A pendulum-type electrochemical aptamer-based sensor for continuous, real-time and stable detection of proteins.
Continuous detection of proteins is crucial for health management and biomedical research. Electrochemical aptamer-based (E-AB) sensor that relies on binding affinity between a recognition oligonucleotide and its specific target is a versatile platform to fulfill this purpose. Yet, the vast majority of E-AB sensors are characterized by voltammetric methods, which suffer from signal drifts and low-frequency data acquisition during continuous operations. To overcome these limitations, we developed a novel E-AB sensor empowered by Gold nanoparticle-DNA Pendulum (GDP). Using chronoamperometric interrogation, the developed sensor enabled drift-resistant, high-frequency, and real-time monitoring of vascular endothelial growth factor (VEGF), a vital signaling protein that regulates angiogenesis, endothelial cell proliferation and vasculogenesis. We assembled VEGF aptamer-anchored GDP probes to a reduced graphene modified electrode, where a fast chronoamperometric current transient occurs as the GDP rapidly transport to the electrode surface. In the presence of target molecules, longer and concentration-dependent time decays were observed because of slower motion of the GDP in its bound state. After optimizing several decisive parameters, including composition ratios of GDP, probe density, and incubation time, the GDP empowered E-AB sensor achieves continuous, selective, and reversible monitoring of VEGF in both phosphate buffered saline (PBS) solutions and artificial urine with a wide detection range from 13 fM to 130 nM. Moreover, the developed sensor acquires signals on a millisecond timescale, and remains resistant to signal degradation during operation. This study offers a new approach to designing E-AB architectures for continuous biomolecular monitoring.


A survey of 1700 women who formed their families using donor spermatozoa.
This paper reports the results of an online survey of 1700 recipients of donor spermatozoa conducted by the Donor Sibling Registry, aiming to understand the perspectives of respondents who had used donor spermatozoa. The survey examined: choice of sperm bank and donor; reporting of births and genetic disorders; disclosure; contact with donor and half-siblings; regulation of sperm donor activity and genetic testing; and access to medical information. The respondents formed three groups: single women; women in a same-sex relationship; and women in a heterosexual relationship. Some differences between the three cohorts were observed: preinsemination counselling; acceptance of donors without medical records or with chronic or late-onset diseases; awareness of choice of bank and type of donor; and views on the right of offspring to know their genetic origins. However, important areas of common ground were identified: the wish by those who had used an anonymous donor that they had used an open-identity donor; support for, and willingness to pay for, comprehensive genetic testing of donors; and desire for access to their donor's family health information. The implications of these results for policies concerning the use and management of donor spermatozoa will be discussed. This paper reports the results of a survey of 1700 women who used donor spermatozoa to conceive a child. The survey considers their views on the following areas: choice of sperm bank and donor; reporting of births and genetic disorders; disclosure; contact with donor and half-siblings; regulation of sperm donor activity and genetic testing; and access to medical information. This was an online survey was designed and conducted by the Donor Sibling Registry (DSR), a US-based non-profit organization that supports donor sperm recipients, donors and donor-conceived people. The survey aimed to understand the experiences, perspectives and concerns of women who had used donor spermatozoa. The respondents formed three groups: single women; women in a same sex relationship; and women in a heterosexual relationship. Some differences between the three groups were observed: preinsemination counselling; acceptance of donors without medical records or with chronic or late-onset diseases; awareness of choice of bank and type of donor; and the right of offspring to know their genetic origins. However, despite these differences, important areas of common ground were identified: the wish by those who had used an anonymous donor that they had used an open-identity donor; support for, and a willingness to pay for, comprehensive genetic testing of donors; and desire for access to their donor's family health information. The implications of these results for policies concerning the use and management of donor spermatozoa will be discussed.


