Molecular recognition of Brucella A and M antigens dissected by synthetic oligosaccharide glycoconjugates leads to a disaccharide diagnostic for brucellosis.
The cell wall O-polysaccharides of pathogenic Brucella species are homopolymers of the rare sugar 4,6-dideoxy-4-formamido-α-D-mannopyranose. Despite the apparent simplicity of the polysaccharide it appears to be a "block copolymer" composed of A and M polysaccharide sequences expressed as a single molecule. The simultaneous presence of both in the cell wall has complicated the understanding of the molecular recognition of these antigens by antibodies present in the serum of infected animals and humans and by monoclonal antibodies. Since presumptive diagnosis of brucellosis, a serious disease in domestic livestock, wild animals, and humans, is based on detection of these antibodies it is important to separate the two antigenic epitopes, one of which is also found in other bacteria. Chemical synthesis provides the only means to achieve this outcome. A series of six oligosaccharides from di to hexasaccharides 1-6 were synthesized and conjugated to proteins to provide glycoconjugate antigens and conjugate vaccines. These chemically defined antigens identified the M antigenic determinant and provided a structural basis for understanding the fine specificity of monoclonal and polyclonal antibodies that bind the M antigen. This resulted in the discovery of a disaccharide that shows considerable potential as an unambiguous diagnostic antigen for detecting brucellosis in humans and animals and two hexasaccharide conjugate vaccine candidates that produce high levels of O-polysaccharide specific antibodies in mice.


Intralesional excision with topical intralesional cryotherapy improves the treatment of keloid scarring in a paediatric patient.
Recurrent keloid scarring has a significant impact on quality of life. Management is complex, particularly for scars resistant to conventional treatments and in paediatric cases where radiotherapy is not a suitable adjunct to surgical excision. We present the case of a nine-year-old African Caribbean girl with multiple large and recurrent keloid scars on both ears and bilateral sensorineural deafness. Following repeated intralesional excisions, corticosteroid and botulinum toxin injections, she continued to experience rapid recurrence of her keloids, worsening pain and pruritus. She was no longer able to wear her hearing aids because of the large size of the keloids. We employed a novel technique using topical intralesional cryotherapy, applying liquid nitrogen intraoperatively to the inside of the skin flaps immediately post-intralesional keloid excision and before wound closure. At 26-month follow-up a good aesthetic and symptomatic result was achieved, with minimal hypopigmentation, significantly reduced scar volume and significantly slowed recurrence. We discuss this case and review the current literature on the use of topical intralesional cryotherapy for keloid scarring.


Physical human-robot interaction of an active pelvis orthosis: toward ergonomic assessment of wearable robots.
In human-centered robotics, exoskeletons are becoming relevant for addressing needs in the healthcare and industrial domains. Owing to their close interaction with the user, the safety and ergonomics of these systems are critical design features that require systematic evaluation methodologies. Proper transfer of mechanical power requires optimal tuning of the kinematic coupling between the robotic and anatomical joint rotation axes. We present the methods and results of an experimental evaluation of the physical interaction with an active pelvis orthosis (APO). This device was designed to effectively assist in hip flexion-extension during locomotion with a minimum impact on the physiological human kinematics, owing to a set of passive degrees of freedom for self-alignment of the human and robotic hip flexion-extension axes. Five healthy volunteers walked on a treadmill at different speeds without and with the APO under different levels of assistance. The user-APO physical interaction was evaluated in terms of: (i) the deviation of human lower-limb joint kinematics when wearing the APO with respect to the physiological behavior (i.e., without the APO); (ii) relative displacements between the APO orthotic shells and the corresponding body segments; and (iii) the discrepancy between the kinematics of the APO and the wearer's hip joints. The results show: (i) negligible interference of the APO in human kinematics under all the experimented conditions; (ii) small (i.e., < 1 cm) relative displacements between the APO cuffs and the corresponding body segments (called stability); and (iii) significant increment in the human-robot kinematics discrepancy at the hip flexion-extension joint associated with speed and assistance level increase. APO mechanics and actuation have negligible interference in human locomotion. Human kinematics was not affected by the APO under all tested conditions. In addition, under all tested conditions, there was no relevant relative displacement between the orthotic cuffs and the corresponding anatomical segments. Hence, the physical human-robot coupling is reliable. These facts prove that the adopted mechanical design of passive degrees of freedom allows an effective human-robot kinematic coupling. We believe that this analysis may be useful for the definition of evaluation metrics for the ergonomics assessment of wearable robots.


Fully relativistic calculations on the potential energy surfaces of the lowest 23 states of molecular chlorine.
The electronic structure and spectroscopic properties (R(e), omega(e), omega(e)x(e), beta(e), and T(e)) of the ground state and the 22 lowest excited states of chlorine molecule were studied within a four-component relativistic framework using the MOLFDIR program package. The potential energy curves of all possible 23 covalent states were calculated using relativistic complete open shell configuration interaction approach. In addition, four component multireference configuration interaction with single and double excitation calculations were performed in order to infer the effects due to dynamical correlation in vertical excitations. The calculated properties are in good agreement with the available experimental data.


Synthesis and pharmacological activity of some 9-substituted delta 8-tetrahydrocannabinol analogues.
Several 9-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues were synthesized and evaluated for biological activity in mice. Compounds with phenyl (2b) and butyl (2c) substituents were prepared by the addition of phenyllithium and n-butyllithium, respectively, to (-)-9-nor-9-oxohexahydrocannabinol (1), followed by dehydration, whereas, isopropyl (2d), PhCH2 (2e), and Ph(CH2)2 (2f) derivatives were synthesized via the Grignard reaction with subsequent dehydration. Compounds with C2H5CH(OH) (2g) and CH3CH(OH) (2h) substituents at C-9 were prepared from (-)-9-nor-9-formyl-delta 8-tetrahydrocannabinol acetate (3) by the reaction of ethyl and methyl Grignard reagents, respectively. Biological activity indicated that a methyl group at the C-9 position is, thus far, optimum for producing hypoactivity and hypothermia in mice. In addition, hydroxyethyl substitution at position 9 reduced and antinociceptive activity of delta 8-THC, in contrast to the increased activity reported for hydroxymethyl substitution.


Microscale gradients of oxygen, hydrogen peroxide, and pH in freshwater cathodic biofilms.
Cathodic reactions in biofilms employed in sediment microbial fuel cells is generally studied in the bulk phase. However, the cathodic biofilms affected by these reactions exist in microscale conditions in the biofilm and near the electrode surface that differ from the bulk phase. Understanding these microscale conditions and relating them to cathodic biofilm performance is critical for better-performing cathodes. The goal of this research was to quantify the variation in oxygen, hydrogen peroxide, and the pH value near polarized surfaces in river water to simulate cathodic biofilms. We used laboratory river-water biofilms and pure culture biofilms of Leptothrix discophora SP-6 as two types of cathodic biofilms. Microelectrodes were used to quantify oxygen concentration, hydrogen peroxide concentration, and the pH value near the cathodes. We observed the correlation between cathodic current generation, oxygen consumption, and hydrogen peroxide accumulation. We found that the 2 e(-) pathway for oxygen reduction is the dominant pathway as opposed to the previously accepted 4 e(-) pathway quantified from bulk-phase data. Biofouling of initially non-polarized cathodes by oxygen scavengers reduced cathode performance. Continuously polarized cathodes could sustain a higher cathodic current longer despite contamination. The surface pH reached a value of 8.8 when a current of only -30 μA was passed through a polarized cathode, demonstrating that the pH value could also contribute to preventing biofouling. Over time, oxygen-producing cathodic biofilms (Leptothrix discophora SP-6) colonized on polarized cathodes, which decreased the overpotential for oxygen reduction and resulted in a large cathodic current attributed to manganese reduction. However, the cathodic current was not sustainable.


7-Mercaptoheptanoylthreonine phosphate substitutes for heat-stable factor (mobile factor) for growth of Methanomicrobium mobile.
Methanomicrobium mobile requires a heat-stable factor present in ruminal fluid and in boiled cell extract from Methanobacterium thermoautotrophicum for growth. By comparing the growth of M. mobile with boiled cell extract with that observed with various methanogenic cofactors, we found that 7-mercaptoheptanoylthreonine phosphate (HS-HTP) supported sustained growth of M. mobile, at an optimal concentration of 100 microM. No derivatives or possible biosynthetic precursors of HS-HTP could replace HS-HTP as the sole source of growth factor. Results suggest that the growth requirement might be satisfied by 7-mercaptoheptanoic acid plus a second, unidentified heat-stable factor.


Evidence-based assessment of potential use of fingolimod in treatment of relapsing multiple sclerosis.
Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system and represents one of the most common causes of chronic neurologic disability in young adults. All the current disease-modifying drugs are administered parenterally, and can be associated with varying degrees of injection site or infusion-related reactions. Together with other side effects, the parenteral route of administration is one of the key factors affecting adherence to therapy in multiple sclerosis. Fingolimod (FTY720) is an immunomodulator that acts on sphingosine 1-phosphate (S1P) receptors and is the first oral drug approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis. Downmodulation of S1P receptor type 1 (S1P(1)) slows the egress of lymphocytes from lymph nodes and recirculation to the central nervous system, reduces astrogliosis, and inhibits angiogenesis during chronic neuroinflammation. Fingolimod also regulates the migration of B cells and dendritic cells, and enhances endothelial barrier function. Results from Phase II and III clinical trials provide robust evidence of the efficacy of fingolimod in relapsing-remitting multiple sclerosis. While some caution should be exercised in terms of safety issues, the introduction of fingolimod represents a great advance in the treatment of relapsing-remitting multiple sclerosis. The pharmacologic data on fingolimod and its efficacy and safety in multiple sclerosis are reviewed in this paper.


Medicare Beneficiaries With Self-Reported Functional Hearing Difficulty Have Unmet Health Care Needs.
Hearing loss is associated with higher health care spending and use, but little is known about the unmet health care needs of people with hearing loss or difficulty. Analysis of 2016 Medicare Current Beneficiary Survey data for beneficiaries ages sixty-five and older reveals that those who reported a lot of trouble hearing in the past year were 49 percent more likely than those who reported no trouble hearing to indicate not having a usual source of care. Compared with those who reported no trouble hearing, those who reported some trouble hearing were more likely to indicate not having obtained medical care in the past year when they thought it was needed, as well as not filling a prescription, with the risk for both behaviors being greater among those reporting a lot of trouble hearing versus a little. Interventions that improve access to hearing services and aid communication may help older Medicare beneficiaries meet their health care needs.


