Forkhead transcription factor 1 inhibits endometrial cancer cell proliferation via sterol regulatory element-binding protein 1.
The morbidity and mortality associated with endometrial cancer (EC) has increased in recent years. Regarded as a tumor suppressor, forkhead transcription factor 1 (FOXO1) has various biological activities and participates in cell cycle progression, apoptosis and differentiation. Notably, FOXO1 also functions in the regulation of lipogenesis and energy metabolism. Lipogenesis is a feature of cancer and is upregulated in EC. Sterol regulatory element-binding protein 1 (SREBP1) is a transcription factor that is also able to regulate lipogenesis. Increased expression of SREBP1 is directly correlated with malignant transformation of tumors. A previous study demonstrated that SREBP1 was highly expressed in EC and directly resulted in tumorigenesis. However, the association between FOXO1 and SREBP1 in EC is not clear. In the present study, lentiviruses overexpressing FOXO1 were used in cell transfection and transduction. Cell viability assays demonstrated that the overexpression of FOXO1 was able to suppress cell proliferation significantly in Ishikawa and AN3 CA cell lines. In addition, FOXO1 overexpression significantly inhibited cell migration and invasion ability in vitro. In xenograft models, overexpression of FOXO1 suppressed cell tumorigenesis, and western blot analysis demonstrated that SREBP1 expression was markedly reduced in the FOXO1-overexpressing cells. It may therefore be concluded that FOXO1 is able to inhibit the proliferative capacity of cells in vitro and in vivo, in addition to the migratory and invasive capacities in vitro by directly targeting SREBP1.


Nutritional assessment and intervention in children with cerebral palsy: a practical approach.
Cerebral palsy (CP) is associated with the presence of feeding disorders in almost 60% of the affected children with subsequent undernutrition reported in up to 46% of the subjects. Since undernutrition may have a detrimental impact on physical and cognitive development, the introduction of an adequate nutritional support should always be considered in children with neurological impairment. The aim of the present review is to provide a practical guide to the assessment of nutritional status in children with CP, in order to identify individuals at risk for malnutrition that need the introduction of an adequate and personalized nutritional support. This review summarizes the methods for the evaluation of oral-motor function, anthropometric parameters, body composition and energy balance in children with CP. Moreover, we reviewed the indications for the introduction of nutritional support, and the suggested modalities of intervention.


The influence of pinnae-based spectral cues on sound localization.
The role of pinnae-based spectral cues was investigated by requiring listeners to locate sound, binaurally, in the horizontal plane with and without partial occlusion of their external ears. The main finding was that the high frequencies were necessary for optimal performance. When the stimulus contained the higher audio frequencies, e.g., broadband and 4.0-kHz high-pass noise, localization accuracy was significantly superior to that recorded for stimuli consisting only of the lower frequencies (4.0- and 1.0-kHz low-pass noise). This finding was attributed to the influence of the spectral cues furnished by the pinnae, for when the stimulus composition included high frequencies, pinnae occlusion resulted in a marked decline in localization accuracy. Numerous front-rear reversals occurred. Moreover, the ability to distinguish among sounds originating within the same quadrant also suffered. Performance proficiency for the low-pass stimuli was not further degraded under conditions of pinnae occlusion. In locating the 4.0-kHz high-pass noise when both, neither, or only one ear was occluded, the data demonstrated unequivocally that the pinna-based cues of the "near" ear contributed powerfully toward localization accuracy.


Application of silicon-based cross-coupling technology to triflates.
Aryl silatranes undergo fluoride-induced cross-coupling with aryl triflates to provide unsymmetrical biaryl derivatives in good to excellent yields. Silatranes also couple with aryl iodides and bromides, although the yields of adduct are lower than with the corresponding siloxane derivates. Aryl siloxanes (which had previously failed to couple with triflates) can be employed for triflate couplings using the Denmark modification, although the yields are lower than the corresponding silatrane reactions.


Trends in Pediatric Cancer Care in Florida From 1981-2020: Changing Patterns in a Growing and Increasingly Diverse Population.
Background The Florida Association of Pediatric Tumor Programs (FAPTP) has used the Statewide Patient Information Reporting System (SPIRS) since 1981 to track all new cases of pediatric cancer. We reviewed the last 40 years of data to see how pediatric cancer care has evolved. Methods We retrospectively analyzed SPIRS data from 1981 through 2020 in five-year increments, looking at numbers of new diagnoses, care delivery sites, and trial enrollment in Children's Oncology Group (COG) studies. Results From 1981-2020 Florida's population increased almost 88% while the pediatric population only grew 61%. New pediatric cancer diagnoses increased 326% to over 1,000 new cases/year. The percentage of patients treated at FAPTP centers grew from 30% to 57% with an annual percentage change (APC) of 10.3% (95% Confidence Interval [CI] of 0.6 to 20.9%). The rate of COG clinical trial enrollment decreased from 32% in 1981-1985 to 20% in 2016-2020, for an APC of 8.91% (95% CI of -13.3 to -4.3%). Conclusions The striking increase in pediatric cancer cases in Florida over the last 40 years was out of proportion to the population growth. More patients received care at FAPTP centers, but a lower percentage were enrolled on COG trials.


Intraoperative antibiotic irrigation as prophylaxis in abdominal hysterectomy: a preliminary report.
A preliminary report regarding the use of an intraoperative, intraperitoneal antibiotic solution in patients having transabdominal hysterectomy reveals that the postoperative morbidity assessed by the diagnosis of cuff cellulitis or pelvic abscess was 4.7%. This morbidity represents a substantial reduction in the incidence of cuff cellulitis (27.0%) noted in a comparison group of 367 patients having abdominal hysterectomy at our institution during a two-year period. These preliminary data strongly suggest that antibiotic solutions given intraperitoneally at the time of abdominal hysterectomy reduce morbidity due to cuff cellulitis.


Interleukin-6 enhances the fertilizing capacity of human sperm by increasing capacitation and acrosome reaction.
The effects of human recombinant interleukin-6 (IL-6) on human sperm penetration of zona-free hamster ova (SPA) and human sperm cell capacitation and acrosome reaction were investigated. IL-6 at higher concentrations (60-600 pg/100 microliters) significantly (P < 0.001) increased rather than decreased the human sperm penetration rates in SPA. The effects were specific because immunoadsorption with the specific neutralizing antibody completely abolished the enhancing effects of IL-6. At the same concentrations, IL-6 also significantly enhanced spontaneous as well as calcium ionophore-induced acrosome reaction and release of acrosin from the human sperm cells. There was no effect of IL-6 on percent sperm motility, although it significantly affected various motility characteristics such as velocity, linearity, amplitude of lateral head displacement (ALH), and beat frequency of sperm cells--the motility parameters involved in hyperactivation phenomenon of sperm cells. These results demonstrate for the first time that IL-6 provides a positive signal in enhancing fertilizing capacity of human sperm by increasing capacitation leading to acrosome reaction, and thus it may have clinical applications in the treatment of male infertility in humans.


[Comparative analysis of gene expression in rat locomotor muscles and diaphragm].
Gene expression profile in diaphragm in comparison to three principally different hindlimb muscles (soleus, red and white gastrocnemius) was studied using quantitative PCR. Expression levels of PGC-1alpha mRNA and myogenin mRNA in diaphragm were in accordance with its myosin phenotype and citrate synthase activity. However, diaphragm was characterised by atypically high content of MyoD mRNA as well as high content of IGF-1 mRNA and low content of myostatin mRNA. The latter two findings suggest high intensity of protein synthesis in diaphragm muscle fibers, although they have smaller cross sectional area than fibers in locomotor muscles.


[A mechanism for limiting reproduction influenza A virus reassortants with incomplete functional compatibility of hemagglutinin and neuraminidase gene products].
The mechanism of decrease in the level of virus accumulation in reassortants with hemagglutinin (HA) and neuraminidase (NA) genes from different parents is studied. The reassortant viruses and their passage variants do not differ by the rate of virus protein production or their stability in infected cells. Electron microscopy and titration of infectious virus in culture fluid and cell-associated virus showed that the variants selected by serial passages accumulated mainly in the culture fluid, whereas the initial reassortant virions were predominantly cell-associated. These data suggest that incomplete removal of sialic acid residues by viral neuraminidase N1 in some reassortants results in re-attachment of virions to the infected cells and thus impairs the virus dissemination, which may be regarded as a reassortant-limiting factor probably significant for virus evolution.


Rotational Analysis of the 210 and 220 Bands of the ã 3B1 <-- &Xtilde; 1A1 System of Jet-Cooled Silicon Difluoride
A combination least-squares and band contour analysis of the 2(1)0 and 2(2)0 bands of the laser-induced phosphorescence spectrum of the ã 3B1 <-- &Xtilde; 1A1 band system silicon difluoride, SiF2, has been completed. Spectra were taken under pyrolysis-jet conditions at a resolution of ca 0.04 cm-1. The rotational (A, B, C), centrifugal distortion (Deltak), spin-rotation (a, a0), and spin-spin (alpha, beta) constants for the upper nu2 state are reported. An effective r0 structure has been calculated for each upper vibronic state. Some minor intensity anomalies have been observed in the spectra of both bands. Copyright 1998 Academic Press.


Exercise training preserves ischemic preconditioning in aged rat hearts by restoring the myocardial polyamine pool.
Ischemic preconditioning (IPC) strongly protects against myocardial ischemia reperfusion (IR) injury. However, IPC protection is ineffective in aged hearts. Exercise training reduces the incidence of age-related cardiovascular disease and upregulates the ornithine decarboxylase (ODC)/polyamine pathway. The aim of this study was to investigate whether exercise can reestablish IPC protection in aged hearts and whether IPC protection is linked to restoration of the cardiac polyamine pool. Rats aging 3 or 18 months perform treadmill exercises with or without gradient respectively for 6 weeks. Isolated hearts and isolated cardiomyocytes were exposed to an IR and IPC protocol. IPC induced an increase in myocardial polyamines by regulating ODC and spermidine/spermine acetyltransferase (SSAT) in young rat hearts, but IPC did not affect polyamine metabolism in aged hearts. Exercise training inhibited the loss of preconditioning protection and restored the polyamine pool by activating ODC and inhibiting SSAT in aged hearts. An ODC inhibitor, α-difluoromethylornithine, abolished the recovery of preconditioning protection mediated by exercise. Moreover, polyamines improved age-associated mitochondrial dysfunction in vitro. Exercise appears to restore preconditioning protection in aged rat hearts, possibly due to an increase in intracellular polyamines and an improvement in mitochondrial function in response to a preconditioning stimulus.


