellow fever vaccination) in 25 healthy individuals. Plasma levels of fibrinogen, CRP and IL-6 were determined at baseline and 7 days after vaccination, and genetic polymorphisms in these genes were determined. After vaccination, fibrinogen levels had changed between -13 and +44% (P = 0.003), CRP levels between -88 and +672% (not significant), and IL-6 levels between -55 and +448% (not significant). Genetic variation partly explained the interindividual variation in response, as IL-6 -174G homozygotes showed a significantly stronger increase in CRP levels than IL-6 -174C allele carriers. In conclusion, this study suggests that a large interindividual variation exists in the acute phase response to yellow fever vaccination, indicating that individuals may be classified as hyper-responders or hypo-responders, and that genetic variation may influence the responsiveness of an individual.


[Instruction in dental radiology].
The diagnostic use of oral radiology is an essential part of daily dental practice. Due to the potentially harmful nature of ionising radiation, the clinical use of oral radiology in the Netherlands is framed by clinical practice guidelines and regulatory requirements. Undergraduate students receive intensive theoretical and practical training in practical and theoretical radiology, with the aim of obtaining the 'Eindtermen Stralingshygiëne voor Tandartsen en Orthodontisten'-certificate, which is required for legal permission to use oral radiology in dental practice. It is recommended that the curriculum be expanded to include the areas of knowledge required to qualify for the 'Eindtermen Stralingshygiëne voor het gebruik van CBCT-toestellen door tandartsen' (the certificate for the use of conebeam radiology by dentists). The general dental practitioner is faced with changing laws and regulations in all areas of practice. One of the most significant legal changes in the field of dental radiology was the introduction of the new radiation protection and safety rules in 2014. Moreover, a large group of dentists is also being confronted with the transition from conventional to digital images, with all its challenges and changes in everyday practice.


Voltage-dependent inhibition of Ca2+ channels in GH3 cells by cloned mu- and delta-opioid receptors.
To study cloned opioid receptor binding and modulation of both adenylyl cyclase and ion channel activity, we stably expressed mu- and delta-opioid receptors in the rodent pituitary-derived GH3 cell line. GH3 cells express G proteins and voltage-activated Ca2+ channels (predominantly of the L-type). Activation of cloned rat mu-opioid receptors expressed in GH3 cells (termed GH3MOR cells) inhibits L-type Ca2+ channel activity. GH3MOR cells, further transfected with mouse delta receptor cDNA (termed GH3MORDOR cells), bound both [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) and [D-Pen2,D-Pen5]enkephalin (DPDPE). These opioid ligands inhibited adenylyl cyclase activity (IC50 = 174 and 0.53 nM, respectively). This action of DAMGO and DPDPE was attenuated selectively by mu- and delta-opioid receptor-specific antagonists. Activation of both opioid receptors also led to inhibition of Ca2+ channel activity, measured with Ba2+ as the charge carrier using the whole-cell patch-clamp technique. Both DAMGO (1 microM) and DPDPE (1 microM) reversibly inhibited Ba2+ currents (by 17.0 +/- 1.4% and 20.7 +/- 1.3%, respectively) in GH3MORDOR cells. The inhibitory action of DPDPE was dose dependent (IC50 = 1.6 nM) and was attenuated by pretreatment with pertussis toxin (200 ng/ml) or by the inclusion of guanosine-5'-O-(2-thio)diphosphate (2 mM) in the recording electrode. Ba2+ current inhibitions by both DAMGO and DPDPE were completely reversed by depolarizing (to > 50 mV) prepulses in GH3MORDOR cells. In summary, cloned mu- and delta-opioid receptors expressed in GH3 cells voltage-dependently couple through Gi/G(o) proteins to L-type Ca2+ channels.


Control of intercellular communication by voltage dependence of gap junctional conductance.
The junctional conductance between coupled amphibian blastomeres exhibits a high degree of voltage dependence, as previously described in voltage clamp studies (Spray, D.C., A.L. Harris, and M.V.L. Bennett (1981) J. Gen. Physiol. 77: 77-95; Harris, A.L., D.C. Spray, and M.V.L. Bennett (1981) J. Gen. Physiol. 77: 95-117). The present study examines the properties which this voltage dependence confers on electrotonic coupling between cells. The effects of applied pulses and ramps of current are studied experimentally and are modeled by calculation. During sufficiently large current pulses applied to one cell of a pair, the cells uncouple and then recouple after termination of the pulses. Ramps of current applied to one of the cells can give voltage-current (V-I) relations with a region of hysteresis within which the cells are stably coupled or stably uncoupled depending on previous history. Intrinsically generated currents are able to cause bistability of coupling in the absence of externally applied current. Calculations from the parameters of junctional conductance defined under voltage clamp fully account for these findings and illustrate how junctional and nonjunctional conductances affect the V-I relations in the region of bistability. Recordings from several cells within a small group show that boundaries of intercellular communication can be altered by applied current, a finding that also can be accounted for by voltage dependence of junctional conductance. The "Appendix" examines quantitatively the criteria required for bistability of coupling and the relevance of bistability for intercellular signaling. The plasticity of coupling which the voltage dependence of junctional conductance confers on cells offers an intriguing mechanism by which patterns of intercellular communication could be determined and changed in developing tissues.


Linoleic acid induces metabolic stress in the intestinal microorganism Bifidobacterium breve DSM 20213.
Despite clinical and research interest in the health implications of the conjugation of linoleic acid (LA) by bifidobacteria, the detailed metabolic pathway and physiological reasons underlying the process remain unclear. This research aimed to investigate, at the molecular level, how LA affects the metabolism of Bifidobacterium breve DSM 20213 as a model for the well-known LA conjugation phenotype of this species. The mechanisms involved and the meaning of the metabolic changes caused by LA to B. breve DSM 20213 are unclear due to the lack of comprehensive information regarding the responses of B. breve DSM 20213 under different environmental conditions. Therefore, for the first time, an untargeted metabolomics-based approach was used to depict the main changes in the metabolic profiles of B. breve DSM 20213. Both supervised and unsupervised statistical methods applied to the untargeted metabolomic data allowed confirming the metabolic changes of B. breve DSM 20213 when exposed to LA. In particular, alterations to the amino-acid, carbohydrate and fatty-acid biosynthetic pathways were observed at the stationary phase of growth curve. Among others, significant up-regulation trends were detected for aromatic (such as tyrosine and tryptophan) and sulfur amino acids (i.e., methionine and cysteine). Besides confirming the conjugation of LA, metabolomics suggested a metabolic reprogramming during the whole growth curve and an imbalance in redox status following LA exposure. Such redox stress resulted in the down-accumulation of peroxide scavengers such as low-molecular-weight thiols (glutathione- and mycothiol-related compounds) and ascorbate precursors, together with the up-accumulation of oxidized (hydroxy- and epoxy-derivatives) forms of fatty acids. Consistently, growth was reduced and the levels of the oxidative stress marker malondialdehyde were higher in LA-exposed B. breve DSM 20213 than in the control.


Role of Contrast-Enhanced Ultrasound With the Enhancement Pattern and Qualitative Analysis for Differentiating Hypovascular Solid Renal Lesions.
The aim of the work described here was to explore the clinical value of contrast-enhanced ultrasound (CEUS) with the enhancement pattern and qualitative analysis in distinguishing different types of hypovascular solid renal lesions. A total of 140 patients with 140 renal tumors (all diagnosed by pathology), which manifested hypo-enhancement on CEUS, were included in this study. We compared conventional ultrasound (US) and CEUS features in five common hypovascular renal tumors, including renal angiomyolipoma (RAML), clear cell renal cell carcinoma (ccRCC), renal pelvic urothelial carcinoma (RPUC), papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (chRCC). The diagnostic value of conventional US and qualitative parameters of CEUS for differentiating hypovascular solid renal lesions were evaluated. The mean age of patients with a benign renal lesion was younger than that of patients with a malignant renal lesion (p < 0.05). Echogenicity and qualitative parameters such as wash-out, perfusion defects and perilesional rim-like enhancement (PRE) in the two groups differed significantly (all p values <0.05). Benign renal lesions exhibited mainly slow wash-out, whereas malignant renal lesions exhibited predominantly fast wash-out on CEUS (p < 0.05). There were significant differences in echogenicity, such as between RAML and ccRCC, between RAML and RPUC and between RAML and pRCC (all p values <0.05). The rates of appearance of perfusion defect in ccRCC (48%, 13/27) and pRCC (53%, 10/19) were significantly higher than the rate in RAML (14%, 6/43) (p < 0.05). The rates of appearance of PRE in ccRCC (15%, 4/27), pRCC (26%, 5/19) and chRCC (24%,4/17) were significantly higher than the rate in RAML (9%, 4/43) (p < 0.05). CEUS with the enhancement pattern and qualitative analysis may be helpful in distinguishing malignant from benign hypovascular renal lesions.


An evaluation of the quantity and quality of empirical research in three pastoral care and counseling journals, 1990-1999: has anything changed?
This article summarizes a review of all articles published in Pastoral Psychology, The Journal of Rleigion and Health, and The Journal of Pastoral Care between 1900 and 1999, identifying a total of 737 scholarly articles, of which 165 (22.4%) were research studies. The proportion of research studies, especially quantitative studies, increased significantly between the first and second half of the study period (p < .05). There was a significant positive correlation between compliance with three out of four criteria of internal validity. Three of five criteria of external validity were also positively related to one another. Compared to previous research using identical criteria to assess quantitative studies in the same journals in 1980-1989, the 1990-1999 sample showed improved compliance with respect to specifying the sampling method (p < .001), reporting the response rate (p < .05), and discussing the limitations of research studies (p < .001). However, the overall findings suggest that many researchers in the field do not have a sophisticated knowledge of statistical sampling, statistical analysis, or research design. Several recommendations for increasing the quality of quantitative research are offered.