Multiparametric MRI combined with liver volume for quantitative evaluation of liver function in patients with cirrhosis.
PURPOSE We aimed to establish a liver function evaluation model by combining multiparametric magnetic resonance imaging (MRI) with liver volume (LV) and further verify the effectiveness of the model to evaluate liver function. METHODS This retrospective study included 101 consecutive cirrhosis patients (69 cases for modeling group and 32 cases for validation group) who underwent gadoxetic acid-enhanced MRI. Five signal intensity parameters were obtained by measuring the signal intensities of the liver, spleen, and erector spinae before and 20 minutes after gadoxetic acid disodium enhancement. The dif fusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) were obtained from intravoxel incoherent motion diffusion-weighted imaging. The LV parameters (Vliver, Vspleen, and Vliver/Vspleen) were obtained using 3-dimensional image generation software. The most effec tive parameter was selected from each of the 3 methods, and a multivariate regression model for liver function evaluation was established and validated. RESULTS In the modeling group, relative enhancement (RE), D*, and Vliver/Vspleen showed significant dif ferences among the different liver function groups (P < .001). Receiver operating characteristic analysis showed that these parameters had the highest area under the curve (AUC) values for dis tinguishing Child-Pugh A from Child-Pugh B and C groups (0.917, 0.929, and 0.885, respectively). The following liver function model was obtained by multivariate regression analysis: F(x)=3.96 - 1.243 (RE) - 0.034 (D*) - 0.080 (Vliver/Vspleen) (R2=0.811, P < .001). In the patients with cirrhosis, the F(x) of Child-Pugh A, B, and C were 1.16 ± 0.44, 1.95 ± 0.29, and 2.79 ± 0.38, respectively. In the validation group, the AUC for F(x) to distinguish Child-Pugh A from Child-Pugh B and C was 0.973. CONCLUSION Combining multiparametric MRI with LV effectively distinguished patients with different Child Pugh grades. This model could hence be useful as a novel radiological marker to estimate the liver function.


Mitochondrial DNA population structure of roan and sable antelope: implications for the translocation and conservation of the species.
Mitochondrial DNA (mtDNA) control region sequences were analysed to determine the geographical genetic structure of Hippotragus niger (sable antelope) and H. equinus (roan antelope). Analyses by AMOVA, minimum evolution networks, parsimony, neighbour joining and maximum likelihood show that the roan antelope populations are geographically partitioned and that their phylogeography corresponds well with subspecific boundaries. In sharp contrast, however, our sequence data group all the sable antelope into two well-delineated maternal clades. One comprising specimens from the strictly east African H.n. roosevelti, and a second geographically diverse group which includes H.n. niger (South Africa, Zimbabwe), H.n. variani (Angola), and H.n. Kirkii (Zambia, Malawi). The differences in the genetic population structure suggest that distinct extrinsic and intrinsic factors have shaped the phylogeography of these two closely related antelope species. In the absence of obvious extrinsic barriers to gene flow, we suggest that behavioural differences may be responsible, at least in part, for the contrasting spatial patterns detected among geographical localities. Although our data reflect only the maternal phylogeny of these important game species, they nonetheless suggest that different management strategies should be applied. We recommend that roan antelope be translocated only within the currently defined subspecies boundaries, while in the case of sable antelope, conservation measures should focus on preserving the genetic integrity of the east African and southern African sable populations. Implicit in this is that translocations of animals between populations comprising these two distinct maternal genetic clades should be actively discouraged.


Micro-RNA profile and proteins in peritoneal fluid from women with endometriosis: their relationship with sterility.
To define the microRNA (miRNA) profile and its relationship with cytokines content in peritoneal fluid (PF) from endometriosis patients. Case-control study. University hospital, research institute. One hundred twenty-six women with endometriosis (EPF) and 45 control women (CPF). MiRNA arrays were prepared from six EPF and six CPF. Quantitative reverse transcription-polymerase chain reaction validation of nine selected miRNAs (miR-29c-3p, -106b-3p, -130a-3p, -150-5p, -185-5p, -195-5p, -451a, -486-5p, and -1343-5p) was performed. Vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1), urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-3 (MMP3), tissue inhibitor of metalloproteinases type 1 (TIMP-1), interleukin (IL)-6, IL-8, IL-17A, macrophage inflammatory protein 1β (MIP1beta), platelet-derived growth factor α-polypeptide A, and regulated on activation, normal T cell expressed and secreted (RANTES) were quantified by ELISA and MILLIPLEX. MiRNA arrays showed 126 miRNAs differentially expressed (fold change ±1.2) (78 down-regulated, 48 up-regulated) in EPF. Validation showed higher levels of miR-106b-3p, -451a, -486-5p, IL-6, IL-8, uPA, and TIMP-1 in EPF. In menstrual phase, EPF presented up-regulation of miR-106b-3p, -130a-3p, -150-5p, -185-5p, -451a, -486-5p, VEGF-A, IL-8, MIF 1β, uPA, and PAI-1 compared with other phases; however, CPF did not. MiRNA-486-5p was up-regulated in sterile EPF compared with sterile controls, and VEGF-A, IL-8, and TIMP-1 were increased in sterile and fertile EPF compared with fertile CPF. MiRNAs seem to be involved in the peritoneal alterations in endometriosis, suggesting new mechanisms by which ectopic lesions could implant in endometriosis patients; and to serve as biomarkers for fertility outcome prediction.


Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia.
Schizophrenia (SCZ) is a devastating psychiatric disorder with a median lifetime prevalence rate of 0.7-0.8%. Elevated plasma total homocysteine has been suggested as a risk factor for SCZ, and various biological effects of hyperhomocysteinemia have been proposed to be relevant to the pathophysiology of SCZ. As increased attention is paid to aberrant DNA methylation in SCZ, homocysteine is attracting additional interest as a potential key substance. Homocysteine is formed in the methionine cycle, which is involved in one-carbon methyl group-transfer metabolism, and it acts as a methyl donor when it is converted to S-adenosyl-methionine. To date, no studies have examined the relationship between homocysteine and genome-wide DNA methylation in SCZ. We examined the relationship between plasma total homocysteine and DNA methylation patterns in the peripheral leukocytes of patients with SCZ (n = 42) using a quantitative high-resolution DNA methylation array (485,764 CpG sites). Significant homocysteine-related changes in DNA methylation were observed at 1,338 CpG sites that were located across whole gene regions, including promoters, gene bodies and 3'-untranslated regions. Of the 1,338 sites, 758 sites (56.6%) were located in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 15.8%; CGI shore: 28.2%; CGI shelf: 12.6%), and positive correlations between plasma total homocysteine and DNA methylation were observed predominantly at CpG sites in the CGIs. Our results suggest that homocysteine might play a role in the pathogenesis of SCZ via a molecular mechanism that involves alterations to DNA methylation.


MultiGran-SMILES: multi-granularity SMILES learning for molecular property prediction.
Extracting useful molecular features is essential for molecular property prediction. Atom-level representation is a common representation of molecules, ignoring the sub-structure or branch information of molecules to some extent; however, it is vice versa for the substring-level representation. Both atom-level and substring-level representations may lose the neighborhood or spatial information of molecules. While molecular graph representation aggregating the neighborhood information of a molecule has a weak ability in expressing the chiral molecules or symmetrical structure. In this article, we aim to make use of the advantages of representations in different granularities simultaneously for molecular property prediction. To this end, we propose a fusion model named MultiGran-SMILES, which integrates the molecular features of atoms, sub-structures and graphs from the input. Compared with the single granularity representation of molecules, our method leverages the advantages of various granularity representations simultaneously and adjusts the contribution of each type of representation adaptively for molecular property prediction. The experimental results show that our MultiGran-SMILES method achieves state-of-the-art performance on BBBP, LogP, HIV and ClinTox datasets. For the BACE, FDA and Tox21 datasets, the results are comparable with the state-of-the-art models. Moreover, the experimental results show that the gains of our proposed method are bigger for the molecules with obvious functional groups or branches. The code and data underlying this work are available on GitHub at https://github. com/Jiangjing0122/MultiGran. Supplementary data are available at Bioinformatics online.


Intracytoplasmic sperm injection outcome using ejaculated sperm and retrieved sperm in azoospermic men.
We aimed to determine pregnancy and miscarriage rates following intracytoplasmic sperm injection (ICSI) cycles using retrieved epididymal and testicular sperm in azoospermic men and ejaculated sperm in oligospermic and normospermic men. This retrospective study was carried out on 517 couples who underwent ICSI. They included 96 couples with azoospermia and 421 with oligospermia or normal sperm count in the male partner. Of the men with azoospermia, 69 underwent percutaneous epididymal aspiration (PESA) and 47 underwent testicular sperm extraction (TESE). In the 421 men with oligospermia or normal sperm count, ejaculated sperm was used for ICSI. The differences in the outcomes of ICSI using PESA or TESE and ejaculated sperm were evaluated. The main outcome measures were pregnancy and miscarriage rates. No significant differences were seen in pregnancy and miscarriage rates with surgically retrieved and ejaculated sperm. The pregnancy rates (including frozen embryo transfer) were 43.5%, 36.2%, and 41.4% in couples with PESA, TESE, and ejaculated sperm, respectively (P = .93). The miscarriage rates were 16.7%, 23.5%, and 12.1%, respectively (P = .37). Intracytoplasmic sperm injection in combination with PESA and TESE is an effective method and can successfully be performed to treat men with azoospermia. The outcomes with these procedures are comparable to ICSI using ejaculated sperm.


[Effect of ethanol on the hepatocarcinogenic action of N-nitrosodiethylamine in rats].
It is shown that the administration of ethanol to male Wistar rats (3 g/kg by gastric tube 3 times a week for 2 months) before or at the beginning of the N-nitrosodiethylamine (NDEA) treatment (2.5 mg/kg 6 times a week in drinking water) reduces the hepatocarcinogenicity of NDEA. This was expressed macroscopically by less important neoplastic changes and biochemically by the higher glucose-6-phosphatase and lower glucose-6-phosphate dehydrogenase activities in the liver.