Effect of farnesol on growth, ergosterol biosynthesis, and cell permeability in Coccidioides posadasii.
Coccidioidomycosis is a systemic mycosis caused by the dimorphic fungi Coccidioides spp. The treatment for chronic and/or disseminated coccidioidomycosis can be prolonged and complicated. Therefore, the search for new drugs is necessary. Farnesol is a precursor in the sterol biosynthesis pathway that has been shown to present antifungal activity. Thus, the objective of this study was to evaluate the in vitro antifungal activity of farnesol alone and in combination with antifungal agents against clinical and environmental strains of Coccidioides posadasii as well as to determine their effect on the synthesis of ergosterol and on cell permeability. This study employed the broth macrodilution method to determine the MIC of farnesol against 18 strains of C. posadasii. Quantification of ergosterol was performed with 10 strains of C. posadasii after exposure to subinhibitory concentrations of farnesol. Finally, the activity of farnesol was evaluated in the presence of osmotic stress, induced by the addition of NaCl to the culture medium, during the susceptibility tests. The results showed that farnesol exhibited low MICs (ranging from 0.00171 to 0.01369 mg/liter) against all tested strains. The combination of farnesol with the antifungals showed synergistic effects (fractional inhibitory concentration index [FICI] ≤ 0.5). As for the ergosterol quantification, it was observed that exposure to subinhibitory concentrations of farnesol decreased the amount of ergosterol extracted from the fungal cells. Furthermore, farnesol also showed lower MIC values when the strains were subjected to osmotic stress, indicating the action of this compound on the fungal membrane. Thus, due to the high in vitro antifungal activity, this work brings perspectives for the performance of in vivo studies to further elucidate the effects of farnesol on the host cells.


Forward and backward second-order Pavlovian conditioning in honeybees.
Second-order conditioning (SOC) is the association of a neutral stimulus with another stimulus that had previously been combined with an unconditioned stimulus (US). We used classical conditioning of the proboscis extension response (PER) in honeybees (Apis mellifera) with odors (CS) and sugar (US). Previous SOC experiments in bees were inconclusive, and, therefore, we attempted to demonstrate SOC in the following three experiments: (Experiment 1) After differential conditioning (pairing odor A with US and presenting odor B without US), the bees experienced two pairs of partially overlapping odors, either a new odor C followed by a previously reinforced odor A (C-A) or a new odor C followed by a previously nonreinforced odor B (C-B). (Experiment 2) After differential conditioning, bees were presented with C-A or A-C. (Experiment 3) Bees were first presented with C-A or A-C before differential conditioning and were tested with odor C. We observed: (Experiment 1) 40% of the bees showed PER to the C-A presentation, but only 20% showed PER to the C-B presentation. (Experiment 2) 40% of the bees showed PER to the C-A presentation, while only 20% showed PER to the reversed sequence A-C. Experiments 1 and 2 showed that a previously reinforced odor can be a secondary reinforcer for excitatory SOC only with forward-pairing. (Experiment 3) PER toward C was lower (15%) in bees presented with A-C than with C-A (25%). This showed that backward SOC is not as effective as forward SOC. These results help to delineate different conditions that are critical for the phenomenon of SOC.


The Early Days of Commercial FT-IR Spectrometry: A Personal Perspective.
The development of Fourier transform infrared (FT-IR) spectrometers in the mid-1960s followed along three lines. Interferometers for far-infrared FT spectrometry typically had a slow scan speed and the beam of radiation was modulated by a rotating chopper. Several instruments based on this system were developed commercially. Very high-resolution near-infrared FT spectrometers were based on cats-eye retroreflectors mounted in a step-scan interferometer; the beam of radiation was usually modulated by dithering one of the cats-eyes (phase modulation). No commercial instruments based on this principle were developed. In the third type of FT spectrometer, the beam was modulated by rapidly scanning one of the mirrors of a Michelson interferometer. While the early instruments based on this principle only gave rise to low-resolution spectra, the incorporation of laser fringe referencing at the end of the decade led to instruments that were the fore-runners of contemporary FT-IR spectrometers. In this article, the author's experiences with instruments of the first and third category are described.


Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection.
To chronicle pituitary-testicular axis dysfunction and its clinicopathologic features in homosexual men. Between 1984 and 1992, 84 homosexual men underwent longitudinal follow-up for 4 years. At entry into the study, 28 were seronegative and 56 were seropositive for human immunodeficiency virus (HIV). Although 40 subjects remained asymptomatic (nonprogressors), 16 had progression to acquired immunodeficiency syndrome (AIDS). Of those 16 patients with progression, 8 had AIDS within 2 years (early progressors) and 8 demonstrated AIDS within 4 years after enrollment (late progressors), and all died. The testes of five patients were examined at autopsy. The control group had similar follow-up. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and bioavailable testosterone (bio-T) were measured in stored sera collected at 2-year intervals. The last hormonal measurement was between 3 and 24 months before autopsy. Comparison was made between autopsied and nonautopsied patients with AIDS as well as between HIV nonprogressors and control seronegative men. The correlation between pathologic findings and hormonal status was examined by regression analysis. At baseline, testosterone, bio-T, LH, and FSH were not significantly different among all patients and subjects. During the study period, testosterone, bio-T, and serum gonadotropin levels remained unchanged in the seronegative homosexual men. In nonprogressors, serum FSH and LH concentrations remained unchanged, whereas testosterone and bio-T levels decreased significantly during this 4-year period. After progression to AIDS (in both groups of progressors), the serum FSH and LH levels were higher and the serum testosterone and bio-T were lower in comparison with values in the seronegative men. In late progressors to AIDS, FSH and LH increased, whereas serum testosterone and bio-T decreased significantly from baseline. All five patients with AIDS on whom autopsy was done had boundary wall thickening of the seminiferous tubules and decreased spermatogenesis. No significant differences were found in serum testosterone, bio-T, and LH between those in whom autopsy was or was not done; however, FSH was significantly higher in the autopsied cases. The serum testosterone and bio-T levels were negatively correlated with the interstitial inflammation. A significant correlation was also observed between change of bio-T and weight loss. We conclude that dysfunction of the pituitary-gonadal axis is common in HIV-infected men. All patients in whom autopsy was done because of AIDS-related diseases had been hypogonadal 3 to 24 months before death. Decreased spermatogenesis, subacute interstitial inflammation, or both were seen at autopsy of patients with AIDS. Pathologic damage to the testes during AIDS was associated with decreased testosterone and bio-T as well as increased serum gonadotropin levels. In a substantial proportion of men with progression to AIDS, compensated hypogonadism (normal serum testosterone and increased serum LH levels) preceded the development of low serum testosterone level.


Creating a SIS-A Annual Review Protocol to Determine the Need for Reassessment.
The Supports Intensity Scale - Adult Version (SIS-A) has been widely adopted throughout North America and the world since its publication a little over a decade ago. Many organizations and jurisdictions operate under regulations that require an annual assessment of people who receive services and supports that are financed through public funds. The time and energy devoted to an annual SIS-A reassessment has become a concern in cases where the resulting information is largely redundant with information from a prior assessment. This article presents findings from an investigation of two approaches to creating a protocol to assist SIS-A users in distinguishing situations where there is a high likelihood that support needs have not changed in meaningful ways from situations where there is a reasonable possibility that support needs have changed. The SIS-A Annual Review Protocol was created based on these analyses as well as consideration of conceptual issues associated with support needs assessment. Ways in which this protocol might be used, as well as data that need to be collected to evaluate its usefulness, are discussed.


[Toxic epidermal necrolysis, a life-threatening skin disease].
Toxic epidermal necrolysis (TEN; Lyell's disease) was diagnosed in three patients: an 8-year-old boy and two women aged 39 and 25. Treatment consisted of daily sterile wound care using a synthetic wound covering, oral as well as tube feeding and administration of fluid, electrolytes and albumin. Sepsis developed in 2 patients, and was treated with specific antibiotics. Irreversible sight loss developed in 1 patient. A burns centre offers optimal conditions for treatment because of the combined availability of both nursing and medical expertise and of the required infrastructure needed for antisepsis, climate control and intensive care.


An unusual cause of cyanosis in a patient with COPD.
We present a case of acquired methaemoglobinaemia related to the prolonged use of dapsone in a patient with chronic hypoxia. The patient was initially successfully treated for infective exacerbation of chronic obstructive pulmonary disease (COPD). However, he remained persistently hypoxic on pulse oximetry despite a normal PaO2 on arterial blood gas sampling. His fraction of methaemoglobin (FMetHb) was found to be elevated at 13%. After cessation of dapsone, his clinical cyanosis recuperated, his exercise tolerance and functional capacity improved and his FMetHb normalised to 1%.


Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition.
Although ∼40% of patients with metastatic melanoma develop brain metastases, the presence of brain metastases often precludes enrolment in clinical trials for advanced melanoma. However, the development of symptomatic brain metastases markedly increases mortality. The antiprogrammed-death-receptor-1 antibody pembrolizumab achieves extracranial metastases disease response rates of up to 50%. Here, we report the rapid and sustained response of symptomatic multifocal brain metastases in a melanoma ipilimumab-pretreated patient under pembrolizumab, combined with high-dose dexamethasone therapy during the induction phase of therapy. Complete remission has been maintained for over 1 year of follow-up and has correlated with the response rate observed in the extracranial metastases. Radiological disease response was identified during the first follow-up visit in the absence of adjuvant radiotherapy. This report highlights the need for further clinical studies to specifically address the therapeutic potential of antiprogrammed-death-receptor-1 monotherapy in the management of untreated brain metastases in melanoma.