Early recognition of anti-N-methyl D-aspartate (NMDA) receptor encephalitis presenting as acute psychosis.
We present a case of anti-N-methyl D-aspartate (NMDA) receptor encephalitis that illustrates the dilemma that psychiatrists face in evaluating patients with first episode psychosis. The discovery that acute psychosis can be the presenting feature of autoimmune encephalitis (in particular encephalitis caused by anti-NMDA receptor antibodies) has both practical and theoretical consequences. First, this condition is an important, but often overlooked, differential diagnosis of first episode psychosis. Antibody testing is not currently part of routine screening, though delayed (or missed) diagnosis can lead to prolonged hospital stay, medical complications and incomplete or delayed recovery. Widespread screening of patients with first presentation psychosis for anti-NMDA receptor and anti-voltage-gated potassium channel (anti-VGKC) antibodies is warranted for a number of reasons: to expedite appropriate treatment, to determine the true proportion of patients with these conditions presenting as psychosis, and to help elucidate the neurochemical causes of psychosis.


In vitro activities of CB-183,315, vancomycin, and metronidazole against 556 strains of Clostridium difficile, 445 other intestinal anaerobes, and 56 Enterobacteriaceae species.
MICs of CB-183,315, a novel lipopeptide antibiotic, vancomycin, and metronidazole were determined for intestinal anaerobes and Enterobacteriaceae. The MIC(90)s for Gram-negative anaerobes were >8,192, 8,192, and 4 μg/ml for CB-183,315, vancomycin, and metronidazole, respectively. Against Enterobacteriaceae, the MIC(90)s were >8,192 μg/ml, 1,024 μg/ml, and 1,024 μg/ml, respectively. The CB-183,315 MIC(90) for Clostridium difficile was 0.5 μg/ml. Its lack of activity against normal fecal organisms makes it a promising new agent for treating C. difficile.


Pandemic preparedness and response: exploring the role of universal health coverage within the global health security architecture.
In response to the COVID-19 pandemic, several international initiatives have been developed to strengthen and reform the global architecture for pandemic preparedness and response, including proposals for a pandemic treaty, a Pandemic Fund, and mechanisms for equitable access to medical countermeasures. These initiatives seek to make use of crucial lessons gleaned from the ongoing pandemic by addressing gaps in health security and traditional public health functions. However, there has been insufficient consideration of the vital role of universal health coverage in sustainably mitigating outbreaks, and the importance of robust primary health care in equitably and efficiently safeguarding communities from future health threats. The international community should not repeat the mistakes of past health security efforts that ultimately contributed to the rapid spread of the COVID-19 pandemic and disproportionately affected vulnerable and marginalised populations, especially by overlooking the importance of coherent, multisectoral health systems. This Health Policy paper outlines major (although often neglected) gaps in pandemic preparedness and response, which are applicable to broader health emergency preparedness and response efforts, and identifies opportunities to reconceptualise health security by scaling up universal health coverage. We then offer a comprehensive set of recommendations to help inform the development of key pandemic preparedness and response proposals across three themes-governance, financing, and supporting initiatives. By identifying approaches that simultaneously strengthen health systems through global health security and universal health coverage, we aim to provide tangible solutions that equitably meet the needs of all communities while ensuring resilience to future pandemic threats.


Current and Emerging Strategies in Osteoporosis Management.
The abnormal loss of bone tissue is defined as osteoporosis. Increased risk of fractures, low bone mineral density (BMD) and loss of the structural and biomechanical properties of the bone tissue characterize this pathological condition. Physiologically bone undergoes a continuous remodeling process involving balance between the activity of osteoblast and osteoclast. Disruption in this balanced condition increases the risk of osteoporosis. Both sexes are affected, but with higher prevalence in women after menopause. This review aims to enlighten the established and emerging trends in prevention and treatment of bone loss. Herbal supplementation and physical exercises are suggested as addition to the well-established therapy in prevention and management of osteoporosis. Treatment strategies of osteoporosis include non- pharmacological treatment - diet rich of calcium and vitamin D, healthy lifestyle, proper exercise plan, and pharmacological therapy. Preventive and treatment strategies have to consider combination of non-pharmacological and pharmacological approaches for minimization of the fracture risk in osteoporosis.


Id1 expression promotes T regulatory cell differentiation by facilitating TCR costimulation.
T regulatory (Treg) cells play crucial roles in the regulation of cellular immunity. The development of Treg cells depends on signals from TCRs and IL-2Rs and is influenced by a variety of transcription factors. The basic helix-loop-helix proteins are known to influence TCR signaling thresholds. Whether this property impacts Treg differentiation is not understood. In this study, we interrogated the role of basic helix-loop-helix proteins in the production of Treg cells using the CD4 promoter-driven Id1 transgene. We found that Treg cells continued to accumulate as Id1 transgenic mice aged, resulting in a significant increase in Treg cell counts in the thymus as well as in the periphery compared with wild-type controls. Data from mixed bone marrow assays suggest that Id1 acts intrinsically on developing Treg cells. We made a connection between Id1 expression and CD28 costimulatory signaling because Id1 transgene expression facilitated the formation of Treg precursors in CD28(-/-) mice and the in vitro differentiation of Treg cells on thymic dendritic cells despite the blockade of costimulation by anti-CD80/CD86. Id1 expression also allowed in vitro Treg differentiation without anti-CD28 costimulation, which was at least in part due to enhanced production of IL-2. Notably, with full strength of costimulatory signals, however, Id1 expression caused modest but significant suppression of Treg induction. Finally, we demonstrate that Id1 transgenic mice were less susceptible to the induction of experimental autoimmune encephalomyelitis, thus illustrating the impact of Id1-mediated augmentation of Treg cell levels on cellular immunity.


Candida carriage and Candida dubliniensis in oropharyngeal samples of type-1 diabetes mellitus patients.
The carriage of Candida dubliniensis in the oral cavities of type-1 diabetic patients were investigated. Of 230 patients 81 (35%) had Candida spp. in their oral cavity; C. albicans was the most frequently isolated species (58%). No C. dubliniensis was found in the study population.


The vocal motor neurons of Xenopus laevis: development of sex differences in axon number.
Sex differences in the number of muscle fibers in the larynx of clawed frogs (Xenopus laevis) develop after metamorphosis. In order to examine possible contributions of neural innervation to this process, we prepared sections of the laryngeal nerve from tadpole stage 56, when the sexes can first be distinguished, through adulthood, and counted axons on electron micrographs. The adult number of axons is achieved by a sexually differentiated pattern of axonal addition and loss. Axon numbers are high at tadpole stage 56 and equal for males and females; thereafter, males have more axons. Sex differences are most pronounced at tadpole stage 62 because between stages 59 and 62 the number of laryngeal axons in males increases by an average of 119 per nerve. Ultrastructural evidence is congruent with the hypothesis that new axons are added to the laryngeal nerve between tadpole stages 56 and 62. The loss of axons from the laryngeal nerve is greater for females than for males. Between tadpole stages 56 and adulthood, overall axon number decreases by 47% in males and by 64% in females. Signs of axonal degeneration are present in both sexes before metamorphosis but are rare at juvenile or adult stages. The numbers of axons in juvenile frogs do not differ from those in adults and continue to be greater in males than in females. In contrast to the amount of axon addition and loss, the timing of axon loss and the percentage of myelinated axons is the same for males and females throughout development. Thus sex differences in the innervation of laryngeal muscle originate before metamorphosis and could contribute to the marked sex differences in muscle fiber addition that occur thereafter.


The Legionella autoinducer LAI-1 is delivered by outer membrane vesicles to promote interbacterial and interkingdom signaling.
Legionella pneumophila is an environmental bacterium, which replicates in amoeba but also in macrophages, and causes a life-threatening pneumonia called Legionnaires' disease. The opportunistic pathogen employs the α-hydroxy-ketone compound Legionella autoinducer-1 (LAI-1) for intraspecies and interkingdom signaling. LAI-1 is produced by the autoinducer synthase Legionella quorum sensing A (LqsA), but it is not known, how LAI-1 is released by the pathogen. Here, we use a Vibrio cholerae luminescence reporter strain and liquid chromatography-tandem mass spectrometry to detect bacteria-produced and synthetic LAI-1. Ectopic production of LqsA in Escherichia coli generated LAI-1, which partitions to outer membrane vesicles (OMVs) and increases OMV size. These E. coli OMVs trigger luminescence of the V. cholerae reporter strain and inhibit the migration of Dictyostelium discoideum amoeba. Overexpression of lqsA in L.pneumophila under the control of strong stationary phase promoters (PflaA or P6SRNA), but not under control of its endogenous promoter (PlqsA), produces LAI-1, which is detected in purified OMVs. These L. pneumophila OMVs trigger luminescence of the Vibrio reporter strain and inhibit D. discoideum migration. L. pneumophila OMVs are smaller upon overexpression of lqsA or upon addition of LAI-1 to growing bacteria, and therefore, LqsA affects OMV production. The overexpression of lqsA but not a catalytically inactive mutant promotes intracellular replication of L. pneumophila in macrophages, indicating that intracellularly produced LA1-1 modulates the interaction in favor of the pathogen. Taken together, we provide evidence that L. pneumophila LAI-1 is secreted through OMVs and promotes interbacterial communication and interactions with eukaryotic host cells.


