Hydrogen gas sensing properties of PdO thin films with nano-sized cracks.
We report on a novel method for the fabrication of highly sensitive hydrogen gas sensors based on palladium oxide thin films and have investigated their hydrogen sensing properties and nanostructures. To our knowledge, this is the first report on the use of palladium oxide and reduced palladium thin films as hydrogen sensors. The palladium oxide thin films were deposited on thermally oxidized Si substrates using a reactive direct current (DC) magnetron sputtering system. Considerable changes in the resistance of the palladium oxide thin films were observed when they were initially exposed to hydrogen gas, as a result of the reduction process. After the initial exposure to hydrogen gas of PdO(30%), its sensitivity increased up to approximately 4.5 x 10(3)%. The morphology of the PdO surface was analyzed using a scanning electron microscope (SEM), in order to investigate the interactions between palladium oxide and hydrogen. The SEM images showed a large number of nano-sized cracks on the surface of the palladium oxide during the reduction process, which acted to increase the effective surface-to-volume ratio. The response behaviors of the reduced Pd films to hydrogen gas were reversible and had an enhanced sensing property when compared with those of the pure Pd films. In addition, their sensitivities and response times were improved due to the nano-sized cracks on the surfaces. The results demonstrate that palladium oxide and reduced palladium thin films can be applied for use in highly sensitive hydrogen sensors.


Differences in cardiovascular disease risk factor management in primary care by sex of physician and patient.
The purpose of this study was to evaluate differences in the management of cardiovascular disease (CVD) risk factors based upon the sex of the patient and physician and their interaction in primary care practice. We evaluated CVD risk factor management in 4,195 patients cared for by 39 male and 16 female primary care physicians in 30 practices in southeastern New England. Many of the sex-based differences in CVD risk factor management on crude analysis are lost once adjusted for confounding factors found at the level of the patient, physician, and practice. In multilevel adjusted analyses, styles of CVD risk factor management differed by the sex of the physician, with more female physicians documenting diet and weight loss counseling for hypertension (odds ratio [OR] = 2.22; 95% confidence interval [CI], 1.12-4.40) and obesity (OR = 2.14; 95% CI, 1.30-3.51) and more physical activity counseling for obesity (OR = 2.03; 95% CI, 1.30-3.18) and diabetes (OR = 6.55; 95% CI, 2.01-21.33). Diabetes management differed by the sex of the patient, with fewer women receiving glucose-lowering medications (OR = 0.49; 95% CI, 0.25-0.94), angiotensin-converting enzyme inhibitor therapy (OR = 0.39; 95% CI, 0.22-0.72), and aspirin prophylaxis (OR = 0.30; 95% CI, 0.15-0.58). Quality of care as measured by patients meeting CVD risk factors treatment goals was similar regardless of the sex of the patient or physician. Selected differences were found in the style of CVD risk factor management by sex of physician and patient.


LytR-CpsA-Psr proteins in Staphylococcus aureus display partial functional redundancy and the deletion of all three severely impairs septum placement and cell separation.
Staphylococcus aureus contains three members of the LytR-CpsA-Psr (LCP) family of membrane proteins: MsrR, SA0908 and SA2103. The characterization of single-, double- and triple-deletion mutants revealed distinct phenotypes for each of the three proteins. MsrR was involved in cell separation and septum formation and influenced β-lactam resistance; SA0908 protected cells from autolysis; and SA2103, although displaying no apparent phenotype by itself, enhanced the properties of msrR and sa0908 mutants when deleted. The deletion of sa0908 and sa2103 also further attenuated the virulence of msrR mutants in a nematode-killing assay. The severely defective growth phenotype of the triple mutant revealed that LytR-CpsA-Psr proteins are essential for optimal cell division in S. aureus. Growth could be rescued to varying degrees by any one of the three proteins, indicating some functional redundancy within members of this protein family. However, differing phenotypic characteristics of all single and double mutants and complemented triple mutants indicated that each protein played a distinct role(s) and contributed differently to phenotypes influencing cell separation, autolysis, cell surface properties and virulence.


Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection.
Hepatitis B virus (HBV) is a major human pathogen, and about one third of the global population will be exposed to the virus in their lifetime. HBV infects hepatocytes, where it replicates its DNA and infection can lead to acute and chronic hepatitis with a high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type 1 interferon (IFN) production; and this occurs through a pathway dependent on the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase and the downstream adaptor protein stimulator of IFN genes (STING). In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type 1 IFN in response to foreign DNA or HBV infection and mice lacking STING or cyclic guanosine monophosphate-adenosine monophosphate synthase exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possesses anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo. The lack of a functional innate DNA-sensing pathway in hepatocytes hampers efficient innate control of HBV infection; this may explain why HBV has adapted to specifically replicate in hepatocytes and could contribute to the weak capacity of this cell type to clear HBV infection. (Hepatology 2016;64:746-759).


Modeling the Epidemiology of Cholera to Prevent Disease Transmission in Developing Countries.
Cholera remains an important global cause of morbidity and mortality, which is capable of causing periodic epidemic disease. A number of mathematical models have been developed to help in understanding the dynamics of cholera outbreaks and for use as a tool in planning interventions, including vaccination campaigns. We have explored the utility of models in assessing the spread of cholera in the recent epidemics in Zimbabwe and Haiti. In both instances, a mathematical model was formulated and fitted to cumulative cholera cases to estimate the basic reproductive number ℛ0, and the partial reproductive numbers reflecting potential differences in environmental-to-human versus human-to-human transmission were quantified. In Zimbabwe, estimated ℛ0 for the epidemic using aggregated data at the national level was 1.15; in Haiti, it was 1.55. However, when calculated at a provincial/departmental level, estimated basic reproductive numbers were highly heterogeneous, with a range of 1.11 to 2.72 in Zimbabwe and 1.06 to 2.63 in Haiti. Our models suggest that the underlying patterns of cholera transmission varied widely from region to region, with a corresponding variation in the amenability of outbreaks to control measures such as immunization. These data underscore the heterogeneity of transmission dynamics, potentially linked to differences in environment, socio-economic conditions, and cultural practices. They also highlight the potential utility of these types of models in guiding development of public health intervention strategies.


Benzodiazepine receptors are coupled to a subpopulation of gamma-aminobutyric acid (GABA) receptors: evidence from a quantitative autoradiographic study.
The colocalization and interaction of gamma-aminobutyric acid (GABA) and benzodiazepine (BZ) receptors in the rat brain were characterized using standardized, quantitative, light microscopic autoradiographic methods. In serial sections, striking differences were observed in the distribution of high affinity GABA and BZ receptors in areas such as the cerebral cortex, globus pallidus, thalamus, hypothalamus and cerebellar cortex. However, in a semiquantitative visual examination of more than 200 brain regions, added exogenous GABA increased BZ binding in all regions. In a quantitative analysis of 19 regions, exogenous GABA uniformly stimulated [3H]flunitrazepam binding, the effect being proportional to the regional density of BZ receptors. No relationship was seen between the magnitude of the stimulation and the distribution of high affinity GABA receptors. In the mounted tissue sections, BZ binding appeared influenced by endogenous GABA since it was reduced by preincubation or by the addition of bicuculline. Taken together, these data suggest that most or all BZ receptors can be influenced by GABA and are coupled to a type of GABA receptor. However, the BZ-linked GABA receptor could represent either a subpopulation of GABA binding sites or a distinct receptor not labeled under the conditions used in these and other experiments.


Functional Toll-like receptors in primary first-trimester trophoblasts.
Toll-like receptors (TLRs) are an important part of the body's danger response system and crucial for initiating inflammation in response to cellular stress, tissue damage, and infections. Proper placental development is sensitive to inflammatory activation, and a role for TLRs in trophoblast immune activation has been suggested, but no overall examination has been performed in primary trophoblasts of early pregnancy. This study aimed to broadly examine cell surface and endosomal TLR gene expression and activation in first-trimester trophoblasts. Gene expression of all ten TLRs was examined by quantitative RT-PCR (RT-qPCR) in primary first-trimester trophoblasts (n = 6) and the trophoblast cell line BeWo, and cytokine responses to TLR ligands were detected by quantitative multiplex immunoassay. Primary first-trimester trophoblasts broadly expressed all ten TLR mRNAs; TLR1, TLR2, TLR3, TLR4, and TLR6 mRNA were expressed by all primary trophoblast populations, while TLR5, TLR7, TLR8, TLR9, and TLR10 mRNA expression was more restricted. Functional response to ligand activation of cell surface TLR2/1, TLR4, and TLR5 increased IL-6 and/or IL-8 release (P < 0.01) from primary trophoblasts. For endosomal TLRs, TLR3 and TLR9 ligand exposure increased receptor-specific production of IL-8 (P < 0.01) and IFN-γ-induced protein 10 (IP-10; P < 0.001) or vascular endothelial growth factor A (VEGFA; P < 0.01). In contrast, BeWo cells expressed lower TLR mRNA levels and did not respond to TLR activation. In conclusion, primary first-trimester trophoblasts broadly express functional TLRs, with inter-individual variation, suggesting that trophoblast TLR2, TLR3, TLR4, TLR5, and TLR9 might play a role in early placental inflammation.