An EST-SSR based genetic linkage map and identification of QTLs for anthracnose disease resistance in water yam (Dioscorea alata L.).
Water yam (Dioscorea alata L.) is one of the most important food yams with wide geographical distribution in the tropics. One of the major constraints to water yam production is anthracnose disease caused by a fungus, Colletotrichum gloeosporioides (Penz.). There are no economically feasible solutions as chemical sprays or cultural practices, such as crop rotation are seldom convenient for smallholder farmers for sustainable control of the disease. Breeding for development of durable genetic resistant varieties is known to offer lasting solution to control endemic disease threats to crop production. However, breeding for resistance to anthracnose has been slow considering the biological constraints related to the heterozygous and vegetative propagation of the crop. The development of saturated linkage maps with high marker density, such as SSRs, followed by identification of QTLs can accelerate the speed and precision of resistance breeding in water yam. In a previous study, a total of 1,152 EST-SSRs were developed from >40,000 EST-sequences generated from two D. alata genotypes. A set of 380 EST-SSRs were validated as polymorphic when tested on two diverse parents targeted for anthracnose disease and were used to generate a saturated linkage map. Majority of the SSRs (60.2%) showed Mendelian segregation pattern and had no effect on the construction of linkage map. All 380 EST-SSRs were mapped into 20 linkage groups, and covered a total length of 3229.5 cM. Majority of the markers were mapped on linkage group 1 (LG 1) comprising of 97 EST-SSRs. This is the first genetic linkage map of water yam constructed using EST-SSRs. QTL localization was based on phenotypic data collected over a 3-year period of inoculating the mapping population with the most virulent strain of C. gloeosporioides from West Africa. Based on threshold LOD scores, one QTL was consistently observed on LG 14 in all the three years and average score data. This QTL was found at position interval of 71.1-84.8 cM explaining 68.5% of the total phenotypic variation in the average score data. The high marker density allowed identification of QTLs and association for anthracnose disease, which could be validated in other mapping populations and used in marker-assisted breeding in D. alata improvement programmes.


Hormesis predicts low-dose responses better than threshold models.
This study evaluated characteristics of the concentration-response relationships of chemicals from the U.S. National Cancer Institute (NCI) Yeast Anticancer Drug Screen database with respect to the threshold and the hormetic dose-response models. The database reported concentration-response studies of 2189 chemicals from a broad range of chemical classes. The biological end point was growth in 13 strains of yeast (Saccharomyces cerevisiae), most of which contain genetic alterations affecting DNA repair or cell cycle control. The analysis was limited to studies that satisfied a priori entry criteria for evaluation, including having two or more concentrations in the nontoxic zone (below a Benchmark Dose). The mean growth response compared to untreated controls of these doses was significantly greater than 100% in all 13 yeast strains, ranging from approximately 105% to approximately 111%. Under a threshold model, one would expect values more closely approximating 100%. Moreover, the distribution of responses below the BMD5 for chemicals was shifted upwardly from the expectations of a threshold model for all strains. These results indicate that for the chemicals and yeast strains studied, the responses are more consistent with a hormetic model than a threshold model, and they strengthen previous results presented by Calabrese et al. (2006, Toxicol. Sci. 94:368-378). Taken together, the analyses provide strong evidence for hormesis, a phenomenon with a broad range of biomedical and toxicological implications.


The mechanism of vascular leakage induced by leukotriene E4. Endothelial contraction.
This study identifies the microvascular target of leukotriene E4 (LTE4) by vascular labeling with carbon black and establishes the mechanism of its action at the cellular level by electron microscopy. LTE4 and its tripeptide precursor, leukotriene C4 (LTC4) were injected subcutaneously in guinea pigs. With LTE4, venular labeling was intense at 1000 and 100 ng and slight at 10 ng, with extinction at 1 ng. LTC4 induced a ring of labeled venules around a blank central area, suggestive of vasospasm. The nonpeptidyl leukotriene LTB4 induced no labeling. Histamine (1000 ng) induced an area of vascular labeling about equal to that by 1000 ng LTE4, but the labeling of individual venules was more intense. By electron microscopy, LTE4 was found to induce gaps in the endothelium of the venules; the endothelial cells adjacent to the gaps bulged into the lumen and showed wrinkled nuclei, consistent with cellular contraction. This ultrastructural evidence suggests that LTE4 increases vascular permeability by contraction of endothelial cells selectively, in the postcapillary venules, as was previously demonstrated for other inflammatory mediators, including histamine, serotonin, and bradykinin.


Basal, but not overload-induced, myonuclear addition is attenuated by NG-nitro-L-arginine methyl ester (L-NAME) administration.
The purpose of this study was to examine the effect of blocking nitric oxide synthase (NOS) activity via NG-nitro-L-arginine methyl ester (L-NAME) on myonuclear addition in skeletal muscle under basal and overloaded conditions. Female Sprague-Dawley rats (approx. 220 g) were placed into 1 of the following 4 groups (n = 7-9/group): 7-day skeletal muscle overload (O), sham operation (S), skeletal muscle overload with L-NAME treatment (OLN), and sham operation with L-NAME treatment (SLN). Plantaris muscles were overloaded via bilateral surgical ablation of the gastrocnemius muscles and L-NAME (0.75 mg/mL) was administered in the animals' daily drinking water starting 2 days prior to surgery and continued until sacrifice. Myonuclear addition was assessed as subsarcolemmal incorporation of nuclei labeled with 5-bromo-2'-deoxyuridine (approx. 25 mg.(kg body mass)-1.day-1) delivered via osmotic pump during the overload period. As expected, muscle wet mass, total protein content, fiber cross-sectional area, and myonuclear addition were significantly higher (p <or= 0.05) in O vs. S; however, only the increase in wet mass and total protein content (per body mass) were attenuated by L-NAME administration. Interestingly, L-NAME significantly reduced myonuclear addition by 75% in non overloaded muscles (SLN vs. S). Muscle hepatocyte growth factor protein content increased with overload, but was unaffected by L-NAME in either loading state. These data indicate that NOS inhibition in rat plantaris muscle attenuates myonuclear addition under basal, but not overloaded, conditions.


The use of MR B+1 imaging for validation of FDTD electromagnetic simulations of human anatomies.
In this study, MR B(+)(1) imaging is employed to experimentally verify the validity of FDTD simulations of electromagnetic field patterns in human anatomies. Measurements and FDTD simulations of the B(+)(1) field induced by a 3 T MR body coil in a human corpse were performed. It was found that MR B(+)(1) imaging is a sensitive method to measure the radiofrequency (RF) magnetic field inside a human anatomy with a precision of approximately 3.5%. A good correlation was found between the B(+)(1) measurements and FDTD simulations. The measured B(+)(1) pattern for a human pelvis consisted of a global, diagonal modulation pattern plus local B(+)(1) heterogeneties. It is believed that these local B(+)(1) field variations are the result of peaks in the induced electric currents, which could not be resolved by the FDTD simulations on a 5 mm(3) simulation grid. The findings from this study demonstrate that B(+)(1) imaging is a valuable experimental technique to gain more knowledge about the dielectric interaction of RF fields with the human anatomy.


A body characteristic index to evaluate the level of risk of heat strain for a group of workers with a test.
The purpose of this study was to develop a body characteristic index (BCI) based on the distribution of maximal oxygen uptake per body mass (VO2max/mass), body surface area per body mass (BSA/mass), and percentage of body fat (Fat%) to evaluate the relative level of individual physiological responses to heat strain in a group of workers. BCI was based upon the data obtained from 10 males and 10 females exercising for 60 min on a treadmill at 2 relative exercise intensities of 25% and 45% VO2max in mild, warm wet, and hot dry climate condition, separately. BCI was developed into 2 formulas, which were proved to be better predictors for heat strain responses than each individual characteristic, and more sensitive than body type to describe the distributions of individual characteristics and distinguish the differences in physiological responses to heat.


[Pasteurella multocida meningitis secondary to functional endoscopic sinus surgery].
Functional endoscopic sinus surgery (FESS) is a common, surgical procedure in Danish ear-nose-throat departments. Surgery is often performed as an outpatient procedure. Major complications are rare, however, they may develop after the patient has been discharged. This is a case report of Pasteurella multocida meningitis secondary to FESS in a 54-year-old male.


Differential tree and shrub production in response to fertilization and disturbance by coastal river otters in Alaska.
We explored the interacting effects of marine-derived nutrient fertilization and physical disturbance introduced by coastal river otters (Lontra canadensis) on the production and nutrient status of pristine shrub and tree communities in Prince William Sound, Alaska, USA. We compared production of trees and shrubs between latrines and non-latrines, while accounting for otter site selection, by sampling areas on and off sites. Nitrogen stable isotope analysis (delta15N) indicated that dominant tree and shrub species assimilated the marine-derived N excreted by otters. In association with this uptake, tree production increased, but shrub density and nonwoody aboveground shrub production decreased. The reduced shrub production was caused by destruction of ramets, especially blueberry (Vaccinium spp.), through physical disturbance by river otters. False azalea (Menziesia ferruginea) ramets were less sensitive to otter disturbance. Although surviving individual blueberry ramets showed a tendency for increased production per plant, false azalea allocated excess N to storage in leaves rather than growth. We found that plant responses to animal activity vary among species and levels of biological organization (leaf, plant, ecosystem). Such differences should be accounted for when assessing the influence of river otters on the carbon budget of Alaskan coastal forests at the landscape scale.


Measuring acculturation among Central American women with the use of a brief language scale.
The purpose of this study was to test the reliability and validity of a brief language usage scale as a measure of acculturation in 197 Central American immigrant women. This study presents an analysis of cross-sectional survey data collected during face-to-face interviews conducted in Spanish as part of the program evaluation of the Infant Feeding for Hispanic Supplemental Nutrition Program for Women, Infants, and Children (WIC) Populations a Peer Education Model. The Short Acculturation Scale, a four-item language usage scale exploring the participants' language preferences, was used as a measure of acculturation. The participant's age, length of time in the United States, and perceived social support for breastfeeding were used as validation measures. Results demonstrated good internal reliability for the acculturation summary scale. Consistent with previous studies, significant correlations (p < 0.01) were found between acculturation and mother's age, perceived social support for breastfeeding, and mother's length of time in the United States. The reliability and validity data from this group of Central American immigrants support the continued use of this brief measure of acculturation in diverse Latino subpopulations when multidimensional measures are neither practical nor feasible.