Heterologous expression of human costimulatory molecule B7-2 and construction of B7-2 immobilized polyhydroxyalkanoate nanoparticles for use as an immune activation agent.
Costimulation of T cells via costimulatory molecules such as B7 is important for eliciting cell-mediated antitumor immunity. Presenting costimulation molecules by immobilizing recombinant B7 on the surface of nanovectors is a novel strategy for complementary therapy. Polyhydroxyalkanoates (PHAs) are a family of biodegradable, non-toxic, biocompatible polyesters, which can be used as a nonspecific immobilizing matrix for protein presentation. Recombinant protein fusion with PHA granule binding protein phasin (PhaP) can be easily immobilized on the surface of PHA nanoparticles through hydrophobic interactions between PhaP and PHA, and therefore provides a low-cost protein presenting strategy. In this study, the extracellular domain of the B7-2 molecule (also named as CD86) was fused with PhaP at its N-terminal and heterogeneously expressed in recombinant Escherichia coli strain BL21 (DE3). The purified B7-2-PhaP protein was immobilized on the surface of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx)-based nanoparticles. Loading of 240 μg (3.2 pMol) of B7-2-PhaP protein per mg nanoparticles was achieved. Immobilized B7-2-PhaP on PHBHHx nanoparticles induced T cell activation and proliferation in vitro. A PHA nanoparticle-based B7-2 costimulation molecule-presenting system was constructed. The PHA-based B7 presenting nanosystem provided costimulation signals to induce T cell activation and expansion in vitro. The B7-2-PhaP immobilized PHA nanosystem is a novel strategy for costimulation molecule presentation and may be used for costimulatory molecule complementary therapy.


Choice in free-ranging wild pigeons.
A flock of free-ranging wild pigeons were trained to peck at buttons which, when operated, allowed brief access to grain. Although only one bird at a time could have access to the buttons, the pecks of the group were treated as an aggregate. When they chose between two buttons, each of which could occasionally produce grain, the ratios of pecks at the buttons approximately equaled the ratios of the grain presentations obtained from them. This accords with a relation well substantiated in the laboratory, the matching law. It suggests that the matching law may apply to the behavior of higher organisms in natural environments.


Management of traumatic intracranial haematoma.
Deciding which head-injured patients should be transferred to a neurosurgical unit can be difficult. Traditional criteria emphasise the development of deteriorating responsiveness but lead to delayed diagnosis and to avoidable mortality and morbidity. To discover if a more liberal admission policy improved results a study was conducted analysing data collected prospectively from 683 patients who had a traumatic intracranial haematoma evacuated in the Glasgow neurosurgical unit between 1974 and 1980. In the first four years, before the change in policy, mortality was 38% but decreased to 29% afterwards. This reflected a reduction in the proportion of patients who talked after injury but who deteriorated into coma before operation--that is, 31% before the change in policy, 16% afterwards. If the potential benefits of CT scanning in the management of head injuries are to be realised patients must be scanned sooner than in the past. This will usually mean that more patients should go to a neurosurgical unit and that simple criteria for transfer should be established.


Controllability of networked higher-dimensional systems with one-dimensional communication.
In this paper, the state controllability of networked higher-dimensional linear time-invariant dynamical systems is considered, where communications are performed through one-dimensional connections. The influences on the controllability of such a networked system are investigated, which come from a combination of network topology, node-system dynamics, external control inputs and inner interactions. Particularly, necessary and sufficient conditions are presented for the controllability of the network with a general topology, as well as for some special settings such as cycles and chains, which show that the observability of the node system is necessary in general and the controllability of the node system is necessary for chains but not necessary for cycles. Moreover, two examples are constructed to illustrate that uncontrollable node systems can be assembled to a controllable networked system, while controllable node systems may lead to uncontrollable systems even for the cycle topology.This article is part of the themed issue 'Horizons of cybernetical physics'.


The coevolution of warning signals.
It has long been recognized that defended prey tend to be conspicuous. Current theories suggest that the association ('aposematism') has arisen because predators more readily learn to avoid attacking defended phenotypes when they are conspicuous. In this paper, I consider why such psychology has evolved. In particular, I argue that aposematism may have evolved not because of an independent and pre-existing receiver bias, but because the conspicuousness of a prey item provides a reliable indicator of its likelihood of being defended. To develop my case I consider how warning signals might coevolve in a system containing a number of predators, whose foraging behaviour is also subject to selection. In these cases, models readily show that the greater the conspicuousness of a novel prey item, the more likely that it has been encountered by other predators and survived. As a consequence, naive predators should be less likely to attack highly conspicuous novel prey on encounter, or at least more inclined to attack them cautiously. This adaptive predator behaviour will greatly facilitate the spread of aposematic phenotypes from extreme rarity, which in turn will enhance selection for forms of predator behaviour under which aposematism will coevolve even more readily.


11 beta-hydroxysteroid dehydrogenase type II in human colon: a new marker of fetal development and differentiation in neoplasms.
The colon plays an important role in water and electrolyte homeostasis and is a major target tissue for aldosterone. 11 beta-Hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) confers specificity to the non-selective mineralocorticoid receptor by inactivating glucocorticoids, thus allowing binding by mineralocorticoids. Using immunohisto/cytochemistry and Northern blot analysis, we examined 11 beta-HSD2 expression in human fetal colon (23 cases ranging in age from 15 to 40 weeks gestation), neonatal colon (2 cases, 6 and 12 months old), normal adult colon (15), adenoma (35), adenocarcinoma (34) and the human colonic epithelial cell line T84, in the presence or absence of sodium butyrate, to study the correlation between enzyme expression and cellular or neoplastic differentiation. In fetal colon, weak 11 beta-HSD2 immunoreactivity was detectable in superficial epithelium from 25 weeks gestation, but normal adult levels were apparent only after 40 weeks gestation, suggesting that fully developed aldosterone induced electrolyte transport can occur only at late gestational stages. In adult normal colon, superficial absorptive cells at the top of crypts were strongly positive for 11 beta-HSD2, whereas immunoreactivity was weak in adenomas and carcinomas, and the pattern of localization varied among patients. Northern blot analysis performed on 4 cases of adenocarcinoma also demonstrated lower levels of mRNA than autologous non-neoplastic colonic mucosa. In carcinomas, 11 beta-HSD2 immunoreactivity was more frequently detected in differentiated structures, such as those forming glandular or tubular structures. Studies with T84 cells showed that expression of 11 beta-HSD2 was markedly enhanced with the addition of sodium butyrate, a well known inducer of cell differentiation in colonic epithelia. These results suggest that the expression of 11 beta-HSD2 is associated with differentiation or maturation in human colonic epithelia and that the enzyme may serve as a useful marker in development and disease.


Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate.
Intoxication with the alcohol-aversive drug disulfiram (Antabuse) and related dithiocarbamates may provoke neuropathies and, in some cases, damage the basal ganglia. Rats received a single administration of disulfiram (7 and 500 mg kg-1 i.p.) and equimolar doses (4 and 290 mg kg-1 i.p.) of its metabolite diethyldithiocarbamate (DDC), roughly corresponding to the daily maximum dose in alcohol abusers or to an estimated nonlethal overdose, respectively. The striatal, extracellular levels of glutamate in freely moving rats previously implanted with a microdialysis probe increased after low and intoxicating doses of disulfiram (126 +/- 3% and 154 +/- 10% of basal values, respectively) and DDC as well (135 +/- 10% and 215 +/- 14%, respectively), a partially Ca++-dependent effect. The prolonged (>7 hr) disulfiram-induced increase in glutamate observed in vivo may reflect the in vitro disulfiram-evoked release of glutamate from striato-cortical synaptic vesicles, where the drug nonspecifically inhibited (Ki approximately 4 microM) the uptake function and abolished the transmembrane proton gradient (DeltapH). In contrast, DDC did not seem to affect DeltapH. The prompt DDC-provoked increase in extracellular levels of glutamate was prevented by 7-nitroindazole, an in vivo specific inhibitor of neuronal nitric oxide synthase, which suggests that the thiol metabolite also acts via the nitric oxide synthesis. At variance, the short-acting 7-nitroindazole did not prevent the sustained in vivo effects of disulfiram and of DDC putatively formed with time. These findings provide new evidence for differential mechanisms underlying disulfiram- and DDC-induced increases in striatal glutamate release. Present glutamatergic changes, although not appearing dramatic enough to represent the only cause for neuronal damage from disulfiram overdose, might contribute to the drug neurotoxicity.


Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).
Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. Tumour DNA was extracted (formalin fixed, paraffin embedded, FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2% to 98.4%), specificity 87.7% (95% CI 77.9% to 94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7% to 76.5%), specificity 98.6% (95% CI 92.4% to 100.0%) for the identification of those with pathogenic MLH1 mutations. Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours.


