Recombinant F(ab') C242-Pseudomonas exotoxin, but not the whole antibody-based immunotoxin, causes regression of a human colorectal tumor xenograft.
We have previously made a Mr 195,000 immunotoxin (IT) composed of mAb C242 coupled to Pseudomonas exotoxin A. This IT inhibited growth but did not cause regression of a human colorectal cancer xenograft growing in nude mice (W. Debinski et al., J. Clin. Invest., 90: 405-411, 1992). Since smaller proteins penetrate into tissues and tumors better than larger proteins, we have made a smaller recombinant (r) IT to overcome the hypothesized poor tumor penetration of the Mr 195,000 conjugate. This was accomplished by making a C242rF(ab')-based Mr 86,000 IT. To make rF(ab')-IT, the Fd and kappa chains of mAb C242 were cloned, and kappa was fused at the gene level to PE38QQR, a mutant form of Pseudomonas exotoxin. Both C242Fd and C242kappa-PE38QQR were expressed in a bacterial expression system, and large amounts of the C242Fd attached via a disulfide bond to the C242kappa-PE38QQR were obtained. The C242rF(ab')-IT covalently linked heterodimer has a 50% inhibitory concentration of 0.2-2.0 ng/ml (2-20 pm, respectively) on human colon adenocarcinoma cell lines that express the C242 antigen. When injected into mice bearing Colo205 tumors, the C242rF(ab')-PE38QQR caused an immediate regression of the tumors, while the C242-PE38QQR conjugate had only a growth inhibitory effect. In addition, several cures were obtained. Our results indicate that rIT C242F(ab')-PE38QQR is a much more potent antitumor agent than an IgG conjugate.


Use of oral contraceptives, alcohol, and risk for invasive breast cancer.
The aim of our study was to examine how the use of oral contraceptives (OCs) interact with alcohol on breast cancer risk within the large prospective follow-up study, Norwegian Women and Cancer Study. Between 1991 and 1997, women aged 30 to 70 years were drawn at random from the central person register and mailed an invitation. Follow-up information was collected throughout 2001 by linkage to national registries. Only women (n = 86,948) with complete information on alcohol consumption and duration of OC use were included in the present analysis. A total of 1,130 invasive breast cancers were diagnosed during 618,638 person-years of follow-up. Consumption of > or =10.0 g/d alcohol was associated with a breast cancer relative risk (95% confidence interval) of 1.69 (1.32-2.15), consistent with a linear relationship (P for trend < 0.0001). Among alcohol consumers, an excess risk of breast cancer was observed for total duration of OC use only among women who consumed <5 g/d alcohol (P for trend = 0.0009). We observed a negative interaction between duration of OC use and alcohol consumption effects (P for interaction = 0.01). After stratification on menopausal status, the association between high alcohol intake and breast cancer was more prominent among postmenopausal women than among premenopausal women (P for heterogeneity = 0.01). No interaction between alcohol and duration of OC use were significant after stratification on menopausal status. Our findings in conjunction with biological data imply that alcohol and OCs have antagonistic effects on breast cancer risk through a common pathway. Whether the interactive effect differs according to menopausal status remains unclear and needs further investigations.


Real-time effect of electron beam on MoS2 field-effect transistors.
Irradiation of MoS2 field-effect transistors (FETs) fabricated on Si/SiO2 substrates with electron beams (e-beams) below 30 keV creates electron-hole pairs (EHP) in the SiO2, which increase the interface trap density (Nit ) and change the current path in the channel, resulting in performance changes. In situ measurements of the electrical characteristics of the FET performed using a nano-probe system mounted inside a scanning electron microscope show that e-beam irradiation enables both multilayer and monolayer MoS2 channels act as conductors. The e-beams mostly penetrate the channel owing to their large kinetic energy, while the EHPs formed in the SiO2 layer can contribute to the conductance by flowing into the MoS2 channel or inducing the gate bias effect. The analysis of the device parameters in the initial state and the vent-evacuation state after e-beam irradiation can clarify the effect of the interplay between the e-beam-induced EHPs and ambient adsorbates on the carrier behavior, which depends on the thickness of the MoS2 layer. DC and low frequency noise analysis reveals that the e-beam-induced EHPs increase Nit from 109-1010 to 1011 cm-2 eV-1 in both monolayer and multilayer devices, while the interfacial Coulomb scattering parameter αSC increases by three times in the monolayer and decreases to one-tenth of its original value in the multilayer. In other words, an MoS2 layer with a thickness of ∼30 nm is less sensitive to adsorbates by surface screening. Thus, the carrier mobility in the monolayer device decreases from 45.7 to 40 cm2 V-1 s-1, while in the 30 nm-thick multilayer device, it increases from 4.9 to 5.6 cm2 V-1 s-1. This is further evidenced by simulations of the distribution of interface traps and channel carriers in the MoS2 FET before and after e-beam irradiation, demonstrating that Coulomb scattering decreases as the effective channel moves away from the interface.


Characterization of Thermobifida fusca cutinase-carbohydrate-binding module fusion proteins and their potential application in bioscouring.
Cutinase from Thermobifida fusca is thermally stable and has potential application in the bioscouring of cotton in the textile industry. In the present study, the carbohydrate-binding modules (CBMs) from T. fusca cellulase Cel6A (CBM(Cel6A)) and Cellulomonas fimi cellulase CenA (CBM(CenA)) were fused, separately, to the carboxyl terminus of T. fusca cutinase. Both fusion enzymes, cutinase-CBM(Cel6A) and cutinase-CBM(CenA), were expressed in Escherichia coli and purified to homogeneity. Enzyme characterization showed that both displayed similar catalytic properties and pH stabilities in response to T. fusca cutinase. In addition, both fusion proteins displayed an activity half-life of 53 h at their optimal temperature of 50°C. Compared to T. fusca cutinase, in the absence of pectinase, the binding activity on cotton fiber was enhanced by 2% for cutinase-CBM(Cel6A) and by 28% for cutinase-CBM(CenA), whereas in the presence of pectinase, the binding activity was enhanced by 40% for the former and 45% for the latter. Notably, a dramatic increase of up to 3-fold was observed in the amount of released fatty acids from cotton fiber by both cutinase-CBM fusion proteins when acting in concert with pectinase. This is the first report of improving the scouring efficiency of cutinase by fusing it with CBM. The improvement in activity and the strong synergistic effect between the fusion proteins and pectinase suggest that they may have better applications in textile bioscouring than the native cutinase.


Risk factors for chronic renal failure in Ivory Coast: a prospective study of 280 patients.
Chronic renal failure (CRF) represents the major cause of mortality in the nephrology unit in Ivory Coast because the means for appropriate management are lacking. The present study was performed to investigate the risk factors for CRF so that strategies for prevention could be elaborated. A case-control study was performed prospectively at the Yopougon Teaching Hospital in Abidjan from January 2006 to December 2006. Factors known to cause CRF were investigated in patients and controls. Their prevalence rates were compared with the general population. A total of 280 patients and 113 controls were recruited. The mean age of the patients was 37.88 ± 13.33 years and that of the controls was 41.5 ± 9.72 years. Both genders were equally represented. The main causes of CRF were chronic glomerulonephritis (47.48%), with HIV infection accounting for 15% of them, and essential hypertension (HTA) (25%). Essential HTA represented the only factor which, if untreated, inevitably leads to CRF. Thus, our study indicates that HTA is a major public health concern. All efforts should be implemented to reduce the high prevalence of HTA and the deleterious effect of this disorder in Ivory Coast.


Prevalence and Risk Factors for Latent Tuberculosis Infection among Healthcare Workers in a Low Incidence Country.
Tuberculosis prevention is a major goal in the hospital setting. Because of the possible progression or reactivation of latent disease, the screening of healthcare workers is an important issue in the TB control program. The aim of the study was to assess the prevalence of LTBI (latent tuberculosis infection) and to evaluate the main risk factors related to this condition in a teaching hospital in Italy. We reviewed the data of a tuberculosis screening conducted on 3622 healthcare professionals in a teaching hospital in Rome. All subjects were evaluated by QuantiFERON test which if positive, was followed by appropriate clinical and diagnostic procedures. Latent Tuberculosis Infection LTBI condition was detected in 2.1% of the cases, most commonly in men. Male gender, higher age class, country of birth and nurse job were statistically related with the positivity to QuantiFERON test. LTBI was relatively uncommon in our population, however, given the potential risk of reactivation and progression to overt disease, the screening of healthcare workers and students is recommended in the hospital of low-incidence countries.


Structural and magnetic properties of spin-1/2 dimer compound Cu2(IPA)2(DMF)(H2O) with a large spin gap.
We present the synthesis and a detailed investigation of structural and magnetic properties of metal-organic compound Cu2(IPA)2(DMF)(H2O) by means of x-ray diffraction, magnetization, and heat capacity measurements. Single crystals of the title compound were synthesized by judicious selection of organic ligand and employing a selective hydrothermal reaction route. It crystallizes in an orthorhombic structure with space group Cmca. The structural analysis revealed that two Cu2+ ions are held together by the organic component (-O-C-O-) in a square paddle-wheel to form spin dimers which are aligned perpendicular to each other and are further coupled through organic ligands (isophthalic acid) forming two-dimensional layers. Temperature dependent magnetic susceptibility [Formula: see text] could be described well using spin-1/2 dimer model. The spin susceptibility [Formula: see text] shows an exponential decrease in the low temperature region, below the broad maximum, confirming the singlet ground state with a large spin gap of [Formula: see text] K. The heat capacity C p measured as a function of temperature also confirms the absence of magnetic long-range-order down to 2 K.