Molecular biology of ovarian cancer.
This minireview, which due to the limitations of space cannot claim to be exhaustive, summarizes major advances in molecular biologic research on ovarian surface epithelial (adeno)carcinomas communicated approximately between the beginning of April 1990 through the end of March 1991. We focus primarily on studies of oncogenes, peptide hormone growth factors and their receptors, steroid hormone receptors, cytogenetics and flow cytometry, and resistance to therapy with cytotoxic agents.


[The so-called "contact" system of plasma: consequences of the activation of the Hageman factor].
The contact system of plasma includes 4 zymogens, Hageman factor, pre-kallikrein, factor XI and plasminogen, and a cofactor, the high molecular weight kininogen (HMWK). The activation of the contact system leads to the production of bradykinin, blood coagulation, fibrinolysis, complement activation and neutrophil stimulation. Consequently these phenomena generate a lot of pro-inflammatory factors which contribute to the local and systemic inflammatory processes.


Visualizing the organization and differentiation of the male-specific nervous system of C. elegans.
Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematode Caenorhabditis elegans, where male animals contain a little-studied set of 93 male-specific neurons. To make these neurons amenable for future study, we describe here how a multicolor reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male-specific neurons. We used NeuroPAL to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression of gfp-tagged reporter genes and for cellular fate analysis by analyzing the effect of removal of several developmental patterning genes on neuronal identity acquisition. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage. This coordinated wave of differentiation, which we call 'just-in-time' differentiation, couples neuronal maturation programs with the appearance of sexual organs.


Requirement of upstream Hfq-binding (ARN)x elements in glmS and the Hfq C-terminal region for GlmS upregulation by sRNAs GlmZ and GlmY.
Hfq is an important RNA-binding protein that helps bacteria adapt to stress. Its primary function is to promote pairing between trans-acting small non-coding RNAs (sRNAs) and their target mRNAs. Identification of essential Hfq-binding motifs in up-stream regions of rpoS and fhlA led us to ask the question whether these elements are a common occurrence among other Hfq-dependent mRNAs as well. Here, we confirm the presence of a similar (ARN)(x) motif in glmS RNA, a gene controlled by two sRNAs (GlmZ and GlmY) in an Hfq-dependent manner. GlmZ represents a canonical sRNA:mRNA pairing system, whereas GlmY is non-canonical, interfacing with the RNA processing protein YhbJ. We show that glmS interacts with both Hfq-binding surfaces in the absence of sRNAs. Even though two (ARN)(x) motifs are present, using a glmS:gfp fusion system, we determined that only one specific (ARN)(x) element is essential for regulation. Furthermore, we show that residues 66-72 in the C-terminal extension of Escherichia coli Hfq are essential for activation of GlmS expression by GlmY, but not with GlmZ. This result shows that the C-terminal extension of Hfq may be required for some forms of non-canonical sRNA regulation involving ancillary components such as additional RNAs or proteins.


Immunoreactive delta sleep-inducing peptide in pituitary adrenocorticotropin/alpha-melanotropin cells and adrenal medullary cells of the pig.
Immunoreactive delta sleep-inducing peptide (DSIP) is known to occur in the central nervous system and in body fluids including cerebrospinal fluid, blood and urine. However, the exact nature of the immunoreactive material demonstrated has been a matter of discussion. In the present study, DSIP-like immunoreactivity was demonstrated in the porcine pituitary and adrenal medulla using radioimmunoassay and immunocytochemistry. In the pituitary, the DSIP-like material was present in a subpopulation of the cells storing adrenocorticotropin and alpha-melanotropin. The DSIP immunoreactive cells in the adrenal medulla were identical with a major population of the noradrenaline-storing cells. High-performance liquid chromatography of tissue extracts revealed one major peak of DSIP-like immunoreactivity which did not coelute with synthetic DSIP. The immunoreactive material may represent N-terminally truncated fragments of DSIP. The present results suggest that the anterior and intermediate lobes of the pituitary and the adrenal medulla are potential sources of DSIP-like peptides.


Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury.
Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 had an impact on the hepatic fibrotic process associated with cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2-deficient (IRS2KO) female mice. Histological and biochemical analyses, together with fibrogenic and inflammatory responses were evaluated in livers from mice at 3, 7 and 28 days following BDL. We also explored whether activation of human hepatic stellate cells (HSCs) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed reduced disruption of liver histology, such hepatocyte damage and excess deposition of extracellular matrix components, compared with WT mice at 3 and 7 days post-BDL. However, no histological differences between genotypes were found at 28 days post-BDL. The less pro-inflammatory profile of bile acids accumulated in the gallbladder of IRS2KO mice after BDL corresponded with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or inhibition of ERK1/2 reduced the activation of human LX2 cells and also reduced induction of MMP9 upon IGF1 stimulation. Furthermore, hepatic MMP9 expression was strongly induced after BDL in WT mice, but only a slight increase was found in mice lacking IRS2. Our results have unravelled the signalling pathway mediated by IGF1R-IRS2-ERK1/2-MMP9 as a key axis in regulating HSC activation, which might be therapeutically relevant for targeting liver fibrosis.


"Ocular moyamoya" syndrome in a patient with features of microcephalic osteodysplastic primordial dwarfism type II.
Primordial dwarfism refers to severely impaired growth beginning early in fetal life. There are many genetic causes of primordial dwarfism, including disorders classified as microcephalic osteodysplastic primordial dwarfism. Microcephalic osteodysplastic primordial dwarfism type II is an autosomal-recessive disease characterized by small stature, bone and dental anomalies, and characteristic facies. Affected patients have a high risk of stroke secondary to progressive cerebral vascular anomalies, which often are classified as moyamoya disease. We present the case of a boy with features suggestive of MOPD II with unilateral moyamoya cerebrovascular changes and correlative moyamoya collaterals involving the iris of the ipsilateral eye.


Cholinesterase inhibitor donepezil dilates cerebral parenchymal arterioles via the activation of neuronal nitric oxide synthase.
An acetylcholinesterase inhibitor donepezil currently is used to treat patients with Alzheimer disease. However, its direct effect on cerebral blood vessels has not been evaluated. The present study was designed to examine whether donepezil induces acute cerebral arteriolar dilation and whether neuronal nitric oxide synthase contributes to this vasodilator response. Brain slices were obtained from neuronal nitric oxide synthase knock-out or C57BL/6J strain (control) mice as well as Wistar rats. Parenchymal arterioles were monitored using videomicroscopy. During constriction to prostaglandin F2alpha (5 x 10 m), donepezil (10-10 m) or acetylcholine (10-10 m) was added. In some experiments, brain slices were treated with a nonselective or a selective nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [10 m] and S-methyl-L-thiocitrulline [10 m], respectively). An immunohistochemical analysis was performed using antibodies for neuronal nitric oxide synthase and acetylcholinesterase. Acetylcholine concentration-dependently dilated rat parenchymal arterioles, while S-methyl-L-thiocitrulline as well as N-nitro-L-arginine methyl ester completely abolished this response. Donepezil produced arteriolar dilation, which was inhibited by S-methyl-L-thiocitrulline or N-nitro-L-arginine methyl ester. Donepezil failed to induce arteriolar dilation in the brain slice from the neuronal nitric oxide synthase knock-out mice. Immunohistochemical analysis revealed spatial relationship between neuronal nitric oxide synthase and acetylcholinesterase in the arteriolar wall. Donepezil produces acute vasodilation induced by a selective activation of neuronal nitric oxide synthase in the cerebral parenchymal arterioles. This agent may be capable of enhancing this enzymatic activity directly or via acetylcholinesterase existing on the arteriolar wall.


IoT in medical diagnosis: detecting excretory functional disorders for Older adults via bathroom activity change using unobtrusive IoT technology.
The Internet of Things (IoT) and Artificial Intelligence (AI) are promising technologies that can help make the health system more efficient, which concurrently can be particularly useful to help maintain a high quality of life for older adults, especially in light of healthcare staff shortage. Many health issues are challenging to manage both by healthcare staff and policymakers. They have a negative impact on older adults and their families and are an economic burden to societies around the world. This situation is particularly critical for older adults, a population highly vulnerable to diseases that needs more consideration and care. It is, therefore, crucial to improve diagnostic and management as well as proposed prevention strategies to enhance the health and quality of life of older adults. In this study, we focus on detecting symptoms in early stages of diseases to prevent the deterioration of older adults' health and avoid complications. We focus on digestive and urinary system disorders [mainly the Urinary Tract Infection (UTI) and the Irritable Bowel Syndrome (IBS)] that are known to affect older adult populations and that are detrimental to their health and quality of life. Our proposed approach relies on unobtrusive IoT and change point detections algorithms to help follow older adults' health status daily. The approach monitors long-term behavior changes and detects possible changes in older adults' behavior suggesting early onsets or symptoms of IBS and UTI. We validated our approach with medical staff reports and IoT data collected in the residence of 16 different older adults during periods ranging from several months to a few years. Results are showing that our proposed approach can detect changes associated to symptoms of UTI and IBS, which were confirmed with observations and testimonies from the medical staff.


ZnO/Graphene Oxide on Halloysite Nanotubes as a Superabsorbent Nanocomposite Photocatalyst for the Degradation of Organic Dyes.
Using renewable photocatalysts for pollutant degradation represents a promising approach to addressing environmental water challenges by harnessing solar energy without additional energy consumption. However, for the practical use of photocatalysts, it is necessary to improve catalyst efficiency, considering cost and biocompatibility. In this study, we developed a new superabsorbent photocatalyst for the degradation of organic dyes in water. Our photocatalyst comprises halloysite nanotubes (HNTs) with a large outer diameter and Si-O and Al-O groups on the outer and inner surfaces, respectively; graphene oxide (GO) possessing numerous sp2 bonds and light-conductive properties; and ZnO, which can degrade organic molecules via a photon source. By exploiting the superabsorbent properties of GOs for organic dyes and stabilizing ZnO nanoparticles on HNTs to inhibit aggregation, our photocatalysts demonstrated significantly improved degradability compared to ZnO nanoparticles alone and combinations of ZnO with HNTs or GO. The structural characteristics of the nanocomposites were characterized using SEM, EDX, Raman spectroscopy, and XRD. Their enhanced photocatalytic activity was demonstrated by the degradation of rhodamine b in water, showing 95% photodegradation under UV illumination for 60 min, while the ZnO nanoparticles showed only 56% dye degradation under the same condition. Additionally, the degradation rate was enhanced by four times. Furthermore, the catalysts maintained their initial activity with no significant loss after four uses, showing their potential for practical implementation in the mass purification of wastewater.