Dispositional pathways to trust: Self-esteem and agreeableness interact to predict trust and negative emotional disclosure.
Expressing our innermost thoughts and feelings is critical to the development of intimacy (Reis & Shaver, 1988), but also risks negative evaluation and rejection. Past research suggests that people with high self-esteem are more expressive and self-disclosing because they trust that others care for them and will not reject them (Gaucher et al., 2012). However, feeling good about oneself may not always be enough; disclosure may also depend on how we feel about other people. Drawing on the principles of risk regulation theory (Murray et al., 2006), we propose that agreeableness-a trait that refers to the positivity of interpersonal motivations and behaviors-is a key determinant of trust in a partner's caring and responsiveness, and may work in conjunction with self-esteem to predict disclosure. We examined this possibility by exploring how both self-esteem and agreeableness predict a particularly risky and intimate form of self-disclosure, the disclosure of emotional distress. In 6 studies using correlational, partner-report, and experimental methods, we demonstrate that self-esteem and agreeableness interact to predict disclosure: People who are high in both self-esteem and agreeableness show higher emotional disclosure. We also found evidence that trust mediates this effect. People high in self-esteem and agreeableness are most self-revealing, it seems, because they are especially trusting of their partners' caring. Self-esteem and agreeableness were particularly important for the disclosure of vulnerable emotions (i.e., sadness; Study 5) and disclosures that were especially risky (Study 6). These findings illustrate how dispositional variables can work together to explain behavior in close relationships. (PsycINFO Database Record


Standardized approach for imaging and measuring Cesarean section scars using ultrasonography.
Incomplete healing of the scar is a recognized sequel of Cesarean section (CS) and may be associated with complications in later pregnancies. These complications can include scar pregnancy, a morbidly adherent placenta, scar dehiscence or rupture. To date there is uncertainty relating to the factors that lead to poor scar healing and how to recognize it. In recent years, there has been an increase in studies using ultrasound that describe scars as deficient, or poorly, incompletely or inadequately healed with few data to associate the morphology of the scar with the functional integrity of the lower segment of the uterus. There have been multiple attempts to describe CS scars using ultrasonography. Different terminology, methods and results have been reported, yet there is still no consensus regarding the prevalence, clinical significance or most appropriate method to describe the appearances of these scars. Developing a test that can predict the likelihood of women having problems associated with a CS scar is becoming increasingly important. On the other hand, understanding whether the ultrasound appearances of the scar can tell us anything about its integrity is not well supported by the research evidence. In this article we present an overview of ultrasound-based definitions and methods used to describe CS scars. We also present information relating to the performance of alternative techniques used to evaluate CS scars. Having examined the current evidence we suggest a standardized approach to describe CS scars using ultrasound so that future studies can be meaningfully compared.


Microfabricated electrophoresis systems for DNA sequencing and genotyping applications: current technology and future directions.
Many routine genomic-analysis assays rely on gel electrophoresis to perform size-selective fractionation of DNA fragments in the size range below 1 kb in length. Over the past decade, impressive progress has been made towards the development of microfabricated electrophoresis systems to conduct these assays in a microfluidic lab-on-a-chip format. Since these devices are inexpensive, require only nanolitre sample volumes, and do not rely on the availability of a pre-existing laboratory infrastructure, they are readily deployable in remote field locations for use in a variety of medical and biosensing applications. The design and construction of microfabricated electrophoresis devices poses a variety of challenges, including the need to achieve high-resolution separations over distances of a few centimetres or less, and the need to easily interface with additional microfluidic components to produce self-contained integrated DNA-analysis systems. In this paper, we review recent efforts to develop devices to satisfy these requirements and live up to the promise of fulfilling the growing need for inexpensive portable genomic-analysis equipment.


Subgroup differences in having a usual source of health care among working-age adults with and without disabilities.
Having a usual source of health care is positively associated with regular health maintenance visits and receipt of preventive services. People with disabilities are, overall, more likely than those without disabilities to have a usual source of care (USC). However, the population of people with disabilities is quite heterogenous, and some segments of the population may have less access to a USC than others. To determine whether there are significant subgroup differences in having a USC within the U.S. population of working-age adults with disabilities, and to compare adults with and without disabilities while controlling for other subgroup differences. We analyzed Medical Expenditure Panel Survey annual data files from 2002 to 2008. We performed both bivariate and multivariate logistic regression analyses to examine the relationship of sociodemographic and disability subgroup variables with having a USC. Within the disability population, individuals who were younger; male; Black, Hispanic, or other (non-White) race; less educated; of lower income; or uninsured for part or all of the year were significantly less likely to have a USC. These differences mirrored those among adults without disabilities. When controlling for these differences, people with physical, hearing, or multiple disabilities had greater odds of having a USC than people without disabilities, but those with vision or cognitive limitations did not differ significantly from the non-disabled referent group. Disparities among people with and without disabilities are similar, underscoring the need for attention to disparities within the disability population.


Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis: A Phenome-Wide Association Study and Inverse Variance-Weighted Meta-Analysis.
This study was undertaken to investigate the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk of 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiologic studies, and to define new genetic pleiotropy present in RA. Two approaches were used to test our hypothesis. First, we constructed a weighted genetic risk score (wGRS) and then examined its association with 10 prespecified disorders. Additionally, a phenome-wide association study (PheWAS) was carried out to identify potential new associations. Second, inverse variance-weighted regression (IVWR) meta-analysis was used to characterize the association between genetic susceptibility to RA and the prespecified disorders, with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). The wGRS for RA was significantly associated with type 1 diabetes mellitus (DM) (OR 1.10 [95% CI 1.04-1.16]; P = 9.82 × 10-4 ) and multiple sclerosis (OR 0.82 [95% CI 0.77-0.88]; P = 1.73 × 10-8 ), but not with other cardiometabolic phenotypes. In the PheWAS, wGRS was also associated with an increased risk of several autoimmune phenotypes including RA, thyroiditis, and systemic sclerosis, and with a decreased risk of demyelinating disorders. In the IVWR meta-analyses, RA was significantly associated with an increased risk of type 1 DM (P = 1.15 × 10-14 ), with evidence of horizontal pleiotropy (Mendelian Randomization-Egger intercept estimate P = 0.001) likely driven by rs2476601, a PTPN22 variant. The association between type 1 DM and RA remained significant (P = 9.53 × 10-9 ) after excluding rs2476601, with no evidence of horizontal pleiotropy (intercept estimate P = 0.939). RA was also significantly associated with type 2 DM and C-reactive protein levels. These associations were driven by variation in the major histocompatibility complex region. This study presents evidence of pleiotropy between the genetic predisposition to RA and associated phenotypes found in other autoimmune and cardiometabolic disorders, including type 1 DM.


[Myocardial infarction in patients with non-insulin-dependent diabetes mellitus and dependence of the quality of life on the individual psychological type].
To examine clinical features, complications, short- and long-term outcomes of myocardial infarction (MI) as well as quality of life (QL) in patients with non-insulin-dependent diabetes mellitus (NIDDM), to analyze relations between the above parameters and psychologic personal traits of the patients. The study entered 240 NIDDM patients with MI (the test group) and 260 control nondiabetic MI patients. The examination was made using standard techniques and AMPI. An anginal variant of initial MI in NIDDM patients was registered significantly less frequently than in the controls (76.7 vs 88.2%). The asthmatic variant occurred in 16.3 and 4.6% of the cases, respectively. In MI, NIDDM patients developed preinfarction and postinfarction angina pectoris less often than control patients (20 and 12.1% vs 71.9 and 25.7%, respectively). Mean psychological profile was high by AMPI scales 1, 2 and 6 in NIDDM patients, by scales 1, 3 and 8 in control patients. Pain syndrome in anginal initial MI in NIDDM patients is less pronounced and becomes weaker with growing duration of diabetes. Concomitant diabetes mellitus has an insignificant influence on deterioration of quality of life in the postinfarction period.


Gene expressions of leptin, insulin receptors and lipogenic enzymes are coordinately regulated by insulin and dietary fat in rats.
Regulation of the gene expressions of leptin, insulin receptors and lipogenic enzymes was investigated after refeeding a fat-free diet or a 10 g/100 g corn oil diet to food-deprived rats. Plasma glucose and insulin concentrations began to increase 30 min after the feeding and further increased up until 8 h. In these rats, the expression of leptin mRNA in adipose tissue began to increase significantly only 30 min after feeding, and reached a maximum at 8-16 h. However, plasma leptin levels did not increase until 4 h after refeeding, then markedly increased and reached the maximal level after 8 h. The expression of leptin mRNA and plasma leptin concentrations generally were greater in rats fed the corn oil diet compared to those fed the fat-free diet. Insulin receptor mRNA concentrations in the liver and adipose tissue began to decrease 30 min after the refeeding, in contrast to the plasma insulin increase, and continued to decrease until 8 h. The expression of acetyl-CoA carboxylase and fatty acid synthase mRNA began to increase 4-8 h after feeding and reached maximal levels at 16-24 h. Leptin treatment suppressed the expression of lipogenic enzyme mRNA in rats fed the fat-free diet but not in corn oil-fed rats, in which the expression was suppressed by polyunsaturated fatty acids and leptin expression was higher. Thus, we suggest that the glucose and insulin-dependent expressions of leptin, insulin receptors and lipogenic enzymes are coordinately and/or mutually regulated by dietary manipulation.