Somatic versus dendritic resonance: differential filtering of inputs through non-uniform distributions of active conductances.
Synaptic inputs to neurons are processed in a frequency-dependent manner, with either low-pass or resonant response characteristics. These types of filtering play a key role in the frequency-specific information flow in neuronal networks. While the generation of resonance by specific ionic conductances is well investigated, less attention has been paid to the spatial distribution of the resonance-generating conductances across a neuron. In pyramidal neurons - one of the major excitatory cell-types in the mammalian brain - a steep gradient of resonance-generating h-conductances with a 60-fold increase towards distal dendrites has been demonstrated experimentally. Because the dendritic trees of these cells are large, spatial compartmentalization of resonant properties can be expected. Here, we use mathematical descriptions of spatially extended neurons to investigate the consequences of such a distal, dendritic localization of h-conductances for signal processing. While neurons with short dendrites do not exhibit a pronounced compartmentalization of resonance, i.e. the filter properties of dendrites and soma are similar, we find that neurons with longer dendrites ([Formula: see text] space constant) can show distinct filtering of dendritic and somatic inputs due to electrotonic segregation. Moreover, we show that for such neurons, experimental classification as resonant versus nonresonant can be misleading when based on somatic recordings, because for these morphologies a dendritic resonance could easily be undetectable when using somatic input. Nevertheless, noise-driven membrane-potential oscillations caused by dendritic resonance can propagate to the soma where they can be recorded, hence contrasting with the low-pass filtering at the soma. We conclude that non-uniform distributions of active conductances can underlie differential filtering of synaptic input in neurons with spatially extended dendrites, like pyramidal neurons, bearing relevance for the localization-dependent targeting of synaptic input pathways to these cells.


Ant-mediated expansion of an obligate seeder species during the first years after fire.
Most obligate seeder species build up a soil seed bank that is associated with massive seed germination in the year immediately after a fire. These species are also shade-intolerant and disappear when vegetation cover closes, creating unsuitable conditions for seedling recruitment. The only way for these plants to expand their populations is when habitats suitable for seedling recruitment arise (i.e. in years immediately after a fire). However, short primary seed dispersal of obligate seeders does not allow these plants to colonise the suitable habitats, and these habitats can only be colonised by secondary seed dispersion. We hypothesised that Fumana ericoides, an obligate-seeding small shrub, not only establishes abundantly in the first year after fire, but also expands its local range in the following years due to secondary dispersal by ants while suitable habitats are still available. We tested this hypothesis using experimental studies and a simulation model of potential population expansion in a recently burned area. Results showed that F. ericoides not only established prolifically in the year immediately after fire, but was also able to recruit new individuals and expand its population in the years following the fire, despite a low germination rate and short primary seed dispersal. Ant-mediated seed dispersal and availability of suitable habitats were key factors in this phenomenon: ants redistributed seeds in suitable habitats while they were available, which accelerated the expansion of F. ericoides because new plants established far away from the core population.


Pregnancy recognition and conceptus implantation in domestic ruminants: roles of progesterone, interferons and endogenous retroviruses.
The present review highlights new information on pregnancy recognition and conceptus development and implantation in sheep with respect to regulation by progesterone, interferons and endogenous retroviruses. After formation of the corpus luteum, progesterone acts on the endometrium and stimulates blastocyst growth and elongation to a filamentous conceptus (embryo/fetus and associated extra-embryonic membranes). The envelope of endogenous retroviruses related to Jaagsiekte sheep retroviruses appears to intrinsically regulate mononuclear trophectoderm cell proliferation and differentiation into trophoblast giant binucleate cells. The mononuclear trophectoderm cells of elongating sheep conceptuses secrete interferon-tau, which acts on the endometrium to prevent development of the luteolytic mechanism by inhibiting transcription of the gene for the oestrogen receptor alpha in the luminal and superficial ductal glandular epithelia. These actions prevent oestrogen-induced transcription of the oxytocin receptor gene and, therefore, oxytocin-induced luteolytic pulses of prostaglandin F2alpha. Progesterone down regulation of its receptors in luminal and glandular epithelia correlates temporally with a reduction in anti-adhesive mucin land induction of secreted galectin 15 (LGALSI5) and secreted phosphoprotein 1, which are proposed to regulate trophectoderm proliferation and adhesion. Interferon-c acts on the endometrial lumenal epithelium to induce WNT7A and to stimulate LGALS 15, cathepsin L and cystatin C, which are candidate regulators of conceptus development and implantation. The number of potential contributors to maternal recognition and establishment of pregnancy continues to grow and this highlights our limited appreciation of the complexity of the key molecules and signal transduction pathways that intersect during these key developmental processes. The goal of improving reproductive efficiency by preventing embryonic losses that occur during the peri-implantation period of pregnancy in domestic ruminants provides the challenge to increase our knowledge of endometrial function and conceptus development.


Real-time ligation chain reaction for DNA quantification and identification on the FO-SPR.
Different assays have been developed in the past years to meet point-of-care diagnostic tests requirements for fast and sensitive quantification and identification of targets. In this paper, we developed the ligation chain reaction (LCR) assay on the Fiber Optic Surface Plasmon Resonance (FO-SPR) platform, which enabled simultaneous quantification and cycle-to-cycle identification of DNA during amplification. The newly developed assay incorporated FO-SPR DNA melting assay, previously developed by our group. This required establishment of several assay parameters, including buffer ionic strength and thermal ramping speed as these parameters both influence the ligation enzyme performance and the hybridization yield of the gold nanoparticles (Au NPs) on the FO-SPR sensor. Quantification and identification of DNA targets was achieved over a wide concentration range with a calibration curve spanning 7 orders of magnitude and LOD of 13.75 fM. Moreover, the FO-SPR LCR assay could discriminate single nucleotide polymorphism (SNPs) without any post reaction analysis, featuring thus all the essential requirements of POC tests.


The ultimate physical limits of privacy.
Among those who make a living from the science of secrecy, worry and paranoia are just signs of professionalism. Can we protect our secrets against those who wield superior technological powers? Can we trust those who provide us with tools for protection? Can we even trust ourselves, our own freedom of choice? Recent developments in quantum cryptography show that some of these questions can be addressed and discussed in precise and operational terms, suggesting that privacy is indeed possible under surprisingly weak assumptions.


Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification?
Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed a fragment screening campaign on the HIV-1 integrase core domain (IN) using similar commercially purchased fragment libraries. The two campaigns used different screening methods for the preliminary identification of fragment hits; one used saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), and the other used surface plasmon resonance (SPR) spectroscopy. Both initial screens were followed by X-ray crystallography. Using the STD-NMR/X-ray approach, 15 IN/fragment complexes were identified, whereas the SPR/X-ray approach found 6 complexes. In this article, we compare the approaches that were taken by each group and the results obtained, and we look at what factors could potentially influence the final results. We find that despite using different approaches with little overlap of initial hits, both approaches identified binding sites on IN that provided a basis for fragment-based lead discovery and further lead development. Comparison of hits identified in the two studies highlights a key role for both the conditions under which fragment binding is measured and the criteria selected to classify hits.


Reversible Local and Global Switching in Multicomponent Supramolecular Networks: Controlled Guest Release and Capture at the Solution/Solid Interface.
Dynamically switchable supramolecular systems offer exciting possibilities in building smart surfaces, the structure and thus the function of which can be controlled by using external stimuli. Here we demonstrate an elegant approach where the guest binding ability of a supramolecular surface can be controlled by inducing structural transitions in it. A physisorbed self-assembled network of a simple hydrogen bonding building block is used as a switching platform. We illustrate that the reversible transition between porous and nonporous networks can be accomplished using an electric field or applying a thermal stimulus. These transitions are used to achieve controlled guest release or capture at the solution-solid interface. The electric field and the temperature-mediated methods of guest release are operative at different length scales. While the former triggers the transition and thus guest release at the nanometer scale, the latter is effective over a much larger scale. The flexibility associated with physisorbed self-assembled networks renders this approach an attractive alternative to conventional switchable systems.


Small nerve fibres, small hands and small feet: a new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation.
The Na(V)1.7 sodium channel is preferentially expressed within dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. Gain-of-function variants of Na(V)1.7 have recently been described in patients with painful small fibre neuropathy and no other apparent cause. Here, we describe a novel syndrome of pain, dysautonomia, small hands and small feet in a kindred carrying a novel Na(V)1.7 mutation. A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). Blood examination and nerve conduction studies were unremarkable. Intra-epidermal nerve fibre density was significantly reduced compared to age- and sex-matched normative values. The patient's brother and father reported similar complaints including distal extremity redness and pain, and demonstrated comparable distal limb under-development. Quantitative sensory testing revealed impaired warmth sensation in the proband, father and brother. Genetic analysis revealed a novel missense mutation in the SCN9A gene encoding sodium channel Na(V)1.7 (G856D; c.2567G > A) in all three affected subjects, but not in unaffected family members. Functional analysis demonstrated that the mutation hyperpolarizes (-9.3 mV) channel activation, depolarizes (+6.2 mV) steady-state fast-inactivation, slows deactivation and enhances persistent current and the response to slow ramp stimuli by 10- to 11-fold compared with wild-type Na(V)1.7 channels. Current-clamp analysis of dorsal root ganglion neurons transfected with G856D mutant channels demonstrated depolarized resting potential, reduced current threshold, increased repetitive firing in response to suprathreshold stimulation and increased spontaneous firing. Our results demonstrate that the G856D mutation produces DRG neuron hyperexcitability which underlies pain in this kindred, and suggest that small peripheral nerve fibre dysfunction due to this mutation may have contributed to distal limb under-development in this novel syndrome.