Sticky plant captures prey for symbiotic bug: is this digestive mutualism?
Many plants capture and kill insects but, until relatively recently, only carnivorous plants with digestive enzymes were known to gain directly from the nutrients of those insects. Recent studies show that some carnivorous plants lack digestive enzymes and have evolved digestive mutualisms with symbiotic insects that digest their prey for them. Rhododendron macrosepalum, a plant with sticky leaves that captures insects, has an association with symbiotic Mirid bugs that consume the insects captured. Here, we determine what the nature of the relationship is between Mirid and plant. We find that R. macrosepalum has no digestive enzymes of its own but that it does not seem to have the ability to absorb hemipteran faeces through its leaf cuticle. Naturally occurring levels of (15) N and (14) N were used to determine that R. macrosepalum gains no nitrogen through its association with the Mirid bugs and that it obtains all of its nitrogen from the soil. The Mirids, on the other hand, seem to obtain nitrogen from insects captured by the plant, as well as from plant tissues. The relationship between plant and Mirid is not a digestive mutualism but more likely an antagonistic relationship. This study adds to our understanding of how digestive mutualisms evolve and shows that insect capture alone, or in combination with a symbiotic insect relationship does not necessarily make a plant 'carnivorous'.


Why mob? Reassessing the costs and benefits of primate predator harassment.
While some primate species attempt to avoid predators by fleeing, hiding or producing alarm calls, others actually approach, harass and sometimes attack potential threats, a behavior known as 'mobbing'. Why individuals risk their safety to mob potential predators remains poorly understood. Here, I review reports of predator harassment by primates to (1) determine the distribution of this behavior across taxa, (2) assess what is known about the costs of mobbing, and (3) evaluate hypotheses about its function. Mobbing is taxonomically widespread and is used against a wide range of predator species. However, inconsistent use of the term 'mobbing' within the primate literature, the lack of systematic studies of primate mobbing, and the likelihood of systematic biases in the existing data pose significant obstacles to understanding this puzzling behavior. Although difficult to quantify, the costs associated with harassing predators appear nontrivial. Many benefits that have been proposed to explain mobbing in birds may also be important in primate systems. There are puzzling aspects of primate mobbing, however, that existing hypotheses cannot explain. Future research should consider the within-group signaling potential of this costly behavior, as well as the ability of behavioral syndromes to explain the distribution of mobbing in primates.


Raman spectroscopy on transition metals.
Surface-enhanced Raman spectroscopy (SERS) has developed into one of the most important tools in analytical and surface sciences since its discovery in the mid-1970s. Recent work on the SERS of transition metals concluded that transition metals, other than Cu, Ag, and Au, can also generate surface enhancement as high as 4 orders of magnitude. The present article gives an overview of recent progresses in the field of Raman spectroscopy on transition metals, including experimental, theory, and applications. Experimental considerations of how to optimize the experimental conditions and calculate the surface enhancement factor are discussed first, followed by a very brief introduction of preparation of SERS-active transition metal substrates, including massive transition metal surfaces, aluminum-supported transition metal electrodes, and pure transition metal nanoparticle assembled electrodes. The advantages of using SERS in investigating surface bonding and reaction are illustrated for the adsorption and reaction of benzene on Pt and Rh electrodes. The electromagnetic enhancement, mainly lightning-rod effect, plays an essential role in the SERS of transition metals, and that the charge-transfer effect is also operative in some specific metal-molecule systems. An outlook for the field of Raman spectroscopy of transition metals is given in the last section, including the preparation of well-ordered or well-defined nanostructures, and core-shell nanoparticles for investigating species with extremely weak SERS signals, as well as some new emerging techniques, including tip-enhanced Raman spectroscopy and an in situ measuring technique.


Cerebral oxygen saturation: graded response to carbon dioxide with isoxia and graded response to oxygen with isocapnia.
Monitoring cerebral saturation is increasingly seen as an aid to management of patients in the operating room and in neurocritical care. How best to manipulate cerebral saturation is not fully known. We examined cerebral saturation with graded changes in carbon dioxide tension while isoxic and with graded changes in oxygen tension while isocapnic. The study was approved by the Research Ethics Board of the University Health Network at the University of Toronto. Thirteen studies were undertaken in healthy adults with cerebral oximetry by near infrared spectroscopy. End-tidal gas concentrations were manipulated using a model-based prospective end-tidal targeting device. End-tidal carbon dioxide was altered ±15 mmHg from baseline in 5 mmHg increments with isoxia (clamped at 110±4 mmHg). End-tidal oxygen was changed to 300, 400, 500, 80, 60 and 50 mmHg under isocapnia (37±2 mmHg). Twelve studies were completed. The end-tidal carbon dioxide versus cerebral saturation fit a linear relationship (R(2) = 0.92±0.06). The end-tidal oxygen versus cerebral saturation followed log-linear behaviour and best fit a hyperbolic relationship (R(2) = 0.85±0.10). Cerebral saturation was maximized in isoxia at end-tidal carbon dioxide of baseline +15 mmHg (77±3 percent). Cerebral saturation was minimal in isocapnia at an end-tidal oxygen tension of 50 mmHg (61±3 percent). The cerebral saturation during normoxic hypocapnia was equivalent to normocapnic hypoxia of 60 mmHg. Hypocapnia reduces cerebral saturation to an extent equivalent to moderate hypoxia.


Reactions following completion of 1 and 2 year multidrug therapy (MDT).
We evaluated the incidence, severity, and duration of reactional states in 139 multibacillary (MB) leprosy patients in the first 2 years after the completion of the 1 year regimen of multidrug therapy (MDT) currently recommended by the World Health Organization (WHO) and compared those findings with 295 MB leprosy patients treated with the same regimen previously recommended for 2 years. During the first year after the completion of 1 year MDT, patients experienced 1 or more reactional states 27% of the time, the vast majority being lepra type 1 reactions (reversal reactions, RR), whereas patients who received 2 year MDT experienced a reactional state during that time period only 8% of the time (P < 0.001). Furthermore, during the first year after the completion of therapy, and during the first 2 years, both the number of reactional states and reversal reactions were significantly (P < or = 0.004) more frequent, severe, of longer duration, and more commonly associated with neuritis.


Effect of cholinergic stimulation in early Alzheimer's disease - functional imaging during a recognition memory task.
Treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors (AChEI) enhances cholinergic activity and alleviates clinical symptoms. In the present functional magnetic resonance imaging (fMRI) study, we investigated the effect of the AChEI rivastigmine on cognitive function and brain activation patterns during a face recognition memory task. Twenty patients with newly-diagnosed mild AD were administered a single oral dose of placebo, a single dose of rivastigmine (acute), and twice-daily treatment with rivastigmine for 4 weeks (chronic). After each treatment, the patients underwent a facial recognition task during fMRI. The prefrontal areas known to be involved in face recognition memory processing demonstrated greater fMRI activity in both the acute and chronic rivastigmine conditions compared to the placebo condition. In the same brain areas, differences in both fMRI activation at the map level and regional fMRI signal intensity measures between the placebo and chronic treatment conditions correlated negatively with the Mini- Mental State Examination score. In the chronic rivastigmine condition, patients with better preserved cognitive abilities demonstrated less enhanced prefrontal activity, whereas patients with poorer cognition showed greater prefrontal activity. These findings suggest that the prefrontal attention/working memory systems are already impaired in the early stages of AD and that the effect of cholinergic medication in the brain areas involved in recognition memory, i.e., increased or decreased fMRI activation patterns, depends on the severity of the disease. These findings also suggest the importance of early AChEI treatment in the course of AD, at the point when there is still some cognitive reserve available and the therapy has the highest potential efficacy.


Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity.
Immunoglobulin (Ig) isotype diversification by class switch recombination (CSR) is an essential process for mounting a protective humoral immune response. Ig CSR deficiencies in humans can result from an intrinsic B cell defect; however, most of these deficiencies are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Here, we show that extracellular adenosine critically contributes to CSR in human naive and IgM memory B cells. In these cells, coordinate stimulation of B cell receptor and toll-like receptors results in the release of ATP stored in Ca(2+)-sensitive secretory vesicles. Plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 CD39 and ecto-5'-nucleotidase CD73 hydrolyze ATP to adenosine, which induces CSR in B cells in an autonomous fashion. Notably, CVID patients with impaired class-switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73-dependent adenosine generation contributes to the pathogenesis of this disease.


Recruitment of a Lineage-Specific Virulence Regulatory Pathway Promotes Intracellular Infection by a Plant Pathogen Experimentally Evolved into a Legume Symbiont.
Ecological transitions between different lifestyles, such as pathogenicity, mutualism and saprophytism, have been very frequent in the course of microbial evolution, and often driven by horizontal gene transfer. Yet, how genomes achieve the ecological transition initiated by the transfer of complex biological traits remains poorly known. Here, we used experimental evolution, genomics, transcriptomics and high-resolution phenotyping to analyze the evolution of the plant pathogen Ralstonia solanacearum into legume symbionts, following the transfer of a natural plasmid encoding the essential mutualistic genes. We show that a regulatory pathway of the recipient R. solanacearum genome involved in extracellular infection of natural hosts was reused to improve intracellular symbiosis with the Mimosa pudica legume. Optimization of intracellular infection capacity was gained through mutations affecting two components of a new regulatory pathway, the transcriptional regulator efpR and a region upstream from the RSc0965-0967 genes of unknown functions. Adaptive mutations caused the downregulation of efpR and the over-expression of a downstream regulatory module, the three unknown genes RSc3146-3148, two of which encoding proteins likely associated to the membrane. This over-expression led to important metabolic and transcriptomic changes and a drastic qualitative and quantitative improvement of nodule intracellular infection. In addition, these adaptive mutations decreased the virulence of the original pathogen. The complete efpR/RSc3146-3148 pathway could only be identified in the genomes of the pathogenic R. solanacearum species complex. Our findings illustrate how the rewiring of a genetic network regulating virulence allows a radically different type of symbiotic interaction and contributes to ecological transitions and trade-offs.


Hepatic veno-occlusive disease induced by Chinese medicinal herbs.
The potential hepatotoxic effects of products containing medicinal herbs, which are increasingly used without adequate control by health authorities, is well known. We report a case of toxic hepatic veno-occlusive disease (HVOD) presumably associated with the use of such herbal remedies.