Use of buddy wire to facilitate Y-configured stent placement in middle cerebral artery bifurcation aneurysms with daughter branches arising from the sac: a technical note.
Endovascular treatment of geometrically complex bifurcation aneurysms using a standard Y-configured stenting technique might be extremely difficult, particularly in aneurysms with daughter branches that acutely arise from the aneurysm sac itself. In those cases, deployment of the second stent through interstices of the first stent could be troublesome because of untoward angular changes in the vascular bifurcation prompted by angular changes resulting from placement of the first stent. Here, we describe a novel application of the buddy wire technique to facilitate Y-configured stenting in middle cerebral artery (MCA) bifurcation aneurysms with unfavorable anatomic configuration. A 60-year-old man with a left-sided MCA bifurcation aneurysm was treated using the buddy wire technique. In addition to the standard Y-configured stenting procedure, we also inserted a 0.014-inch exchange microguidewire into the superior daughter branch, which more acutely emanated from the sac, to attain a favorable bifurcation configuration before deployment of the stents in the Y configuration. The new technique was successful, and the postprocedural course of the treatment was uneventful. Use of a buddy wire in MCA bifurcation aneurysms with unfavorable anatomic configurations may be a promising method to facilitate Y-configured stent placement.


Synapse-specific opioid modulation of thalamo-cortico-striatal circuits.
The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.


Calculating the proportion of avoidable attendances at UK emergency departments: analysis of the Royal College of Emergency Medicine's Sentinel Site Survey data.
Avoidable attendances (AAs; defined as non-urgent, self-referred patients who could be managed more effectively and efficiently by other services) have been identified as a contributor to ED crowding. Internationally, AAs have been estimated to constitute 10%-90% of ED attendances, with the UK 2013 Urgent and Emergency Care Review suggesting a figure of 40%. This pilot study used data from the Royal College of Emergency Medicine's Sentinel Site Survey to estimate the proportion of AAs in 12 EDs across England on a standard day (20 March 2014). AAs were defined by an expert panel using questions from the survey. All patients attending the EDs were recorded with details of investigations and treatments received, and the proportion of patients meeting criteria for AA was calculated. Visits for 3044 patients were included. Based on these criteria, a mean of 19.4% (95% CI 18.0% to 20.8%) of attendances could be deemed avoidable. The lowest proportion of AAs reported was 10.7%, while the highest was 44.3%. Younger age was a significant predictor of AA with mean age of 38.6 years for all patients attending compared with 24.6 years for patients attending avoidably (p≤0.001). The proportion of AAs in this study was lower than many estimates in the literature, including that reported by the 2013 Urgent and Emergency Care Review. This suggests the ED is the most appropriate healthcare setting for many patients due to comprehensive investigations, treatments and capability for urgent referrals.The proportion of AAs is dependent on the defining criteria used, highlighting the need for a standardised, universal definition of an appropriate/avoidable ED attendance. This is essential to understanding how AAs contribute to the overall issue of crowding.


Activation mechanism of ATP-sensitive K+ channels explored with real-time nucleotide binding.
The response of ATP-sensitive K+ channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATP in channel gating. Binding to NBS2 was Mg2+-independent, but Mg2+ was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinates bound nucleotides increased the EC50 for trinitrophenyl-ADP binding to NBS2, but only in the presence of Mg2+, indicating that this mutation disrupts the ligand-induced conformational change. Comparison of nucleotide-binding with ionic currents suggests a model in which each nucleotide binding event to NBS2 of SUR1 is independent and promotes KATP activation by the same amount.


Brief report: independent validation of autism spectrum disorder case status in the Utah Autism and Developmental Disabilities Monitoring (ADDM) Network Site.
An independent validation was conducted of the Utah Autism and Developmental Disabilities Monitoring Network's (UT-ADDM) classification of children with autism spectrum disorder (ASD). UT-ADDM final case status (n = 90) was compared with final case status as determined by independent external expert reviewers (EERs). Inter-rater reliability (ICC = 0.84), specificity [0.83 (95 % CI 0.74-0.90)], and sensitivity [0.99 (95 % CI 0.96-1.00)] were high for ASD case versus non-case classification between UT-ADDM and EER. At least one EER disagreed with UT-ADDM on ASD final case status on nine out of 30 records; however, all three EERs disagreed with UT-ADDM for only one record. Findings based on limited data suggest that children with ASD as identified by UT-ADDM are consistently classified as ASD cases by independent autism experts.


The M1 and M2 paradigm of macrophage activation: time for reassessment.
Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.


Extensively drug-resistant Klebsiella pneumoniae ST307 outbreak, north-eastern Germany, June to October 2019.
From June to October 2019, 17 patients (six infected, 11 colonised) with an extensively drug-resistant (XDR) Klebsiella pneumoniae strain were notified from four Western Pomerania medical facilities. The XDR K. pneumoniae produced carbapenemases NDM-1 and OXA-48, and was only susceptible to chloramphenicol, tigecycline and cefiderocol. Synergistic activity was observed for the combination of aztreonam plus ceftazidime-avibactam. Genomic analyses showed all isolates belonged to K. pneumoniae sequence type 307. Control measures and further investigations are ongoing.


A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children.
An open randomized clinical trial study was carried out to compare efficacy and tolerability of artesunate mefloquine 25 mg/kg body weight (Artequin paediatric) versus artemether lumefantrine (Coartem) in the treatment of uncomplicated Plasmodium falciparum malaria in children. In each arm, 160 patients were assigned to receive either AS + MQ or AL with 28 days follow-up. The adequate clinical and parasitological response at Day 28 for per protocol analysis was after polymerase chain reaction correction, 100% for AS + MQ and 96.8% for AL. In the intention-to-treat analysis, the respective cure rates were 96.2% for AS + MQ and 93.7% for AL. No serious adverse events (AEs) were reported. The most frequent AE was vomiting, 30% in AS + MQ arm and 36% in AL arm. No biological significant abnormal values related to the study drug have been reported. The new pediatric artesunate mefloquine formulated in granule fixed dose combination is well adapted to children in Africa.


Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity.
Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10-9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.


LateNight Penn State alcohol-free programming: students drink less on days they participate.
Despite the public health importance of alcohol-free social programs for college students, the majority of existing campus strategies have not been empirically evaluated. This study utilized repeated daily reports to examine the association between attendance at campus-led alcohol-free programming and alcohol use on specific days while controlling for individuals' typical rates of use. The current study assessed students' participation in the LateNight Penn State (LNPS) alcohol-free programming and amount of alcohol use at a daily level, in order to determine whether students consumed less alcohol on days they attended LNPS compared to weekend days they did not attend. First-year college students reported their daily social activity involvement and alcohol use via 14 consecutive daily web-based surveys. Multilevel regression analyses modeled variation in alcohol use on weekend days (N = 3,350) nested within people (N = 689 people, 51% women). Analyses focused on within-individual differences between nights attending and not attending LNPS, thereby controlling for stable individual differences, measured and unmeasured. Results indicated that students drank less on days they attended LNPS and on days they stayed in (rather than going to bars/parties, other campus events, or entertainment), both especially among women. These results suggest that alcohol-free social programs may be an effective strategy for decreasing alcohol use on days when students attend alcohol-free events rather than going to other events or gatherings.


Prospective memory deficits in patients with bipolar disorder: a preliminary study.
Prospective memory (PM) is the ability to remember to do something in the future without explicit prompts. To date, little has been known about PM deficits in bipolar disorder (BD). This study examined the nature and correlates of PM in patients with BD. Forty clinically stable BD patients and 40 matched healthy controls formed the study sample. Socio-demographic characteristics, PM, psychosocial functioning, retrospective memory (RM), and IQ were measured in all participants, whereas clinical condition was measured in patients with standardized assessment instruments. Patients performed significantly more poorly on the time-based PM task than controls (10.6 ± 5.0 vs. 14.6 ± 3.0, p < .001). In correlation analyses, older age, lower education, more severe depressive and manic symptoms, poor psychosocial functioning, poor RM, and lower scores in IQ were significantly associated with poor performance in the time-based PM task, whereas poor RM and lower scores in IQ associated with poorer performance in the event-based PM task in patients. In multivariate analyses, severity of depression and older age significantly contributed to poor performance in the time-based PM task, whereas poor RM contributed to poor performance in the event-based PM task in patients. The time-based PM is impaired in BD patients. Depressive symptoms, age, and RM were determinants of certain aspects of impaired PM performance in BD patients.