Structural characterization of zinc-deficient human superoxide dismutase and implications for ALS.
Over 130 mutations to copper, zinc superoxide dismutase (SOD) are implicated in the selective death of motor neurons found in 25% of patients with familial amyotrophic lateral sclerosis (ALS). Despite their widespread distribution, ALS mutations appear positioned to cause structural and misfolding defects. Such defects decrease SOD's affinity for zinc, and loss of zinc from SOD is sufficient to induce apoptosis in motor neurons in vitro. To examine the importance of the zinc site in the structure and pathogenesis of human SOD, we determined the 2.0-A-resolution crystal structure of a designed zinc-deficient human SOD, in which two zinc-binding ligands have been mutated to hydrogen-bonding serine residues. This structure revealed a 9 degrees twist of the subunits, which opens the SOD dimer interface and represents the largest intersubunit rotational shift observed for a human SOD variant. Furthermore, the electrostatic loop and zinc-binding subloop were partly disordered, the catalytically important Arg143 was rotated away from the active site, and the normally rigid intramolecular Cys57-Cys146 disulfide bridge assumed two conformations. Together, these changes allow small molecules greater access to the catalytic copper, consistent with the observed increased redox activity of zinc-deficient SOD. Moreover, the dimer interface is weakened and the Cys57-Cys146 disulfide is more labile, as demonstrated by the increased aggregation of zinc-deficient SOD in the presence of a thiol reductant. However, equimolar Cu,Zn SOD rapidly forms heterodimers with zinc-deficient SOD (t1/2 approximately 15 min) and prevents aggregation. The stabilization of zinc-deficient SOD as a heterodimer with Cu,Zn SOD may contribute to the dominant inheritance of ALS mutations. These results have general implications for the importance of framework stability on normal metalloenzyme function and specific implications for the role of zinc ion in the fatal neuropathology associated with SOD mutations.


An adhesion-dependent switch between mechanisms that determine motile cell shape.
Keratocytes are fast-moving cells in which adhesion dynamics are tightly coupled to the actin polymerization motor that drives migration, resulting in highly coordinated cell movement. We have found that modifying the adhesive properties of the underlying substrate has a dramatic effect on keratocyte morphology. Cells crawling at intermediate adhesion strengths resembled stereotypical keratocytes, characterized by a broad, fan-shaped lamellipodium, clearly defined leading and trailing edges, and persistent rates of protrusion and retraction. Cells at low adhesion strength were small and round with highly variable protrusion and retraction rates, and cells at high adhesion strength were large and asymmetrical and, strikingly, exhibited traveling waves of protrusion. To elucidate the mechanisms by which adhesion strength determines cell behavior, we examined the organization of adhesions, myosin II, and the actin network in keratocytes migrating on substrates with different adhesion strengths. On the whole, our results are consistent with a quantitative physical model in which keratocyte shape and migratory behavior emerge from the self-organization of actin, adhesions, and myosin, and quantitative changes in either adhesion strength or myosin contraction can switch keratocytes among qualitatively distinct migration regimes.


Organic light-emitting-diode-based plasmonic dark-field microscopy.
We propose and demonstrate a compact, alignment-free dark-field microscopy technique, termed as organic light-emitting-diode-based plasmonic dark-field microscopy. Experimental results show that it is capable of forming dark-field images of the specimens utilizing a highly integrated chip-scale plasmonic condenser. This technique has high z resolution and high imaging contrast and is suitable for the dynamics study near the contact regions of living cells and the substrate.


Is diabetes mellitus a risk factor for ovarian cancer? A case-control study in Utah and Washington (United States).
Insulin resistance characterizes non-insulin dependent diabetes (NIDDM). Insulin resistance may coexist in clinical syndromes with hyperestrogenism and hyperandrogenism, suggesting that the ovary may be sensitive to effects of insulin. In addition, insulin-like growth factor-I receptors, which are capable of binding insulin, have been identified in ovarian cancer tissue and are proposed to regulate cell growth. We evaluated the association between a history of diabetes mellitus and ovarian cancer in a case-control study in seven counties in Washington and in Utah (United States) during the years 1975-87. Cases included women newly diagnosed with ovarian cancer over a five-year period who were identified through population-based cancer reporting. Controls similar to cases with regard to age and county of residence were identified via household surveys or random digit dialing. The study included 595 cases and 1,587 controls. Twenty-seven cases (4.5 percent) and 72 controls (4.5 percent) reported a history of diabetes. Logistic regression analysis of the association between diabetes and ovarian cancer controlling for age, body mass index, and race resulted in an odds ratio (OR) of 0.9 (95 percent confidence interval [CI] = 0.6-1.5). The OR was not changed with further controlling for prior oral contraceptive use or prior pregnancy. None of the 20 women with nonepithelial tumors (15 of which were stromal tumors) had a history of diabetes (upper CI = 4.0). These results, together with findings of two earlier cohort studies, do not support the hypothesis that diabetes is a risk factor for epithelial ovarian cancer.


Coherent and incoherent combination of Gaussian beams employing lens array distributed on the spherical chamber.
Coherent and incoherent combination of Gaussian beams employing a lens array distributed on the spherical chamber is theoretically analyzed. The output field of each source in the array is coupled through an individual optical system whose local optical axis coincides with the radial direction of the chamber. The resulting intensity profile near the origin is derived. The intensity profile and power in the bucket on the target for rectangular and hexagonal arrangement are numerically calculated. The influences of the center-to-center separation and the ring number of the focusing lens array are given. The synthetic intensity profile of incoherent combination changes little for a lens array scale much smaller than the chamber size. In contrast, the synthetic intensity profile of coherent combination shows an interference pattern with a sharp central peak and sidelobes.


Breast implant associated anaplastic large cell lymphoma: The UK experience. Recommendations on its management and implications for informed consent.
Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare, Non-Hodgkin lymphoma arising in the capsule of breast implants. BIA-ALCL presents as a recurrent effusion and/or mass. Tumours exhibit CD30 expression and are negative for Anaplastic Lymphoma Kinase (ALK). We report the multi-disciplinary management of the UK series and how the stage of disease may be used to stratify treatment. Between 2012 and 2016, 23 cases of BIA-ALCL were diagnosed in 15 regional centres throughout the UK. Data on breast implant surgeries, clinical features, treatment and follow-up were available for 18 patients. The mean lead-time from initial implant insertion to diagnosis was 10 years (range: 3-16). All cases were observed in patients with textured breast implants or expanders. Fifteen patients with breast implants presented with stage I disease (capsule confined), and were treated with implant removal and capsulectomy. One patient received adjuvant chest-wall radiotherapy. Three patients presented with extra-capsular masses (stage IIA). In addition to explantation, capsulectomy and excision of the mass, all patients received neo-/adjuvant chemotherapy with CHOP as first line. One patient progressed on CHOP but achieved pathological complete response (pCR) with Brentuximab Vedotin. After a mean follow-up of 23 months (range: 1-56) all patients reported here remain disease-free. BIA-ALCL is a rare neoplasm with a good prognosis. Our data support the recommendation that stage I disease be managed with surgery alone. Adjuvant chemotherapy may be required for more invasive disease and our experience has shown the efficacy of Brentuximab as a second line treatment.


Reading speed does not benefit from increased line spacing in AMD patients.
Crowding, the adverse spatial interaction due to the proximity of adjacent targets, has been suggested as an explanation for slow reading in peripheral vision. Previously, we showed that increased line spacing, which presumably reduces crowding between adjacent lines of text, improved reading speed in the normal periphery (Chung, Optom Vis Sci 2004;81:525-35). The purpose of this study was to examine whether or not individuals with age-related macular degeneration (AMD) would benefit from increased line spacing for reading. Experiment 1: Eight subjects with AMD read aloud 100-word passages rendered at five line spacings: the standard single spacing, 1.5x, 2x, 3x, and 4x the standard spacing. Print sizes were 1x and 2x of the critical print size. Reading time and number of reading errors for each passage were measured to compute the reading speed. Experiment 2: Four subjects with AMD read aloud sequences of six 4-letter words, presented on a computer monitor using the rapid serial visual presentation (RSVP) paradigm. Target words were presented singly, or flanked above and below by two other words that changed in synchrony with the target word, at various vertical word separations. Print size was 2x the critical print size. Reading speed was calculated based on the RSVP exposure duration that yielded 80% of the words read correctly. Averaged across subjects, reading speeds for passages were virtually constant for the range of line spacings tested. For sequences of unrelated words, reading speeds were also virtually constant for the range of vertical word separations tested, except at the smallest (standard) separation at which reading speed was lower. Contrary to the previous finding that reading speed improved in normal peripheral vision, increased line spacing in passages, or increased vertical separation between words in RSVP, did not lead to improved reading speed in people with AMD.