Medical and legal implications of testing for sexually transmitted infections in children.
Testing for sexually transmitted infections (STIs) in children presents a number of problems for the practitioner that are not usually faced when testing adults for the same infections. The identification of an STI in a child can have, in addition to medical implications, serious legal implications. The presence of an STI is often used to support the presence or allegations of sexual abuse, and conversely, the identification of an STI in a child will prompt an investigation of possible abuse. The purpose of this paper is to review the epidemiology of child sexual abuse, including the epidemiology of major STIs including Neisseria gonorrhoeae, Chlamydia trachomatis, syphilis, herpes simplex virus (HSV), Trichomonas vaginalis, and human papillomavirus, and the current recommendations for diagnostic testing in this population.


Electrofluorochromic detection of cyanide anions using a nanoporous polymer electrode and the detection mechanism.
An electrofluorochromic (EFC) conjugated copolymer (PEFC) containing carbazole and benzothiadiazole (BTD) moieties is synthesized through Suzuki coupling followed by electrochemical polymerization, resulting in a nanoporous EFC polymer electrode. The electrode exhibits high sensitivity and selectivity in the EFC detection of cyanide anions (CN(-)) in largely aqueous electrolyte (67 vol % water) because electrochemical oxidation of PEFC leads to significant fluorescence quenching, and the presence of different concentrations (1 to 100 μM) of CN(-) in the electrolyte can weaken the oxidative quenching to substantially different extents. Although PEFC is hydrophobic in the neutral state, it is converted to radical cation/dication states upon oxidation, rendering the PEFC some hydrophilicity. Moreover, its nanoporous morphology provides a large surface area and short diffusion distance, facilitating the movement of CN(-) in the electrolyte into the PEFC film to interact with receptors. Density functional theory calculations show that the noncovalent interaction between electron-deficient BTD and nucleophilic CN(-) is energy favorable in the oxidized states in both aqueous and organic media, suggesting that the specific π(-)-π(+) interaction plays the main role in the CN(-) detection.


Providing contact cards for relatives following bereavement.
This article describes the implementation of a Welsh Assembly Government policy to improve customer service and provide an opportunity for relatives to seek further information about the death of a loved one in an acute hospital setting. A new relative-centred pathway has been developed. It offers a single point of contact for recently bereaved relatives and provides an opportunity to discuss any concerns or anxieties in relation to the care and/or treatment in the final hours of their loved one's life. The pathway includes a contact card with the name and number of a designated person and is a more informal, empathetic and person-centred service than the formal complaint process.


The large Hsp70 Grp170 binds to unfolded protein substrates in vivo with a regulation distinct from conventional Hsp70s.
The Hsp70 superfamily is a ubiquitous chaperone class that includes conventional and large Hsp70s. BiP is the only conventional Hsp70 in the endoplasmic reticulum (ER) whose functions include: assisting protein folding, targeting misfolded proteins for degradation, and regulating the transducers of the unfolded protein response. The ER also possesses a single large Hsp70, the glucose-regulated protein of 170 kDa (Grp170). Like BiP it is an essential protein, but its cellular functions are not well understood. Here we show that Grp170 can bind directly to a variety of incompletely folded protein substrates in the ER, and as expected for a bona fide chaperone, it does not interact with folded secretory proteins. Our data demonstrate that Grp170 and BiP associate with similar molecular forms of two substrate proteins, but while BiP is released from unfolded substrates in the presence of ATP, Grp170 remains bound. In comparison to conventional Hsp70s, the large Hsp70s possess two unique structural features: an extended C-terminal α-helical domain and an unstructured loop in the putative substrate binding domain with an unknown function. We find that in the absence of the α-helical domain the interaction of Grp170 with substrates is reduced. In striking contrast, deletion of the unstructured loop results in increased binding to substrates, suggesting the presence of unique intramolecular mechanisms of control for the chaperone functions of large Hsp70s.


Emotion processing in words: a test of the neural re-use hypothesis using surface and intracranial EEG.
This study investigates the spatiotemporal brain dynamics of emotional information processing during reading using a combination of surface and intracranial electroencephalography (EEG). Two different theoretical views were opposed. According to the standard psycholinguistic perspective, emotional responses to words are generated within the reading network itself subsequent to semantic activation. According to the neural re-use perspective, brain regions that are involved in processing emotional information contained in other stimuli (faces, pictures, smells) might be in charge of the processing of emotional information in words as well. We focused on a specific emotion-disgust-which has a clear locus in the brain, the anterior insula. Surface EEG showed differences between disgust and neutral words as early as 200 ms. Source localization suggested a cortical generator of the emotion effect in the left anterior insula. These findings were corroborated through the intracranial recordings of two epileptic patients with depth electrodes in insular and orbitofrontal areas. Both electrodes showed effects of disgust in reading as early as 200 ms. The early emotion effect in a brain region (insula) that responds to specific emotions in a variety of situations and stimuli clearly challenges classic sequential theories of reading in favor of the neural re-use perspective.


Echocardiographic estimation of pulmonary artery wedge pressure - invasive derivation, validation, and prognostic association beyond diastolic dysfunction grading.
Grading of diastolic function can be useful, but indeterminate classifications are common. We aimed to invasively derive and validate a quantitative echocardiographic estimation of pulmonary artery wedge pressure (PAWP), and to compare its prognostic performance to diastolic dysfunction grading. Echocardiographic measures were used to derive an estimated PAWP (ePAWP) using multivariable linear regression in patients undergoing right heart catheterization (RHC). Prognostic associations were analyzed in the National Echocardiography Database of Australia (NEDA). In patients who had undergone both RHC and echocardiography within two hours (n=90), ePAWP was derived using left atrial volume index, mitral peak early velocity (E), and pulmonary vein systolic velocity (S). In a separate external validation cohort (n=53, simultaneous echocardiography and RHC), ePAWP showed good agreement with invasive PAWP (mean±SD difference 0.5±5.0 mmHg) and good diagnostic accuracy for estimating PAWP>15mmHg (area under the curve [95% confidence interval] 0.94 [0.88-1.00]). Among patients in NEDA (n=38,856, median [interquartile range] follow-up 4.8 [2.3-8.0] years, 2,756 cardiovascular deaths), ePAWP was associated with cardiovascular death even after adjustment for age, sex, and diastolic dysfunction grading (hazard ratio (HR) 1.08 [1.07-1.09] per mmHg) and provided incremental prognostic information to diastolic dysfunction grading (improved C-statistic from 0.65 to 0.68, p<0.001). Increased ePAWP was associated with worse prognosis across all grades of diastolic function (HR normal: 1.07 [1.06-1.09]; indeterminate: 1.08 [1.07-1.09]; abnormal: 1.08 [1.07-1.09], p<0.001 for all). Echocardiographic ePAWP is an easily acquired continuous variable with good accuracy that associates with prognosis beyond diastolic dysfunction grading.


Effects of stream predator richness on the prey community and ecosystem attributes.
It is important to understand the role that different predators can have to be able to predict how changes in the predator assemblage may affect the prey community and ecosystem attributes. We tested the effects of different stream predators on macroinvertebrates and ecosystem attributes, in terms of benthic algal biomass and accumulation of detritus, in artificial stream channels. Predator richness was manipulated from zero to three predators, using two fish and one crayfish species, while density was kept equal (n = 6) in all treatments with predators. Predators differed in their foraging strategies (benthic vs. drift feeding fish and omnivorous crayfish) but had overlapping food preferences. We found effects of both predator species richness and identity, but the direction of effects differed depending on the response variable. While there was no effect on macroinvertebrate biomass, diversity of predatory macroinvertebrates decreased with increasing predator species richness, which suggests complementarity between predators for this functional feeding group. Moreover, the accumulation of detritus was affected by both predator species richness and predator identity. Increasing predator species richness decreased detritus accumulation and presence of the benthic fish resulted in the lowest amounts of detritus. Predator identity (the benthic fish), but not predator species richness had a positive effect on benthic algal biomass. Furthermore, the results indicate indirect negative effects between the two ecosystem attributes, with a negative correlation between the amount of detritus and algal biomass. Hence, interactions between different predators directly affected stream community structure, while predator identity had the strongest impact on ecosystem attributes.


On the neutrality of molecular genetic markers: pedigree analysis of genetic variation in fragmented populations.
Many studies employ molecular markers to infer ecological and evolutionary processes, assuming that variation found at genetic loci offers a reliable representation of stochastic events in natural populations. Increasingly, evidence emerges that molecular markers might not always be selectively neutral. However, only a few studies have analysed how deviations from neutrality could affect estimates of genetic variation, using populations with known genealogy. We monitored changes in allozyme variation over eight generations in captive metapopulations of the butterfly Bicyclus anynana. Population demography was recorded by individually marking 35 000 butterflies and constructing pedigrees. We designed a computer program that simulated the inheritance of founder allozyme alleles in butterfly pedigrees. We thus tested whether the observed transmission of allozyme alleles could be explained by random genetic drift alone, or whether there was evidence for positive or negative selection. This analysis showed that in the smallest metapopulations the loss of allozyme variation exceeded the neutral rate. Possibly, linkage disequilibria between deleterious mutations and marker alleles resulted in background selection and a faster erosion of allozyme variation. In larger metapopulations, one locus (MDH) showed a significant heterozygote excess and smaller than expected loss in heterozygosity, observations consistent with (associative) overdominance. This study demonstrates that the neutrality of molecular markers cannot always be assumed, particularly in small populations with a high mutation load.


Immunological and biochemical characterization of coxsackie virus A16 viral particles.
Coxsackie virus A16 (CVA16) infections have become a serious public health problem in the Asia-Pacific region. It manifests most often in childhood exanthema, commonly known as hand-foot-and-mouth disease (HFMD). There are currently no vaccine or effective medical treatments available. In this study, we describe the production, purification and characterization of CVA16 virus produced from Vero cells grown on 5 g/L Cytodex 1 microcarrier beads in a five-liter serum-free bioreactor system. The viral titer was found to be >10(6) the tissue culture's infectious dose (TCID(50)) per mL within 7 days post-infection when a multiplicity of infection (MOI) of 10(-5) was used for initial infection. Two CVA16 virus fractions were separated and detected when the harvested CVA16 viral concentrate was purified by a sucrose gradient zonal ultracentrifugation. The viral particles detected in the 24-28% sucrose fractions had low viral infectivity and RNA content. The viral particles obtained from 35-38% sucrose fractions were found to have high viral infectivity and RNA content, and composed of four viral proteins (VP1, VP2, VP3 and VP4), as shown by SDS-PAGE analyses. These two virus fractions were formalin-inactivated and only the infectious particle fraction was found to be capable of inducing CVA16-specific neutralizing antibody responses in both mouse and rabbit immunogenicity studies. But these antisera failed to neutralize enterovirus 71. In addition, rabbit antisera did not react with any peptides derived from CVA16 capsid proteins. Mouse antisera recognized a single linear immunodominant epitope of VP3 corresponding to residues 176-190. These results provide important information for cell-based CVA16 vaccine development. To eliminate HFMD, a bivalent EV71/CVA16 vaccine formulation is necessary.