Upper extremity deep vein thrombosis (Paget-Schroetter syndrome) after surfing: a case report.
This case report summarises the presentation of a 28-year-old female with signs and symptoms characteristic of thoracic outlet syndrome, but who was later found to have an effort-induced Upper Extremity Deep Vein Thrombosis (UEDVT), otherwise known as Paget-Schroetter syndrome. Effort-induced UEDVT is rare, but the similarity between the signs and symptoms of thoracic outlet syndrome and this type of thrombosis can result in patients with this condition presenting to musculoskeletal therapists. The key features of the case are described, followed by an overview of UEDVT and the importance of recognising this condition in musculoskeletal therapy practice. The role of therapists in referring for early medical diagnostics is key to ensuring management of the thrombosis is instigated early, therefore reducing the risk of life threatening consequences such as pulmonary embolism.


Multilocus sequence typing and evolutionary relationships among the causative agents of melioidosis and glanders, Burkholderia pseudomallei and Burkholderia mallei.
A collection of 147 isolates of Burkholderia pseudomallei, B. mallei, and B. thailandensis was characterized by multilocus sequence typing (MLST). The 128 isolates of B. pseudomallei, the causative agent of melioidosis, were obtained from diverse geographic locations, from humans and animals with disease, and from the environment and were resolved into 71 sequence types. The utility of the MLST scheme for epidemiological investigations was established by analyzing isolates from captive marine mammals and birds and from humans in Hong Kong with melioidosis. MLST gave a level of resolution similar to that given by pulsed-field gel electrophoresis and identified the same three clones causing disease in animals, each of which was also associated with disease in humans. The average divergence between the alleles of B. thailandensis and B. pseudomallei was 3.2%, and there was no sharing of alleles between these species. Trees constructed from differences in the allelic profiles of the isolates and from the concatenated sequences of the seven loci showed that the B. pseudomallei isolates formed a cluster of closely related lineages that were fully resolved from the cluster of B. thailandensis isolates, confirming their separate species status. However, isolates of B. mallei, the causative agent of glanders, recovered from three continents over a 30-year period had identical allelic profiles, and the B. mallei isolates clustered within the B. pseudomallei group of isolates. Alleles at six of the seven loci in B. mallei were also present within B. pseudomallei isolates, and B. mallei is a clone of B. pseudomallei that, on population genetics grounds, should not be given separate species status.


Snapin: a SNARE-associated protein implicated in synaptic transmission.
Synaptic vesicle docking and fusion are mediated by the assembly of a stable SNARE core complex of proteins, which include the synaptic vesicle membrane protein VAMP/synaptobrevin and the plasmalemmal proteins syntaxin and SNAP-25. We have now identified another SNAP-25-binding protein, called Snapin. Snapin was enriched in neurons and exclusively located on synaptic vesicle membranes. It associated with the SNARE complex through direct interaction with SNAP-25. Binding of recombinant Snapin-CT to SNAP-25 blocked the association of the SNARE complex with synaptotagmin. Introduction of Snapin-CT and peptides containing the SNAP-25 binding sequence into presynaptic superior cervical ganglion neurons in culture reversibly inhibited synaptic transmission. These results suggest that Snapin is an important component of the neurotransmitter release process through its modulation of the sequential interactions between the SNAREs and synaptotagmin.


Resampling Images to a Regular Grid From a Non-Regular Subset of Pixel Positions Using Frequency Selective Reconstruction.
Even though image signals are typically defined on a regular 2D grid, there also exist many scenarios where this is not the case and the amplitude of the image signal only is available for a non-regular subset of pixel positions. In such a case, a resampling of the image to a regular grid has to be carried out. This is necessary since almost all algorithms and technologies for processing, transmitting or displaying image signals rely on the samples being available on a regular grid. Thus, it is of great importance to reconstruct the image on this regular grid, so that the reconstruction comes closest to the case that the signal has been originally acquired on the regular grid. In this paper, Frequency Selective Reconstruction is introduced for solving this challenging task. This algorithm reconstructs image signals by exploiting the property that small areas of images can be represented sparsely in the Fourier domain. By further considering the basic properties of the optical transfer function of imaging systems, a sparse model of the signal is iteratively generated. In doing so, the proposed algorithm is able to achieve a very high reconstruction quality, in terms of peak signal-to-noise ratio (PSNR) and structural similarity measure as well as in terms of visual quality. The simulation results show that the proposed algorithm is able to outperform state-of-the-art reconstruction algorithms and gains of more than 1 dB PSNR are possible.


Structures of segments of α-synuclein fused to maltose-binding protein suggest intermediate states during amyloid formation.
Aggregates of the protein α-synuclein are the main component of Lewy bodies, the hallmark of Parkinson's disease. α-Synuclein aggregates are also found in many human neurodegenerative diseases known as synucleinopathies. In vivo, α-synuclein associates with membranes and adopts α-helical conformations. The details of how α-synuclein converts from the functional native state to amyloid aggregates remain unknown. In this study, we use maltose-binding protein (MBP) as a carrier to crystallize segments of α-synuclein. From crystal structures of fusions between MBP and four segments of α-synuclein, we have been able to trace a virtual model of the first 72 residues of α-synuclein. Instead of a mostly α-helical conformation observed in the lipid environment, our crystal structures show α-helices only at residues 1-13 and 20-34. The remaining segments are extended loops or coils. All of the predicted fiber-forming segments based on the 3D profile method are in extended conformations. We further show that the MBP fusion proteins with fiber-forming segments from α-synuclein can also form fiber-like nano-crystals or amyloid-like fibrils. Our structures suggest intermediate states during amyloid formation of α-synuclein.


Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin.
The crystal structure of a complex between a bivalent peptidyl pyridinium methyl ketone inhibitor and human alpha-thrombin has been solved and refined at 2.0 A to an R factor of 0.18. The inhibitor, (D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp- Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which forms a reversible covalent complex with thrombin, is highly potent with a Ki = 4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant hirudin. The N-terminal, active-site-directed portion of the inhibitor is linked to the fibrinogen recognition exosite binding portion by a tetraglycine segment. The strong electron-withdrawing effect provided by the permanent positive charge on the pyridinium nitrogen makes the arginyl carbonyl carbon more susceptible to nucleophilic attack. In the crystal, a covalent P596-thrombin complex is observed. The electron density surrounding the active site portion and the pyridinium of the inhibitor is very well defined, clearly showing the existence of a covalent bond between the Ser195 O gamma and the now tetrahedral carbon of the inhibitor. The decreased binding ability of thrombin inhibitors containing N-terminal acetylation is discussed as is the effect of replacing the P3 (D)phenylalanine with (D)cyclohexylalanine. The electron density surrounding the remainder of the inhibitor is generally well defined, the exceptions being the C-terminal (D)Glu, the highly flexible tetraglycine linker, and some of the solvent-directed side chains.(ABSTRACT TRUNCATED AT 250 WORDS)


Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 3: Treatment.
The treatment of gout is based on several principles. Symptom control and termination of the inflammatory process are important early goals, whereas the urate level should be lowered in the long term to prevent further gout attacks and complications. The non-pharmacological approach is based on individually informing the patient on dietary measures and changes of life style. Besides physical measures, such as cold applications on the affected joint, various medications are available for treatment of an acute gout attack. The choice of drug depends on the individual risk profile. If non-steroidal anti-inflammatory drugs (NSAID) and coxibs are chosen it should be taken into account that the use is restricted in patients with renal insufficiency. Moreover, these drugs may have gastrointestinal side effects and are associated with increased cardiovascular morbidity and mortality. Colchicine has gastrointestinal side effects at high dosages but can also be used for differential diagnostics if there is a quick response to treatment. Steroids are an effective alternative and can be given orally or parenterally in patients with dysphagia. Moreover, steroids can be used in cases of renal insufficiency. After symptoms of the acute attack have subsided, urate lowering therapy should be initiated to prevent further attacks. Low-dose urate lowering therapy can be started during an acute gout attack when acute therapy is initiated. Allopurinol is still the medication of choice but its use is restricted in patients with renal insufficiency. A rare but serious side effect is allopurinol hypersensitivity syndrome. Febuxostat can be an alternative in patients who do not tolerate allopurinol. In February 2016, lesinurad, an URAT-1 and OAT-4 inhibitor, was approved in combination with allopurinol or febuxostat. Data on the effectiveness and safety of synthetic uricases and biologicals are still sparse for elderly patients. These substances are reserved for severe cases of gout.