Cranberry Extract for Symptoms of Acute, Uncomplicated Urinary Tract Infection: A Systematic Review.
Effective alternatives to antibiotics for alleviating symptoms of acute infections may be appealing to patients and enhance antimicrobial stewardship. Cranberry-based products are already in wide use for symptoms of acute urinary tract infection (UTI). The aim of this review was to identify and critically appraise the supporting evidence. The protocol was registered on PROSPERO. Searches were conducted of Medline, Embase, Amed, Cinahl, The Cochrane library, Clinicaltrials.gov and WHO International Clinical Trials Registry Platform. We included randomised clinical trials (RCTs) and non-randomised studies evaluating the effect of cranberry extract in the management of acute, uncomplicated UTI on symptoms, antibiotic use, microbiological assessment, biochemical assessment and adverse events. Study risk of bias assessments were made using Cochrane criteria. We included three RCTs (n = 688) judged to be at moderate risk of bias. One RCT (n = 309) found that advice to consume cranberry juice had no statistically significant effect on UTI frequency symptoms (mean difference (MD) -0.01 (95% CI: -0.37 to 0.34), p = 0.94)), on UTI symptoms of feeling unwell (MD 0.02 (95% CI: -0.36 to 0.39), p = 0.93)) or on antibiotic use (odds ratio 1.27 (95% CI: 0.47 to 3.43), p = 0.64), when compared with promoting drinking water. One RCT (n = 319) found no symptomatic benefit from combining cranberry juice with immediate antibiotics for an acute UTI, compared with placebo juice combined with immediate antibiotics. In one RCT (n = 60), consumption of cranberry extract capsules was associated with a within-group improvement in urinary symptoms and Escherichia coli load at day 10 compared with baseline (p < 0.01), which was not found in untreated controls (p = 0.72). Two RCTs were under-powered to detect differences between groups for outcomes of interest. There were no serious adverse effects associated with cranberry consumption. The current evidence base for or against the use of cranberry extract in the management of acute, uncomplicated UTIs is inadequate; rigorous trials are needed.


Tau protein function in living cells.
Tau protein from mammalian brain promotes microtubule polymerization in vitro and is induced during nerve cell differentiation. However, the effects of tau or any other microtubule-associated protein on tubulin assembly within cells are presently unknown. We have tested tau protein activity in vivo by microinjection into a cell type that has no endogenous tau protein. Immunofluorescence shows that tau protein microinjected into fibroblast cells associates specifically with microtubules. The injected tau protein increases tubulin polymerization and stabilizes microtubules against depolymerization. This increased polymerization does not, however, cause major changes in cell morphology or microtubule arrangement. Thus, tau protein acts in vivo primarily to induce tubulin assembly and stabilize microtubules, activities that may be necessary, but not sufficient, for neuronal morphogenesis.


Medicaid waivers and public sector mental health service penetration rates for youth.
To assist families of youth with serious emotional disturbance in financing youth's comprehensive care, some states have sought and received Medicaid waivers. Medicaid waivers waive or relax the Medicaid means test for eligibility to provide insurance coverage to nonpoor families for expensive, otherwise out-of-reach treatment for youth with Serious Emotional Disturbance (SED). Waivers promote treatment access for the most troubled youth, and the present study investigated whether any of several Medicaid waiver options-and those that completely omit the means test in particular-are associated with higher state-wide public sector treatment penetration rates. The investigators obtained data from the U.S. Census, SAMHSA's Uniform Reporting System, and the Centers for Medicare and Medicaid Services. Analysis employed random intercept and random slope linear regression models, controlling for a variety of state demographic and fiscal variables, to determine whether a relationship between Medicaid waiver policies and state-level public sector penetration rates could be observed. Findings indicate that, whether relaxing or completely waiving Medicaid's qualifying income limits, waivers increase public sector penetration rates, particularly for youth under age 17. However, completely waiving Medicaid income limits did not uniquely contribute to penetration rate increases. States offering Medicaid waivers that either relax or completely waive Medicaid's means test to qualify for health coverage present higher public sector treatment rates for youth with behavioral health care needs. There is no evidence that restricting the program to waiving the means test for accessing Medicaid would increase treatment access. (PsycINFO Database Record


Diffusion tensor imaging-based fiber tracking for prediction of the position of the facial nerve in relation to large vestibular schwannomas.
The reliable preoperative visualization of facial nerve location in relation to vestibular schwannoma (VS) would allow surgeons to plan tumor removal accordingly and may increase the safety of surgery. In this prospective study, the authors attempted to validate the reliability of facial nerve diffusion tensor (DT) imaging-based fiber tracking in a series of patients with large VSs. Furthermore, the authors evaluated the potential of this visualization technique to predict the morphological shape of the facial nerve (tumor compression-related flattening of the nerve). Diffusion tensor imaging and anatomical images (constructive interference in steady state) were acquired in a series of 22 consecutive patients with large VSs and postprocessed with navigational software to obtain facial nerve fiber tracking. The location of the cerebellopontine angle (CPA) part of the nerve in relation to the tumor was recorded during surgery by the surgeon, who was blinded to the results of the fiber tracking. A correlative analysis was performed of the imaging-based location of the nerve compared with its in situ position in relation to the VS. Fibers corresponding to the anatomical location and course of the facial nerve from the brainstem to the internal auditory meatus were identified with the DT imaging-based fiber tracking technique in all 22 cases. The location of the CPA segment of the facial nerve in relation to the VS determined during surgery corresponded to the location of the fibers, predicted by the DT imaging-based fiber tracking, in 20 (90.9%) of the 22 patients. No DT imaging-based fiber tracking correlates were found with the 2 morphological types of the nerve (compact or flat). The current study of patients with large VSs has shown that the position of the facial nerve in relation to the tumor can be predicted reliably (in 91%) using DT imaging-based fiber tracking. These are preliminary results that need further verification in a larger series.


The resting human brain and motor learning.
Functionally related brain networks are engaged even in the absence of an overt behavior. The role of this resting state activity, evident as low-frequency fluctuations of BOLD (see [1] for review, [2-4]) or electrical [5, 6] signals, is unclear. Two major proposals are that resting state activity supports introspective thought or supports responses to future events [7]. An alternative perspective is that the resting brain actively and selectively processes previous experiences [8]. Here we show that motor learning can modulate subsequent activity within resting networks. BOLD signal was recorded during rest periods before and after an 11 min visuomotor training session. Motor learning but not motor performance modulated a fronto-parietal resting state network (RSN). Along with the fronto-parietal network, a cerebellar network not previously reported as an RSN was also specifically altered by learning. Both of these networks are engaged during learning of similar visuomotor tasks [9-22]. Thus, we provide the first description of the modulation of specific RSNs by prior learning--but not by prior performance--revealing a novel connection between the neuroplastic mechanisms of learning and resting state activity. Our approach may provide a powerful tool for exploration of the systems involved in memory consolidation.


Use of a support vector machine for categorizing free-text notes: assessment of accuracy across two institutions.
Electronic health record (EHR) users must regularly review large amounts of data in order to make informed clinical decisions, and such review is time-consuming and often overwhelming. Technologies like automated summarization tools, EHR search engines and natural language processing have been shown to help clinicians manage this information. To develop a support vector machine (SVM)-based system for identifying EHR progress notes pertaining to diabetes, and to validate it at two institutions. We retrieved 2000 EHR progress notes from patients with diabetes at the Brigham and Women's Hospital (1000 for training and 1000 for testing) and another 1000 notes from the University of Texas Physicians (for validation). We manually annotated all notes and trained a SVM using a bag of words approach. We then used the SVM on the testing and validation sets and evaluated its performance with the area under the curve (AUC) and F statistics. The model accurately identified diabetes-related notes in both the Brigham and Women's Hospital testing set (AUC=0.956, F=0.934) and the external University of Texas Faculty Physicians validation set (AUC=0.947, F=0.935). Overall, the model we developed was quite accurate. Furthermore, it generalized, without loss of accuracy, to another institution with a different EHR and a distinct patient and provider population. It is possible to use a SVM-based classifier to identify EHR progress notes pertaining to diabetes, and the model generalizes well.


Leptin and the immune system: how nutritional status influences the immune response.
Several observations suggest the presence of an interaction between immune and the endocrine systems. Leptin is an adipocyte-derived hormone, that belongs structurally to the long-chain helical cytokine family such as interleukin-2 (IL-2), interleukin-12 (IL-12), growth hormone (GH), and signals by a class I cytokine receptor (Ob-R). This cytokine represents an important link between fat mass on the one side and the regulation of energy balance and reproductive function on the other. Indeed, obese leptin-deficient ob/ob mice display low body temperature, hyperphagia, infertility and evidence of immune defects with lymphoid organ atrophy, mainly affecting thymic size and cellularity. Acute starvation, associated with decreased leptin levels, causes thymic atrophy and reduces the delayed type hypersensitivity (DTH) reaction to antigens in normal mice, resembling that observed in ob/ob mice. Leptin replacement reverses the immunosuppressive effects of acute starvation in mice. Leptin differentially affects the in vitro proliferation and cytokine production by naive and memory T cells, increasing IL-2 secretion and proliferation of naive T cells, while inducing IFN-g production in memory T cells with little effect on their proliferation. Presence of leptin seems to be necessary for the induction and maintenance of the pro-inflammatory Th1 immune response. These findings support the hypothesis that leptin plays a key role in linking nutritional state to the T cell function. According to this view, leptin might represent an important target for immune intervention in a variety of pathophysiological conditions.