[Prognostic factors in temporal lobe epilepsy surgery].
Temporal lobe epilepsy surgery represents the majority of surgical interventions in patients with refractory epilepsy. In consequence, knowledge of prognostic factors in this type of epilepsy surgery is of major importance. The objective of this study is to study series of prognostic factors in a group of patients who underwent temporal lobe epilepsy surgery and to correlate Engel's Classification of Postoperative Outcome, now used in most epilepsy centers, and the Proposal for New Classification in regards to Epileptic Seizures Following Epilepsy Surgery of the International League Against Epilepsy (ILAE). We analyzed 41 consecutive patients who underwent temporal lobe epilepsy surgery in the Epilepsy Surgery Program of the Epilepsy Unit in the Fundación Jiménez Díaz. The following prognostic factors were analyzed: age at surgery, time since the first seizure (excluding febrile seizures), risk factors for the development of epilepsy, presence of simple partial seizures, presurgical complex partial seizure frequency, findings in brain magnetic resonance imaging, interictal and ictal electroencephalogram, neuropsychological assessment, Wada test and neuropathological study of the surgical specimen. Two outcome classifications were used: Engel's classification of postoperative outcome and the proposal for a new classification of outcome in regards to epileptic seizures following epilepsy surgery of the ILAE. Statistical analysis was performed using non-parametric tests. The presence of temporal unilateral interictal epileptiform activity and the presence of less than 20 seizures complex partial seizures per month before surgery were associated with a better prognosis using both classifications. The electronencephalographic unilateral temporal ictal onset recording was associated with a better prognosis using Engel's classification but not ILAE's outcome classification. The presence of febrile seizures was associated with a better prognosis in regards to ILAE's outcome classification but not in regards to Engel's classification. The remaining factors were not associated with outcome. The following factors were associated with a good prognosis: presence of unilateral temporal interictal epileptiform activity, presurgery seizure frequency below 20 complex partial seizures per month, unilateral temporal ictal onset, and presence of febrile seizures. A good correlation was found between both outcome classifications in regards to most of the analyzed prognostic factors.


The unique expression and function of miR-424 in human placental trophoblasts.
Placental hypoperfusion causes cellular hypoxia and is associated with fetal growth restriction and preeclampsia. In response to hypoxia, the repertoire of genes expressed in placental trophoblasts changes, which influences key cellular processes such as differentiation and fusion. Diverse miRNAs were recently found to modulate the cellular response to hypoxia. Here we show that miR-424, which was previously shown to be upregulated by hypoxia in nontrophoblastic cell types, is uniquely downregulated in primary human trophoblasts by hypoxia or chemicals known to hinder cell differentiation. We also identify FGFR1 as a direct target of miR-424 in human trophoblasts. This effect is unique to miR-424 and is not seen with other members of this miRNA family that are expressed in trophoblasts, such as miR-15 and miR-16. Our findings establish a unique role for miR-424 during differentiation of human trophoblasts.


Intraosseous Temperature Change during Installation of Dental Implants with Two Different Surfaces and Different Drilling Protocols: An In Vivo Study in Sheep.
The intraosseous temperature during implant installation has never been evaluated in an in vivo controlled setup. The aims were to investigate the influence of a drilling protocol and implant surface on the intraosseous temperature during implant installation, to evaluate the influence of temperature increase on osseointegration and to calculate the heat distribution in cortical bone. Forty Brånemark implants were installed into the metatarsal bone of Finnish Dorset crossbred sheep according to two different drilling protocols (undersized/non-undersized) and two surfaces (moderately rough/turned). The intraosseous temperature was recorded, and Finite Element Model (FEM) was generated to understand the thermal behavior. Non-decalcified histology was carried out after five weeks of healing. The following osseointegration parameters were calculated: Bone-to-implant contact (BIC), Bone Area Fraction Occupancy (BAFO), and Bone Area Fraction Occupancy up to 1.5 mm (BA1.5). A multiple regression model was used to identify the influencing variables on the histomorphometric parameters. The temperature was affected by the drilling protocol, while no influence was demonstrated by the implant surface. BIC was positively influenced by the undersized drilling protocol and rough surface, BAFO was negatively influenced by the temperature rise, and BA1.5 was negatively influenced by the undersized drilling protocol. FEM showed that the temperature at the implant interface might exceed the limit for bone necrosis. The intraosseous temperature is greatly increased by an undersized drilling protocol but not from the implant surface. The temperature increase negatively affects the bone healing in the proximity of the implant. The undersized drilling protocol for Brånemark implant systems increases the amount of bone at the interface, but it negatively impacts the bone far from the implant.


Thermally ruggedized ITO transparent electrode films for high power optoelectronics.
We present two strategies to minimize laser damage in transparent conductive films. The first consists of improving heat dissipation by selection of substrates with high thermal diffusivity or by addition of capping layer heatsinks. The second is reduction of bulk energy absorption by lowering free carrier density and increasing mobility, while maintaining film conductance with thicker films. Multi-pulse laser damage tests were performed on tin-doped indium oxide (ITO) films configured to improve optical lifetime damage performance. Conditions where improvements were not observed are also described. When bulk heating is not the dominant damage process, discrete defect-induced damage limits damage behavior.


Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature.
The incidence of inflammatory bowel disease (IBD) is increasing. Dietary factors such as the spread of the "Western" diet, high in fat and protein but low in fruits and vegetables, may be associated with the increase. Although many studies have evaluated the association between diet and IBD risk, there has been no systematic review. We performed a systematic review using guideline-recommended methodology to evaluate the association between pre-illness intake of nutrients (fats, carbohydrates, protein) and food groups (fruits, vegetables, meats) and the risk of subsequent IBD diagnosis. Eligible studies were identified via structured keyword searches in PubMed and Google Scholar and manual searches. Nineteen studies were included, encompassing 2,609 IBD patients (1,269 Crohn's disease (CD) and 1,340 ulcerative colitis (UC) patients) and over 4,000 controls. Studies reported a positive association between high intake of saturated fats, monounsaturated fatty acids, total polyunsaturated fatty acids (PUFAs), total omega-3 fatty acids, omega-6 fatty acids, mono- and disaccharides, and meat and increased subsequent CD risk. Studies reported a negative association between dietary fiber and fruits and subsequent CD risk. High intakes of total fats, total PUFAs, omega-6 fatty acids, and meat were associated with an increased risk of UC. High vegetable intake was associated with a decreased risk of UC. High dietary intakes of total fats, PUFAs, omega-6 fatty acids, and meat were associated with an increased risk of CD and UC. High fiber and fruit intakes were associated with decreased CD risk, and high vegetable intake was associated with decreased UC risk.


Perceptions of health and health service utilization among homeless and housed psychiatric consumer/survivors.
Homelessness has a direct impact on health. Homeless individuals report several barriers to accessing health care. Although research exists regarding the utilization of health services for homeless and housed psychiatric consumer/survivors, few studies have compared the perceived health and service utilization of these two groups. The objective of this study was to determine whether or not differences exist between the utilization of health services and the perceptions of health of homeless and housed psychiatric consumer/survivors in London, Ontario, Canada. It was hypothesized that differences would exist between homeless and housed psychiatric consumer/survivors on all health-related variables examined. A secondary analysis of quantitative data was conducted in a Community-University Research Alliance on Mental Health and Housing project funded by the Social Sciences and Humanities Research Council of Canada. Key findings include significant differences in the characteristics of each population, the use of health services and their perceptions of health. Implications for practice and policy are discussed.


Effect of maternal intravenous infusions on fetal extracellular fluid composition in pregnant ewes.
Infusion of intravenous solutions to women in labor is common clinical practice. Since these infusions may change the volume and electrolyte balance between the mother and fetus, we investigated the influence of acute maternal volume expansion upon fetal and maternal fluid and electrolyte equilibrium in the chronically catheterized fetal lamb. Paired measurements of maternal and fetal plasma sodium and potassium concentrations, osmolality, and colloid osmotic pressure (COP), plus measurements in the fetal-placental plasma volume were obtained following rapid maternal infusions with saline, dextrose, and dextran solutions. Maternal infusions resulted in changes in fetal electrolyte concentrations as well as alterations in transplacental COP differences. Despite these changes, however, no changes in fetal plasma volume were noted.


[Bad breath from the oral cavity].
Halitosis, or bad breath, is a clinical problem for many people. In the majority of cases the problem has been shown to originate in the oral cavity. All conditions that favour the retention of anaerobic, mainly gram-negative, bacteria will predispose for the development of bad breath. In addition to periodontal pockets, the most important retention site is the dorsum of the tongue with its numerous papillae. The bacteria metabolize sulphur-containing amino acids to yield the volatile sulphur-containing compounds hydrogen sulphide and methylmercaptane. These substances have an offensive odour in very low concentrations. The sulphur compounds may also damage the surrounding tissue directly, and thereby contribute to the initiation and development of periodontal disease. During the night and between meals the conditions are optimal for odour production. The importance of regular meals is therefore emphasized. To supplement conventional oral hygienic measures the patients are advised to brush their tongue. The use of oral care products which contain metal ions, especially zinc, will inhibit odour formation because of the affinity of the metal ion to sulphur. It is also possible to measure the level of volatile sulphur-containing compounds in the air in the mouth directly by means of a portable sulphide monitor. Dentists and physicians are both advised to discuss the problem of halitosis with their patients, since this should be regarded as an important aspect of the patient's health.