Community health improvement plan: Study protocol for Kansas City's intervention and implementation evaluation.
Community health improvement plans (CHIPs) are foundational public health practice, yet no studies have been conducted to understand implementation of these plans. This evaluation study of the Kansas City CHIP aims to 1) identify implementation strategies used in the CHIP, 2) assess changes in implementation, service, and client outcomes, 3) assess contextual factors associated with implementation, and 4) understand social networks of coalitions who implement the Kansas City CHIP. This study protocol uses a unique, mixed methods approach to evaluating process and outcomes of the Kansas City CHIP. This study is supported by Proctor's Model of Implementation, RE-AIM (reach, effectiveness, adoption, implementation, maintenance), and the practical, robust implementation and sustainability model (PRISM). Staff and community members involved in implementing the Kansas City, Missouri CHIP will be invited to participate in an annual online survey, a series of focus groups, and quarterly implementation logs to assess implementation and sustainability. RE-AIM and PRISM constructs are the primary and secondary outcomes of interest. Results of this study will be available from the first year of implementation in 2023, with future results provided annually. This project will fill a much-needed gap in the literature by understanding how large-scale coalitions implement projects that aim to improve population health and health equity. CHIPs have the potential to improve population health, yet few studies have been conducted on CHIPs, with no studies to date assessing outcomes. To support effective implementation and sustainability as well as improve public health outcomes, researchers need to evaluate CHIPs and develop models of implementation that can quickly be integrated into practice to improve populations' health.


Development of root resorption during orthodontic tooth movement after cleft repair using different grafting materials in rats.
The aim of the present study was to investigate the influence of three grafting materials for cleft repair on orthodontic tooth movement in rats. Artificial alveolar clefts were created in 21 Wistar rats and were repaired 4 weeks later using autografts, human xenografts and synthetic bone substitute (beta-tricalcium phosphate/hydroxyapatite [β-TCP/HA]). A further 4 weeks later, the first molar was moved into the reconstructed maxilla. Microfocus computed tomography (μCT) was performed six times (T0-T5) to assess the tooth movement and root resorption. After 8 weeks, the affected reconstructed jaw was resected for histopathological investigation. Total distances reached ranged from 0.82 ± 0.72 mm (β-TCP/HA) to 0.67 ± 0.27 mm (autograft). The resorption was particularly determined at the mesiobuccal root. Descriptive tooth movement slowed and root resorption increased slightly. However, neither the radiological changes during tooth movement (µCT T1 vs. µCT T5: autograft 1.85 ± 0.39 mm3 vs. 2.38 ± 0.35 mm3, p = 0.30; human xenograft 1.75 ± 0.45 mm3 vs. 2.17 ± 0.26 mm3, p = 0.54; β-TCP/HA: 1.52 ± 0.42 mm3 vs. 1.88 ± 0.41 mm3, p = 0.60) nor the histological differences after tooth movement (human xenograft: 0.078 ± 0.05 mm2; β-TCP/HA: 0.067 ± 0.049 mm2; autograft: 0.048 ± 0.015 mm2) were statistically significant. The autografts, human xenografts or synthetic bone substitute used for cleft repair seem to have a similar effect on the subsequent orthodontic tooth movement and the associated root resorptions. Development of root resorptions seems to have a secondary role in choosing a suitable grafting material for cleft repair.


The effect of climatic factors on the number of malaria cases in an inland and a coastal setting from 2011 to 2017 in the equatorial rain forest of Cameroon.
Weather fluctuation affects the incidence of malaria through a network of causuative pathays. Globally, human activities have ultered weather conditions over time, and consequently the number of malaria cases. This study aimed at determining the influence of humidity, temperature and rainfall on malaria incidence in an inland (Muyuka) and a coastal (Tiko) settings for a period of seven years (2011-2017) as well as predict the number of malaria cases two years after (2018 and 2019). Malaria data for Muyuka Health District (MHD) and Tiko Health District (THD) were obtained from the Regional Delegation of Public Health and Tiko District Health service respectively. Climate data for MHD was obtained from the Regional Delegation of Transport while that of THD was gotten from Cameroon Development Coorporation. Spearman rank correlation was used to investigate the relationship between number of malaria cases and the weather variables and the simple seasonal model was used to forecast the number of malaria cases for 2018 and 2019. The mean monthly rainfall, temperature and relative humidity for MHD were 200.38 mm, 27.050C, 82.35% and THD were 207.36 mm, 27.57 °C and 84.32% respectively, with a total number of malaria cases of 56,745 and 40,160. In MHD, mean yearly humidity strongly correlated negatively with number of malaria cases (r = - 0.811, p = 0.027) but in THD, a moderate negative yearly correlation was observed (r = - 0.595, p = 0.159). In THD, the mean seasonal temperature moderately correlated (r = 0.599, p = 0.024) positively with the number of malaria cases, whereas MHD had a very weak negative correlation (r = - 0.174, p = 0.551). Likewise mean seasonal rainfall in THD moderately correlated (r = - 0.559, p = 0.038) negatively with malaria cases, contrary to MHD which showed a very weak positive correlation (r = 0.425, p = 0.130). The simple seasonal model predicted 6,842 malaria cases in Muyuka, for 2018 and same number for 2019, while 3167 cases were observed in 2018 and 2848 in 2019. Also 6,738 cases of malaria were predicted for MHD in 2018 likewise 2019, but 7327 cases were observed in 2018 and 21,735 cases in 2019. Humidity is the principal climatic variable that negatively influences malaria cases in MHD, while higher seasonal temperatures and lower seasonal rain fall significantly increase malaria cases in THD.


Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol.
Few effective therapies exist for the treatment of neurodegenerative diseases that have been characterized as protein misfolding disorders. Upregulation of heat shock proteins (Hsps) mitigates against the accumulation of misfolded, aggregation-prone proteins and synaptic dysfunction, which is recognized as an early event in neurodegenerative diseases. Enhanced induction of a set of Hsps in differentiated human SH-SY5Y neuronal cells was observed following co-application of celastrol and arimoclomol, compared to their individual application. The dosages employed did not affect cell viability or neuronal process morphology. The induced Hsps included the little studied HSPA6 (Hsp70B'), a potentially neuroprotective protein that is present in the human genome but not in rat and mouse and hence is missing in current animal models of neurodegenerative disease. Enhanced induction of HSPA1A (Hsp70-1), DNAJB1 (Hsp40), HO-1 (Hsp32), and HSPB1 (Hsp27) was also observed. Celastrol activates heat shock transcription factor 1 (HSF1), the master regulator of Hsp gene transcription, and also exhibits potent anti-inflammatory and anti-oxidant activities. Arimoclomol is a co-activator that prolongs the binding of activated HSF1 to heat shock elements (HSEs) in the promoter regions of inducible Hsp genes. Elevated Hsp levels peaked at 10 to 12 h for HSPA6, HSPA1A, DNAJB1, and HO-1 and at 24 h for HSPB1. Co-application of celastrol and arimoclomol induced higher Hsp levels compared to heat shock paired with arimoclomol. The co-application strategy of celastrol and arimoclomol targets multiple neurodegenerative disease-associated pathologies including protein misfolding and protein aggregation, inflammatory and oxidative stress, and synaptic dysfunction.


Screening and diagnosis of chromosomal abnormalities in twin pregnancy.
Twin pregnancies are at an increased risk of adverse pregnancy and perinatal outcome as compared to singleton gestations, mainly as the consequence of the higher rate of preterm birth, chromosomal as well as structural anomalies, placental abnormalities, and complications unique to monochorionic placentation. Screening for chromosomal anomalies poses diagnostic and management challenges when applied to twin pregnancies. The recent implementation of cell-free fetal DNA (cffDNA) in clinical practice raises the questions whether a more accurate test should be offered to twin pregnancies in view of the higher false positive rate of traditional screening and the higher risk of fetal loss following amniocentesis or chorionic villus sampling (CVS) in multiple gestations. Finally, twin pregnancies require a tailored approach for aneuploidy screening, such as nuchal translucency (NT) or crown rump length discordance, discordant fetal anomalies, or monoamniotic gestations. The present review aims to provide an up-to-date critical appraisal of screening and prenatal diagnosis of chromosomal abnormalities in twin pregnancies.


The relationship between impulsivity and anxiety and recurrent metacarpal fractures due to punch injury.
The study aimed to determine the relationship between impulsivity and anxiety and recurrent metacarpal fractures (RMF) due to punching injury. Consecutive 368 patients (301 men and 67 women) with metacarpal fracture who met the inclusion criteria and 214 healthy controls were included in the study. The study group was divided into two as the first metacarpal fracture (FMF) (245 patients) and RMF (123 patients). The control group consisted of sex- and age-matched 214 healthy participants (175 men and 39 women). Beck anxiety inventory (BAI), Barratt impulsiveness scale (BIS 11), and Quick DASH scores were the assessment of the patients in the sixth month of treatment. The groups were compared in terms of demographic features (including education status, marital status, work status, and level of income), fracture side, fracture location, dominant hand, treatment, anxiety, impulsivity, and functional results. In the RMF, BIS 11, BAI, and Quick DASH scores were significantly higher than the FMF and the healthy controls (p = 0.001 and p = 0.001, respectively). The patients with RMF have higher impulsivity and anxiety, worse short-term functional outcomes, and lower level of income and education status compared with healthy controls and FMF. Anxiety and impulsivity are higher in patients with RMF. It adversely affects the clinical outcome after the treatment. Psychiatric consultation is an important step for especially intentional RMF patients to prevent recurrent hand injuries and metacarpal fractures and to improve clinical outcomes associated with these injuries.