Accurate and efficient extraction of fringe orientation from the poor-quality ESPI fringe pattern with a convolutional neural network.
The fringe orientation is an important feature of the electronic speckle interferometry (ESPI) fringe pattern. Accurate and efficient calculation of the fringe orientation is very important for subsequent electronic speckle processing such as skeleton extraction and image filtering. To accurately and efficiently estimate fringe orientation, we propose an effective method based on a convolutional neural network. In the proposed method, the network needs clean-noisy image pairs to train and noisy images with theoretical value to test. The aligned noise-free ESPI fringe pattern orientation fields are fairly good estimations for the corresponding noise ones. After the model training is done, the other multiple ESPI fringe patterns are fed to the trained network simultaneously; the corresponding orientation results can be obtained accurately and efficiently. The advantage of using this method to extract the orientation is that the fringe orientation information can be extracted accurately and efficiently without complicated parameter adjustment. We evaluate the performance of our method via applying our method to the computer-simulated and experimentally acquired ESPI fringe patterns and comparing the results with those of three extensively used methods.


JAM-A expression positively correlates with poor prognosis in breast cancer patients.
The cell-cell adhesion protein junctional adhesion molecule-A (JAM-A) influences epithelial cell morphology and migration. As migration is required for tumor cell invasion and metastasis, we sought to elucidate the role of JAM-A in invasive breast cancer. A breast cancer tissue microarray was analyzed for JAM-A protein expression, in parallel with analysis of JAM-A gene expression data from a breast cancer clinical dataset. Our data demonstrate a novel association between JAM-A gene and protein upregulation and poor prognosis in breast cancer. To mechanistically dissect this process, we used lentiviral technology to stably knock down JAM-A gene expression by shRNA in MCF7 breast cancer cells, which express high-endogenous levels of JAM-A. We also antagonized JAM-A function in wild-type MCF7 cells using an inhibitory antibody that blocks JAM-A dimerization. Knockdown or functional antagonism of JAM-A decreased breast cancer cell migration in scratch-wound assays. Reductions in beta1-integrin protein levels were observed after JAM-A-knockdown in MCF7 cells, suggesting a mechanism for reduced motility after loss of JAM-A. Consistent with this hypothesis, tissue microarray analysis of beta1-integrin protein expression in invasive breast cancer tissues revealed a trend toward high beta1-integrin protein levels being indicative of poor prognosis. Twenty-two percent of patients were observed to coexpress high levels of JAM-A and beta1-integrin protein, and MDA-MB-231 breast cells stably overexpressing JAM-A showed an increase in beta1-integrin protein expression. Our results are consistent with a previously unreported role for JAM-A overexpression as a possible mechanism contributing to progression in primary breast cancer; and a potential therapeutic target.


Peptide B12: emerging trends at the interface of inorganic chemistry, chemical biology and medicine.
The sophisticated and efficient delivery of vitamin B(12) ("B(12)") into cells offers promise for B(12)-bioconjugates in medicinal diagnosis and therapy. It is therefore surprising that rather little attention is presently paid to an alternative strategy in drug design: the development of structurally perfect, but catalytically inactive semi-artificial B(12) surrogates. Vitamin B(12) cofactors catalyse important biological transformations and are indispensible for humans and most other forms of life. This strong metabolic dependency exhibits enormous medicinal opportunities. Inhibitors of B(12) dependent enzymes are potential suppressors of fast proliferating cancer cells. This perspective article focuses on the design and study of backbone modified B(12) derivatives, particularly on peptide B(12) derivatives. Peptide B(12) is a recently introduced class of biomimetic cobalamins bearing an artificial peptide backbone with adjustable coordination and redox-properties. Pioneering biological studies demonstrated reduced catalytic activity, combined with inhibitory potential that is encouraging for future efforts in turning natural cofactors into new anti-proliferative agents.


Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma.
Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.


A real-time medical cartography of epidemic disease (Nodding syndrome) using village-based lay mHealth reporters.
Disease surveillance in rural regions of many countries is poor, such that prolonged delays (months) may intervene between appearance of disease and its recognition by public health authorities. For infectious disorders, delayed recognition and intervention enables uncontrolled disease spread. We tested the feasibility in northern Uganda of developing real-time, village-based health surveillance of an epidemic of Nodding syndrome (NS) using software-programmed smartphones operated by minimally trained lay mHealth reporters. We used a customized data collection platform (Magpi) that uses mobile phones and real-time cloud-based storage with global positioning system coordinates and time stamping. Pilot studies on sleep behavior of U.S. and Ugandan medical students identified and resolved Magpi-programmed cell phone issues. Thereafter, we deployed Magpi in combination with a lay-operator network of eight mHealth reporters to develop a real-time electronic map of child health, injury and illness relating to NS in rural northern Uganda. Surveillance data were collected for three consecutive months from 10 villages heavily affected by NS. Overall, a total of 240 NS-affected households and an average of 326 children with NS, representing 30 households and approximately 40 NS children per mHealth reporter, were monitored every week by the lay mHealth team. Data submitted for analysis in the USA and Uganda remotely pinpointed the household location and number of NS deaths, injuries, newly reported cases of head nodding (n = 22), and the presence or absence of anti-seizure medication. This study demonstrates the feasibility of using lay mHealth workers to develop a real-time cartography of epidemic disease in remote rural villages that can facilitate and steer clinical, educational and research interventions in a timely manner.


[Ambulatory medical practice in the French-speaking region of Switzerland (1981-1987). Preliminary results].
Between 1981 and 1987, population in the two "cantons" of Vaud and Fribourg increased by 4.5 percent (from 709200 to 740700) but private medical practitioners increased by 26.1 percent (from 971 to 1,224). How did the medical profession adjust itself to such a challenge? The average weekly number of visits reduced (e.g. from 118 to 109 in paediatrics, from 96 to 85 in internal medicine...). Nevertheless, the average duration of each visit did not significantly increase. Consequently, the weekly time devoted to contacts with patients in the office decreased in most specialities (e.g. from 33.9 hours to 31.1 hours in general practice). But the most salient feature was the reduction of time spent by private practitioners in institutions, hospitals or other "medical/social" organizations. The reduction was obvious among internists, surgeons, paediatricians... It was probably caused by the increased number of practitioners. However, "cohort effect" might have played a role in the matter: as the physicians aged, they were less attracted by activities outside their private office. It is noteworthy that all the above figures were observed among the same practitioners, in 1981 and 1987. Moreover, the proportion of patients invited to come back to the physician's office did not grow, the behaviour of the practitioners remaining unchanged during the period. The study also displayed data about a new group of physicians, who were surveyed for the first time in 1987.


Absorption of non-haem iron in normal women measured by the incorporation of two stable isotopes into erythrocytes.
1. Iron absorption has been quantitatively measured as the incorporation of physiological doses of stable iron isotopes into erythrocytes. Five milligrams of 57Fe (orally) and 250 micrograms of 58Fe (intravenously) were given to five healthy women on 2 consecutive days. Fourteen days later the changes in the 57Fe/56Fe and 58Fe/56Fe ratios in the erythrocytes of each subject were measured using an inductively coupled plasma mass spectrometer. Isotope ratios were also measured in two subjects who were not given any enriched isotope. Concomitant measurements of plasma volume using a dye-dilution technique enabled the estimation of body iron mass and the calculation of iron absorption. 2. The mean coefficients of variation for the 57Fe/56Fe ratio and the 58Fe/56Fe ratio were 0.22% and 0.47%, respectively. This precision allowed enrichments of basal ratios to be reliably detected in all cases. The mean change in the 57Fe/56Fe ratio was 0.00116 (SD 0.00052, P < 0.001) and the mean change in the 58Fe/56Fe ratio was 0.00035 (SD 0.00004, P < 0.001). Control subjects showed no enrichment. 3. The calculated iron absorption ranged from 10% to 34%, and the amount of absorption was related to the iron stores of the subjects. Percentage iron absorption was identical when estimates of the plasma volume (derived from a body mass equation) were used instead of the plasma volume determined by dye-dilution measurements. Incorporation of intravenous iron into erythrocytes was on average 81% (range 68-93%). 4. The method is especially applicable to the study of iron absorption during pregnancy when incorporation into erythrocytes cannot be predicted.


The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin.
Matriptase-2 (MT2) is a type-II transmembrane, trypsin-like serine protease that is predominantly expressed in the liver. It is a key suppressor for the expression of hepatic hepcidin, an iron-regulatory hormone that is induced via the bone morphogenetic protein signaling pathway. A current model predicts that MT2 suppresses hepcidin expression by cleaving multiple components of the induction pathway. MT2 is synthesized as a zymogen that undergoes autocleavage for activation and shedding. However, the biologically active form of MT2 and, importantly, the contributions of different MT2 domains to its function are largely unknown. Here we examined the activities of truncated MT2 that were generated by site-directed mutagenesis or Gibson assembly master mix, and found that the stem region of MT2 determines the specificity and efficacy for substrate cleavage. The transmembrane domain allowed MT2 activation after reaching the plasma membrane, and the cytoplasmic domain facilitated these processes. Further in vivo rescue studies indicated that the entire extracellular and transmembrane domains of MT2 are required to correct the low-hemoglobin, low-serum iron, and high-hepcidin status in MT2-/- mice. Unlike in cell lines, no autocleavage of MT2 was detected in vivo in the liver, implying that MT2 may also function independently of its proteolytic activity. In conjunction with our previous studies implicating the cytoplasmic domain as an intracellular iron sensor, these observations reveal the importance of each MT2 domain for MT2-mediated substrate cleavage and for its biological function.