Re-entry into the cell cycle is required for bFGF-induced oligodendroglial dedifferentiation and survival.
Remyelination in the CNS following demyelinating disease may be accomplished by surviving mature oligodendrocytes that dedifferentiate, proliferate, migrate, and finally regenerate myelin. We previously reported that basic fibroblast growth factor (bFGF) induces oligodendrocytes in primary mixed glial cultures to dedifferentiate and synthesize DNA (Grinspan et al.: J Neurosci Res 36:672-680, 1993). We now show that this effect is direct and not mediated through the effects of bFGF on other cell types, because we were able to demonstrate similar changes in oligodendrocyte phenotype in enriched oligodendrocyte cultures prepared by immunopanning. The bFGF-induced reversion to the precursor stage of the oligodendroglial lineage can be blocked by agents that inhibit entry to the cell cycle; thus oligodendroglial dedifferentiation is dependent on proliferation. We also report that 2 days of bFGF treatment inhibits oligodendroglial apoptosis. However, when oligodendroglia are prevented from entering the cell cycle in the presence of bFGF, apoptotic cell death is increased. Thus, bFGF induces oligodendroglial dedifferentiation if oligodendroglial DNA synthesis can occur but causes oligodendroglial apoptosis when oligodendroglial DNA synthesis is prevented.


Effects of 2 Types of Resistance Training Models on Obese Adolescents' Body Composition, Cardiometabolic Risk, and Physical Fitness.
Magnani Branco, BH, Carvalho, IZ, Garcia de Oliveira, H, Fanhani, AP, Machado dos Santos, MC, Pestillo de Oliveira, L, Macente, SB, and Nelson, NJ. Effects of 2 types of resistance training models on obese adolescents' body composition, cardiometabolic risk, and physical fitness. J Strength Cond Res 34(9): 2672-2682, 2020-The main objective of this study was to investigate the effects of 2 types of resistance training (RT) models in conjunction with interdisciplinary interventions by other health professionals to reduce the body fat and cardiometabolic risk of obese adolescents while improving their general health-related physical fitness. The 12-week analyses involved 18 male adolescents who were split into 2 groups (weight lifting: n = 9 and functional: n = 9), with equalization according to the primary muscle group (whenever possible), the effort:pause ratio, and intensity. The results showed reductions in fat mass and body fat, as well as in waist and hip circumferences (p < 0.05) after the intervention period. However, no significant differences were observed in terms of the body mass, body mass index, neck circumference, systolic and diastolic blood pressures, and for lean mass (p > 0.05) after the respective period. Maximal isometric strength, abdominal strength resistance, flexibility, and maximal oxygen consumption all produced significant increases after the interventions (p < 0.05). There were reductions in low-density lipoproteins and triglyceride levels after the intervention period (p < 0.05). For fasting glycemia, high-density lipoproteins, and alanine aminotransferase, no differences were observed (p > 0.05). In addition, no differences were observed in rating of perceived recovery, internal training load, or caloric intake (p > 0.05). With the results presented, it is concluded that both RT methods were effective at reducing both fat mass and body fat, thus improving health-related physical fitness components and decreasing cardiometabolic risk.


Tetrahydrobiopterin in the treatment of infantile hypertrophic pyloric stenosis.
Evidence is emerging that reduced nitric oxide production may be involved in the pathogenesis of hypertrophic pyloric stenosis. Nitric oxide synthase (NOS) requires tetrahydrobiopterin (BH4) for activity. Four infants with hypertrophic pyloric stenosis were treated with oral BH4 (10 mg/kg/day) for 2.5 days. Although plasma total biopterin increased significantly at 3, 27, and 51 h after BH4 administration, there was no effect on the production of plasma cGMP, nitrite, nitrate, or citrulline. Ultrasound investigations before and after the ingestion of BH4 revealed no changes in the hypertrophic pyloric stenosis. We conclude that oral BH4, in the dose utilized in our investigations, does not modify the cause of hypertrophic pyloric stenosis, presumably because it did not restore nitric oxide production in the nonadrenergic noncholinergic nerves of the enteric nervous system.


Backbone NMR assignments and H/D exchange studies on the ferric azide- and cyanide-inhibited forms of Pseudomonas aeruginosa heme oxygenase.
The 198 amino acid long heme oxygenase from Pseudomonas aeruginosa (pa-HO) was studied by multinuclear and multidimensional NMR spectroscopy in its paramagnetic cyanide-inhibited (pa-HO-CN) and azide-inhibited (pa-HO-N3) forms. Nearly complete backbone assignments (>93%) of all non-proline residues have been obtained, with the majority of the nonassigned residues corresponding to the first 10 amino terminal residues. Resonances strongly affected by heme iron paramagnetism were assigned with the aid of selective amino acid labeling and experiments tailored to detect fast relaxing signals, whereas the rest of the polypeptide was assigned using conventional three-dimensional NMR experiments. Amide chemical shift assignments were used to monitor the rate of exchange of backbone protons in hydrogen-deuterium exchange experiments. The polypeptide in the pa-HO-N3 complex was found to be significantly less prone to exchange than the polypeptide in pa-HO-CN, which we interpret to indicate that pa-HO-N3 is conformationally less flexible than pa-HO-CN. The differences in protection factors extend to regions of the protein remote from the heme iron and distal ligand. Mapping the differences in protection factors into the X-ray crystal structure of pa-HO [Friedman, J., Lad, L., Li, H., Wilks, A. Poulos, T. L. (2004) Biochemistry 43, 5239-5345] suggests that the distinct chemical properties imparted by the coordination of azide or cyanide to the heme iron [Zeng, Y. Caignan, G. A., Bunce, R. A., Rodríguez, J. C., Wilks, A., Rivera, M. (2005) J. Am. Chem. Soc. 127, 9794-9807] are transmitted to the polypeptide by a network of structural water molecules extending from the active site to the surface of the enzyme. Finally, while the 1H amide resonance of Gly125 was too broad to detect, the corresponding 15N resonance exhibits a large downfield shift, large line width, steep temperature dependence, and a larger than usual upfield deuterium isotope effect. These properties indicate unpaired spin delocalization from the heme iron into the Gly 15N atom via formation of a hydrogen bond between the coordinated azide nitrogen and the Gly125 N-H.


Sex hormone effects on physical activity levels: why doesn't Jane run as much as Dick?
The relationship between physical activity levels and disease rates has become an important health-related concern in the developed world. Heart disease, certain cancers and obesity persist at epidemic rates in the US and Western Europe. Increased physical activity levels have been shown to reduce the occurrence of many chronic diseases leading to reductions in the burden on the healthcare system. Activity levels in humans are affected by many cultural and environmental factors; nevertheless, current research points to a strong biological input with potential genetic, neurological and endocrinological origins. Of unique interest, the sex hormones appear to have a very strong influence on activity levels. The current animal literature suggests that females tend to be more active than males due to biological pathways of estrogenic origin. The majority of human epidemiological and anthropological data, on the contrary, suggest women are less active than men in spite of this inherent activity-increasing mechanism. The purpose of this study is to review the current literature regarding the control of physical activity levels by the sex hormones in humans. Using the natural transitional phases of the aging endocrine system, natural periodicity of the menstrual cycle and pharmacological/hormone replacement therapy as variable experimental stages, some authors have been able to provide some information regarding the existence of an inherent activity-increasing mechanism in humans. In brief, activity levels during life stages prior to and after menopause do not significantly differ, despite the vast changes in sex hormone levels and function. Sex hormone differences throughout a regular menstrual cycle do not appear to influence activity levels in humans either; an effect that is pronounced in the female rodent. The use of hormone replacement therapies provides researchers with more systematic controls over hormone modulation in human subjects; however, this benefit comes with additional confounding variables, mostly due to disease or other states of malfunction. Despite the addition of these confounding factors, minor changes to the activity pattern have been observed in women, especially during the initial administration of the therapy. Observations are yet to be made in male subjects during replacement therapy. In general, some evidence exists suggesting that a biological mechanism extending from the sex hormones influences activity in humans. Unfortunately, despite a small number of investigative reports, the paucity of human research investigating how the sex hormones affect activity levels in humans prevents conclusive delineation of the mechanisms involved. Future research in this unique sub-field of endocrinology and exercise science utilizing more appropriate research protocols and effective techniques will provide definitive evidence of such mechanisms.


When danger strikes: A linguistic tool for tracking America's collective response to threats.
In today's vast digital landscape, people are constantly exposed to threatening language, which attracts attention and activates the human brain's fear circuitry. However, to date, we have lacked the tools needed to identify threatening language and track its impact on human groups. To fill this gap, we developed a threat dictionary, a computationally derived linguistic tool that indexes threat levels from mass communication channels. We demonstrate this measure's convergent validity with objective threats in American history, including violent conflicts, natural disasters, and pathogen outbreaks such as the COVID-19 pandemic. Moreover, the dictionary offers predictive insights on US society's shifting cultural norms, political attitudes, and macroeconomic activities. Using data from newspapers that span over 100 years, we found change in threats to be associated with tighter social norms and collectivistic values, stronger approval of sitting US presidents, greater ethnocentrism and conservatism, lower stock prices, and less innovation. The data also showed that threatening language is contagious. In all, the language of threats is a powerful tool that can inform researchers and policy makers on the public's daily exposure to threatening language and make visible interesting societal patterns across American history.