Separation of human thymocytes at different stages of maturation by centrifugation on a discontinuous gradient of colloidal silica gel.
Separation of human intrathymic cells on a discontinuous gradient of colloidal silica gel (Percoll) yielded four layers. The first (density 1.054 +/- 0.002 g/ml) contained stromal cells and a few thymocytes positive for terminal deoxynucleotidyl transferase (Tdt), most of which were bound to large Tdt-negative non-T cells. The second layer (1.069+/- 0.003 g/ml) contained large Tdt-negative thymocytes. The third and forth layers (1.075 +/-0.004 and 1.085 +/- 0.003 g/ml, respectively) contained smaller T cells, more than 95% of which were Tdt-positive. Functional studies revealed that cells from the first layer had a high level of spontaneous [3H]thymidine uptake but did not respond to lectins; the second layer responded to PHA, ConA, and allogeneic stimuli; and the third and fourth layers did not respond to lectin stimulation. Addition of cells from the first layer to the other layers at a 1 : 10 ratio significantly increased the mitogenic responses of the cells from the second layer, but not of those from the third or fourth layer. These results suggest that, as in mice and rats, low-density intrathymic thymocytes in humans represent more mature T cells, the percentage of which increases with age.


Stroke Hexagon; Protocol for Reduction of Stroke Burden in Resource-Poor Settings.
Stroke is a neurological emergency, with high prevalence, especially in developing countries where it assumes an epidemic proportion. It is globally the second most common cause of death after ischemic heart disease. The poor indices reported in developing countries are multifactorial and related to late case presentation, ignorance, poverty, and unavailability of comprehensive and well-coordinated stroke care. This manuscript identified and highlighted the available and cheap stroke management pillars in developing countries and recommended measures to strengthen the system to maximize the benefits in the reduction of morbidity and mortality from stroke. The identified stroke management pillars include stroke prevention, hyperacute stroke management, acute stroke management, stroke rehabilitation, stroke research, and stroke support. A coordinated and concerted stroke management protocol involving the stroke hexagon will reduce stroke morbidity and mortality in resource-poor settings. There is a need to sensitize the stakeholders in stroke management to assume more responsibility.


In vivo Evaluation of an Engineered Cyclotide as Specific CXCR4 Imaging Reagent.
The CXCR4 chemokine receptor plays a key regulatory role in many biological functions, including embryonic development and controlling leukocyte functions during inflammation and immunity. CXCR4 has been also associated with multiple types of cancers where its overexpression/activation promotes metastasis, angiogenesis, and tumor growth and/or survival. Furthermore, CXCR4 is involved in HIV replication, as it is a co-receptor for viral entry into host cells. Altogether, these features make CXCR4 a very attractive target for the development of imaging and therapeutic agents. Here, the in vivo evaluation of the MCoTI-based cyclotide, MCo-CVX-5c, for the development of imaging agents that target CXCR4 is reported. Cyclotide MCo-CVX-5c is a potent CXCR4 antagonist with a remarkable in vivo resistance to biological degradation in serum. A [64 Cu]-DOTA-labeled version of this cyclotide demonstrated high and significant uptake in U87-stb-CXCR4 tumors compared to the control U87 tumors. Furthermore, protracted imaging studies demonstrated radiotracer retention in the U87-stb-CXCR4 tumor at 24 h post injection. Uptake in U87-stb-CXCR4 tumors could be blocked by unlabeled MCo-CVX-5c, showing high in vivo specificity. These results demonstrate the in vivo specificity and retention of a bioactive molecularly targeted cyclotide and highlight the potential of bioactive cyclotides for the development of new imaging agents that target CXCR4.


Eosinophil Extracellular Traps and Inflammatory Pathologies-Untangling the Web!
Eosinophils are an enigmatic white blood cell, whose immune functions are still under intense investigation. Classically, the eosinophil was considered to fulfill a protective role against parasitic infections, primarily large multicellular helminths. Although eosinophils are predominantly associated with parasite infections, evidence of a role for eosinophils in mediating immunity against bacterial, viral, and fungal infections has been recently reported. Among the mechanisms by which eosinophils are proposed to exert their protective effects is the production of DNA-based extracellular traps (ETs). Remarkably, DNA serves a role that extends beyond its biochemical function in encoding RNA and protein sequences; it is also a highly effective substance for entrapment of bacteria and other extracellular pathogens, and serves as valuable scaffolding for antimicrobial mediators such as granule proteins from immune cells. Extracellular trap formation from eosinophils appears to fulfill an important immune response against extracellular pathogens, although overproduction of traps is evident in pathologies. Here, we discuss the discovery and characterization of eosinophil extracellular traps (EETs) in response to a variety of stimuli, and suggest a role for these structures in the pathogenesis of disease as well as the establishment of autoimmunity in chronic, unresolved inflammation.


An immediate generalized reaction to iopamidol.
Intravascularly administered lower-osmolality contrast media cause fewer adverse effects than do higher-osmolality media. Immediate generalized reactions such as acute urticaria or bronchospasm have been documented occasionally in patients receiving lower-osmolality contrast media. To our knowledge, this is the first reported case of an immediate generalized reaction to a lower-osmolality contrast medium in which significant hypotension also occurred. During cardiac catheterization, in a patient who had never been exposed to a contrast medium, a 69-year old man developed chest tightness, periorbital and facial edema, slight uvular edema, and a decline in blood pressure from 150/71 to 97/67 mm Hg. Epinephrine hydrochloride, diphenhydramine hydrochloride, and hydrocortisone were administered. The lack of absolute safety of lower-osmolality contrast media emphasizes the need for clinical awareness and availability of emergency therapy when these agents are utilized.


[The sutureless lung resection with Ligasure device: the possibilities and perspectives].
The experimental study of the durability of the "collagen" suture of the lung, performed with the use of the Ligasure device, was conducted. 17 patients, whom 21 lung resection was performet took part in the study. In the experimental part of the study the average rupture pressure of the collagen plomb was 413±99.4 mm Hg for the intact lung parenchyma and 212±66.7 mm Hg for the emphisematously changed tissue. The prolonged aerostatic insufficiency was registered only in two cases. The Ligasure suturing device proved to be the highly effective and safe for the use in thoracic surgery.


Guidance in selecting analytical techniques for identification and quantification of non-intentionally added substances (NIAS) in food contact materials (FCMS).
There are numerous approaches and methodologies for assessing the identity and quantities of non-intentionally added substances (NIAS) in food contact materials (FCMs). They can give different results and it can be difficult to make meaningful comparisons. The initial approach was to attempt to prepare a prescriptive methodology but as this proved impossible; this paper develops guidelines that need to be taken into consideration when assessing NIAS. Different approaches to analysing NIAS in FCMs are reviewed and compared. The approaches for preparing the sample for analysis, recommended procedures for screening, identification, and quantification of NIAS as well as the reporting requirements are outlined. Different analytical equipment and procedures are compared. Limitations of today's capabilities are raised along with some research needs.


Plasticity of airway epithelial cell transcriptome in response to flagellin.
Airway epithelial cells (AEC) are critical components of the inflammatory and immune response during exposure to pathogens. AECs in monolayer culture and differentiated epithelial cells in air-liquid interface (ALI) represent two distinct and commonly used in vitro models, yet differences in their response to pathogens have not been investigated. In this study, we compared the transcriptional effects of flagellin on AECs in monolayer culture versus ALI culture using whole-genome microarrays and RNA sequencing. We exposed monolayer and ALI AEC cultures to flagellin in vitro and analyzed the transcriptional response by microarray and RNA-sequencing. ELISA and RT-PCR were used to validate changes in select candidates. We found that AECs cultured in monolayer and ALI have strikingly different transcriptional states at baseline. When challenged with flagellin, monolayer AEC cultures greatly increased transcription of numerous genes mapping to wounding response, immunity and inflammatory response. In contrast, AECs in ALI culture had an unexpectedly muted response to flagellin, both in number of genes expressed and relative enrichment of inflammatory and immune pathways. We conclude that in vitro culturing methods have a dramatic effect on the transcriptional profile of AECs at baseline and after stimulation with flagellin. These differences suggest that epithelial responses to pathogen challenges are distinctly different in culture models of intact and injured epithelium.


Impact of Question Bank Use for In-Training Examination Preparation by OBGYN Residents - A Multicenter Study.
To examine the impact of access to and utilization of a commercially available question bank (TrueLearn) for in-training examination (ITE) preparation in Obstetrics and Gynecology (OBGYN). This was a retrospective cohort study examining the impact of TrueLearn usage on ITE examination performance outcomes. Produced by the educational arm of the American College of Obstetricians and Gynecologists, the Council on Resident Education in Obstetrics and Gynecology (CREOG) exam is a multiple-choice test given to all residents annually. Residency programs participating in this study provided residency program mean CREOG scores from the year prior (2015), and the first (2016) and second (2017) years of TrueLearn usage. Programs also contributed resident-specific CREOG scores for each resident for 2016 and 2017. This data was combined with each resident's TrueLearn usage data that was provided by TrueLearn with residency program consent. The CREOG scores consisted of the CREOG score standardized to all program years, the CREOG score standardized to the same program year (PGY) and the total percent (%) correct. TrueLearn usage data included number of practice questions completed, number of practice tests taken, average number of days between successive tests, and percent correct of answered practice questions. OBGYN Residency Training Programs. OBGYN residency programs that purchased and utilized TrueLearn for the 2016 CREOG examination were eligible for participation (n = 14). Ten residency programs participated, which consisted of 212 residents in 2016 and 218 residents in 2017. TrueLearn was used by 78.8% (167/212) of the residents in 2016 and 84.9% (185/218) of the residents in 2017. No significant difference was seen in the average CREOG scores available on a per- program level before versus after the first year of implementation either using the CREOG score standardized to all PGYs (mean difference 1.0; p = 0.58) or standardized to the same PGY (mean difference 3.1; p = 0.25). Using resident-level data, there was no significant difference in mean CREOG score standardized to all PGYs between users and non-users of TrueLearn in 2016 (mean, 199.4 vs 196.7; p = 0.41) or 2017 (mean, 198.2 vs 203.4; p = 0.19). The percent of practice questions answered correctly on TrueLearn was positively correlated with the CREOG score standardized to all PGYs (r = 0.47 for 2016 and r = 0.60 for 2017), as well as with the CREOG total percent correct (r = 0.47 for 2016 and r = 0.61 for 2017). Based on a simple linear regression, for every 500 practice questions completed, the CREOG score significantly increased for PGY-2 residents by an average (±SE) of 7.3 ± 2.8 points (p = 0.013); the average increase was 0.7 ± 2.5 (p = 0.79) for PGY-3 residents and 5.8 ± 3.3 points (p = 0.09) for PGY-4 residents. Adoption of an online question bank did not result in higher mean CREOG scores at participating institutions. However, performance on the TrueLearn questions correlated with ITE performance, supporting predictive validity and the use of this question bank as a formative assessment for resident education and exam preparation.