Label-free, ultrahigh-speed, 3D observation of bidirectional and correlated intracellular cargo transport by coherent brightfield microscopy.
The investigation of intracellular transport at the molecular scale requires measurements at high spatial and temporal resolutions. We demonstrate the label-free, direct imaging and tracking of native cell vesicles in live cells at an ultrahigh spatiotemporal resolution. Using coherent brightfield (COBRI) microscopy, we monitor individual cell vesicles traveling inside the cell with nanometer spatial precision in 3D at 30 000 frames per second. The stepwise directional motion of the vesicle on the cytoskeletal track is clearly resolved. We also observe the repeated switching of the transport direction of the vesicle in a continuous trajectory. Our high-resolution measurement unveils the transient pausing and subtle bidirectional motion of the vesicle, taking place over tens of nanometers in tens of milliseconds. By tracking multiple particles simultaneously, we found strong correlations between the motions of two neighboring vesicles. Our label-free ultrahigh-speed optical imaging provides the opportunity to visualize intracellular cargo transport at the nanoscale in the microsecond timescale with minimal perturbation.


Out-of-hospital cardiac arrests and outdoor air pollution exposure in Copenhagen, Denmark.
Cardiovascular disease is the number one cause of death globally and air pollution can be a contributing cause. Acute myocardial infarction and cardiac arrest are frequent manifestations of coronary heart disease. The objectives of the study were to investigate the association between 4 657 out-of-hospital cardiac arrests (OHCA) and hourly and daily outdoor levels of PM(10), PM(2.5), coarse fraction of PM (PM(10-2.5)), ultrafine particle proxies, NO(x), NO(2), O(3) and CO in Copenhagen, Denmark, for the period 2000-2010. Susceptible groups by age and sex was also investigated. A case-crossover design was applied. None of the hourly lags of any of the pollutants were significantly associated with OHCA events. The strongest association with OHCA events was observed for the daily lag4 of PM(2.5), lag3 of PM(10), lag3 of PM(10-2.5), lag3 of NO(x) and lag4 of CO. An IQR increase of PM(2.5) and PM(10) was associated with a significant increase of 4% (95% CI: 0%; 9%) and 5% (95% CI: 1%; 9%) in OHCA events with 3 days lag, respectively. None of the other daily lags or other pollutants was significantly associated with OHCA events. Adjustment for O(3) slightly increased the association between OHCA and PM(2.5) and PM(10). No susceptible groups were identified.


Pseudomonas aeruginosa clinical blood isolates display significant phenotypic variability.
Pseudomonas aeruginosa is a significant threat in healthcare settings where it deploys a wide host of virulence factors to cause disease. Many virulence-related phenotypes such as pyocyanin production, biofilm formation, and twitching motility have been implicated in causing disease in a number of hosts. In this study, we investigate these three virulence factors in a collection of 22 clinical strains isolated from blood stream infections. Despite the fact that all 22 strains caused disease and came from the same body site of different patients, they show significant variability in assays for each of the three specific phenotypes examined. There was no significant correlation between the strength of the three phenotypes across our collection, suggesting that they can be independently modulated. Furthermore, strains deficient in each of the virulence-associated phenotypes examined could be identified. To understand the genetic basis of this variability we sequenced the genomes of the 22 strains. We found that the majority of genes responsible for pyocyanin production, biofilm formation, and twitching motility were highly conserved among the strains despite their phenotypic variability, suggesting that the phenotypic variability is likely due to regulatory changes. Our findings thus demonstrate that no one lab-assayed phenotype of pyocyanin production, biofilm production, and twitching motility is necessary for a P. aeruginosa strain to cause blood stream infection and that additional factors may be needed to fully predict what strains will lead to specific human diseases.


Evaluation of a student-run smoking cessation clinic for a medically underserved population.
Smoking is common among medically underserved populations. Accessible resources to encourage and support smoking cessation among these patients are limited. Volunteer medical student-run free smoking cessation clinics may provide an effective option to help these individuals achieve smoking abstinence. In order to demonstrate the feasibility and cost-effectiveness of a student-run clinic, we analyzed a case series of patients receiving care in a medical student-run Smoking Cessation Clinic (SCC) at the Rochester, Minnesota Salvation Army Good Samaritan Health Clinic (GSHC). Between January 2005 and March 2009, 282 cigarette smokers seeking care at the SCC were analyzed. Student providers at the SCC conducted 1652 weekly individual counseling sessions averaging 18 minutes per encounter. Patients were offered a choice of pharmacotherapies including nicotine replacement therapy (NRT), bupropion, and varenicline for up to 12 weeks. Smoking abstinence was confirmed with exhaled carbon monoxide (CO). Thirty-two patients completed the entire 12-week program (11.3%). At last contact, 94 patients (33.3%) abstained from smoking for ≥ 7 days and 39 patients (13.8%) were continuously abstinent for ≥ 4 weeks. The 7-day point prevalence abstinence rates at last contact were 58.6% for varenicline, 41.2% for bupropion, 33.9% for NRT, and 23.5% for bupropion and NRT. Analyzing missing patients as smoking, the 7-day point prevalence abstinence rates were 7.1%, 8.9%, and 8.2%, at 1 month, 2 months, and 3 months after program enrollment, respectively. No serious adverse drug reactions were recorded. Our medical student-run smoking cessation clinic provided an effective and safe experience for medically underserved patients who might not otherwise have access to conventional smoking cessation programs because of high cost, lack of insurance, or other disparities. Similar medical student initiatives focusing on healthy lifestyles may be feasible and beneficial for individuals with limited access to healthcare resources.


A randomized trial to compare exercise treatment methods for patients after total knee replacement: protocol paper.
Although the outcome of total knee replacement (TKR) is favorable, surgery alone fails to resolve the functional limitations and physical inactivity that existed prior to surgery. Exercise is likely the only intervention capable of improving these persistent limitations, but exercises have to be performed with intensity sufficient to promote significant changes, at levels that cannot be tolerated until later stages post TKR. The current evidence is limited regarding the effectiveness of exercise at a later stage post TKR. To that end, this study aims to compare the outcomes of physical function and physical activity between 3 treatment groups: clinic-based individual outpatient rehabilitative exercise during 12 weeks, community-based group exercise classes during 12 weeks, and usual medical care (wait-listed control group). The secondary aim is to identify baseline predictors of functional recovery for the exercise groups. This protocol paper describes a comparative effectiveness study, designed as a 3-group single-blind randomized clinical trial. Two hundred and forty older adults who underwent TKR at least 2 months prior will be randomized into one of the three treatment approaches. Data will be collected at baseline, 3 months, and 6 months. The wait-listed control group will be randomized to one of the 2 exercise groups after 6 months of study participation, and will complete a 9-month follow-up. Primary outcome is physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index Physical Function Subscale (WOMAC-PF). Physical function is also measured by performance-based tests. Secondary outcomes include performance-based tests and physical activity assessed by a patient-reported survey and accelerometry-based physical activity monitors. Exploratory outcomes include adherence, co-interventions, attrition, and adverse events including number of falls. Linear mixed models will be fitted to compare the changes in outcome across groups. Logistic regression will identify patient characteristics that predict functional recovery in the exercise groups. Instrumental variable methods will be used to estimate the efficacy of the interventions in the presence of non-compliance. Results will inform recommendations on exercise programs to improve physical function and activity for patients at the later stage post TKR and help tailor interventions according with patients' characteristics. ClinicalTrials.gov Identifier NCT02237911.


Linking MLL and the HGF-MET signaling pathway in liver cancer.
Mixed-lineage leukemia (MLL; also known as myeloid/lymphoid), the human homolog of trithorax in Drosophila, is a transcriptional coactivator that plays an essential role during early development and hematopoiesis. Furthermore, MLL is critically involved in the epigenetic regulation of cell cycle, senescence, DNA damage, and stem cell self-renewal. Chromosomal aberrations of MLL in acute leukemias are well documented, but the role of this gene in solid malignancies remains unclear. In this issue of the JCI, Takeda et al. describe a novel epigenetic link between MLL and the HGF-MET signaling pathway conferring invasive and metastatic properties to hepatocellular carcinoma cells.


Institutional care for elders in rural China.
The long-term care (LTC) literature has been generally associated with industrialized countries. However, LTC needs are increasing in the developing world at a rate that far exceeds than experienced by industrialized countries. Using China as a case study, the purpose of this report is to provide an example of an emerging institutional care system for rural elders in a rapidly developing country. It covers two major domains of the system: service delivery and financing. The report presents several main issues involved in the development of institutional care for elders and discusses relevant policy implications.


Self-cross-linking polyelectrolyte complexes for therapeutic cell encapsulation.
Self-cross-linking polyelectrolytes are used to strengthen the surface of calcium alginate beads for cell encapsulation. Poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride), containing 30 mol % 2-aminoethyl methacrylate, and poly(sodium methacrylate), containing 30 mol % 2-(methacryloyloxy)ethyl acetoacetate, were prepared by radical polymerization. Sequential deposition of these polyelectrolytes on calcium alginate films or beads led to a shell consisting of a covalently cross-linked polyelectrolyte complex that resisted osmotic pressure changes as well as challenges with citrate and high ionic strength. Confocal laser fluorescence microscopy revealed that both polyelectrolytes were concentrated in the outer 7-25 microm of the calcium alginate beads. The thickness of this cross-linked shell increased with exposure time. GPC studies of solutions permeating through analogous flat model membranes showed molecular weight cut-offs between 150 and 200 kg/mol for poly(ethylene glycol), suitable for cell encapsulation. C 2C 12 mouse cells were shown to be viable within calcium alginate capsules coated with the new polyelectrolytes, even though some of the capsules showed fibroid overcoats when implanted in mice due to an immune response.