Functional characterization of a short neuropeptide F-related receptor in a lophotrochozoan, the mollusk Crassostrea gigas.
Members of the short neuropeptide F (sNPF) family of peptides and their cognate receptors play key roles in a variety of physiological processes in arthropods. In silico screening of GigasDatabase, a specific expressed sequence tag database from the Pacific oyster Crassostrea gigas, resulted in the identification of a receptor (Cg-sNPFR-like) phylogenetically closely related to sNPF receptors (sNPFRs) of insects. A reverse endocrinology approach was undertaken to identify the peptide ligand(s) of this orphan receptor. Though structurally distinct from insect sNPFs, three RFamide peptides derived from the same precursor, i.e. GSLFRFamide, SSLFRFamide and GALFRFamide, specifically activate the receptor in a dose-dependent manner, with respective EC50 values (half-maximal effective concentrations) of 1.1, 2.1 and 4.1 μmol l(-1). We found that both Cg-sNPFR-like receptor and LFRFamide encoding transcripts are expressed in the oyster central nervous system and in other tissues as well, albeit at lower levels. Mass spectrometry analysis confirmed the wide distribution of LFRFamide mature peptides in several central and peripheral tissues. The Cg-sNPFR-like receptor was more abundantly expressed in ganglia of females than of males, and upregulated in starved oysters. In the gonad area, highest receptor gene expression occurred at the start of gametogenesis, when storage activity is maximal. Our results suggest that signaling of LFRFamide peptides through the Cg-sNPFR-like receptor might play a role in the coordination of nutrition, energy storage and metabolism in C. gigas, possibly by promoting storage at the expense of reproduction.


Lack of evidence for the efficacy of memantine in mild Alzheimer disease.
We directly assessed the clinical trials' evidence for memantine's efficacy in mild Alzheimer disease (AD). Memantine is indicated in the United States and Europe for moderate to severe AD, which is diagnosed if a patient has a Mini-Mental State Examination (MMSE) score of less than 15 or less than 20, respectively. Yet memantine is very frequently prescribed for mild AD and mild cognitive impairment, and a manufacturer-sponsored meta-analysis claimed its efficacy in mild AD. Manufacturer-sponsored meta-analyses, registries, presentations, and publications were systematically searched for randomized placebo-controlled, parallel-group clinical trials of memantine in patients with mild to moderate AD. The trials' characteristics and outcomes were extracted by one reviewer and checked by another. Meta-analyses were performed as inverse variance-weighted averages of mean differences using fixed-effects models. Summary results for patients with mild AD were obtained by contrasting the summary results for patients with mild or moderate AD with the summary results for the subset of patients with moderate AD. Three trials were identified that included 431 patients with mild AD (ie, with MMSE scores of 20-23) and 697 patients with moderate AD (ie, with MMSE scores of 10-19). There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined: mean differences (95% confidence intervals [CIs]) on the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC-plus), the Alzheimer Disease Cooperative Study-activities of daily living (ADCS-ADL) scale, and the Neuropsychiatric Inventory (NPI) were -0.17 (95% CI, -1.60 to 1.26), -0.09 (95% CI, -0.30 to 0.12), 0.62 (95% CI, -1.64 to 2.71), and 0.09 (95% CI, -2.11 to 2.29), respectively. For patients with moderate AD, there were small differences on the ADAS-cog and the CIBIC-plus, -1.33 (95% CI, -2.28 to -0.38) and -0.16 (95% CI, -0.32 to 0.00), respectively, but no differences on the ADCS-ADL scale (-0.57 [95% CI, -1.75 to 0.60]) or the NPI (0.25 [95% CI, -1.48 to 1.99]). Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD. Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.


Contextual control of delay discounting by pathological gamblers.
The present study demonstrated the relative impact of gambling and nongambling contexts on the degree of delay discounting by pathological gamblers. We used a delay-discounting task with 20 pathological gamblers in and out of the natural context in which they regularly gambled. For 16 of the 20 participants, it appeared that the difference of context altered the subjective value of delayed rewards, thereby producing relative changes in delay-discounting rates that were generally consistent with a hyperbolic model of intertemporal choice. The current data suggest that empirically derived k values from delay-discounting tasks are context sensitive and are not constant across various settings for the individual. Implications for future transitional research on addictive disorders generally, and gambling specifically, are discussed.


New insights into pectin methylesterase structure and function.
In bacteria, fungi and plants, pectin methylesterases are ubiquitous enzymes that modify the degree of methylesterification of pectins, which are major components of plant cell walls. Such changes in pectin structure are associated with changes in cellular adhesion, plasticity, pH and ionic contents of the cell wall and influence plant development and stress responses. In plants, pectin methylesterases belong to large multigene families, are regulated in a highly specific manner, and are involved in vegetative and reproductive processes, including wood and pollen formation, in addition to plant-pathogen interactions. Although, overall, protein structures are highly conserved between isoforms, recent data indicate that structural variations might be associated with the targeting and functions of specific pectin methylesterases.


Dispersion compensation in Fourier domain optical coherence tomography using the fractional Fourier transform.
We address numerical dispersion compensation based on the use of the fractional Fourier transform (FrFT). The FrFT provides a new fundamental perspective on the nature and role of group-velocity dispersion in Fourier domain OCT. The dispersion induced by a 26 mm long water cell was compensated for a spectral bandwidth of 110 nm, allowing the theoretical axial resolution in air of 3.6 μm to be recovered from the dispersion degraded point spread function. Additionally, we present a new approach for depth dependent dispersion compensation based on numerical simulations. Finally, we show how the optimized fractional Fourier transform order parameter can be used to extract the group velocity dispersion coefficient of a material.


Nationwide study of the susceptibility of the Bacteroides fragilis group in the United States.
A nationwide susceptibility survey of the Bacteroides fragilis group was continued at New England Medical Center in 1983. A total of 555 strains were obtained from eight centers in the United States. In addition to the nine antimicrobial agents studied in the two previous years, three other agents were added to the evaluation: cefamandole, cefuroxime, and cefonicid. The results for the strains tested with the original nine drugs in 1983 were compared with those for 1,292 isolates tested in 1981 and 1982. The most active beta-lactam drug was piperacillin, which had an 8% resistance rate. Cefoxitin resistance increased from 10% in 1982 to 16% in 1983. High rates of resistance to cefotaxime, cefoperazone, cefamandole, cefonicid, and cefuroxime were encountered. No metronidazole- or chloramphenicol-resistant isolates were found during the 3 years of the study. Susceptibility patterns varied at the eight hospitals: the outbreak of cefoxitin resistance reported in 1982 at New England Medical Center remitted, while a high clindamycin resistance rate was documented at one hospital in 1983. These data indicate the need for determining the susceptibility patterns for the B. fragilis group of organisms at each hospital.


An examination of amphibian sensitivity to environmental contaminants: are amphibians poor canaries?
Nearly two decades ago, the global biodiversity crisis was catapulted to the front pages of newspapers with the recognition of worldwide amphibian declines. Amphibians earned their appellation, 'canaries in a coal mine', because of apparent high sensitivity to human-mediated environmental change. The most frequently cited causes for high susceptibility include permeable skin, a dual aquatic-terrestrial life cycle and a relatively rudimentary immune system. While some researchers have questioned the basis for the canary assertion, there has been no systematic evaluation of amphibian sensitivity to environmental challenges relative to other taxa. Here, we apply a database representing thousands of toxicity tests to compare the responses of amphibians relative to that of other taxonomic groups. The use of standardized methods combined with large numbers of identical challenges enables a particularly powerful test of relative effect size. Overall, we found that amphibians only exhibit moderate relative responses to water-borne toxins. Our findings imply that, as far as chemical contaminants are concerned, amphibians are not particularly sensitive and might more aptly be described as 'miners in a coal mine'. To the extent that amphibian declines have been mediated by chemical contaminants, our findings suggest that population losses and extinctions may have already occurred in a variety of taxa much more sensitive than amphibians.


Comparison of FTIR transmission and transfection substrates for canine liver cancer detection.
FTIR spectroscopy is a widely used technique that provides insights into disease processes at the molecular level. Due to its numerous advantages it is becoming an increasingly powerful tool for the study of biological materials and has the potential to become an excellent diagnostic method, especially considering the low cost of transflection substrates. However, questions about the usefulness of the transflection measurement mode due to the complicated nature of physical processes occurring during the measurement and in particular the Electric Field Standing Wave (EFSW) effect have been raised. In this paper we present a comparison of the two most common FT-IR measurement modes: transmission and transfection using healthy and pathologically altered tissue (histiocytic sarcoma). We found that the major differences between normal and cancerous tissue were associated with changes DNA and carbohydrate content. In particular we identified a band at 964 cm(-1) assigned to a nucleic acid phosphodiester backbone mode, which appeared more pronounced in cancerous tissue irrespective of the substrate. We applied Principal Component Analysis, Unsupervised Hierarchical Cluster Analysis and k-means clustering to transmission and transflection substrates and found that both measurement modes were equally capable of discrimination normal form cancerous tissue. Moreover, the differences between spectra from cancerous and normal tissue were significantly more important than the ones arising from the measurement modes.


Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency--the most common known enzymopathy--is associated with neonatal jaundice and hemolytic anemia usually after exposure to certain infections, foods, or medications. Although G6PD-deficient alleles appear to confer a protective effect against malaria, the link with clinical protection from Plasmodium infection remains unclear. We investigated the effect of a common G6PD deficiency variant in Southeast Asia--the G6PD-Mahidol(487A) variant--on human survival related to vivax and falciparum malaria. Our results show that strong and recent positive selection has targeted the Mahidol variant over the past 1500 years. We found that the G6PD-Mahidol(487A) variant reduces vivax, but not falciparum, parasite density in humans, which indicates that Plasmodium vivax has been a driving force behind the strong selective advantage conferred by this mutation.


Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway.
Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.


Settling taxonomic and nomenclatural problems in brine shrimps, Artemia (Crustacea: Branchiopoda: Anostraca), by integrating mitogenomics, marker discordances and nomenclature rules.
High morphological plasticity in populations of brine shrimp subjected to different environmental conditions, mainly salinity, hindered for centuries the identification of the taxonomic entities encompassed within Artemia. In addition, the mismatch between molecular and morphological evolution rates complicates the characterization of evolutionary lineages, generating taxonomic problems. Here, we propose a phylogenetic hypothesis for Artemia based on two new complete mitogenomes, and determine levels of congruence in the definition of evolutionary units using nuclear and mtDNA data. We used a fossil of Artemia to calibrate the molecular clock and discuss divergence times within the genus. The hypothesis proposed herein suggests a more recent time frame for lineage splitting than previously considered. Phylogeographic analyses were performed using GenBank available mitochondrial and nuclear markers. Evidence of gen e flow, identified through discordances between nuclear and mtDNA markers, was used to reconsider the specific status of some taxa. As a result, we consider Artemia to be represented by five evolutionary units: Southern Cone, Mediterranean-South African, New World, Western Asian, and Eastern Asian Lineages. After an exhaustive bibliographical revision, unavailable names for nomenclatural purposes were discarded. The remaining available names have been assigned to their respective evolutionary lineage. The proper names for the evolutionary units in which brine shrimps are structured remain as follows: Artemia persimilis Piccinelli & Prosdocimi, 1968 for the Southern Cone Lineage, Artemia salina (Linnaeus, 1758) for the Mediterranean-SouthAfrican Lineage, Artemia urmiana Günther, 1899 for the Western Asian Lineage, and Artemia sinica Cai, 1989 for the Eastern Asian Lineage. The name Artemia monica Verrill, 1869 has nomenclatural priority over A. franciscana Kellogg, 1906 for naming the New World Lineage. New synonymies are proposed for A. salina (= C. dybowskii Grochowski, 1896 n. syn., and A. tunisiana Bowen & Sterling, 1978 n. syn.), A. monica (= A. franciscana Kellogg, 1906 n. syn., and A. salina var. pacifica Sars, 1904 n. syn.); A. urmiana (= B. milhausenii Fischer de Waldheim, 1834 n. syn., A. koeppeniana Fischer, 1851 n. syn., A. proxima King, 1855 n. syn., A. s. var. biloba Entz, 1886 n. syn., A. s. var. furcata Entz, 1886 n. syn., A. asiatica Walter, 1887 n. syn., A. parthenogenetica Bowen & Sterling, 1978 n. syn., A. ebinurica Qian & Wang, 1992 n. syn., A. murae Naganawa, 2017 n. syn., and A. frameshifta Naganawa & Mura, 2017 n. syn.). Internal deep nuclear structuring within the A. monica and A. salina clades, might suggest the existence of additional evolutionary units within these taxa.


Incidence of alcohol-related deaths in the veterinary profession in England and Wales, 1993-2005.
It has recently been shown that the proportional mortality ratio for suicide by veterinarians is one of the highest of all occupational groups. The reasons for this alarming statistic are unclear although it has been postulated that alcohol or drug misuse may be significant risk factors which contribute towards the high incidence of suicide within the profession. However, there have been few studies on alcohol misuse by veterinarians and so the aim of this study was to investigate the incidence of alcohol-related deaths in the veterinary profession in England and Wales between 1993 and 2005. The proportional mortality ratio for alcohol-related deaths for veterinarians was not significantly higher than the general population during this time period. Future studies should focus on establishing the incidence of sub-lethal alcohol misuse within the veterinary profession.


The contribution of intracellular Ca2+ release to contraction in human bladder smooth muscle.
1. The importance of Ca2+ release from the sarcoplasmic reticulum (SR) in excitation contraction (EC) coupling in human detrusor muscle remains controversial. In this paper the contribution of Ca2+ release to agonist induced contraction is assessed. 2. Dose response curves to carbachol (0.01 - 10 microM) were constructed before and after exposure to 200 nM Thapsigargin (Tg). Tg pre-treatment reduced the force of contraction at all agonist concentrations however, the reduction was dose dependent. At 0.1 microM the contractions were reduced to 14.5 +/- 7% (mean +/- s.e.mean) of controls (n = 8) while at 10 microM the contractions were only reduced to 92 +/- 3% of controls (n = 10). 3. The role of external Ca2+ was examined by measuring the magnitude of contraction to low and high doses of agonist in the presence and absence of external Ca2+. With (0.1-0.3 microM) carbachol the contractions in nominally Ca2+ free media were 4+/-4% of controls (n = 7) whilst with (1 - 10 microM) carbachol the contractions were 36 +/- 8% of controls (n=7) suggesting that at low agonist concentrations the release of Ca2+ has a requirement for external Ca2+. 4. Pre-treatment of muscle strips with the Ca2+ channel blocking agent diltiazem reduced the contractile responses to carbachol. Contractions induced by 0.1 microM were reduced to 29+/-11% (P<0.05) of controls while those activated by 10 microM were reduced to 86+/-6% (P= 0.1) of controls (n = 4) suggesting the Ca2+ influx needed to activate internal store release at low agonist stimulation is through L-type Ca2+ channels. 5. These observations confirm the importance of thapsigargin sensitive intracellular Ca2+ store release in the activation of contraction of detrusor smooth muscle and suggest the overall contribution of this store depends upon the magnitude of the agonist stimulation.


Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease.
The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.


Wear of unsound pebbles in river headwaters.
Pebbles that are initially weathered, inhomogeneous, angular, or fractured ("unsound") become sound with transport. The Sternberg law describes well the wear of sound pebbles found in large rivers, but describes poorly that of unsound pebbles in river headwaters. For unsound pebbles the Sternberg coefficient (which is assumed to be a constant) decreases appreciably downstream. An alternative to the Sternberg law is derived in which the coefficient is proportional to the reciprocal of the downstream distance traveled. The laws are compared by using data from the Clutha basin in New Zealand.


Clinical, Refractive and Histological Reversibility of Corneal Additive Surgery in Deep Stroma in an Animal Model.
The aim was to evaluate the reversibility of the clinical and histological changes induced in the corneas of an animal model after removing an intracorneal ring segment (ICRS). Surgery for this study was performed in 38 eyes of an experimental animal model (Gallus domesticus) for ICRS surgery (Ferrara technique). The animals without complications were randomized to two groups; in all of them, 1 segment was implanted in each eye and later removed at different times (1 and 3 months after implantation). In each group, after explantation, corneas were processed at different times for histological analysis with hematoxylin and eosin (H&E) stain and electronic microscopy. The refractive state of the eyes was also measured. In corneas without complications (88.23%), explantation was performed correctly. During the first few days, around the area where the ICRS was implanted we observed deposits of cells and a moderate degree of corneal opacity (haze). These signs decreased progressively without disappearing completely. Histologically, at 7 days, we observed hyperplasia and abnormal arrangement of collagen fibers. Later, these findings also decreased in both groups, albeit at a faster rate in group 1. Minimal changes were observed in electron microscopy up to the end of the study in both groups. Preoperative refractive state was achieved at 1 month after explantation in both groups. ICRS can safely be explanted from the cornea. Refractive reversibility was achieved at 1 month after explantation. However, the clinical and histological findings after ICRS explantation depend on the time from implantation to explantation.