TopiaryExplorer: visualizing large phylogenetic trees with environmental metadata.
Microbial community profiling is a highly active area of research, but tools that facilitate visualization of phylogenetic trees and associated environmental data have not kept up with the increasing quantity of data generated in these studies. TopiaryExplorer supports the visualization of very large phylogenetic trees, including features such as the automated coloring of branches by environmental data, manipulation of trees and incorporation of per-tip metadata (e.g. taxonomic labels). http://topiaryexplorer.sourceforge.net. firstname.lastname@example.com.


Analysis of the anisotropic dimension in the RIACT (II) multiple quantum MAS NMR experiment for I = 3/2 nuclei.
Numerical simulations of the anisotropic dimension of the Rotation-Induced Adiabatic Coherence Transfer (RIACT) MQ experiment have been performed as a function of the asymmetry parameter, eta, for different spacings between the triple quantum (3Q) excitation and 3Q to single quantum (1Q) reconversion pulses. Large distortions of the spectra are observed, in comparison to the spectra obtained with 1D MAS NMR methods. The method is very sensitive to the relative orientation of the quadrupolar tensor and rotor axis, and signal can only be obtained from a maximum of 60% of the powder. The intensity varies with the spacing between the two pulses, t1, reaching a minimum of 30% when t1 is either a multiple of a full rotor period (n tau(r)) or for (n + 1/2) rotor periods, for pulse lengths (tau1SL) of a quarter of a rotor period. The maximum of 60% is obtained when t1 = n tau(r) - tau1SL. Experimental spectra were acquired for anhydrous Na2HPO4. Good fits were obtained between the experimental and simulated spectra, even for the non-rotor synchronized experiment, by choosing fixed values of t1. The simulations allowed the quadrupole coupling constants and asymmetry parameters to be extracted from the experimental data.


Elucidation of the nifedipine-quinidine interaction.
Four case reports have been published that document a clinically significant drug interaction between nifedipine and quinidine in patients with left ventricular dysfunction. To define the population at risk and the mechanisms involved in manifestations of this interaction, 12 patients currently treated with quinidine for either ventricular or supraventricular arrhythmias were stratified into two groups based on left ventricular ejection fraction (EF) measurements (group A greater than 35%; group B less than 35%). The interaction was conducted through two phases: oral quinidine (Q) and oral quinidine plus nifedipine (N + Q). Pharmacokinetic modeling of total body clearance (CL) and AUC were assessed for each phase. One patient (group A, 70% EF) exhibited the interaction with a 41% decrease in steady-state serum quinidine concentrations. The patient's AUC and CL were 48.2 micrograms/ml.hr (Q) versus 28.6 micrograms/ml.hr (N + Q) and 94.4 ml/min (Q) versus 159.1 ml/min (N + Q), respectively. There was no difference in AUC or CL between the Q and N + Q phases or between groups A and B for the entire population. The N + Q interaction is not hemodynamically mediated. Clinical consideration of the possibility of this low-frequency interaction should be noted.


Latitudinal gradients in avian colourfulness.
It has long been suggested that tropical species are generally more colourful than temperate species, but whether latitudinal gradients in organismal colourfulness exist remains controversial. Here we quantify global latitudinal trends in colourfulness (within-individual colour diversity) by collating and analysing a photographic dataset of whole-body plumage reflectance information for >4,500 species of passerine birds. We show that male and female birds of tropical passerine species are generally more colourful than their temperate counterparts, both on average and in the extreme. We also show that these geographic gradients can be explained in part by the effects of several latitude-related factors related to classic hypotheses for climatic and ecological determinants of organismal colourfulness. Taken together, our results reveal that species' colourfulness peaks in the tropics for passerine birds, confirming the existence of a long-suspected yet hitherto elusive trend in the distribution of global biodiversity.