[Atypical acral hyperkeratosis in a black woman].
This report describes the case of a 33-year-old black woman who presented atypical hyperkeratosis. Atypical features included location on the dorsum of the foot and presence of punctate pits. The lesion was classified as intermediate between keratosis punctata of the palmar creases and focal acral hyperkeratosis. The main elements of differential diagnosis are Hyperkeratosis lenticularis perstans and punctuated porokeratosis. The clinical and histological features of these lesions are discussed based on a review of the literature. Therapy including application of topical emollients is problematic.


Combination of mouse models and genomewide association studies highlights novel genes associated with human kidney function.
Genomewide association studies have identified numerous chronic kidney disease-associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics with human genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium. After multiple testing corrections, significant associations with estimated GFR in humans were identified for single-nucleotide polymorphisms in 2, 7, and 17 genes causing abnormal GFR, abnormal physiology, and abnormal morphology in mice, respectively. Genes identified for abnormal kidney morphology showed significant enrichment for estimated GFR-associated single-nucleotide polymorphisms. In total, 19 genes contained variants associated with estimated GFR or the urinary albumin-to-creatinine ratio of which 16 mapped into previously reported genomewide significant loci. CYP26A1 and BMP4 emerged as novel signals subsequently validated in a large, independent study. An additional gene, CYP24A1, was discovered after conditioning on a published nearby association signal. Thus, our novel approach to combine comprehensive mouse phenotype information with human genomewide association studies data resulted in the identification of candidate genes for kidney disease pathogenesis.


Using x-ray micro computed tomography to quantify intracochlear fibrosis after cochlear implantation in a Guinea pig model.
Cochlear implants (CIs) allow individuals with profound hearing loss to understand speech and perceive sounds. However, not all patients obtain the full benefits that CIs can provide and the cause of this disparity is not fully understood. One possible factor for the variability in outcomes after cochlear implantation, is the development of fibrotic scar tissue around the implanted electrode. It has been hypothesised that limiting the extent of fibrosis after implantation may improve overall CI function, and longevity of the device. Currently, histology is often used to quantify the extent of intracochlear tissue growth after implantation however this method is labour intensive, time-consuming, often involves significant user bias, and causes physical distortion of the fibrosis. Therefore, this study aimed to evaluate x-ray micro computed tomography (μCT) as a method to measure the amount and distribution of fibrosis in a guinea pig model of cochlear implantation. Adult guinea pigs were implanted with an inactive electrode, and cochleae harvested eight weeks later (n = 7) and analysed using μCT, to quantify the extent of tissue reaction, followed by histological analysis to confirm that the tissue was indeed fibrotic. Cochleae harvested from an additional six animals following implantation were analysed by μCT, before and after contrast staining with osmium tetroxide (OsO4), to enhance the visualisation of soft tissues within the cochlea, including the tissue reaction. Independent analysis by two observers showed that the quantification method was robust and provided additional information on the distribution of the response within the cochlea. Histological analysis revealed that μCT visualised dense collagenous material and new bone formation but did not capture loose, areolar fibrotic tissue. Treatment with OsO4 significantly enhanced the visible tissue reaction detected using μCT. Overall, μCT is an alternative and reliable method that can be used to quantify the extent of the CI-induced intracochlear tissue response and will be a useful tool for the in vivo assessment of novel anti-fibrotic treatments.


Oxidative Stress Is Associated With Diastolic Dysfunction in Women With Ischemia With No Obstructive Coronary Artery Disease.
Background Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have evidence of diastolic dysfunction. Oxidative stress (OS) is associated with cardiovascular risk factors and adverse outcomes. The relationship between systemic OS and diastolic dysfunction is unknown. Methods and Results A subgroup of women (n=75) with suspected ischemia and no obstructive coronary artery disease who had both cardiac magnetic resonance imaging and OS measurements were enrolled in the WISE-CVD (Women Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction) study. Left ventricular end-diastolic pressure was measured invasively. Left ventricular end-diastolic volume and peak filling rate were assessed using cardiac magnetic resonance imaging. Aminothiol levels of plasma cystine and glutathione were measured as markers of OS. Spearman correlation and linear regression analyses were conducted. The group mean age was 54±11 years, and 61% had a resting left ventricular end-diastolic pressure >12 mm Hg. Cystine levels correlated negatively with the peak filling rate (r=-0.31, P=0.007) and positively with left ventricular end-diastolic pressure (r=0.25; P=0.038), indicating that increased OS was associated with diastolic dysfunction. After multivariate adjustment including multiple known risk factors for diastolic dysfunction and cardiovascular medications, cystine levels continued to be associated with peak filling rate (β=-0.27, P=0.049) and left ventricular end-diastolic pressure (β=0.25; P=0.035). Glutathione levels were not associated with indices of diastolic function. Conclusions OS, measured by elevated levels of cystine, is associated with diastolic dysfunction in women with evidence of ischemia and no obstructive coronary artery disease, indicating the role of OS in patients with ischemia and no obstructive coronary artery disease. Its role in the progression of heart failure with preserved ejection fraction should be explored further.


Primary structure of Lep d I, the main Lepidoglyphus destructor allergen.
The most relevant allergen of the storage mite Lepidoglyphus destructor (Lep d I) has been characterized. Lep d I is a monomer protein of 13273 Da. The primary structure of Lep d I was determined by N-terminal Edman degradation and partially confirmed by cDNA sequencing. Sequence polymorphism was observed at six positions, with non-conservative substitutions in three of them. No potential N-glycosylation site was revealed by peptide sequencing. The 125-residue sequence of Lep d I shows approximately 40% identity (including the six cysteines) with the overlapping regions of group II allergens from the genus Dermatophagoides, which, however, do not share common allergenic epitopes with Lep d I.


Altitude-related illness in two California national parks.
High-altitude illness encompasses a spectrum of disorders related to the hypoxia experienced by individuals at elevation. Altitude-related illness has been well described in the United States, but there are no studies published in the medical literature looking at the occurrence of high-altitude illness within the US National Parks system. The purpose of this study is to describe the incidence, treatment, and outcomes of visitors to Sequoia and Kings Canyon National Parks who presented to emergency medical services (EMS) personnel with signs and symptoms consistent with high-altitude illness. We conducted a retrospective review of all EMS patient care records (PCRs) from Sequoia and Kings Canyon National Parks during the study period of June 1992 to August 1995. There were 23 cases of altitude-related illness identified by EMS personnel in the parks during the 38-month study period, including five cases of high-altitude pulmonary edema and 19 cases of acute mountain sickness. One patient died, nine patients were transported to local hospitals, nine patients were assisted in their descent and then released from medical care, and four patients were treated and then allowed to continue their travels. There was an average of 5.9 cases per year of high-altitude illness and an incidence of one case per 27 EMS contacts. We conclude that altitude-related illness does occur in Sequoia and Kings Canyon National Parks and, although high-altitude illness accounts for only 4% of EMS contacts, caring for these patients uses a significant amount of national park resources. We suggest continued training of emergency medical technicians and park medics in the recognition and treatment of these disorders. We also support education of hikers to reduce or prevent the morbidity associated with altitude-related illness.


[Cardiovascular risk in patients with chronic renal failure. Patients in renal replacement therapy].
Dialysis patients constitute a high-risk subset of patients for developing cardiovascular disease, which accounts for nearly 50% of deaths. After stratification for age, race and gender, cardiovascular mortality is 10-20 times higher in dialysis patients than in the general population. Cardiovascular disease in this population cannot be fully explained by the high prevalence of classical cardiovascular risk factors (age, hypertension, diabetes, hyperlipidemia, smoking, etc.). Thus, the involvement of "new" cardiovascular risk factors (hyperhomocysteinemia, hyperfibrinogenemia, high lipoprotein (a) levels, oxidative stress, inflammation, etc.), and uremia-related factors (anemia, impaired calcium-phosphorus metabolism, hyperparathyroidism, accumulation of endogenous inhibitors of nitric oxide synthesis, etc.) has been also invoked to play a role in the increased cardiovascular risk in these patients. Endothelial dysfunction is the initial event in the development of atherosclerosis. Uremic patients exhibit an endothelial dysfunction, even before starting dialysis, which persists o is even aggravated under dialysis treatment. Uremic patients must be considered at high risk of developing cardiovascular disease. Thus cardiovascular risk factors in these patients should be managed early, aggressive and multifactorially in order to reduce their high cardiovascular morbidity and mortality.


Inferring the shallow phylogeny of true salamanders (Salamandra) by multiple phylogenomic approaches.
The rise of high-throughput sequencing techniques provides the unprecedented opportunity to analyse controversial phylogenetic relationships in great depth, but also introduces a risk of being misinterpreted by high node support values influenced by unevenly distributed missing data or unrealistic model assumptions. Here, we use three largely independent phylogenomic data sets to reconstruct the controversial phylogeny of true salamanders of the genus Salamandra, a group of amphibians providing an intriguing model to study the evolution of aposematism and viviparity. For all six species of the genus Salamandra, and two outgroup species from its sister genus Lyciasalamandra, we used RNA sequencing (RNAseq) and restriction site associated DNA sequencing (RADseq) to obtain data for: (1) 3070 nuclear protein-coding genes from RNAseq; (2) 7440 loci obtained by RADseq; and (3) full mitochondrial genomes. The RNAseq and RADseq data sets retrieved fully congruent topologies when each of them was analyzed in a concatenation approach, with high support for: (1) S. infraimmaculata being sister group to all other Salamandra species; (2) S. algira being sister to S. salamandra; (3) these two species being the sister group to a clade containing S. atra, S. corsica and S. lanzai; and (4) the alpine species S. atra and S. lanzai being sister taxa. The phylogeny inferred from the mitochondrial genome sequences differed from these results, most notably by strongly supporting a clade containing S. atra and S. corsica as sister taxa. A different placement of S. corsica was also retrieved when analysing the RNAseq and RADseq data under species tree approaches. Closer examination of gene trees derived from RNAseq revealed that only a low number of them supported each of the alternative placements of S. atra. Furthermore, gene jackknife support for the S. atra - S. lanzai node stabilized only with very large concatenated data sets. The phylogeny of true salamanders thus provides a compelling example of how classical node support metrics such as bootstrap and Bayesian posterior probability can provide high confidence values in a phylogenomic topology even if the phylogenetic signal for some nodes is spurious, highlighting the importance of complementary approaches such as gene jackknifing. Yet, the general congruence among the topologies recovered from the RNAseq and RADseq data sets increases our confidence in the results, and validates the use of phylotranscriptomic approaches for reconstructing shallow relationships among closely related taxa. We hypothesize that the evolution of Salamandra has been characterized by episodes of introgressive hybridization, which would explain the difficulties of fully reconstructing their evolutionary relationships.