Molecular diagnostics on lymphoid malignancies.
Molecular diagnostics for lymphoid malignancies traditionally has focused on helping to provide a diagnosis on a tissue sample. The field has undergone substantial technical and conceptual evolution during the past 2 decades, and its role has expanded to new arenas, such as monitoring disease activities and detecting alterations in genes that are known to have a significant impact on disease outcome. To review the advances in molecular diagnostics on lymphoid malignancies, including recent developments that may facilitate the development of mechanism-based diagnosis for individualized therapy. The development of molecular diagnostics in lymphoid malignancies is briefly reviewed with emphasis on the recent use of gene expression profiling for identifying important diagnostic and prognostic signatures. Genome-scale investigations are becoming technically feasible and have provided promising results in the identification of new disease entities and new, molecularly defined prognosticators. This development can potentially revolutionize diagnostic medicine in the near future. As new genes or genetic pathways that affect the clinical and biologic behavior of tumors are defined and can be readily assayed, molecular diagnostics will be expected to provide this relevant information. Ideally, therapy will be based on this information, delivering the most appropriate treatment with the least toxicity. Molecular diagnostics in the future will be moving toward a mechanism-based diagnosis for individualized therapy.


Therapeutic targeting of misfolding and conformational change in α1-antitrypsin deficiency.
Misfolding and conformational diseases are increasing in prominence and prevalence. Both misfolding and 'postfolding' conformational mechanisms can contribute to pathogenesis and can coexist. The different contexts of folding and native state behavior may have implications for the development of therapeutic strategies. α1-antitrypsin deficiency illustrates how these issues can be addressed with therapeutic approaches to rescue folding, ameliorate downstream consequences of aberrant polymerization and/or maintain physiological function. Small-molecule strategies have successfully targeted structural features of the native conformer. Recent developments include the capability to follow solution behavior of α1-antitrypsin in the context of disease mutations and interactions with drug-like compounds. Moreover, preclinical studies in cells and organisms support the potential of manipulating cellular response repertoires to process misfolded and polymer states.


New insights into sex chromosome evolution in anole lizards (Reptilia, Dactyloidae).
Anoles are a clade of iguanian lizards that underwent an extensive radiation between 125 and 65 million years ago. Their karyotypes show wide variation in diploid number spanning from 26 (Anolis evermanni) to 44 (A. insolitus). This chromosomal variation involves their sex chromosomes, ranging from simple systems (XX/XY), with heterochromosomes represented by either micro- or macrochromosomes, to multiple systems (X1X1X2X2/X1X2Y). Here, for the first time, the homology relationships of sex chromosomes have been investigated in nine anole lizards at the whole chromosome level. Cross-species chromosome painting using sex chromosome paints from A. carolinensis, Ctenonotus pogus and Norops sagrei and gene mapping of X-linked genes demonstrated that the anole ancestral sex chromosome system constituted by microchromosomes is retained in all the species with the ancestral karyotype (2n = 36, 12 macro- and 24 microchromosomes). On the contrary, species with a derived karyotype, namely those belonging to genera Ctenonotus and Norops, show a series of rearrangements (fusions/fissions) involving autosomes/microchromosomes that led to the formation of their current sex chromosome systems. These results demonstrate that different autosomes were involved in translocations with sex chromosomes in closely related lineages of anole lizards and that several sequential microautosome/sex chromosome fusions lead to a remarkable increase in size of Norops sagrei sex chromosomes.


Complications of robotic-assisted laparoscopic surgery distant from the surgical site.
With the ever-increasing popularity of robotic-assisted laparoscopic surgery over the past decades, the literature reporting complications distant from the surgical site involving the use of this technology has also grown. The goal of this non-systematic review is to summarise these reports with a systems-based presentation of these complications. The most commonly observed complications were related to the peripheral nervous system and the most devastating occurring in cardiac and ophthalmic systems. There were no reports of patient complications directly related to the robot itself. While several of the reported complications are not unique to robotic surgery, they are included to maintain awareness of their possibility. The limitation of surgical time, judicious fluid administration, and constant vigilance of patient positioning are all recommended as possible preventative measures.


Gliding resistance versus work of flexion--two methods to assess flexor tendon repair.
Two methods for measuring the ability of the flexor tendon to glide following repair are commonly cited in the literature; gliding resistance (GR) at the tendon-pulley interface and work of flexion. The GR measures the friction force at the tendon-pulley interface, while the work of flexion characterizes whole finger function during flexion. Since a portion of the total work of flexion (TWOF), termed the internal work of flexion (IWOF), is expended due to the tendon-pulley interaction, a relationship between the work of flexion and GR should be present. The purpose of this study was to quantify this correlation. Forty-eight flexor digitorum profundus tendons in 48 mongrel dogs were transected and repaired with a modified Kessler technique and an epitenon running suture. Post-operatively, the operated paw was immobilized in a cast. Dogs were sacrificed at 1, 3, 5 or 7 days after surgery. In each repaired digit work of flexion and GR were measured. While the GR was not significantly different over the time points, the TWOF decreased at 5 days after surgery and then increased at 7 days (p<0.05). There was little correlation between TWOF and GR (r=0.25, p=0.07). However, there was a strong correlation between IWOF and GR (r=0.76, p<0.05) suggesting that measurement of GR could be used as a predictor of IWOF within the short term after tendon repair.


Plasmid transfer and genetic recombination by protoplast fusion in staphylococci.
The experimental conditions for plasmid transfer and genetic recombination in Staphylococcus aureus and some coagulase-negative staphylococci by protoplast fusion are described. Protoplasts were prepared by treatment with lysostaphin and lysozyme in a buffered medium with 0.7 to 0.8 M sucrose. Regeneration of cell walls was accomplished on a hypertonic agar medium containing succinate and bovine serum albumin. Transfer of plasmids occurred after treatment of the protoplast mixtures with polyethylene glycol (molecular weight, 6,000) not only between strains of the same species but also between parents of different species, although at approximately 100 times lower frequency in the latter case. Recombination of the chromosomal genes in fused protoplasts required simultaneous treatment of the mixed protoplasts with polyethylene glycol and CaCl2. A method was developed for isolation of recombinants after fusion between mutants of S. areus carrying unselectable markers. Antibiotic resistance plasmids were introduced into the parental strains and used as primary markers to detect protoplast fusion. Chromosomal recombinants were found among the clones with both parental plasmids at a high frequency. The method appears to have simple applications in the construction of strains with multiple mutant characters.


Comparison of Gravity Flow Rates Between ENFit and Legacy Feeding Tubes.
Misconnections between enteral supplies and other access devices have led to significant morbidity and mortality. To reduce misconnections, a standard small-bore connector has been developed (International Organization for Standards 80369-8; ENFit). The full impact of transition to this connector is not known, however. Working with major manufacturers and Food and Drug Administration, we obtained ENFit and comparative legacy tubes of variable sizes (low-profile, 14F, 18F, 20F, and 24F balloon gastrostomies). Gravity enteral feeding was simulated with an empty bolus syringe attached to the feeding tube to be tested. The tube was clamped and filled to the 60-mL mark with liquid (water, Jevity 1 Cal, Isosource HN, Isosource 1.5 Cal, Two Cal HN, and Nourish). The clamp was released, and time for formula to leave the syringe was recorded. There was no difference in flow rate between the aggregate legacy and ENFit tubes for the low-profile, 18F, and 20F sizes. The ENFit 14F tubes had a lower flow rate vs the legacy tubes, largely due to the low flow rates seen with the 1 ENFit tube. Similarly, 24F ENFit tubes with some formulas yielded lower flow rates as opposed to legacy. Overall, for the low-profile, 18F, and 20F sizes, the ENFit tubes had similar flow rates when compared with the legacy tubes. For the 14F and 24F sizes, the flow rate of ENFit tubes was significantly lower, which could result in longer EN delivery for patients who are using these tubes to provide gravity feeding.


Recent Advances in Human Genetics and Epigenetics of Adiposity: Pathway to Precision Medicine?
Obesity is a heritable trait that contributes to substantial global morbidity and mortality. Here, we summarize findings from the past decade of genetic and epigenetic research focused on unravelling the underpinnings of adiposity. More than 140 genetic regions now are known to influence adiposity traits. The genetics of general adiposity, as measured by body mass index, and that of abdominal obesity, as measured by waist-to-hip ratio, have distinct biological backgrounds. Gene expression associated with general adiposity is enriched in the nervous system. In contrast, genes associated with abdominal adiposity function in adipose tissue. Recent population-based epigenetic analyses have highlighted additional distinct loci. We discuss how associated genetic variants can lead to understanding causal mechanisms, and to disentangling reverse causation in epigenetic analyses. Discoveries emerging from population genomics are identifying new disease markers and potential novel drug targets to better define and combat obesity and related diseases.


Nutritional aspects of β-carotene and resveratrol antioxidant synergism in giant unilamellar vesicles.
Giant unilamellar vesicles of soy phosphatidylcholine are found to undergo budding when sensitized with chlorophyll a ([phosphatidylcholine] : [chlorophyll a] = 1500 : 1) under light irradiation (400-440 nm, 16 mW mm(-2)). 'Entropy' as a dimensionless image heterogeneity measurement is found to increase linearly with time during an initial budding process. For β-carotene addition ([phosphatidylcholine] : [β-carotene] = 500 : 1), a lag phase of 23 s is observed, followed by a budding process at an initial rate lowered by a factor of 3.8, whereas resveratrol ([phosphatidylcholine] : [resveratrol] = 500 : 1) has little if any protective effect against budding. However, resveratrol, when combined with β-carotene, is found to further reduce the initial budding rate by a total factor of 4.7, exhibiting synergistic antioxidation effects. It is also interesting that β-carotene alone determines the lag phase for the initiation of budding, while resveratrol supports β-carotene in reducing the rate of the budding process following the lag phase; however, it alone has no observable effect on the lag phase. Resveratrol is suggested to regenerate β-carotene following its sacrificial protection of unsaturated lipids from oxidative stress, modeling the synergistic effects in cell membranes by combinations of dietary antioxidants.