Independent recurrent evolution of MICRORNA genes converging onto similar non-canonical organisation across green plant lineages is driven by local and segmental duplication events in species, family and lineages.
The relationship between evolutionary history, organisation and transcriptional regulation of genes are intrinsically linked. These have been well studied in canonically organised protein-coding genes but not of MIRNAs. In the present study, we investigated the non-canonical arrangement of MIRNAs across taxonomic boundaries from algae to angiosperms employing a combination of genome organization, phylogeny and synteny. We retrieved the complete dataset of MIRNA from twenty-five species to identify and classify based on organisational patterns. The median size of cluster was between 2-5 kb and between 1-20 % of all MIRNAs are organized in head-to-head (with bidirectional promoter), head-to-tail (tandem), and overlapping manner. Although majority of the clusters are composed of MIRNA homologs, 25% of all clusters comprises of non-homologous genes with a potential of generating functional and regulatory complexity. A comparison of phylogeny and organizational patterns revealed that multiple independent events, some of which are species-specific, and some ancient, in different lineages, are responsible for non-canonical organization. Detailed investigation of MIR395 family across the plants revealed a complex origin of non-canonical arrangement through ancient and recent, segmental and local duplications; analysis of MIR399 family revealed major expansion occurred prior to monocot-dicot split, with few lineage-specific events. Evolution of "convergent" organization pattern of non-canonical arrangement originating from independent loci through recurrent event highlights our poor understanding of evolutionary process of MIRNA genes. The present investigation thus paves way for comparative functional genomics to understand the role of non-canonical organization on transcriptional regulation and regulatory diversity in MIRNA gene families.


Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90.
Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.


k-t GRAPPA: a k-space implementation for dynamic MRI with high reduction factor.
A novel technique called "k-t GRAPPA" is introduced for the acceleration of dynamic magnetic resonance imaging. Dynamic magnetic resonance images have significant signal correlations in k-space and time dimension. Hence, it is feasible to acquire only a reduced amount of data and recover the missing portion afterward. Generalized autocalibrating partially parallel acquisitions (GRAPPA), as an important parallel imaging technique, linearly interpolates the missing data in k-space. In this work, it is shown that the idea of GRAPPA can also be applied in k-t space to take advantage of the correlations and interpolate the missing data in k-t space. For this method, no training data, filters, additional parameters, or sensitivity maps are necessary, and it is applicable for either single or multiple receiver coils. The signal correlation is locally derived from the acquired data. In this work, the k-t GRAPPA technique is compared with our implementation of GRAPPA, TGRAPPA, and sliding window reconstructions, as described in Methods. The experimental results manifest that k-t GRAPPA generates high spatial resolution reconstruction without significant loss of temporal resolution when the reduction factor is as high as 4. When the reduction factor becomes higher, there might be a noticeable loss of temporal resolution since k-t GRAPPA uses temporal interpolation. Images reconstructed using k-t GRAPPA have less residue/folding artifacts than those reconstructed by sliding window, much less noise than those reconstructed by GRAPPA, and wider temporal bandwidth than those reconstructed by GRAPPA with residual k-space. k-t GRAPPA is applicable to a wide range of dynamic imaging applications and is not limited to imaging parts with quasi-periodic motion. Since only local information is used for reconstruction, k-t GRAPPA is also preferred for applications requiring real time reconstruction, such as monitoring interventional MRI.


Podophyllotoxin and nocodazole counter the effect of IKP104 on tubulin decay.
Tubulin, the subunit protein of microtubules, undergoes a time-dependent loss of functional properties known as decay. We have previously shown that the drug 2-(4-fluorophenyl)- -(2-chloro-3,5-dimethoxyphenyl)-3-methyl-6-phenyl-4(1H)-pyridinone (IKP104) accelerates decay, but that in the presence of colchicine, IKP104 becomes a stabilizer of tubulin. To see if this is due to conformational effects specific to colchicine or simply to occupancy at the colchicine site, we examined the effects of nocodazole and podophyllotoxin, two well-known competitive inhibitors of colchicine for binding to tubulin, on IKP104's acceleration of decay. We found that podophyllotoxin abolished IKP104's accelerating effect and, like colchicine, turned it into a stabilizer of tubulin. Nocodazole's effects were similar to those of podophyllotoxin and colchicine, in that it abolished IKP104-induced enhancement of decay; however, in the presence of nocodazole, IKP104 caused little or no stabilization of tubulin. Since colchicine, nocodazole, and podophyllotoxin have very different interactions with tubulin, but all inhibit the IKP104-induced enhancement of decay, our findings suggest that this inhibition arises from occupancy of the colchicine site rather than from a direct conformational effect of these two drugs.