Relationship between multiple paternity and reproductive parameters for Podocnemis sextuberculata (Testudines: Podocnemididae) in the Trombetas River, Brazil.
Genetic studies of multiple paternity are a valuable tool to gain information on the reproductive biology of turtles. We analyzed paternity type in Podocnemis sextuberculata and related number of fathers per nest to nesting period (beginning, middle, or end of nesting season); clutch size (number of eggs); female size; and hatchling success. Females were captured and maximum linear carapace lengths measured during the 60 days that encompass the nesting season at Rio Trombetas Biological Reserve (Pará, Brazil). Nests were marked and blood samples collected from hatchlings. Six heterologous loci were used: five from Podocnemis unifilis and one from Podocnemis expansa. Hatchlings were analyzed from 23 nests, and the rate of multiple paternity was 100%. The mean number of fathers per nest was six (± 0.9), and no significant difference between number of fathers in a nest and nesting period. Similarly there was no significant relationship between number of fathers in a nest and female size or hatchling success rate. Number of fathers was, however, positively correlated with clutch size (Spearman correlation rho = 0.47; P > 0.05). To our knowledge, this is the first study to test the relationship between multiple paternity and ecological aspects of the reproductive ecology of turtles in the genus Podocnemis.


Palmprint and face multi-modal biometric recognition based on SDA-GSVD and its kernelization.
When extracting discriminative features from multimodal data, current methods rarely concern themselves with the data distribution. In this paper, we present an assumption that is consistent with the viewpoint of discrimination, that is, a person's overall biometric data should be regarded as one class in the input space, and his different biometric data can form different Gaussians distributions, i.e., different subclasses. Hence, we propose a novel multimodal feature extraction and recognition approach based on subclass discriminant analysis (SDA). Specifically, one person's different bio-data are treated as different subclasses of one class, and a transformed space is calculated, where the difference among subclasses belonging to different persons is maximized, and the difference within each subclass is minimized. Then, the obtained multimodal features are used for classification. Two solutions are presented to overcome the singularity problem encountered in calculation, which are using PCA preprocessing, and employing the generalized singular value decomposition (GSVD) technique, respectively. Further, we provide nonlinear extensions of SDA based multimodal feature extraction, that is, the feature fusion based on KPCA-SDA and KSDA-GSVD. In KPCA-SDA, we first apply Kernel PCA on each single modal before performing SDA. While in KSDA-GSVD, we directly perform Kernel SDA to fuse multimodal data by applying GSVD to avoid the singular problem. For simplicity two typical types of biometric data are considered in this paper, i.e., palmprint data and face data. Compared with several representative multimodal biometrics recognition methods, experimental results show that our approaches outperform related multimodal recognition methods and KSDA-GSVD achieves the best recognition performance.


Validation of Three Body Composition Techniques with a Comparison of Ultrasound Abdominal Fat Depths against an Octopolar Bioelectrical Impedance Device.
The aims of this study were to cross-validate three clinical-grade measures of body composition, using an octopolar Bioelectrical Impedance (BIA), an ultrasound analyzer (US) and Air-Displacement Plethysmography (ADP) and second to compare the US scans of total abdominal, subcutaneous and visceral fat depths (mm) against the trunk percent fat (%BF) from the octopolar BIA. Twenty-six college-aged (22.9 ± 1.35 years) men (n = 18) and women (n = 8) volunteered to participate in this study. Body composition was assessed using BIA (total and by segments), ADP and US. In addition, total abdominal, subcutaneous and visceral fat layers were measured using the US. All measurements were done in accordance with manufacturers' guidelines. The %BF comparing the three clinical grade machines were all significantly correlated and no significant differences were found using a 1-way ANOVA. All three fat depths were significantly correlated to the trunk fat % via BIA, while significant differences were found for the 1-way ANOVA. A Tukey post-hoc test showed significant differences between the BIA trunk %BF and both subcutaneous and visceral US fat depths. Having valid ways to measure body composition and visceral fat that is accessible in terms of being transportable, cost effective, and simple to use, should become a part of preventive medicine.


Quality of life outcome measures following partial glossectomy: assessment using the UW-QOL scale.
The consequences of a diagnosis of head and neck cancer and the impact of treatment have a clear and direct influence on well-being and associated quality of life (QOL) in these patients. To determine the QOL in head and neck cancer patients following a partial glossectomy operation. Cross-sectional cohort study; Head and Neck Oncology Unit, tertiary referral center. 38 patients with partial glossectomy were assessed with the University of Washington head and neck quality of life (UW-QOL) scale, version 4. Statistical analysis was performed using the Statistical Package for Social Sciences 10.0 (SPSS Inc, Chicago version III). Information from the scale was correlated using the Mann Whitney test. A P value less than/equal to 0.05 was considered as significant. The mean (sd) composite score of the QOL in our series was 73.6 (16.1). The majority (71.8%) quoted their QOL as good or very good. Swallowing (n = 16, 47.1%), speech (n = 15, 44.1%) and saliva (n = 15, 44.1%) were most commonly cited issues over the last 7 days. On the other hand, the groups with reconstruction, neck dissection, complications and radiotherapy demonstrated a significant reduction of quality of life scores (Mann Whitney test, P < 0.005). The composite score and overall QOL as assessed using the UW-QOL scale (version 4) were modestly high in our series of partial glossectomy patients. Swallowing, speech, and saliva are regarded as the most important issues. Stage of the disease, neck dissection, reconstruction, complications, radiotherapy and time since operation were seen to significantly affect domain scores.


Two distinct pathways for developmental coordination disorder: persistence and resolution.
This article describes the perceptual motor, educational and social outcome of early motor delay in a group of 17-18 year old Finnish adolescents who were originally evaluated at age 5. The study group consisted of 65 adolescents: 22 with significant motor problems (or developmental coordination disorder, DCD), 23 with minor motor problems (intermediate group) and 20 controls. The goal of this study was to reassess the results obtained when they were age 15 and to determine whether the variables used earlier could still discriminate the adolescents at age 17. The results showed that at age 17 all perceptual motor tasks differentiated the three groups. The DCD group performed less well than the control group on all tasks, with the intermediate group situated between these two. Discriminant function analyses showed that more classification errors occurred between the control and intermediate groups at age 17 than at age 15, suggesting that the distinction between these groups becomes more difficult with age. In the educational domain, similar to the findings at age 15, the adolescents with DCD had the lowest WAIS scores and shortest school careers of the three groups. In the social domain, as found two years earlier, the DCD group had the lowest perceptions of athletic and scholastic competence while the intermediate and control groups did not differ. In addition, the interview results indicated that the three groups were in different stages of identity development. In sum, the outcome at age 17 was a replication of the results obtained at age 15 and suggests two developmental paths for those with early perceptual motor problems: 'persistence' and 'catching up'.


Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1.
Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the development of Kaposi's sarcoma (KS), a highly inflammatory angiogenic tumor of endothelial cells commonly found in untreated AIDS patients. Angiopoietin 2 (Ang-2) modulates the vasculature during inflammation and angiogenesis, but the mechanism by which KSHV regulates Ang-2 expression has not been investigated. Here, we show that KSHV infection of primary human umbilical vein endothelial cells induced the expression and release of Ang-2, which in turn was required for KSHV-induced paracrine-dependent angiogenesis in vivo. Ang-2 was strongly expressed in small vessels and spindle tumor cells in KS tumors. Mechanistically, KSHV activated the Ang-2 promoter via AP-1 and Ets1 transcriptional factors, which were mediated by ERK, JNK, and p38 mitogen-activated protein kinase (MAPK) pathways. Our findings demonstrate the importance of Ang-2 in KS angiogenesis and define a novel role for AP-1 and MAPK pathways in regulating angiogenesis. This study also illustrates a distinct mechanism by which a tumor virus modulates vasculature to promote tumorigenesis and exemplifies the convergence of oncogenesis and angiogenesis pathways in tumor development.


Evolution of DNA Methylation in Papio Baboons.
Changes in gene regulation have long been thought to play an important role in primate evolution. However, although a number of studies have compared genome-wide gene expression patterns across primate species, fewer have investigated the gene regulatory mechanisms that underlie such patterns, or the relative contribution of drift versus selection. Here, we profiled genome-scale DNA methylation levels in blood samples from five of the six extant species of the baboon genus Papio (4-14 individuals per species). This radiation presents the opportunity to investigate DNA methylation divergence at both shallow and deeper timescales (0.380-1.4 My). In contrast to studies in human populations, but similar to studies in great apes, DNA methylation profiles clearly mirror genetic and geographic structure. Divergence in DNA methylation proceeds fastest in unannotated regions of the genome and slowest in regions of the genome that are likely more constrained at the sequence level (e.g., gene exons). Both heuristic approaches and Ornstein-Uhlenbeck models suggest that DNA methylation levels at a small set of sites have been affected by positive selection, and that this class is enriched in functionally relevant contexts, including promoters, enhancers, and CpG islands. Our results thus indicate that the rate and distribution of DNA methylation changes across the genome largely mirror genetic structure. However, at some CpG sites, DNA methylation levels themselves may have been a target of positive selection, pointing to loci that could be important in connecting sequence variation to fitness-related traits.