Geographical variation of cancer mortality in Italy.
The distribution of death certification rates from various cancers or groups of cancers in broad Italian geographical areas (north/centre/south) was analysed. In both sexes, total cancer mortality was considerably elevated in the north of the country compared to southern regions (around 70% for males and 30% for females in the truncated 35-64 rate), and generally intermediate in central areas. Northern mortality rates were higher for respiratory cancers and other tobacco related neoplasms (excluding bladder), with a north/south ratio ranging from 1.5 for lung and most respiratory sites to about 4.0 for oesophageal cancer in males. There was little tendency towards a leveling of these differences in younger (40-49 year old) males. Northern areas showed higher death certification rates for cancers of the stomach, large bowel, liver and most other digestive sites. The lower gastric cancer mortality registered in southern Italy is curious, since this is the poorest part of the country. Death certification rates from all other common neoplasms (uterus apart) were also elevated in the north. The geographical variation, however, appeared more limited for non-epithelial neoplasms. The substantial differences in cancer mortality between various Italian geographical areas can hardly be dismissed as due to lower death certification accuracy in the south. Some of the differences can be explained in terms of available knowledge of the causes of cancer (eg reproductive factors for breast and ovarian neoplasms, alcohol plus tobacco for oesophageal cancer). However, the lower mortality from respiratory cancers in southern areas can only with some difficulty be totally explained in terms of tobacco consumption. Likewise, the north/south variation cannot be related to non-specific consequences of industrialization, since cancer mortality was similarly elevated in highly industrialized and chiefly rural northern areas. It is conceivable that dietary factors may also explain some of the differences. However, at present, there is no obvious general explanation for this quite peculiar geographical distribution of cancer mortality within a single country.


Copper-Catalyzed Enantioselective Formation of C-CF3 Centers from β-CF3 -Substituted Acrylates and Acrylonitriles.
The catalytic asymmetric synthesis of β-trifluoromethylated esters or nitriles is reported. The use of an in situ formed chiral Cu-H complex allowed the enantioselective reduction of β-trifluoromethylated acrylates or acrylonitriles. The reaction proceeds smoothly affording the corresponding enantioenriched products in good to excellent yields and outstanding enantioselectivities (up to 98 % ee). The mechanism of the reaction was studied, and a plausible reaction pathway was suggested accordingly. Finally, the versatility of the products was highlighted through functional group manipulations.


Drosophila melanogaster has only one myosin alkali light-chain gene which encodes a protein with considerable amino acid sequence homology to chicken myosin alkali light chains.
A chimeric lambda DNA molecule containing the myosin alkali light-chain gene of Drosophila melanogaster was isolated. The encoded amino acid sequence was determined from the nucleic acid sequence of a cDNA homologous to the genomic clone. The identity of the encoded protein was established by two criteria: (i) sequence homology with the chicken alkali light-chain proteins and (ii) comparison of the two-dimensional gel electrophoretic pattern of the peptides synthesized by in vitro translation of hybrid-selected RNA to that of myosin alkali light-chain peptides extracted from Drosophila myofibrils. There is only one myosin alkali light-chain in D. melanogaster; its chromosomal location is region 98B . This gene is abundantly expressed during the development of larval as well as adult muscles. The Drosophila protein appears to contain one putative divalent cation-binding domain (an EF hand) as compared with the three EF hands present in chicken alkali light chains.


Biochemical markers in the management of suspected acute myocardial infarction in the emergency department.
To compare cardiac troponin T, myoglobin, CK, CKMB activity, CKMB mass and the initial electrocardiogram in the early diagnosis of myocardial infarction in the emergency department. Methods-Biochemical markers were measured at presentation in patients with a possible diagnosis of acute myocardial infarction. Based on the clinical notes, patients were grouped as "definite myocardial infarction" (n = 50), "definite no myocardial infarction" (n = 81) and "uncertain" (n = 96). Sensitivity and specificity and positive and negative predictive values were calculated using the 131 patients with definitely present or absent myocardial infarction. The initial electrocardiogram was more sensitive than any of the markers in the first six hours from symptom onset-sensitivity 74% (95%CI 61% to 88%). The positive predictive value of the initial electrocardiogram was 97% in the first six hours; the markers ranged from 47% to 67%. The negative predictive value of the initial electrocardiogram was 85% in the first six hours; the markers ranged from 61% to 70%. Four patients with non-diagnostic electrocardiograms presenting beyond six hours after pain onset had a myocardial infarct detected by at least three of the biochemical markers in each case. The electrocardiogram is of more diagnostic use than biochemical markers in the first six hours after the onset of pain, but biochemical markers give additional positive diagnostic information in patients presenting later than this. The negative predictive accuracy of biochemical markers is too low for a single sample to be useful for excluding myocardial infarction in the first six hours after onset of symptoms.


Local Dynamics of the Hydration Water and Poly(Methyl Methacrylate) Chains in PMMA Networks.
The dynamic behavior of water molecules and polymer chains in a hydrated poly(methyl methacrylate) (PMMA) matrix containing a small amount of water molecules was investigated. Water molecules have been widely recognized as plasticizers for activating the segmental motion of polymer chains owing to their ability to reduce the glass transition temperature. In this study, combined with judicious hydrogen/deuterium labeling, we conducted quasi-elastic neutron scattering (QENS) experiments on PMMA for its dry and hydrated states. Our results clearly indicate that the dynamics of hydrated polymer chains are accelerated, and that individual water molecules are slower than bulk water. It is therefore suggested that the hydration water affects the local motion of PMMA and activates the local relaxation process known as restricted rotation, which is widely accepted to be generally insensitive to changes in the microenvironment.


Screening for glaucomatous visual field loss with frequency-doubling perimetry.
To conduct a preliminary evaluation of the efficacy of the frequency-doubling contrast test as a means of screening for glaucomatous visual field loss. Contrast thresholds for frequency-doubled stimuli were obtained under four test conditions: superior hemifield, inferior hemifield, and central (5 degrees radius) targets using a method of adjustment (MOA); superior hemifield, inferior hemifield, and central targets using a modified binary search (MOBS); four quadrant stimuli and the central target using MOBS; and 16 stimuli (four per quadrant) and the central target using MOBS. One eye each of 36 patients with early (12), moderate (12), and advanced (12) glaucomatous visual field loss was tested, as was one eye each of 36 age-matched normal control subjects. For hemifield stimuli, the MOBS test procedure had better test-retest reliability, lower individual variation, and greater separation of the normal population and the population with glaucoma than did the MOA procedure. The use of progressively smaller, more localized stimuli produced successively better separation of glaucomatous and age-matched normal control eyes. Area under the Receiver Operating Characteristic curve was 0.81 for hemifield stimuli (sensitivity and specificity, 70% to 75%), 0.91 for quadrant stimuli (sensitivity and specificity, 83% to 85%), and 0.965 for the 16 stimuli (sensitivity 93%, specificity 100%). Test time was approximately 1.3 minutes for hemifields, 1.5 minutes for quadrants, and 5 minutes for the 16 targets. Preliminary results indicate that the frequency-doubled contrast test provides a quick, efficient means of screening for glaucomatous visual field loss. Test time is relatively short, test-retest reliability is good, and sensitivity and specificity for detection of glaucomatous visual field loss is very good. The use of the MOBS staircase procedure and small, localized stimuli result in the best performance for screening purposes. An expanded normative database and the use of more rapid suprathreshold screening strategies should enhance further the efficacy of this test.


Small graft for living donor liver transplantation.
To evaluate the impact of graft size on recipients in living donor liver transplantation (LDLT) to establish a clinical guideline for the minimum requirement. Although the minimum graft size required for LDLT has been reported to be 30% to 40% of graft volume (GV)/standard liver volume (SLV), the safety limit of the graft size was unknown. A total of 33 cases of LDLT, excluding auxiliary transplantation, were reviewed with a minimum observation period of 4 months. The 33 patients were divided into three groups according to GV/SLV: medium-size graft group, small-size graft group, and extra-small graft group. The effect of GV/SLV on graft function, graft regeneration, and survival was evaluated. The overall patient survival rate was 94% at a mean follow-up of 15 months with a minimum observation period of 4 months. There were no statistically significant differences in postoperative bilirubin clearance, alanine aminotransferase, prothrombin time, and frequency of postoperative complications among the three groups. One week after transplantation, the regeneration rate (GV at 1 week/harvested GV) in the extra-small and small groups was significantly higher than that of the medium group. The graft and patient survival rates were both 100% in the extra-small group, 75% and 88% in the small group, and 90% and 95% in the medium group. Small-for-size grafts less than 30% of SLV can be used with careful intraoperative and postoperative management until the grafts regenerate.