Scientific, professional and experiential validation of the model of preventive behaviours at work: protocol of a modified Delphi Study.
To offer an in-depth understanding of preventive behaviours, those complex behaviours considered as levers to foster work prevention, recent theoretical and empirical studies permitted to develop the model of preventive behaviours at work. The next step is to validate the model with researchers, professionals and workers. This article aims to describe the study protocol that will be used to validate the model of preventive behaviours at work. This Delphi Study proposes seven systematic steps to conduct a scientifically rigorous validation study based on scientific and professional experts' opinion. A focus group to collect workers' opinion about the model has also been included in the protocol. Thirty experts (researchers and professionals) will be selected regarding their experience (eg, at least 5 years of experience) and expertise (eg, having published at least one article as the first author in the last 3 years) towards workers' health or organisational behaviours. Workers will be recruited to have a diversity in terms of age, gender and working conditions. Quantitative data will be analysed to calculate the percentage of experts' agreement on four content validity indicators (ie, comprehensiveness, representativeness, relevance and clarity). Qualitative data will be examined through a thematic analysis strategy. Approval of the research ethics board of the Centre intégré universitaire de santé et de services sociaux de la Capitale Nationale has been obtained. Findings will be shared with various stakeholders inclusive of researchers, professionals and workers. Findings will be disseminated in workshops, peer-reviewed journals and conferences.


Unequal Access to Newly Registered Cancer Drugs Leads to Potential Loss of Life-Years in Europe.
Many new cancer medicines have been developed that can improve patients' outcomes. However, access to these agents comes later in Europe than in the United States (US). The aim of this study is to assess the access in Europe to newly registered cancer drugs and to get more insight in the implications of these variations for patients. A retrospective database study was conducted. Analyses involved 12 cancer drugs and 28 European countries in the period 2011-2018. Time to patient access, speed of drug uptake, and the potential loss of life years due to a delay in access have been studied. Marketing approval for the cancer drugs came on average 242 days later in Europe than in the US, and actual patient access varied extensively across Europe. The average time to market in Europe was 403 days (range 17-1187 days). The delay in patient access of ipilimumab and abiraterone may have led to a potential loss of more than 30,000 life years. It takes a long time for patients to get access to newly registered cancer drugs and there is great variation in access. The health outcomes can be substantially improved by faster processes.


The relationship between pre-operative anxiety and post-operative delirium.
Forty five elderly patients undergoing total hip replacements were assessed one day before and two days after surgery in order to explore the relationship between pre-operative anxiety and post-operative delirium. Anxiety was measured by the State-Trait Anxiety Inventory and delirium was measured by a decrease in various measures of cognitive functioning. No relationship was found and this is discussed in the light of two theories which would have predicted one. Other secondary findings are reported and discussed.


Cell association and degradation of alpha 2-macroglobulin-trypsin complexes in hepatocytes and adipocytes.
125I-Labelled alpha 2-macroglobulin-trypsin complex (125I-labelled alpha 2-macroglobulin X trypsin) was associated to isolated rat adipocytes and hepatocytes with a half-time of about 60 min at 37 degrees C. The association of 0.5 micrograms/ml 125I-labelled alpha 2-macroglobulin X trypsin was inhibited by unlabelled alpha 2-macroglobulin X trypsin with a half-inhibition constant of about 8 micrograms/ml (11 nM). 125I-Labelled alpha 2-macroglobulin became cell-associated to a smaller extent (10-40% of that of alpha 2-macroglobulin X trypsin) and the half-inhibition constant was about 35 micrograms/ml in adipocytes. The cell association of 125I-labelled alpha 2-macroglobulin X trypsin was markedly inhibited by dansylcadaverine, bacitracin, omission of Ca2+ from the medium or pretreatment of the cells with trypsin. After incubation for 180 min more than 60% of the cell-associated 125I-labelled alpha 2-macroglobulin X trypsin was not removed by treatment of the cells with trypsin-EDTA and represented probably internalized material. 125I-Labelled alpha 2-macroglobulin X trypsin was degraded to trichloroacetic acid-soluble fragments by suspensions of both cell types but only to a negligible extent by incubation media preincubated with these cells. The rate of degradation of 0.5 micrograms/ml 125I-labelled alpha 2-macroglobulin was approx. 40% of that of 125I-labelled alpha 2-macroglobulin X trypsin. Degradation of 125I-labelled alpha 2-macroglobulin X trypsin was abolished by a high concentration (0.5 mg/ml) of alpha 2-macroglobulin X trypsin. It is concluded that alpha 2-macroglobulin X trypsin by a specific and saturable mechanism is bound to, internalized and degraded by isolated rat adipocytes and hepatocytes.