Smoking during pregnancy: how reliable are maternal self reports in New Zealand?
To determine the reliability of self reports of smoking during pregnancy. Residual sera from early and late antenatal blood samples were tested for cotinine for all pregnancies over a six month period. Over an overlapping 12 month period, a postal questionnaire on smoking was also sent to all new mothers (n = 4857) when their baby was 4-8 weeks old. Smoking status from obstetric booking notes was also obtained. The cotinine-validated smoking prevalence was 31.3% for the first trimester and 27.7% for the third trimester. Questionnaire self reported prevalences were 19.2% and 15.7% for the first and third trimesters respectively, and 18.9% for obstetric booking. Of cotinine-validated smokers, 22% denied smoking-self deceivers. Of mothers who replied to the questionnaire, a half appeared to systematically under report the amount they smoked. Nearly a quarter of smoking pregnant women did not report smoking. Moreover, of those who did, the amount smoked was often under reported. This tendency to under report may rise as pressures to stop smoking increase. Accurate measures of smoking prevalence in pregnant women will require objective testing.


To give or not to give antibiotics is not the only question.
In a 1945 Nobel Lecture, Sir Alexander Fleming warned against the overuse of antibiotics, particularly in response to public pressure. In the subsequent decades, evidence has shown that bacteria can become resistant to almost any available molecule. One key question is how the emergence and dissemination of resistant bacteria or resistance genes can be delayed. Although some clinicians remain sceptical, in this Personal View, we argue that the prescription of fewer antibiotics and shorter treatment duration is just as effective as longer regimens that remain the current guideline. Additionally, we discuss the fact that shorter antibiotic treatments exert less selective pressure on microorganisms, preventing the development of resistance. By contrast, longer treatments associated with a strong selective pressure favour the emergence of resistant clones within commensal organisms. We also emphasise that more studies are needed to identify the optimal duration of antibiotic therapy for common infections, which is important for making changes to the current guidelines, and to identify clinical biomarkers to guide antibiotic treatment in both hospital and ambulatory settings.


Evaluating patient-reported outcome measurement comparability between paper and alternate versions, using the lung function questionnaire as an example.
The goal of this study was to provide recommended steps to assess measurement comparability using a crossover study design and to demonstrate these steps using a short patient-reported outcome (PRO) instrument as an example. The example PRO instrument was administered via paper, Web, interactive voice response system, and interview; a randomized crossover design was used to gather data across the multiple administration types. Participants completed the PRO instrument, demographic and health questions, and a short preference questionnaire. Evaluation included comparisons of the item-level responses and agreement, comparison of mean scale scores, score classifications, and questions designed to collect usability and administration preference. Here the authors provide a four-step evaluation guide to evaluate measurement comparability and illustrate these steps using a case-finding tool. In the example, item-level kappa statistics between the paper and the alternate versions ranged from good to excellent, intraclass correlation coefficient for mean scores were above 0.70, and the rate of disagreement ranged from 2% to 14%. In addition, although participants had an administration preference, they reported few difficulties with the versions they were assigned. The steps described in this article provide a guide for evaluating whether to combine scores across administration versions to simplify analyses and interpretation under a crossover design. The guide recommends the investigation of item-level responses, summary scores, and participant usability/preference when comparing versions, with each step providing unique information to support comprehensive evaluation and informed decisions regarding whether to combine data.


A modified simplified reference tissue model for the quantification of dopamine D2/3 receptors with [18F]fallypride images.
Defluorination of [18F]fallypride and accumulation of 18F in skull and glands leads to the contamination of brain structures with spillover activity due to partial volume effects, leading to considerable errors in binding potential estimations. Here we propose a modification of the simplified reference tissue model (SRTM) to take into account the contribution of skull activity to the radioactivity kinetic pattern in cerebellum and target regions. It consists of the introduction of an additional parameter for each volume of interest (sT) and one for the cerebellum (sR), corresponding to the fraction of skull activity contaminating these structures. Using five rat positron emission tomography experiments, we applied the modified SRTM (SRTMc), which resulted in excellent fits. As a relative means of comparison of results, we applied factor analysis (FA) to decompose dynamic data into images corresponding to brain and skull activity. With the skull factor images, we estimated the "true" sT and sR values, ultimately permitting us to fix the sR value. Parameters obtained with the SRTMc were closely correlated with values obtained from FA-corrected data. In conclusion, we propose an efficient method for reliable quantification of dopamine D2/3 receptors with single-injection [18F]fallypride scans that is potentially applicable to human studies where 18F skull accumulation compromises binding parameter estimation.


Integrating information from different senses in the auditory cortex.
Multisensory integration was once thought to be the domain of brain areas high in the cortical hierarchy, with early sensory cortical fields devoted to unisensory processing of inputs from their given set of sensory receptors. More recently, a wealth of evidence documenting visual and somatosensory responses in auditory cortex, even as early as the primary fields, has changed this view of cortical processing. These multisensory inputs may serve to enhance responses to sounds that are accompanied by other sensory cues, effectively making them easier to hear, but may also act more selectively to shape the receptive field properties of auditory cortical neurons to the location or identity of these events. We discuss the new, converging evidence that multiplexing of neural signals may play a key role in informatively encoding and integrating signals in auditory cortex across multiple sensory modalities. We highlight some of the many open research questions that exist about the neural mechanisms that give rise to multisensory integration in auditory cortex, which should be addressed in future experimental and theoretical studies.


Use of a surface magnet in the extraction of another magnet aspirated into the bronchus of a 7-year-old girl.
A 7-year-old girl presented to the emergency room (ER) with alleged history of aspiration of a toy magnet. The challenge was to safely extract the foreign body. A bronchoscopic approach with forceps, or Dormia basket, or Fogarty catheter, was considered, but these approaches had disadvantages, such as slipping or impaction of the object, and oxygen desaturation. Applying principles of removal of intraocular metallic objects in ophthalmologic surgery using magnetism, the object was removed with the help of another larger surface magnet. The location of the foreign body was confirmed by bronchoscopy. A Fogarty catheter was introduced distal to the object, under bronchoscopic guidance. A strong surface magnet was then placed on the surface of the chest and under C-arm guidance, the object was moved from the bronchus to the trachea. Once at the vocal cords, the Fogarty catheter was inflated to prevent it from slipping back and the magnet was extracted using forceps.


Electromechanical modulation of catabolic and anabolic pathways in chronically inactive, but neurally intact, muscles.
The extent and mechanisms by which neural input regulates skeletal muscle mass remain largely unknown. Adult spinal cord isolated (SI) rats were implanted unilaterally with a microstimulator, whereas the contralateral limb served as SI control (SI-C). A 100-HZ, 1-s stimulus was delivered every 30 s for 5 min, followed by a 5-min rest. This was repeated six times consecutively (SI-Stim1) or with a 9-h interval after the third bout (SI-Stim2) for 30 days (1 min of daily activity). SI-Stim1 and SI-Stim2 paradigms attenuated plantaris atrophy by 20% and 38%, respectively, whereas only SI-Stim2 blunted soleus atrophy (24%) relative to SI-C. Muscle mass changes occurred independent of the IGF-1/PI3K/Akt pathway. No relationships between SI or electromechanical stimulation and expression of several atrophy markers were observed. These data suggest that regulatory mechanisms for maintaining muscle mass previously shown in acute states of atrophy differ substantially from those observed in chronic states.


Genetic variation supports a causal role for valproate in prevention of ischemic stroke.
Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.


A new picture of cell wall protein dynamics in elongating cells of Arabidopsis thaliana: confirmed actors and newcomers.
Cell elongation in plants requires addition and re-arrangements of cell wall components. Even if some protein families have been shown to play roles in these events, a global picture of proteins present in cell walls of elongating cells is still missing. A proteomic study was performed on etiolated hypocotyls of Arabidopsis used as model of cells undergoing elongation followed by growth arrest within a short time. Two developmental stages (active growth and after growth arrest) were compared. A new strategy consisting of high performance cation exchange chromatography and mono-dimensional electrophoresis was established for separation of cell wall proteins. This work allowed identification of 137 predicted secreted proteins, among which 51 had not been identified previously. Apart from expected proteins known to be involved in cell wall extension such as xyloglucan endotransglucosylase-hydrolases, expansins, polygalacturonases, pectin methylesterases and peroxidases, new proteins were identified such as proteases, proteins related to lipid metabolism and proteins of unknown function. This work highlights the CWP dynamics that takes place between the two developmental stages. The presence of proteins known to be related to cell wall extension after growth arrest showed that these proteins may play other roles in cell walls. Finally, putative regulatory mechanisms of protein biological activity are discussed from this global view of cell wall proteins.