[Structural-biological characteristics of tubulin interaction with dinitroanilines].
The interaction of dinitroaniline compounds with tubulin molecules is characterized by extraordinary selectivity--these matters effectively associate with plant as well as protozoan tubulin and practically don't interact with fungal and animal tubulin in spite of extraordinarily high level of similarity of their sequences. Structural features and mechanisms of this interaction are generalized and in detail analysed in this research. In particular, the regularities of dinitroaniline binding sites' structure and localization on surfaces of tubulin different subunits and tubulins of different origin are characterized. Dinitroaniline binding sites are disposed on the surfaces of longitudinal contacts between tubulin subunits, contain residues of diamine amino acids (lysine or arginine) coupling al nitrile group (s) of dinitroanilines. Binding site location on the surfaces of the same subunit of different origin (for example, plant and protozoan alpha-tubulins) is coincided, however site localisation on surface of alpha- and beta-subunits is distinct. The described sites potentially can be the binding areas for another antimicrotubular compounds, in particular, cyanoacrilates.


How safe are childcare products, toys and playground equipment? A Swedish analysis of mild brain injuries at home and during leisure time 1998-1999.
The aim was to highlight the role of childcare products as causes for mild brain injury (concussion) in small children (0-4 years of age) and to determine the most dangerous products. By childcare products this report means the following items: child and baby furniture, nursing tables, baby walkers, toys, baby carriages, sport equipment for children, playground equipment and security equipment for children. The data were derived from the EHLASS (European Home and Leisure Accident Surveillance System) for 1998 and 1999 and covered a restricted population of Sweden (approximately 5 per cent). According to this register 182 mild brain injuries (concussions) were recorded following a fall, an accident or a blow to the head among children (0-4 years of age) during 1998 and 158 for 1999. Of those injuries, childcare products were the cause of the accident in 84 (46 per cent) and 76 (48 per cent) cases respectively for 1998 and 1999. The number of children admitted for hospital care was 68 (57/84) and 74 (56/76) per cent respectively. The home was the most common place of the accident and play and leisure activity were the most common activities. More than 50 per cent of these accidents took place during daytime. The product type that caused most accidents was nursery furniture and, in this category, the baby walker was the most dangerous. The product type that caused the second most frequent accidents was playground equipment.


Household food security is associated with early childhood language development: results from a longitudinal study in rural Bangladesh.
Although household food security (HHFS) has been linked to academic performance in school children, its association with early childhood development has received less attention, particularly in low-income countries. We investigated the association of HHFS with subsequent language development of children at 18 months of age in rural Bangladesh. We followed 1439 infants born in 2002-2003 to the mothers in Maternal and Infant Nutrition Intervention in Matlab study, a large intervention trial conducted in rural Bangladesh. A HHFS scale was created from data collected from mothers during pregnancy. At 18 months, children's language (expression and comprehension) development was assessed using a Bengali adaptation of MacArthur's Communicative Development Inventory which was based on mothers' report of their children's ability to comprehend and express words in different categories. General linear regression models were used to examine the association between HHFS and language development at 18 months of age adjusting for potential confounders. Household food security was associated with language comprehension (B = 0.19, 95% CI = 0.09, 0.30, P < 0.001) and expression (B = 1.01, 95% CI = 1.00, 1.02, P < 0.01) at 18 months of age. Mean language comprehension and expression at 18 months of the children in higher quartiles of HHFS were higher (P < 0.05) than those of the children in lower quartiles. Household food security is positively associated with subsequent language development of rural Bangladeshi children. Early language development has been reported to predict later child development. Therefore, strategies to ensure HHFS status in Bangladesh and similar settings should be considered for optimum child development.


Computer-aided-design-model-assisted absolute three-dimensional shape measurement.
Conventional three-dimensional (3D) shape measurement methods are typically generic to all types of objects. Yet, for many measurement conditions, such a level of generality is inessential when having the preknowledge of the object geometry. This paper introduces a novel adaptive algorithm for absolute 3D shape measurement with the assistance of the object computer-aided-design (CAD) model. The proposed algorithm includes the following major steps: (1) export the 3D point cloud data from the CAD model; (2) transform the CAD model into the camera perspective; (3) obtain a wrapped phase map from three phase-shifted fringe images; and (4) retrieve absolute phase and 3D geometry assisted by the CAD model. We demonstrate that if object CAD models are available, such an algorithm is efficient in recovering absolute 3D geometries of both simple and complex objects with only three phase-shifted fringe images.


Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1.
Growing evidence indicates that cell cycle arrest and neurogenesis are highly coordinated and interactive processes, governed by cell cycle genes and neural transcription factors. The gene PC3 (Tis21/BTG2) is expressed in the neuroblast throughout the neural tube and inhibits cell cycle progression at the G1 checkpoint by repressing cyclin D1 transcription. We generated inducible mouse models in which the expression of PC3 was upregulated in neuronal precursors of the neural tube and of the cerebellum. These mice exhibited a marked increase in the production of postmitotic neurons and impairment of cerebellar development. Cerebellar granule precursors of PC3 transgenic mice displayed inhibition of cyclin D1 expression and a strong increase in the expression of Math1, a transcription factor required for their differentiation. Furthermore, PC3, encoded by a recombinant adenovirus, also induced Math1 in postmitotic granule cells in vitro and stimulated the Math1 promoter activity. In contrast, PC3 expression was unaffected in the cerebellar primordium of Math1 null mice, suggesting that PC3 acts upstream to Math1. As a whole, our data suggest that cell cycle exit of cerebellar granule cell precursors and the onset of cerebellar neurogenesis are coordinated by PC3 through transcriptional control of cyclin D1 and Math1, respectively.


Luigi Amaducci memorial award winner's paper 2003. A neurologist's view of Alzheimer's disease and dementia.
Senile dementia was the third most common admission diagnosis for New York psychiatric hospitals at the start of the twentieth century and the distinction between vascular and senile dementia was understood by psychiatrists even then. The term Alzheimer's disease (AD) was originally introduced to distinguish a pre-senile dementia from the common general paresis, but Alzheimer raised the possibility that pre-senile AD might not be distinguishable in clinical or histological terms from senile dementia. By the late 1970s it had become clear that the most common disorder producing dementia in elderly people was clinically and pathologically identical to pre-senile AD. AD is malignant, reducing remaining life expectancy by almost half and raising the risk of death over five years threefold (cancer raises it fourfold). Synapse loss associated with beta amyloid oligomers is a strong determinant of cognitive decline in patients with AD. Tau-containing neurofibrillary tangles usefully track disease severity. Unmodifiable risk factors include mutations in three genes which affect the production or metabolism of beta amyloid, the risk factor gene for Apolipoprotein [see symol in text]4 and female gender. The overriding risk factor is age, the prevalence of AD doubling with every five years of age until 90. Low education, head injury and low folate levels are examples of potentially modifiable risk factors. Since a delay of onset of five years would halve the number of patients with the disease, clinical trials for such putative protective factors as estrogens, folic acid, vitamin E, statins, and NSAIDs have begun. Cognitive and leisure activity may be protective against the development of AD but any protective function can only be confirmed by clinical trials.


Isolation rearing significantly perturbs brain metabolism in the thalamus and hippocampus.
Psychosocial neglect during childhood severely impairs both behavioral and physical health. The isolation rearing model in rodents has been employed by our group and others to study this clinical problem at a basic level. We previously showed that immediate early gene (IEG) expression in the hippocampus and medial prefrontal cortex (mPFC) is decreased in isolation-reared (IR) compared to group-reared (GR) rats. In the current study, we sought to evaluate: (1) whether these changes in IEG expression would be detected by the measurement of brain glucose metabolism using positron emission tomography (PET) with fluorodeoxyglucose (FDG) and (2) whether PET FDG could illuminate other brain regions with different glucose metabolism in IR compared to GR rats. We found that there were significant differences in FDG uptake in the hippocampus that were consistent with our findings for IEG expression (decreased mean FDG uptake in IR rats). In contrast, in the mPFC, the FDG uptake between IR and GR rats did not differ. Finally, we found decreased mean FDG uptake in the thalamus of the IR rats, a region we had not previously examined. The results suggest that PET FDG has the potential to be utilized as a biomarker of molecular changes in the hippocampus. Further, the differences found in thalamic brain FDG uptake suggest that further investigation of this region at the molecular and cellular levels may provide an important insight into the neurobiological basis of the adverse clinical outcomes found in children exposed to psychosocial deprivation.


From drought sensing to developmental control: evolution of cyclic AMP signaling in social amoebas.
Amoebas and other protists commonly encyst when faced with environmental stress. Although little is known of the signaling pathways that mediate encystation, the analogous process of spore formation in dictyostelid social amoebas is better understood. In Dictyostelium discoideum, secreted cyclic AMP (cAMP) mediates the aggregation of starving amoebas and induces the differentiation of prespore cells. Intracellular cAMP acting on cAMP-dependent protein kinase (PKA) triggers the maturation of spores and prevents their germination under the prevalent conditions of high osmolality in the spore head. The osmolyte-activated adenylate cyclase, ACG, produces cAMP for prespore differentiation and inhibition of spore germination. To retrace the origin of ACG function, we investigated ACG gene conservation and function in species that span the dictyostelid phylogeny. ACG genes, osmolyte-activated ACG activity, and osmoregulation of spore germination were detected in species that represent the 4 major groups of Dictyostelia. Unlike the derived species D. discoideum, many basal Dictyostelia have retained the ancestral mechanism of encystation from solitary amoebas. In these species and in solitary amoebas, encystation is independently triggered by starvation or by high osmolality. Osmolyte-induced encystation was accompanied by an increase in cAMP and prevented by inhibition of PKA, indicating that ACG and PKA activation mediate this response. We propose that high osmolality signals drought in soil amoebas and that developmental cAMP signaling in the Dictyostelia has evolved from this stress response.