On the Electronic Structure of 2H-MoS2: Correlating DFT Calculations and In-Situ Mechanical Bending on TEM.
We present a systematic density functional theory study to determine the electronic structure of bending 2H-MoS2 layers up to 75° using information from in-situ nanoindentation TEM observations. The results from HOMO/LUMO and density of states plots indicate a metallic transition from the typical semiconducting phase, near Fermi energy level (EF) as a function of bending, which can mainly occur due to bending curvatures inducing a stretching and contracting of sulfur-sulfur chemical bonds located mostly over basal (001)-plane; furthermore, molybdenum ions play a major role in such transitions due to reallocation of their metallic d-character orbitals and the creation of "free electrons", possibly having an overlap between Mo-dx2-y2 and Modz2 orbitals. This research on the metallic transition of 2H-MoS2 allows us to understand the high catalytic activity for MoS2 nanostructures as extensively reported in the literature.


Non-Penetrating Deep Sclerectomy versus Trabeculectomy in Primary Congenital Glaucoma.
To evaluate the safety and efficacy of non-penetrating deep sclerectomy with a collagen implant versus trabeculectomy in primary congenital glaucoma. This was a retrospective interventional comparative non-randomized clinical study that included 80 eyes of 80 children presenting with primary congenital glaucoma under the age of 3 years. Forty eyes have undergone non-penetrating deep sclerectomy (NPDS) and the other 40 eyes have undergone penetrating trabeculectomy. The main outcome measure was the reduction in intraocular pressure (IOP). Secondary outcomes included percentage of patients with complete and qualified success, need for topical antiglaucoma medications, rate of complications, and need for further interventions. Complete success of the surgical outcome was considered an IOP ≤16 mmHg with no antiglaucoma medications. Qualified success was considered an IOP ≤16 mmHg using antiglaucoma medications. The mean preoperative IOP was 27.4 ± 6.9 and 28.5 ± 6.6 mmHg in NPDS and trabeculectomy groups, respectively (p = 0.175). At the end of the follow-up period, the mean IOP was 11.2 ± 4.5 and 11.1 ± 3.4 mmHg with a mean reduction of 16.2 and 17.4 mmHg in NPDS and trabeculectomy groups, respectively. At the end of the follow-up period, ie at 36 months postoperative, the complete success rate was 60% (24 eyes) versus 57.5% (23 eyes), the qualified success rate was 25% (10 eyes) versus 25% (10 eyes), the overall success rate was 85% (34 eyes) versus 82.5% (33 eyes), and the rate of failure was 15% (6 eyes) versus 17.5% (7 eyes) in NPDS and trabeculectomy groups, respectively (p = 0.952). Eight cases (20%) of the trabeculectomy group had shallow anterior chamber. None of the NPDS group cases suffered from shallow anterior chamber. Non-penetrating deep sclerectomy appears to be an efficient and safe surgical alternative to penetrating trabeculectomy in treatment of primary congenital glaucoma. Non-penetrating deep sclerectomy has fewer postoperative complications in comparison to penetrating trabeculectomy with a comparative postoperative reduction in the intraocular pressure and overall success rates. The trial was registered on 11/01/2020 with number PACTR202002874953456 (https://pactr.samrc.ac.za).


International survey of nephrologists' perceptions and attitudes about rewards and compensations for kidney donation.
Payment for organ donation, whether in the form of incentives, rewards or compensation is highly debated and has been denounced by many professional and legislative bodies. Despite the passionate discussion in the literature, there is very limited data on attitudes and perceptions of physicians about providing rewards or compensation to organ donors. We investigated the relationship between demographic and practice characteristics of nephrologists and their perceptions and attitudes about rewards and compensations for organ donation. Using a web-based survey, we explored the views of nephrologists around the world about rewards and compensations for kidney donation. The relationship between attitudes and demographic characteristics of 1280 nephrologists from 74 countries was examined by univariate and multivariable analyses. Seventy-five percent agreed with donor health insurance, 26% favored direct financial compensation and 31% agreed with financial rewards for unrelated donors. Sixty-six percent believed that rewards will lead to increased donation. Seventy-three percent indicated that rewards will lead to exploitation of the poor and 78% agreed with legislation prohibiting organ sales. Thirty-seven percent believed that rewards will negatively impact deceased-donor transplantation. Nephrologists from India/Pakistan and the Middle East had more favorable views about rewards, while respondents from Latin America and Europe, older than 50, female nephrologists and those practicing in rural areas had less favorable views. We conclude that a minority of nephrologists favor rewards for donation, many agree with some compensation and a considerable majority favor donor health insurance. Perceptions of nephrologists about rewards and compensation are influenced by age, sex, urban versus rural location and geographic region of practice.


Articular ankle fracture results in increased synovitis, synovial macrophage infiltration, and synovial fluid concentrations of inflammatory cytokines and chemokines.
The inflammatory response following an articular fracture is thought to play a role in the development of posttraumatic arthritis (PTA) but has not been well characterized. The objective of this study was to characterize the acute inflammatory response, both locally and systemically, in joint synovium, synovial fluid (SF), and serum following articular fracture of the ankle. We hypothesized that intraarticular fracture would alter the synovial environment and lead to increased local and systemic inflammation. Synovial tissue biopsy specimens, SF samples, and serum samples were collected from patients with an acute articular ankle fracture (n = 6). Additional samples (normal, ankle osteoarthritis [OA], and knee OA [n = 6 per group]) were included for comparative analyses. Synovial tissue was assessed for synovitis and macrophage count. SF and serum were assessed for cytokines (interferon-γ [IFNγ], interleukin-1β [IL-1β], IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor α) and chemokines (eotaxin, eotaxin 3, IFNγ-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], MCP-4, macrophage-derived chemokine, macrophage inflammatory protein 1β, and thymus and activation-regulated chemokine). Synovitis scores were significantly higher in ankle fracture tissue compared with normal ankle tissue (P = 0.007), and there was a trend toward an increased abundance of CD68+ macrophages in ankle fracture synovium compared with normal knee synovium (P = 0.06). The concentrations of all cytokines and chemokines were elevated in the SF of patients with ankle fracture compared with those in SF from OA patients with no history of trauma. Only the concentration of IL-6 was significantly increased in the serum of patients with ankle fracture compared with normal serum (P = 0.027). Articular fracture of the ankle increased acute local inflammation, as indicated by increased synovitis, increased macrophage infiltration into synovial tissue, and increased SF concentrations of biomarkers of inflammation. Characterizing the acute response to articular fracture provides insight into the healing process and may help to identify patients who may be at greater risk of PTA.


Thrombus aspiration in acute myocardial infarction.
The success of primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is often hampered by incomplete microvascular myocardial reperfusion owing to distal embolization of thrombus resulting in microvascular obstruction. To address this problem, thrombus aspiration devices have been developed that can be used to evacuate coronary thrombus either manually or mechanically. Thrombus aspiration has the potential to reduce the local thrombus load, minimize the need for balloon predilatation, facilitate direct stenting, prevent distal embolization, and ultimately improve myocardial reperfusion. Furthermore, thrombus aspiration has enabled us to study coronary thrombus in vivo, and has facilitated recognition of distinct mechanisms of coronary thrombosis. Clinical trials focusing on manual thrombus aspiration in primary PCI have generally shown improved myocardial reperfusion. However, in two large trials powered for clinical end points, no reduction in 1-year mortality or other adverse clinical events was observed with the use of this strategy. Moreover, one of these trials showed a marginally increased risk of stroke. Consequently, current guidelines do not recommend routine use of thrombus aspiration. Future studies should focus on the identification of subgroups of patients with STEMI who might derive benefit from manual thrombus aspiration, and establish the effect of operator performance on the efficacy and safety of the procedure.


Knowledge of human papillomavirus (HPV) testing in the USA, the UK and Australia: an international survey.
To measure knowledge and awareness of human papillomavirus (HPV) testing in the USA, the UK and Australia. Participants in the USA, UK and Australia completed an anonymous web-based survey measuring awareness and knowledge of HPV (n=2409). We report analyses on a subsample of 1473 men and women in the USA (n=617), UK (n=404) and Australia (n=452) who had heard of HPV and completed questions about HPV testing. Overall, 50% of the sample (742/1473) had heard of HPV testing. Awareness of HPV testing was higher in the USA (62%) than in the UK (44%) and Australia (40%) (p<0.001). Among those who had heard of HPV testing, the mean knowledge score (out of 6) was 2.78 (SD: 1.49). No significant differences in knowledge score were found between the countries but, overall, women scored significantly higher than men (2.96 vs 2.52, p<0.001). Awareness of HPV testing among people who have heard of HPV is higher in the USA than in the UK and Australia, but overall knowledge is low. This has important implications in those countries where HPV testing is being used in cervical screening. Increasing knowledge about the implications of HPV test results may help minimise any negative psychological consequences associated with HPV testing. Raising awareness in men could become increasingly important if HPV testing is introduced into the management of other cancers where HPV plays an aetiological role.