Microbiologic effect of two topical anti-infective treatments on ligature-induced peri-implantitis: A pilot study in dogs.
The aim of this split-mouth design pilot study in dogs was to assess microbiologic effects of two topical anti-infective treatment protocols on dental implants subjected to ligature-induced peri-implantitis, without use of systemic antibiotics. Eight adult Beagle dogs each received four dental implants in contralateral, edentulated, mandibular jaw quadrants. After 8 weeks, silk ligatures were installed, to be removed after another 8 weeks. After 6 additional weeks, induced peri-implantitis lesions were subjected to either antimicrobial photodynamic therapy (aPDT) or a topical tetracycline (TTC) hydrochloride (50 mg/mL) solution. Microbiologic samples were collected from the deepest proximal peri-implantitis site in each jaw quadrant before and after treatment. The samples were analyzed using DNA-DNA hybridization checkerboard technique. Peri-implantitis induction successfully produced lesions with microbiologic characteristics similar to those found in humans. Overall results showed effective bacterial count reductions for both protocols. aPDT demonstrated major reductions of the red complex, but no statistical differences between groups were observed when adjusted for multiple comparisons. aPDT and TTC successfully decontaminated infected implant surfaces. Implant decontamination with aPDT appears to be a viable alternative to TTC in the management of peri-implantitis infection.


A predictive framework to understand forest responses to global change.
Forests are one of Earth's critical biomes. They have been shown to respond strongly to many of the drivers that are predicted to change natural systems over this century, including climate, introduced species, and other anthropogenic influences. Predicting how different tree species might respond to this complex of forces remains a daunting challenge for forest ecologists. Yet shifts in species composition and abundance can radically influence hydrological and atmospheric systems, plant and animal ranges, and human populations, making this challenge an important one to address. Forest ecologists have gathered a great deal of data over the past decades and are now using novel quantitative and computational tools to translate those data into predictions about the fate of forests. Here, after a brief review of the threats to forests over the next century, one of the more promising approaches to making ecological predictions is described: using hierarchical Bayesian methods to model forest demography and simulating future forests from those models. This approach captures complex processes, such as seed dispersal and mortality, and incorporates uncertainty due to unknown mechanisms, data problems, and parameter uncertainty. After describing the approach, an example by simulating drought for a southeastern forest is offered. Finally, there is a discussion of how this approach and others need to be cast within a framework of prediction that strives to answer the important questions posed to environmental scientists, but does so with a respect for the challenges inherent in predicting the future of a complex biological system.


Regional cerebral blood flow and cognitive function in patients with chronic liver disease.
Subtle impairments of cognitive function may be an important cause of occupational and psychosocial morbidity in patients with chronic liver disease. Correlation of structural brain abnormalities with cognitive deficits has yielded inconsistent results. 10 patients with cirrhotic liver disease were compared with 10 age, education, and intelligence matched control subjects. Neuropsychological assessment revealed significant overall cognitive impairments in cirrhotic patients compared with controls (p = 0.02). Regional cerebral blood flow was measured by single photon emission computed tomography (SPET or SPECT) and showed increased uptake of radiotracer in the right and left posterior parts of the basal ganglia and right occipital lobe, together with reduced uptake in the right anterior cingulate region. The degree of cognitive impairment was directly correlated with functional abnormalities in the basal ganglia and limbic cortex (p less than 0.05). Our results suggest that impaired cognitive status may be associated with abnormalities of regional brain function in patients with chronic liver disease. Since these deficits are clinically inapparent, our findings have important implications for identification and management of patients with chronic liver disease.


Serum lactate dehydrogenase in childhood neuroblastoma. A Pediatric Oncology Group recursive partitioning study.
On the basis of an extensive recursive partitioning analysis of 668 patients with newly diagnosed neuroblastoma registered on Pediatric Oncology Group (POG) studies between October 1981 and May 1987, four major subsets of patients were created. Important prognostic factors included the patient's stage of disease, age, and level of serum lactate dehydrogenase (LDH). After adjusting for these factors, no other clinical prognostic factors were significant. The implications for protocol design are that (a) fine tuning of current therapy should be sought for the two favorable disease patient subsets, while (b) novel aggressive therapies are needed for the two unfavorable disease patient subsets where the overwhelming majority are dying. This article may serve as a model for others investigating prognostic factors. The data were divided into two subsets: one was used for an exploratory analysis; the other was used to confirm the exploratory findings. Despite spite the large number of statistical tests performed, the likelihood that the findings can be attributed to chance can be dismissed as virtually zero.


Rapidly growing mycobacterial infections after pedicures.
Rapidly growing mycobacteria (RGM) can cause a variety of cutaneous and systemic diseases. The causative organisms are typically Mycobacterium fortuitum or Mycobacterium chelonae (also known as Mycobacterium abscessus). Primary cutaneous lesions may develop after a variable latent period, from weeks to several months, and usually result from direct inoculation after trauma, from injections, or during surgery via contaminated medical instruments. Recently, investigators from the Centers for Disease Control and Prevention, Atlanta, Ga, and the California Department of Health Services, Berkeley, documented a large, unprecedented outbreak of community-acquired RGM infection, during which more than 100 patrons of a northern California nail salon contracted furunculosis in their legs as a result of exposure to whirlpool footbaths that were contaminated with M fortuitum. We report the clinical and epidemiological findings in 3 cases of lower extremity RGM infections that occurred after similar whirlpool footbath exposure at several different nail salons in southern California. These infections typically presented as recurrent furunculosis, causing considerable morbidity as a result of scarring, delayed diagnosis, and the need for long-term polymicrobial therapy. Rapidly growing mycobacterial infections related to pedicures may continue to occur in a sporadic fashion. Clinicians should consider the possibility of RGM infection and inquire about recent pedicures in a patient with recurrent lower extremity furunculosis and abscesses that are unresponsive to conventional antibiotic therapy.


Integrating a primary oral health care approach in the dental curriculum: a Tanzanian experience.
This paper is based on a conference presentation made during the inauguration of the Faculty of Dentistry, Kuwait University, as a World Health Organization Collaborating Centre for Primary Oral Health Care (POHC) on November 27-28, 2012. The aim of this paper is to review how the POHC approach has been integrated into the dental curriculum, sharing the Tanzanian experience as a case presentation from a developing country. The burden of oral diseases worldwide is high, and the current oral health workforce is inadequate to meet the challenges. Curative oral health care is very costly and not accessible to the poor and minorities. To tackle the problem, the POHC approach rooted in primary health care that emphasizes equity, community involvement, prevention, appropriate technology and a multi-sectorial approach was developed and has been operating for more than 3 decades now. Execution of a comprehensive POHC requires a trained oral health workforce mix with essential competencies. For this case study, a literature search was done using the search engines subscribed to by the library of Muhimbili University of Health and Allied Sciences, including PubMed, Cochrane, ScienceDirect and Scopus, Wiley-Blackwell Interscience, Sage and the Health InterNetwork Access to Research Initiative (HINARI) that gives access to Scirus and Google Scholar. Challenges are discussed with an emphasis more on addressing the common risk factors and determinants of oral health. Integration of the POHC approach in the dental curriculum for training a competent workforce is crucial in attaining better oral health. Resources are still a major challenge, and the impact of the POHC approach in the curriculum is yet to be evaluated.


Intermolecular interaction among Remdesivir, RNA and RNA-dependent RNA polymerase of SARS-CoV-2 analyzed by fragment molecular orbital calculation.
COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A' base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.


Resonance ionization spectroscopy in a thermal lithium beam by means of diode lasers.
We measured two-step photoion current spectra by using a semiconductor laser and a Q-switched Nd:YAG laser with fourth-harmonic generation in an atomic lithium beam. The number of ions measured was compared with an estimate from the diode laser absorption measurement that uses a set of precisely solved rate equations. We explain the saturation effects on absorption by using transit time relaxation and detailed calculations of the ionization levels.


Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice.
Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by approximately 30% of patients. We used CRISPR/Cas9 genome engineering to introduce the equivalent of the human SUR2[R1154Q] mutation into the mouse ABCC9 gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower KATP current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and KATP in homozygous R1154Q ventricles revealed underlying diazoxide-sensitive SUR1-dependent KATP channel activity. Surprisingly, sequencing of SUR2 cDNA revealed 2 distinct transcripts, one encoding full-length SUR2 protein; and the other with an in-frame deletion of 93 bases (corresponding to 31 amino acids encoded by exon 28) that was present in approximately 40% and approximately 90% of transcripts from hetero- and homozygous R1154Q tissues, respectively. Recombinant expression of SUR2A protein lacking exon 28 resulted in nonfunctional channels. CS tissue from SUR2[R1154Q] mice and human induced pluripotent stem cell-derived (hiPSC-derived) cardiomyocytes showed only full-length SUR2 transcripts, although further studies will be required in order to fully test whether SUR2[R1154Q] or other CS mutations might result in aberrant splicing and variable expressivity of disease features in human CS.