The effects of time and dose on the relative beta 1- and beta 2-adrenoceptor antagonism of betaxolol and atenolol.
1. Six normal subjects were given single oral doses of betaxolol 10 mg (B10), 40 mg (B40), 80 mg (B80); atenolol 50 mg (A50), 200 mg (A200); or placebo (PL). Measurements of beta 1-adrenoceptor blockade (reduction of exercise heart rate) and of beta 2-adrenoceptor blockade (attenuation of isoprenaline responses) were made at baseline, and at 2, 4, 6, 8 and 24 h after drug ingestion. 2. Mean values for Cmax and tmax were as follows: B10 (33 ng ml-1, 3.7 h), B40 (84 ng ml-1, 4.0 h), B80 (179 ng ml-1, 3.7 h); A50 (261 ng ml-1, 2.7 h), A200 (1369 ng ml-1, 2.0 h). 3. Reduction of exercise heart rate (EHR) occurred in dose-dependent fashion up to a ceiling at B40 (as % reduction c.f. placebo, at peak and 24 h): B10 16.2 to 10.2%, B40 27.1 to 16.2%, B80 27.0 to 18.7%; A50 20.9 to 9.1%, A200 28.8 to 15.8%. There were also dose-related increases in beta 2-adrenoceptor antagonism (IT100 dose ratios, at peak and 24 h): B10 2.1 to 1.2, B40 4.7 to 2.6, B80 6.0 to 4.7; A50 2.0 to 1.2, A200 4.7 to 1.8. There were similar trends for attenuation of heart rate and DBP responses to isoprenaline. 4. Ratios of beta 1:beta 2-adrenoceptor antagonism were calculated (as % reduction EHR divided by IT100 dose ratio); to provide an index of beta 1-adrenoceptor selectivity at peak and 24 h: B10 7.7 to 8.5, B40 5.8 to 6.2, B80 4.5 to 4.0; A50 10.5 to 7.6, A200 6.1 to 8.8.(ABSTRACT TRUNCATED AT 250 WORDS)


Pathobiology of infection in prosthetic devices.
Because of the growing use of implants, infections in prosthetic devices are probably becoming commoner, even though the risk of infection remains low. Multiple factors appear to be involved in the development of these infections, including foreign body-associated tissue damage, impairment of host defenses, bacterial trapping by fibrin, sequestration of bacteria in implant interstices, and the generation of a biofilm on implant surfaces. Although there is a direct association between the tissue reactivity of implants and their ability to potentiate infection, bacterial slime production and adherence to implant surfaces (generation of the biofilm) appear to play a primary role in the pathogenesis of device infections, contemporary prosthetic devices generally being quite nonreactive with respect to host tissues. While virtually any organism can cause these infections, gram-positive bacteria, especially staphylococci, predominate. Infections due to gram-negative organisms and fungi, however, tend to be more serious, often requiring prompt removal of the implant.


Clade 18.104.22.168 H5 North American Highly Pathogenic Avian Influenza Viruses Infect, but Do Not Cause Clinical Signs in, American Black Ducks (Anas rubripes).
Highly pathogenic avian influenza virus (HPAIV) from the goose/Guangdong/1996 clade 126.96.36.199 H5 lineage spread from Asia into North America in 2014, most likely by wild bird migrations. Although several variants of the virus were detected, H5N8 and H5N2 were the most widespread in North American wild birds and domestic poultry. In early 2015, the H5N2 virus spread through commercial poultry in the Midwest, and >50 million chickens and turkeys died or had to be culled. Related H5 HPAIVs are still endemic in much of the Eastern Hemisphere. The wild bird species that were involved with dissemination of the virus in North America are not known. Dabbling ducks, especially mallards (Anas platyrhynchos), typically have the highest detection rates for avian influenza viruses. To better characterize the wild avian species that could spread the virus, American black ducks (Anas rubripes), which are closely related to mallards, were challenged with the North American H5N2 and H5N8 index HPAIV isolates: A/Northern Pintail/WA/40964/2014 H5N2 and A/Gyrfalcon/WA/41088/2014 H5N8. Although the American black ducks could be infected with low doses of both isolates (≤102 50% egg infective doses), ducks shed the H5N2 longer than the H5N8 (10 vs. 7 days) and the titers of virus shed were higher. Although there were too few ducks available on which to draw definitive conclusions, this suggests that American black ducks could serve as a more efficient reservoir for the H5N2 virus than the H5N8 virus.


Enzymatic synthesis of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) with CoA recycling using polyhydroxyalkanoate synthase and acyl-CoA synthetase.
We succeeded in developing a novel method for in vitro poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3 HB-co-4 HB)] synthesis with CoA recycling using polyhydroxyalkanoate synthase and an acyl-CoA synthetase. Using this method, the monomer compositions in P(3 HB-co-4 HB)s could be controlled strictly by the ratios of the monomers in the reaction mixtures.


Surgical strategies in treating brainstem cavernous malformations.
Optimal therapy of brainstem cavernous malformations (BSCMs) remains controversial because their biological behavior is unpredictable and surgical removal is challenging. To analyze our experience with BSCMs and to conduct a review of the literature to identify a rational approach to the management of these lesions. Fifty-five patients harboring 57 BSCMs underwent surgery and 17 patients were treated conservatively during the 10-year period from 1999 to 2008. The operative strategy was to perform complete CM resection and to preserve any associated venous malformation with minimal functional brainstem tissue sacrificed. The National Institutes of Health Strength Scale (NIHSS) was used to assess neurological status. The average hemorrhagic and rehemorrhagic rates were 4.7% and 32.7% per patient-year, respectively. Total lesional resection was achieved in all operated patients. Their mean NIHSS score was 4.6 after the first episode, 3.5 preoperatively, 3.2 at discharge, and 1.4 after a mean follow-up of 49 months. Complete recovery rates of motor deficits and sensory disturbances from the preoperative state were 70.4% and 51.7%, respectively. Complete recovery rates for cranial nerves III, V, VI, and VII and the lower group were 60%, 63.2%, 25%, 57.1%, and 80%, respectively. For the conservative patients, the mean NIHSS score was 5.9 after the first episode and 1.7 after a mean follow-up of 40 months. NIHSS is optimal for evaluating the natural history and surgical effect of patients harboring BSCMs. Surgical resection remains the primary therapeutic option after careful patient screening and preoperative planning.


Relationships between muscular impairments, pain, and disability in patients with chronic nonspecific low back pain: a cross sectional study.
To clarify the significance of mechanical impairments, pain, and functional limitations as predictors of chronic low back pain (LBP). Ninety patients with chronic nonspecific low back pain (CNSLBP) were prospectively studied with clinical tests and questionnaires. Changes in muscle extensibility and endurance tests were evaluated and changes assessed in LBP intensity on numeric rating scale 0-10 and severity with Oswestry Disability Index (ODI) 0-100. In the present study we found significant associations between the 4 muscle extensibility and 2 endurance tests and pain at nonspecific patients with chronic LBP (P<0.005). The 2 muscle extensibility and 1 endurance tests were in complete equilibrium with ODI disability and hence showed similar results (P<0.005). The associations between the muscle extensibility and endurance tests and pain were significantly elevated in patients with nonspecific chronic LBP.


Atractylenolide III Enhances Energy Metabolism by Increasing the SIRT-1 and PGC1α Expression with AMPK Phosphorylation in C2C12 Mouse Skeletal Muscle Cells.
Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes. AIII significantly increased the glucose uptake levels, and significantly increased the expressions of peroxisome proliferator-activated receptor coactivator-1α (PGC1α) and mitochondrial biogenesis-related markers, such as, nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) and mitochondrial mass and total ATP contents. In addition, AIII significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of sirtuin1 (SIRT1). These results suggest that AIII may have beneficial effects on obesity and T2DM by improving energy metabolism in skeletal muscle.


Autocatalytic Decomplexation of Cu(II)-EDTA and Simultaneous Removal of Aqueous Cu(II) by UV/Chlorine.
Traditional processes usually cannot enable efficient water decontamination from toxic heavy metals complexed with organic ligands. Herein, we first reported the removal of Cu(II)-EDTA by a UV/chlorine process, where the Cu(II)-EDTA degradation obeyed autocatalytic two-stage kinetics, and Cu(II) was simultaneously removed as CuO precipitate. The scavenging experiments and EPR analysis indicated that Cl• accounted for the Cu(II)-EDTA degradation at diffusion-controlled rate (∼1010 M-1 s-1). Mechanism study with mass spectrometry evidence of 11 key intermediates revealed that the Cu(II)-EDTA degradation by UV/chlorine was an autocatalytic successive decarboxylation process mediated by the Cu(II)/Cu(I) redox cycle. Under UV irradiation, Cu(I) was generated during the photolysis of the Cl•-attacked complexed Cu(II) via ligand-to-metal charge transfer (LMCT). Both free and organic ligand-complexed Cu(I) could form binary/ternary complexes with ClO-, which were oxidized back to Cu(II) via metal-to-ligand charge transfer (MLCT) with simultaneous production of Cl•, resulting in the autocatalytic effect on Cu(II)-EDTA removal. Effects of chlorine dosage and pH were examined, and the technological practicability was validated with authentic electroplating wastewater and other Cu(II)-organic complexes. This study shed light on a new mechanism of decomplexation by Cl• and broadened the applicability of the promising UV/chlorine process in water treatment.