Diabetes mellitus and breast cancer: a retrospective population-based cohort study.
Evidence suggests that women with type 2 diabetes may be at increased risk of breast cancer, possibly due to chronic exposure to insulin resistance and/or hyperinsulinemia. The purpose of this study was to compare the incidence of breast cancer in postmenopausal women with and without diabetes. Using population-based validated health databases from Ontario, Canada, this retrospective cohort study compared breast cancer incidence between women, aged 55-79 years, with newly diagnosed diabetes (n=73,796) to women without diabetes (n=391,714). Women with diabetes were slightly older, were more likely to reside in a lower income neighborhood, had greater comorbidity, and had more annual physician visits than women without diabetes. After 2.2 million person-years of follow-up from 1994 to 2002, breast cancer incidence was 2.97/1000 person-years in the diabetes group and 2.75/1000 person-years in the non-diabetes group. After adjustment for age and income, there was a significant increase in breast cancer among women with diabetes (hazard ratio, HR, 1.08, 95% confidence interval, CI, 1.01-1.16, p=0.021). This study found a small but significant increase in incident breast cancer in a predominantly postmenopausal population of women with diabetes, when compared to women without diabetes. These results support the possibility that insulin resistance or some other aspect of type 2 diabetes may promote breast cancer, and may further direct treatment and prevention strategies.


Arsenite Disrupts Zinc-Dependent TGFβ2-SMAD Activity During Murine Cardiac Progenitor Cell Differentiation.
TGFβ2 (transforming growth factor-β2) is a key growth factor regulating epithelial to mesenchymal transition (EMT). TGFβ2 triggers cardiac progenitor cells to differentiate into mesenchymal cells and give rise to the cellular components of coronary vessels as well as cells of aortic and pulmonary valves. TGFβ signaling is dependent on a dynamic on and off switch in Smad activity. Arsenite exposure of 1.34 μM for 24-48 h has been reported to disrupt Smad phosphorylation leading to deficits in TGFβ2-mediated cardiac precursor differentiation and transformation. In this study, the molecular mechanism of acute arsenite toxicity on TGFβ2-induced Smad2/3 nuclear shuttling and TGFβ2-mediated cardiac EMT was investigated. A 4-h exposure to 5 μM arsenite blocks nuclear accumulation of Smad2/3 in response to TGFβ2 without disrupting Smad phosphorylation or nuclear importation. The depletion of nuclear Smad is restored by knocking-down Smad-specific exportins, suggesting that arsenite augments Smad2/3 nuclear exportation. The blockage in TGFβ2-Smad signaling is likely due to the loss of Zn(2+) cofactor in Smad proteins, as Zn(2+) supplementation reverses the disruption in Smad2/3 nuclear translocation and transcriptional activity by arsenite. This coincides with Zn(2+) supplementation rescuing arsenite-mediated deficits in cardiac EMT. Thus, zinc partially protects cardiac EMT from developmental toxicity by arsenite.


Acoustic modal analysis and control in w-shaped triple-layer optical fibers with highly-germanium-doped core and F-doped inner cladding.
The numerical study of acoustic modal properties in w-shaped optical fibers with high-delta germanium-doped core and F-doped inner cladding (F-HDF) is demonstrated. The cutoff conditions of acoustic modes in the F-HDF show opposite behaviors in contrast with those of optical ones because F-doped inner cladding contributes differently to acoustic and optical waveguides. The acoustic dispersion characteristics vary to a great extent with respect to the location of the acoustic modes in the fiber's core or in the fiber's inner cladding. The resonance frequency spacing between neighboring acoustic modes is theoretically and experimentally found to have a quadratic relation to the core's germanium concentration. We also investigate the critical conditions to move high-order acoustic modes into the F-doped inner cladding and validate the optimal feasibility of employing L(01) and L(03) acoustic modes to fiber-optic Brillouin-based discriminative sensing of strain and temperature.


A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.
Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance explains the insignificant narrow-sense and significant broad-sense heritability by using a combination of careful statistical epistatic analyses and functional genetic experiments.


The neuro-hormonal control of rapid dynamic skin colour change in an amphibian during amplexus.
Sexual signalling using dynamic skin colouration is a key feature in some vertebrates; however, it is rarely studied in amphibians. Consequently, little is known about the hormonal basis of this interesting biological phenomenon for many species. Male stony creek frogs (Litoria wilcoxii) are known to change dorsal colouration from brown to lemon yellow within minutes. This striking change is faster then what has been seen most amphibians, and could therefore be under neuronal regulation, a factor that is rarely observed in amphibians. In this study, we observed colour changes in wild frogs during amplexus to determine the natural timing of colour change. We also investigated the hypothesis that colour change is mediated by either reproductive or neuro- hormones. This was achieved by injecting frogs with epinephrine, testosterone, saline solution (control 1) or sesame oil (control 2). A non-invasive approach was also used wherein hormones and controls were administered topically. Male frogs turned a vivid yellow within 5 minutes of initiation of amplexus and remained so for 3-5 hours before rapidly fading back to brown. Epinephrine-treated frogs showed a significant colour change from brown to yellow within 5 minutes, however, testosterone-treated frogs did not change colour. Our results provide evidence of the role neuronal regulation plays in colour change systems.


Nonadiabatic quantum dynamics calculations of transition state spectroscopy of I + HI and I + DI reactions: the existence of long life vibrational bonding resonances.
We present the results of nonadiabatic quantum wave packet calculations to analyze the experimental transition state spectra for the I(2P3/2,1/2) + XI (X = H and D) hydrogen exchange reactions based on photodetachment of the IXI- anion. We developed (3 × 3) diabatic potential energy surfaces that can reasonably describe the nonadiabatic transitions induced by spin-orbit interactions. A good agreement was obtained between theory and experiment and it was found that nonadiabatic transitions play a role in the reaction dynamics. We also found that the calculated spectra showed very sharp resonance states with a vibrational bonding character, where the resonance wavefunctions are highly localized around the transition state region. Our calculated results suggest that one may experimentally detect these vibrational bonding resonances using time-domain transition state spectroscopy techniques since those states have picosecond-order lifetimes.


Control of ADAM17 activity by regulation of its cellular localisation.
An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface. We found that ADAM17 is constitutively internalised by clathrin-coated pits and that physiological stimulators such as GPCR ligands induce ADAM17-mediated shedding, but do not alter the cell-surface abundance of the protease. In contrast, the PKC-activating phorbol ester PMA, often used as a strong inducer of ADAM17, causes not only proteolysis by ADAM17 but also a rapid increase of the mature protease at the cell surface. This is followed by internalisation and subsequent degradation of the protease. Eventually, this leads to a substantial downregulation of mature ADAM17. Our results therefore imply that physiological activation of ADAM17 does not rely on its relocalisation, but that PMA-induced PKC activity drastically dysregulates the localisation of ADAM17.


Novel neuroanatomical pathways for thyroid hormone action in the human anterior pituitary.
An increasing number of proteins appear to be involved in thyroid hormone feedback action at the level of the anterior pituitary, but the cell types expressing these proteins are largely unknown. The aim of the present study was to identify cell types in the human anterior pituitary that express type II and type III deiodinase (D2 and D3), the recently described thyroid hormone transporter (MCT8) and thyroid hormone receptor (TR) isoforms by means of double-labeling immunocytochemistry. We found TR isoforms to be expressed most prominently in gonadotropes and - although to a lesser extent - in thyrotropes, corticotropes, lactotropes and somatotropes. D3 staining showed a distribution pattern that was remarkably similar. By contrast, D2 immunoreactivity was observed exclusively in folliculostellate (FS) cells showing coexpression with human leukocyte antigen (HLA), a marker of major histocompatibility complex (MHC)-class II. MCT8 immunostaining was present in FS cells without HLA coexpression. From these results, we propose a novel neuroanatomical model for thyroid hormone feedback on the human pituitary, with a central role for FS cells in thyroid hormone activation, which thus play an important role in the suppression of TSH secretion by circulating thyroxine (T(4)).


Modular assembly of a protein nanotriangle using orthogonally interacting coiled coils.
Synthetic protein assemblies that adopt programmed shapes would support many applications in nanotechnology. We used a rational design approach that exploits the modularity of orthogonally interacting coiled coils to create a self-assembled protein nanotriangle. Coiled coils have frequently been used to construct nanoassemblies and materials, but rarely with successful prior specification of the resulting structure. We designed a heterotrimer from three pairs of heterodimeric coiled coils that mediate specific interactions while avoiding undesired crosstalk. Non-associating pairs of coiled-coil units were strategically fused to generate three chains that were predicted to preferentially form the heterotrimer, and a rational annealing process led to the desired oligomer. Extensive biophysical characterization and modeling support the formation of a molecular triangle, which is a shape distinct from naturally occurring supramolecular nanostructures. Our approach can be extended to design more complex nanostructures using additional coiled-coil modules, other protein parts, or templated surfaces.


The evolution of mate choice and mating biases.
We review the current status of three well-established models (direct benefits, indirect benefits and sensory drive) and one newcomer (antagonistic chase-away) of the evolution of mate choice and the biases that are expressed during choice. We highlight the differences and commonalities in the underlying genetics and evolutionary dynamics of these models. We then argue that progress in understanding the evolution of mate choice is currently hampered by spurious distinctions among models and a misguided tendency to test the processes underlying each model as mutually exclusive alternatives. Finally, we suggest potentially fruitful directions for future theoretical and empirical research.


HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.
Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.