The distinction between exclusivity and comorbidity within NSSI.
Based on notions posited by problem behavior theory, the primary goal of the current study was to examine the possibility that adolescents who engage in NSSI are not a homogeneous group but are rather divided into 2 subgroups: (a) adolescents who exclusively engage in NSSI, and (b) adolescents who are involved in NSSI alongside other problem behaviors (e.g., drug abuse, unprotected sexual intercourse). Participants were a school sample of 436 adolescents from 6 high schools across Israel, who completed self-report questionnaires during school hours on engagement in NSSI and other problem behaviors, self-esteem, self-criticism, ego clarity, coping strategies, self-efficacy to regulate affect, and sociodemographic information. Findings indicated that 22% of the sample reported engaging in NSSI. Adolescents who reported engaging in NSSI had higher prevalence rates of involvement in other problem behaviors compared to those who did not report engaging in NSSI. However, a comparison between those who exclusively engaged in NSSI and those who were involved in NSSI alongside other problem behaviors indicated that lower ego clarity, lower self-esteem, and poorer self-efficacy to regulate affect, alongside higher self-criticism and greater use of disengagement coping mechanisms characterized exclusive engagement in NSSI. Distinct theoretical models are needed to characterize different forms of NSSI: NSSI, which is an exclusive and singular phenomenon, for which problems related to the self are prominent, versus NSSI, which is accompanied by other problem behaviors. Accordingly, the implications related to school psychologists' work in the assessment, treatment, and prevention of NSSI are suggested. (PsycINFO Database Record


Role of the acidic carboxyl-terminal domain of the single-stranded DNA-binding protein of bacteriophage T7 in specific protein-protein interactions.
The gene 2.5 single-stranded DNA (ssDNA) binding protein of bacteriophage T7 is essential for T7 DNA replication and recombination. Earlier studies have shown that the COOH-terminal 21 amino acids of the gene 2.5 protein are essential for specific protein-protein interaction with T7 DNA polymerase and T7 DNA helicase/primase. A truncated gene 2.5 protein, in which the acidic COOH-terminal 21 amino acid residues are deleted no longer supports T7 growth, forms dimers, or interacts with either T7 DNA polymerase or T7 helicase/primase in vitro. The single-stranded DNA-binding protein encoded by Escherichia coli (SSB protein) and phage T4 (gene 32 protein) also have acidic COOH-terminal domains, but neither protein can substitute for T7 gene 2.5 protein in vivo. To determine if the specificity for the protein-protein interaction involving gene 2.5 protein resides in its COOH terminus, we replaced the COOH-terminal region of the gene 2.5 protein with the COOH-terminal region from either E. coli SSB protein or T4 gene 32 protein. Both of the two chimeric proteins can substitute for T7 gene 2.5 protein to support the growth of phage T7. The two chimeric proteins, like gene 2.5 protein, form dimers and interact with T7 DNA polymerase and helicase/primase to stimulate their activities. In contrast, chimeric proteins in which the COOH terminus of T7 gene 2.5 protein replaced the COOH terminus of E. coli SSB protein or T4 gene 32 protein cannot support the growth of phage T7. We conclude that an acidic COOH terminus of the gene 2.5 protein is essential for protein-protein interaction, but it alone cannot account for the specificity of the interaction.


Effects of Intracortical Microstimulation and Vestibular Stimulation on Pelvic Floor Muscles in the Cat.
Experimental anatomical data in primates and transcranial stimulation of the motor cortex in humans indicate that this region projects to pelvic floor musculature. We investigated this problem in intact, anesthetized cats with intracortical microstimulation (ICMS). Further, we explored the characteristics of projection to pelvic floor muscles from the lateral vestibular nucleus of the brainstem. ICMS reliably produced responses from both recorded muscles, levator ani (LA) and external ani sphincter (EAS). Responses could be obtained both from ipsi and contralateral sides, being shorter for the contralateral ones. In contrast, vestibular stimulation activates only the EAS. It is proposed that these high level inputs to pelvic floor musculature are important for appropriate coordination of defecation and micturition.


Kinetic and chemical mechanisms of the sheep liver 6-phosphogluconate dehydrogenase.
A complete kinetic characterization of sheep liver 6-phosphogluconate dehydrogenase including product and dead-end inhibition patterns, primary deuterium isotope effects, and the pH dependence of kinetic parameters has been completed in order to determine the kinetic mechanism and obtain information on the chemical mechanism of the enzyme. A rapid equilibrium random kinetic mechanism has been proposed, with product and dead-end inhibition patterns both being symmetric. Ribulose 5-phosphate and 6-sulfogluconate are both competitive with 6-phosphogluconate (6-PG) and noncompetitive with NADP, and NADPH and ATP-ribose are both competitive with NADP and noncompetitive with 6-phosphogluconate. Equal primary deuterium isotope effects of 1.5-2 on DV, DV/KNADP, and DV/K6-PG with 3-deuterio-6-PG confirm a rapid equilibrium random mechanism and show that hydride transfer is at least partially rate limiting in the overall reaction. The maximum velocity is pH dependent, decreasing at low and high pH with slopes of 1 and -1, respectively, and pK values of 6.4 and 8.6. The V/KNADP and V/K6-PG also decrease at low and high pH with slopes of 1 and -1, giving pK values of 6.8 and 8.7 and of 6.9 and 7.8, respectively. The pH rate profiles are consistent with a general acid/general base mechanism where the catalytic residues are involved in binding. Reverse protonation states between the general acid and the general base are proposed where an unprotonated general base accepts a proton from the C-3 hydroxyl of 6-PG concomitant with hydride transfer followed by decarboxylation of the resulting 3-keto intermediate to give an enediol which is protonated by the general acid to form ribulose 5-phosphate. The pH dependence of the pKi profile of the inhibitory analog 5-phosphoribonate decreases at low and high pH with slopes of 1 and -1, respectively, and pKs of 6.2 and 7.4 and suggests that intrinsic pKs are observed in the V/K profiles. The pKs of both the general base and general acid in the E:6-PG complex appears to be perturbed such that the general base decreases from 7.4-7.8 to a value of 6.4-6.8, and the pK of the general acid increases from 6. 2-6.9 to a value of 8.6-8.7, as a result of direct interaction with 6PG. Data are interpreted with regard to the published crystal structures of the E:6-PG, E:NADP, and E:NADPH complexes.


[Polymorphism of GPIIIA platelet glycoprotein gene PIA1/A2 compared to plasma hemostasis in myocardial infarction patients].
To investigate gene PIA1/A2 polymorphism and some parameters of plasma hemostasis in postmyocardial infarction (PMI) patients with chronic cardiac failure (CCF). A total of 58 PMI patients with CCF, pulmonary artery thromboembolism (PATE), phlebothrombosis (PT) were examined. The age of the patients ranged from 24 to 84 years. Polymorphism of platelet glycoprotein GPIIIa gene was assessed according to the standard PCR-RFLP. Occurrence of genotypes PIA1/A2, PIA1/A2 was 70.8 and 29.2%, respectively; of allele PIA1 and PIA2 84.5 and 15.5%, respectively. In PMI patients genotype PIA1/A1 occurred in 71.7% of cases, genotype PIA1/A2--in 28.3%. Incidence of alleles was: 84.0% (PIA1), 16.0% (PIA2). PATE patients had genotype PIA1/A1, PT patients had distribution of the genotypes 50.0% and 50.0%, respectively. In patients who had suffered MI at the age under 45 years prevalence of the genotypes was 63.2% PIA1A1, 36.8% PIA1A2, of alleles 83.6% PIA1, 16.4% PIA2. In patients with a history of MI at the age over 50 the incidence of the genotypes and alleles was, respectively, 75.0% PIA1A1, 25.0% PIA1A2, 87.7% PIA1, 12.3% PIA2. Patients with genotype PIA1/A2 had a significantly higher fibrinogen than PIA1A1. Concentration of soluble fibrin monomeric complex was higher in patients with genotype PIA1/A2 reflecting activation of intravascular clotting. AT-III decrease by 5.4% indicated lower anticoagulant activity in patients with genotype PIA1A2. In patients with MI at the age under 45 years gene PIA1A2 and allel PIA2 occurred more frequently than in patients who had MI at older age. Allele PIA2 was associated with the risk of MI onset at young age. It is suggested that patients with genotype PIA1/A2 are at higher risk of thrombotic conditions, of coronary artery thrombosis in particular, than patients with genotype PIA1/A1.


Endoscopic Findings in Patients Presenting with Upper Gastrointestinal Bleeding.
Upper gastrointestinal bleeding (UGIB) is one of the most common and grave emergencies encountered by the emergency medicine doctors. The aim of this study is to assess the endoscopic findings in patients presenting with acute UGIB. This is a retrospective study which included all endoscopy records of the Department of Gastroenterology, Ghulam Mohammad Maher Hospital, Sukkur from 1st January 2017 till 30th June 2018. There were 100 males (49.3%) and 103 females (50.7%) who underwent endoscopy in the study duration. The mean ± standard deviation (SD) age of the participants was 41.03 ± 14.94 years. Esophageal varices were found in 65% cases. There were more men (68%) with varices than women (32%). Almost 10% patients were with gastric erosions, 9% had antral gastritis, 6.4% had pangastritis, and peptic ulcer disease was found in 5.8% cases. Variceal bleeding is the most common endoscopic finding in the patients with UGIB. Other lesser common causes include erosions of the gastric and esophageal mucosa.


Knowledge, Attitude, and Behavior Levels of Postmenopausal Women about Osteoporosis.
Osteoporosis can be delayed by providing accurate and adequate information to people at risk. Therefore, we aimed to determine the knowledge, attitude, and behavior levels of women in the postmenopausal period, which is the largest group at risk. The study was conducted in a tertiary Training and Research Hospital between 1 December 2018 and 1 May 2019 in 225 postmenopausal women who applied to the Family Medicine outpatient clinic and bone mineral density (BMD) outpatient clinics for BMD measurement or had previously had this measurement at least once. A questionnaire evaluating the knowledge, attitudes, and behavior levels related to osteoporosis was applied to all patients included in the study. The mean age was 58.05±9.1 years. The median osteoporosis knowledge score was 7 out of 19 points. A total of 119 (52.9%) had low knowledge scores and 106 (47.1%) had higher knowledge scores. Of the individuals with high scores, 40 (37.7%) were smoking, 64 (60.4%) did not sunbathe, 89 (84%) did not consume the recommended daily amount of calcium, and 58 (54.7%) were not exercising in the recommended time. It was seen that those who were university graduates, who had previously learned about osteoporosis from a health professional, and who had a family history of osteoporosis had higher knowledge levels. Even in postmenopausal women who are aware that they are in the risk group and that they should have BMD, their knowledge, attitude, and behavior levels on osteoporosis were found to be quite low.


A review of experimental models for studying the tissue penetration of antibiotics in man.
Measurement of tissue antibiotic levels is of great importance in developing rational treatment for infection, particularly in patients whose host defense systems are compromised. This review outlines some of the main approaches to this problem, giving examples of the application of the new techniques in different clinical situations.