Characteristics of opiate dependent patients who attempt suicide.
To describe the characteristics of opiate dependent patients who attempt suicide. Opiate dependent patients (DSM-IV criteria) who had (N = 105) or had not (N = 141) attempted suicide were compared for family history of suicide, childhood trauma, personality traits, and experience of comorbidity with cocaine and/or alcohol dependence, major depressive disorder. and physical disorder. Significantly more opiate dependent patients who had attempted suicide were female (p < .0001) and unemployed (p < .0006). Patients who had attempted suicide reported significantly more family history of suicide and more childhood trauma; scored significantly higher for introversion, hostility, and neuroticism; and had experienced significantly more comorbidity with lifetime cocaine and alcohol dependence, major depressive disorder, and current physical disorder (p < .05 for all). Suicidal behavior in opiate dependent patients may involve risk factors from the family, childhood, personality, psychiatric, and physical domains.


Cognitive decline and oral health in middle-aged adults in the ARIC study.
Even before dementia becomes apparent, cognitive decline may contribute to deterioration in oral health. This cohort study of middle-aged adults evaluated associations of six-year change in cognitive function with oral health behaviors and conditions in the Atherosclerosis Risk in Communities (ARIC) study. Cognitive function was measured at study visits in 1990-1992 and 1996-1998 with three tests: (a) Delayed Word Recall (DWR), (b) Digit Symbol Substitution (DSS), and (c) Word Fluency (WF). Cognitive decline scores were computed as 'studentized' residuals of 1996-1998 scores regressed against 1990-1992 scores. In 1996-1998, 10,050 participants answered dental screening questions, and 5,878 of 8,782 dentate participants received a comprehensive oral examination. Multiple regression models used cognitive change to predict oral health behaviors and conditions with adjustment for covariates. In the fully adjusted models, greater decline in all three measures of cognitive function was associated with increased odds of complete tooth loss. Greater decline in DSS and WF scores was associated with infrequent toothbrushing. Decline in WF scores was also associated with higher plaque levels. In these middle-aged adults, six-year cognitive decline was modestly associated with less frequent toothbrushing, plaque deposit, and greater odds of edentulism, but not with other oral behaviors or diseases.


Selective use of superficial temporal artery cannulation in infants undergoing cardiac surgery.
Arterial cannulation is routinely performed in children undergoing cardiac surgery to aid the intraoperative and intensive care management. Most commonly cannulated peripheral site in children is radial artery, and alternatives include posterior tibial, dorsalis pedis, and rarely superficial temporal artery (STA). Two specific situations in cardiac surgery where STA cannulation and monitoring was useful during the surgical procedure are reported. To our knowledge, such selective use of STA pressure monitoring has not been reported in the literature previously. Our experience suggests that STA monitoring can be useful and reliable during repair of coarctation of aorta or administration of anterograde cerebral perfusion in patients having associated aberrant origin of the right subclavian artery.


Healthcare service utilization and cost among transition-age youth with autism spectrum disorder and other special healthcare needs.
Youth with autism spectrum disorder often have complex medical needs. Disruptions of healthcare during the transition from pediatric to adult healthcare may put youth with autism spectrum disorder at higher risk of medical emergencies and high medical costs. To understand healthcare utilization during the transition years, we conducted a study among transition-age youth (14-25 years old) receiving healthcare at Kaiser Permanente Northern California during 2014-2015. We examined differences in healthcare utilization and costs among youth with autism spectrum disorder (n = 4123), attention deficit and hyperactivity disorder (n = 20,6015), diabetes mellitus (n = 2156), and general population controls (n = 20,615). Analyses were also stratified by age and sex. Youth with autism spectrum disorder had the highest utilization of outpatient primary care, mental health, and psychotropic medications and the lowest utilization of obstetrics/gynecology and urgent care. Costs for youth with autism spectrum disorder were higher than those for attention deficit and hyperactivity disorder and general population peers and lower than for diabetes mellitus. Healthcare utilization patterns varied by age. Transition-age youth with autism spectrum disorder generally used healthcare at higher rates relative to attention deficit and hyperactivity disorder and general population peers but at similar or lower rates than diabetes mellitus peers, indicating this group's complex combination of psychiatric and medical healthcare needs. The relatively high utilization of psychiatric services and low utilization of women's health services in transition-age youth with autism spectrum disorder may have implications for long-term health and warrants additional research.


How does aging affect recognition-based inference? A hierarchical Bayesian modeling approach.
The recognition heuristic (RH) is a simple strategy for probabilistic inference according to which recognized objects are judged to score higher on a criterion than unrecognized objects. In this article, a hierarchical Bayesian extension of the multinomial r-model is applied to measure use of the RH on the individual participant level and to re-evaluate differences between younger and older adults' strategy reliance across environments. Further, it is explored how individual r-model parameters relate to alternative measures of the use of recognition and other knowledge, such as adherence rates and indices from signal-detection theory (SDT). Both younger and older adults used the RH substantially more often in an environment with high than low recognition validity, reflecting adaptivity in strategy use across environments. In extension of previous analyses (based on adherence rates), hierarchical modeling revealed that in an environment with low recognition validity, (a) older adults had a stronger tendency than younger adults to rely on the RH and (b) variability in RH use between individuals was larger than in an environment with high recognition validity; variability did not differ between age groups. Further, the r-model parameters correlated moderately with an SDT measure expressing how well people can discriminate cases where the RH leads to a correct vs. incorrect inference; this suggests that the r-model and the SDT measures may offer complementary insights into the use of recognition in decision making. In conclusion, younger and older adults are largely adaptive in their application of the RH, but cognitive aging may be associated with an increased tendency to rely on this strategy.


Review of patients in general practice with a diagnosis of epilepsy: development of a practice nurse checklist and an assessment of resource implications.
SIGN has recommended annual review of all patients with epilepsy. Annual review is rewarded in the new GMS contract. There is no information on how or by whom reviews should be carried out, nor on resource implications for secondary care. To determine whether a practice nurse can deliver annual review of patients with epilepsy, and to estimate the resource implications of such review. Evaluation of a practice nurse checklist against review by neurologist in 62 patients with epilepsy identified from a practice list of 6240 from Southwest Glasgow LHCC, and audit of case records in 1259 patients with epilepsy identified from the whole LHCC population of 96,565. There were 8 discrepancies between nurse and doctor reviews in a first iteration, but none in the second. Changes suggested a training effect. The review process generated 19 epilepsy nurse appointments, 7 requests for cerebral imaging and 3 requests for video EEG. Twelve patients required continuing follow up. The LHCC audit identified a large number of patients who had inadequate documentation of information and advice (over 90% in some domains). 28.6% had not been seen by a specialist, 40.7% had not had cerebral imaging, and only 37.4% were seizure free. Annual reviews of patients with epilepsy can be carried out by practice nurses, but some training is required. The review process is likely to increase the burden on secondary care and have a significant adverse effect on neurology waiting times.


The ribotoxin α-sarcin can cleave the sarcin/ricin loop on late 60S pre-ribosomes.
The ribotoxin α-sarcin belongs to a family of ribonucleases that cleave the sarcin/ricin loop (SRL), a critical functional rRNA element within the large ribosomal subunit (60S), thereby abolishing translation. Whether α-sarcin targets the SRL only in mature 60S subunits remains unresolved. Here, we show that, in yeast, α-sarcin can cleave SRLs within late 60S pre-ribosomes containing mature 25S rRNA but not nucleolar/nuclear 60S pre-ribosomes containing 27S pre-rRNA in vivo. Conditional expression of α-sarcin is lethal, but does not impede early pre-rRNA processing, nuclear export and the cytoplasmic maturation of 60S pre-ribosomes. Thus, SRL-cleaved containing late 60S pre-ribosomes seem to escape cytoplasmic proofreading steps. Polysome analyses revealed that SRL-cleaved 60S ribosomal subunits form 80S initiation complexes, but fail to progress to the step of translation elongation. We suggest that the functional integrity of a α-sarcin cleaved SRL might be assessed only during translation.


Microencapsulation of borage oil with blends of milk protein, β-glucan and maltodextrin through spray drying: physicochemical characteristics and stability of the microcapsules.
Borage oil is a rich commercial source of γ-linolenic acid (18:3n-6). However, borage oil is rich in omega-6 polyunsaturated fatty acids and vulnerable to oxidation. Thus, selecting appropriate wall materials is critical to the encapsulation of borage oil. The present study investigated the influence of wall materials on the physicochemical characteristics and stability of microencapsulated borage oil by spray drying. Blends of milk protein [sodium caseinate (CAS) or whey protein concentrate], β-glucan (GLU) and maltodextrin (MD) were used as the wall materials for encapsulating borage oil. The microencapsulation of borage oil with different wall materials attained high encapsulation efficiencies. The microencapsulated borage oil prepared with CAS-MD achieved the optimal encapsulation efficiency of 96.62%. The oxidative stabilities of borage oil and microencapsulated borage oil were measured by accelerated storage test at 45 °C and 33% relative humidity for 30 days. The microencapsulated borage oil presented lower peroxide values than those of borage oil, and the microcapsules prepared with CAS-10GLU-MD (consisting of CAS 50 g kg-1 , GLU 100 g kg-1 and MD 475 g kg-1 of microencapsulation) conferred borage oil with high protection against lipid oxidation. The results of the present study demonstrate that the CAS-GLU-MD blend is appropriate for microencapsulating borage oil. © 2017 Society of Chemical Industry.


Multi-scale non-local denoising method in neuroimaging.
Non-local means algorithm can remove image noise in a unique way that is contrary to traditional techniques. This is because it not only smooths the image but it also preserves the information details of the image. However, this method suffers from high computational complexity. We propose a multi-scale non-local means method in which adaptive multi-scale technique is implemented. In practice, based on each selected scale, the input image is divided into small blocks. Then, we remove the noise in the given pixel by using only one block. This can overcome the low efficiency problem caused by the original non-local means method. Our proposed method also benefits from the local average gradient orientation. In order to perform evaluation, we compared the processed images based on our technique with the ones by the original and the improved non-local means denoising method. Extensive experiments are conducted and results shows that our method is faster than the original and the improved non-local means method. It is also proven that our implemented method is robust enough to remove noise in the application of neuroimaging.