The degradative action of peroxynitrite on high-molecular-weight hyaluronan.
This contribution presents the results of the kinetics of HA degradation by peroxynitrite, which represents one of the main reactive oxygen species degrading various biomacromolecules under inflammatory conditions. Two simple procedures have been adapted to prepare sodium peroxynitrite: the first containing an excess of H(2)O(2), and the second in which the H(2)O(2) excess had been decomposed by MnO(2) treatment. The kinetics of hyaluronan degradation by action of peroxynitrite was monitored by rotational viscometry. High-molecular-weight hyaluronan was degraded by peroxynitrite. The degradation was increased in the presence of ONOO(-) previously treated by MnO(2) in order to remove residual hydrogen peroxide. One of the reasons of this finding could be that by the action of the residual metal the pathway of ONOO(-) decomposition starts to be manifested immediately on mixing traces of metals originally present in the HA sample with the ions of manganese. Trace amounts of transition metal(s) should be taken into consideration on evaluating the experimental results. Purchase of the marketed peroxynitrite product appears to be the appropriate approach to simplify and standardize the quality of ONOONa.


Release of Major Peanut Allergens from Their Matrix under Various pH and Simulated Saliva Conditions-Ara h2 and Ara h6 Are Readily Bio-Accessible.
The oral mucosa is the first immune tissue that encounters allergens upon ingestion of food. We hypothesized that the bio-accessibility of allergens at this stage may be a key determinant for sensitization. Light roasted peanut flour was suspended at various pH in buffers mimicking saliva. Protein concentrations and allergens profiles were determined in the supernatants. Peanut protein solubility was poor in the pH range between 3 and 6, while at a low pH (1.5) and at moderately high pHs (>8), it increased. In the pH range of saliva, between 6.5 and 8.5, the allergens Ara h2 and Ara h6 were readily released, whereas Ara h1 and Ara h3 were poorly released. Increasing the pH from 6.5 to 8.5 slightly increased the release of Ara h1 and Ara h3, but the recovery remained low (approximately 20%) compared to that of Ara h2 and Ara h6 (approximately 100% and 65%, respectively). This remarkable difference in the extraction kinetics suggests that Ara h2 and Ara h6 are the first allergens an individual is exposed to upon ingestion of peanut-containing food. We conclude that the peanut allergens Ara h2 and Ara h6 are quickly bio-accessible in the mouth, potentially explaining their extraordinary allergenicity.


Racial Disparities in Perioperative Morbidity Following Oncological Spine Surgery.
Retrospective cohort study. To assess the impact of race on complications following spinal tumor surgery. Adults with cancer who underwent spine tumor surgery were identified in the American College of Surgeons National Surgical Quality Improvement Program datasets from 2012 to 2016. Clavien-Dindo Grade I-II (minor complications) and Clavien-Dindo Grade III-V (major complications including 30-day mortality) complications were compared between non-Hispanic Whites (NHW) and Black patients. A multivariable analysis was also conducted. Of 1,226 identified patients, 85.9% were NHW (n = 1,053) and 14.1% were Black (n = 173). The overall rate of Grade I-II complications was 16.2%; 15.1% for NHW patients and 23.1% for Black patients (P = .008). On multivariable analysis, Black patients had significantly higher odds of having a minor complication (OR 1.87; 95% CI, 1.16-3.01; P = .010). On the other hand, the overall rate of Grade III-V complications was 13.3%; 12.5% for NHW patients and 16.2% for Black patients (P = .187). On multivariable analysis, Black race was not independently associated with major complications (OR 1.26; 95% CI, 0.71-2.23; P = .430). Median length of stay was 8 days (IQR 5-13) for NHW patients and 10 days (IQR 6-15) for Black patients (P = .011). Black patients who underwent metastatic spinal tumor surgery were at a significantly increased risk of perioperative morbidity compared to NHW patients independent of baseline and operative characteristics. Major complications did not differ between groups. Race should be further studied in the context of metastatic spine disease to improve our understanding of these disparities.


Creativity in savant artists with autism.
Individuals with autism spectrum disorder (ASD) often display impairments in creativity, yet savant artists with ASD are reported to produce highly novel and original artistic outputs. To explore this paradox, we assessed nine savant artists with ASD, nine talented art students, nine non-artistically talented individuals with ASD, and nine individuals with mild/moderate learning difficulties (MLD) on tasks in and out of their domain of expertise. This was to ascertain whether the performance of the savant artists was related to their artistic ability, their diagnosis of ASD or their level of intellectual functioning. Results demonstrated that the responses of the art students were more creative (as assessed on measures of fluency, originality, elaboration, and flexibility) than the savant, ASD, and MLD groups on a drawing task. Although the savants did produce more elaborative responses than the ASD and MLD groups, no differences were observed on the other indices of creativity. On a non-drawing task, the savants produced more original outputs than the ASD and MLD groups (scoring similarly to the art students), but group differences were not observed on the other measures.


Intracellular reduced glutathione content in normal and type 2 diabetic erythrocytes: effect of insulin and (-)epicatechin.
Catechins, polyphenolic compounds belonging to flavanoid family, have been reported to posses insulin-like properties and their antidiabetic actions have also been documented. Recently catechins have received much attention as strong anti-oxidative agents. Since oxidative stress has been implicated in the development of diabetic complications and GSH plays an important role in protection against oxidative damages, we have studied the in vitro effect of (-)epicatechin and insulin on the reduced glutathione content in normal and type 2 diabetic erythrocytes. The GSH content was significantly lower (p < 0.001) in type 2 diabetic patients as compared to normal individuals. In vitro insulin treatment (10(-9) M) resulted in increase in the GSH content in both normal and type 2 diabetic erythrocytes. (-)Epicatechin (1mM) also resulted in an increase in erythrocyte GSH content in both normal and type 2 diabetic erythrocytes. Insulin gave a pronounced dose-responsive effect: maximum increase in GSH content at physiological hormone concentration and a lower increase at higher and lower insulin concentrations. (-)Epicatechin did not show a similar dose-responsive effect. Although the exact mechanism by which (-)epicatechin causes elevation of erythrocyte GSH is not clear nevertheless this finding may have important therapeutic implications. A higher content of dietary flavanoids may thus protect diabetic patients against long-term complications.


Epinephrine proactive retardation of amygdala-kindled epileptogenesis.
Recent findings indicate that a single injection (ip) of epinephrine can proactively retard the development of amygdala-kindled seizures. In these experiments, these findings were extended by examining the dose and temporal properties of this phenomenon. Rats were prepared with stimulating electrodes placed in the amygdala. At 30 min or 24, 48, or 72 hr before the first kindling trial, the animals received an epinephrine injection (0.01-1.0 mg/kg). The results indicate that the high epinephrine dose delayed the onset of kindling when injected within 24 hr before kindling, the intermediate dose delayed kindling when injected at 30 min before the first kindling trial, and the low dose was ineffective at all intervals. Injections administered after kindling had been established had no effect on later seizures, although injections during early kindling stages had a small effect on the further development of seizures. Examination of the time courses of increases in plasma catecholamine levels, blood pressure, and heart rate demonstrated that long-term changes in these measures cannot account for the retardation of kindling. The findings of these experiments indicate that although epinephrine does not directly affect seizure production with these procedures, the hormone does have long-lasting proactive effects on kindled epileptogenesis.


Two PALB2 germline mutations found in both BRCA1+ and BRCAx familial breast cancer.
Partner and localizer of BRCA2 (PALB2), plays an important functional role in DNA damage repair. Recent studies indicate that germline mutations in PALB2 predispose individuals to a high risk of developing familial breast cancer. Therefore, comprehensive identification of PALB2 germline mutations is potentially important for understanding their roles in tumorigenesis and for testing their potential utility as clinical targets. Most of the previous studies of PALB2 have focused on familial breast cancer cases with normal/wild-type BRCA1 and BRCA2 (BRCAx). We hypothesize that PALB2 genetic mutations also exist in individuals with BRCA mutations (BRCA+). To test this hypothesis, PALB2 germline mutations were screened in 107 exome data sets collected from familial breast cancer families who were either BRCA1+ or BRCAx. Two novel heterozygous mutations predicted to alter the function of PALB2 were identified (c.2014G>C, p.E672Q and c.2993G>A, p.G998E). Notably, both of these mutations co-existed in BRCA1+ and BRCA1x families. These studies show that mutations in PALB2 can occur independent of the status of BRCA1 mutations, and they highlight the importance to include BRCA1+ families in PALB2 mutation screens.


Primary Tubal Choriocarcinoma Presented as Ruptured Ectopic Pregnancy.
The primary tubal choriocarcinoma associated with ectopic pregnancy is very rare. A 31-year-old woman was admitted to the emergency room due to amenorrhea, left lower abdominal pain and fatigue. Her β-Hcg level was 29251.4 mIU/ml and transvaginal ultrasund revealed a 24x21 mm of left tubal ectopic pregancy mass with large amount of free fluid in pelvic cavity. The patient was diagnosed with ruptured tubal ectopic pregnancy and thus, she underwent laparotomy with left total salpingectomy. The pathological assessment was reported as primary tubal choriocarcinoma with the involvement of whole tubal layer. The patient was defined to have stage I choriocarcinoma with good prognostic factors and methotrexate monotherapy was administered. Serum β- Hcg levels of the patient gradually declined and eventually became negative at the first month of the treatment. With this case report we aimed to implicate that when diagnosing the ectopic pregnancy, even very rare, the tubal choriocarcinoma should be kept in mind.


Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma.
Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gq signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gq inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gq proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.