The videofluorographic swallowing study.
This article describes the evidence for the physiologic foundation and interpretation of the videofluorographic swallowing study (VFSS). The purpose and clinical efficacy of VFSS are explained. Standardization of the VFSS procedure, protocol, interpretation, and reporting is highlighted as a critical step in future clinical practice and research. Individualized evidenced-based rehabilitation strategies are presented as key components that are systematically applied during the VFSS procedure and integrated into the swallowing management plan. A new tool that has been developed and tested for the quantification of swallowing impairment is introduced.


What is Interpretability?
We argue that artificial networks are explainable and offer a novel theory of interpretability. Two sets of conceptual questions are prominent in theoretical engagements with artificial neural networks, especially in the context of medical artificial intelligence: (1) Are networks explainable, and if so, what does it mean to explain the output of a network? And (2) what does it mean for a network to be interpretable? We argue that accounts of "explanation" tailored specifically to neural networks have ineffectively reinvented the wheel. In response to (1), we show how four familiar accounts of explanation apply to neural networks as they would to any scientific phenomenon. We diagnose the confusion about explaining neural networks within the machine learning literature as an equivocation on "explainability," "understandability" and "interpretability." To remedy this, we distinguish between these notions, and answer (2) by offering a theory and typology of interpretation in machine learning. Interpretation is something one does to an explanation with the aim of producing another, more understandable, explanation. As with explanation, there are various concepts and methods involved in interpretation: Total or Partial, Global or Local, and Approximative or Isomorphic. Our account of "interpretability" is consistent with uses in the machine learning literature, in keeping with the philosophy of explanation and understanding, and pays special attention to medical artificial intelligence systems.


Reproducibility of two 3-D ultrasound carotid plaque quantification methods.
Compared with single 2-D images, emerging 3-D ultrasound technologies hold the promise of reducing variability and increasing sensitivity in the quantification of carotid plaques for individual cardiovascular risk stratification. Inter- and intra-observer agreement between a manual, cross-sectional, 2-D freehand sweep and a mechanical 3-D ultrasound investigation of 62 carotid artery plaques is reported with intra-class correlation coefficients (with 95% confidence intervals). Inter-observer agreement was 0.60 (0.29-0.77) for the freehand method and 0.89 (0.83-0.93) for the mechanical 3-D acquisition. The use of semi-automated computerized planimetric measurements of plaque burden has high intra-observer repeatability, but is vulnerable to systematic inter-observer differences. For the 2-D freehand sweep, a considerable contribution to variation is introduced by the scanning procedure itself, that is, the lack of controlled motion along the third dimension. Future implementation of 3-D ultrasound quantification in large-scale studies of inter-individual cardiovascular risk assessment seems justified using the methods described.


Bifidobacterium animalis: the missing link for the cancer-preventive effect of Gynostemma pentaphyllum.
Colorectal cancer (CRC) ranks the third most common cancer type in both men and women. Besides the known genetic and epigenetic changes in the gut epithelial cells, we now know that disturbed gut microbes could also contribute to the onset and progression of CRC. Hence, keeping a balanced gut microbiota (GM) has become a novel pursue in the medical field, particularly in the area of gastrointestinal disorders. Gynostemma pentaphyllum (Gp) is a dietary herbal medicine. In our previous study, Gp saponins (GpS) displayed prebiotic and cancer-preventive properties through the modulation of GM in ApcMin/+ mice. However, the specific group(s) of GM links to the health effects of GpS remains unknown. To track down the missing link, we first investigated and found that inoculation with fecal materials from GpS-treated ApcMin/+ mice effectively reduces polyps in ApcMin/+ mice. From the same source of the fecal sample, we successfully isolated 16 bacterial species. Out of the 16 bacteria, Bifidobacterium animalis stands out as the responder to the GpS-growth stimulus. Biochemical and RNAseq analysis demonstrated that GpS enhanced expressions of a wide range of genes encoding biogenesis and metabolic pathways in B. animalis culture. Moreover, we found that colonization of B. animalis markedly reduces the polyp burden in ApcMin/+ mice. These findings reveal a mutualistic interaction between the prebiotic and a probiotic to achieve anticancer and cancer-preventive activities. Our result, for the first time, unveils the anticancer function of B. animalis and extend the probiotic horizon of B. animalis.