The Thermoregulatory Behavior of Nectar Foraging Polistine Wasps (Polistes dominula and Polistes gallicus) in Different Climate Conditions.
Polistine wasps collect nectar for their energetic demand and for the provision of the brood. They are mainly ectothermic during different behavioral tasks. We investigated the body temperature of two species living in differing habitats and climate regions, in order to reveal the environmental influence on their thermoregulatory behavior. The species were Polistes dominula in the temperate climate of Central Europe, and Polistes gallicus in the warm Mediterranean climate of Southern Europe. The wasp's body temperature was measured during foraging on lovage (Levisticum officinale) and fennel (Foeniculum vulgare) by infrared thermography in the entire ambient temperature range they are usually exposed to (Ta ~ 20-40 °C). The temperature of all body parts increased nearly linearly with ambient temperature, with the thorax as the warmest part. To achieve optimal foraging temperatures, they preferably use solar radiation. An "operative temperature model" enabled the evaluation of the endothermic effort. Polistes dominula foraging on lovage exhibited no endothermic activity. However, while foraging on fennel they had a weak and almost constant endothermic performance of about 1 °C. Polistes gallicus, by contrast, exhibited mostly no or only minor endothermy during foraging. Both wasps avoid a high energetic effort and this way reduce their foraging costs.


LUCID: A Quantitative Assay of ESCRT-Mediated Cargo Sorting into Multivesicular Bodies.
Endosomes are transportation nodes, mediating selective transport of soluble and transmembrane cargos to and from the Golgi apparatus, plasma membrane and lysosomes. As endosomes mature to become multivesicular bodies (MVBs), Endosomal Sorting Complexes Required for Transport (ESCRTs) selectively incorporate transmembrane cargos into vesicles that bud into the endosome lumen. Luminal vesicles and their cargoes are targeted for destruction when MVBs fuse with lysosomes. Common assays of endosomal luminal targeting, including fluorescence microscopy and monitoring of proteolytic cargo maturation, possess significant limitations. We present a quantitative assay system called LUCID (LUCiferase reporter of Intraluminal Deposition) that monitors exposure of chimeric luciferase-cargo reporters to cytosol. Luciferase-chimera signal increases when sorting to the endosome lumen is disrupted, and silencing of signal from the chimera depends upon luminal delivery of the reporter rather than proteolytic degradation. The system presents several advantages, including rapidity, microscale operation and a high degree of reproducibility that enables detection of subtle phenotypic differences. Luciferase reporters provide linear signal over an extremely broad dynamic range, allowing analysis of reporter traffic even at anemic levels of expression. Furthermore, LUCID reports transport kinetics when applied to inducible trafficking reporters.


[Combination of Targeted Therapy and Immunotherapy for Cancer].
Targeted therapies and immunotherapies attack tumor cells through different mechanisms. In addition, these therapies exhibit quick and delayed effects, respectively, and therefore, these therapies are complementary. Furthermore, targeted therapies may enhance the function of immune cells, and therefore, both the therapies are expected to have a synergistic effect. Antitumor immune responses comprise several steps including dendritic cell activation, T cell activation, and dampening tumor-induced immunosuppression; targeted drugs that work at each step have been reported. Clinical trials of rational combinations of both therapies, while avoiding severe adverse events, will greatly advance cancer treatments in the near future.


[Cervical lipoma or Launois-Bensaude syndrome].
The authors report a clinical case of a borderline form between two types of lipomatosis: simple lipoma and Made-lung's disease. The authors review the clinical features of these two diseases and stress the fundamental importance of the intraoperative appearance. The diagnosis in the present case was that of cervial lipoma.


Convergence of approximate two-component Hamiltonians: how far is the Dirac limit.
A systematic elimination of the off-diagonal parts of the Dirac Hamiltonian is carried out in the spirit of the Douglas-Kroll [Ann. Phys. 82, 87 1974] approach and the recently proposed infinite-order two-component method. The present approach leads to a series of approximate two-component Hamiltonians which are exact through a certain order in the external potential. These Hamiltonians are used to study the convergence pattern of approximate two-component theories. It is shown that to achieve an acceptably high accuracy for low-lying one-electron levels in heavy and superheavy systems one needs to use approximate Hamiltonians of prohibitively high order in the external potential. One can conclude that the finite-order two-component Hamiltonians are of limited usefulness in accurate relativistic calculations for heavy and superheavy systems.


Early Eocene fossils suggest that the mammalian order Perissodactyla originated in India.
Cambaytheres (Cambaytherium, Nakusia and Kalitherium) are recently discovered early Eocene placental mammals from the Indo-Pakistan region. They have been assigned to either Perissodactyla (the clade including horses, tapirs and rhinos, which is a member of the superorder Laurasiatheria) or Anthracobunidae, an obscure family that has been variously considered artiodactyls or perissodactyls, but most recently placed at the base of Proboscidea or of Tethytheria (Proboscidea+Sirenia, superorder Afrotheria). Here we report new dental, cranial and postcranial fossils of Cambaytherium, from the Cambay Shale Formation, Gujarat, India (~54.5 Myr). These fossils demonstrate that cambaytheres occupy a pivotal position as the sister taxon of Perissodactyla, thereby providing insight on the phylogenetic and biogeographic origin of Perissodactyla. The presence of the sister group of perissodactyls in western India near or before the time of collision suggests that Perissodactyla may have originated on the Indian Plate during its final drift toward Asia.


Cytotoxic and Antibiotic Potential of Secondary Metabolites from the Lichen Umbilicaria muhlenbergii.
Lichens are emerging as a promising natural source of bioactivities of pharmaceutical interest. The present study aims to contribute to the knowledge of the lichen Umbilicaria muhlenbergii as a potential source of pharmaceutically relevant anticancer and antibiotic lichen chemicals. The crude acetone extract of U. muhlenbergii exhibited 13.3 μg mL-1 cytotoxic activity (EC50) against breast cancer cells (MCF-7), as compared to a cisplatin positive control with EC50 of 5.8 μg mL-1. The antibiotic activity of the crude extract against a gram-positive Staphylococcus aureus was 22.5 μg mL-1 as MIC. Using silica gel 60 (SG60) column chromatography, the crude extract was then separated into eight fractions, which were further evaluated for their anticancer activities against MCF-7 cells. By means of propidium iodide flow cytometry, two of the eight SG60 fractions were found to cause cell cycle arrest in MCF-7 cells (73.14% of cells) at the G2 phase, which is indicative of apoptosis and inhibition of cellular proliferation. Identification of chemical constituents present in these two SG60 fractions was carried out with Thin-Layer Chromatography (TLC) and a lichen metabolite database (Wintabolites). The two fractions (SG60-5 and SG60-6) were found to contain compounds belonging to the chemical families depsides, depsidones, anthraquinones, and xanthones. The SG60-5 and SG60-6 fractions were further fractionated with Sephadex LH-20. Over 15% of the 46 LH-20 fractions obtained from the SG60-5 fraction caused 100% cell death, whereas 32% of the LH-20 fractions derived from SG60 6 fraction reduced cell survival to below 20%. This work extends the evaluation of the cytotoxic and antibiotic activities of lichen secondary metabolites to the species U. muhlenbergii. It presents encouraging results of pharmaceutical interest that set up lichens as an effective source of new bioactive natural products. Further investigations are underway to reveal the full biopharmaceutical potential of U. muhlenbergii.


Effects of levodopa on regional cerebral metabolism and blood flow.
Levodopa (L-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to the understanding of the effects of L-dopa and other dopaminergic treatment on the activity of abnormal motor and cognitive brain circuits in Parkinson's disease patients. Progress has also been made in understanding the functional pathology of dyskinesias, a common side effect of l-dopa treatment, at both regional and network levels. Here, we review these studies, focusing mainly on the new mechanistic insights provided by metabolic brain imaging and network analysis.


Glucagon secretory responses to insulin-induced hypoglycemia and arginine in streptozotocin-induced diabetic dogs.
To clarify whether the reactivity of A cells is regulated by B cell function in the pancreas, plasma glucagon (IRG) responses to insulin-induced hypoglycemia and to arginine infusion were evaluated in streptozotocin (STZ; total 40 mg/kg) treated and control dogs. There was no significant rise in plasma IRG levels during the insulin-induced hypoglycemia in the STZ-treated dogs. In contrast, arginine enhanced the IRG secretion from the pancreas to a similar extent in the two groups. This was deduced from the difference between IRG levels in the pancreaticoduodenal and peripheral veins. Neither intravenous glucose nor arginine infusion resulted in a significant rise in plasma insulin (IRI) levels in the STZ-treated dogs. IRI content in the pancreas of STZ-treated dogs was significantly reduced to 5 percent below the levels in the control dogs. The IRG content for control and STZ-treated dogs did not differ. These results indicate that while the responsiveness of A cells to hypoglycemia may depend on the secretory capacity of B cells, such is not the case with arginine.


Eating behaviours in relation to emotional intelligence.
The purpose of the study was to examine the abnormal eating attitudes in judoists and the possible relationships between eating attitudes, emotional intelligence, and body dissatisfaction. A total of 20 national judoists and 25 control participants were enrolled in the study. Subjects completed the following questionnaires: The Eating Attitudes Test, The Body Image Assessment Scale-Body Dimensions and the Bar-On Emotional Intelligence Questionnaire. 30 % of the athletes (n=6) and 20% of the controls (n=5) presented disordered eating attitudes although these subjects were of normal weight. They also presented body dissatisfaction and had lower levels of emotional intelligence in comparison to the groups without disordered eating attitudes, particularly in factors such as intrapersonal (p<0.01), adaptability (p<0.05), stress tolerance (p<0.04) and general mood (p<0.04). The athletes reported using different weight loss methods such as self-induced vomiting (20%), fasting (40%), diuretics (15%), and laxatives (50%). Among disordered eating attitude groups (Controls+Judoists), Global EAT-26 was negatively correlated with stress tolerance (p<0.04: r=-0.64), emotional self-awareness (p<0.05: r=-0.70), general mood (p<0.01: r=-0.74), and positively correlated with body dissatisfaction (p<0.01: r=0.79). Results highlight the role of emotion in disordered eating attitudes, which is an important finding in terms of the prevention and management of disordered eating.