Acute beriberi following liver transplantation.
Patients scheduled for orthotopic liver transplantation (OLT) undergo extensive routine preoperative cardiac assessment. We describe a 32-year-old male who underwent uneventful OLT for endstage liver failure on the basis of chronic hepatitis C and alcoholism. Despite a normal preoperative cardiac workup, the patient developed acute pulmonary edema on the second postoperative day. A diagnosis of beriberi was entertained and confirmed by (1) the thiamine diphosphate effect and (2) the dramatic response to intravenous thiamine. Possible precipitating factors are described. Thiamine, which has no significant toxicity, should probably be routinely supplemented in all patients undergoing OLT, especially those with a previous history of alcohol abuse.


Evaluation of [18F]FHPG as PET tracer for HSVtk gene expression.
In rats, the relationship between [(18)F]FHPG accumulation and HSVtk expression was studied with PET and autoradiography. [(18)F]FHPG distribution closely corresponded with HSVtk immunohistochemical staining. ROI analysis of tracer uptake 2 hours p.i. and Patlak graphical analysis were applied to quantify the PET data. For both analysis methods, the [(18)F]FHPG PET signal correlated well with the fraction of HSVtk expressing cells implanted, but showed a plateau when plotted against HSVtk protein levels. This might be due to rate limiting [(18)F]FHPG membrane transport.


Cosuppression of limonene-3-hydroxylase in peppermint promotes accumulation of limonene in the essential oil.
cDNA clones encoding limonene synthase and limonene-3-hydroxylase, both driven by the CaMV 35S promoter, were independently transformed into peppermint (Menthaxpiperita) to alter the production and disposition of (-)-limonene, the first committed intermediate of essential oil biosynthesis in this species. Although both genes were constitutively expressed in leaves of transformed plants, the corresponding enzyme activities were not significantly increased in the glandular trichome sites of essential oil biosynthesis; thus, there was no effect on oil yield or composition in the regenerated plants. Cosuppression of the hydroxylase gene, however, resulted in the accumulation of limonene (up to 80% of the essential oil compared to about 2% of the oil in wild type plants), without influence on oil yield. These results indicate that limonene does not impose negative feedback on the synthase, or apparently influence other enzymes of monoterpene biosynthesis in peppermint, and suggests that pathway engineering can be employed to significantly alter essential oil composition without adverse metabolic consequences.


Diagnostic accuracy of contrast-enhanced digital mammography in breast cancer detection in comparison to tomosynthesis, synthetic 2D mammography and tomosynthesis combined with ultrasound in women with dense breast.
To assess the diagnostic efficacy of contrast-enhanced digital mammography (CEDM) in breast cancer detection in comparison to synthetic two-dimensional mammography (s2D MG), digital breast tomosynthesis (DBT) alone and DBT supplemented with ultrasound examination in females with dense breast with histopathology as the gold-standard. It was a prospective study, where consecutive females presenting to symptomatic breast clinic between April 2019 and June 2020 were evaluated with DBT. Females who were found to have heterogeneously dense (ACR type C) or extremely dense (ACR type D) breast composition detected on s2D MG were further evaluated with high-resolution breast ultrasound and thereafter with CEDM, but before the core biopsy or surgical excision, were included in the study. s2D MG was derived from post-processing reconstruction of DBT data set. Females with pregnancy, renal insufficiency or prior allergic reaction to iodinated contrast agent were excluded from the study. Image interpretation was done by two experienced breast radiologists and both were blinded to histological diagnosis. This study included 166 breast lesions in130 patients with mean age of 45 ± 12 years (age range 24-72 years). There were 87 (52.4%) malignant and 79 (47.6%) benign lesions. The sensitivity of CEDM was 96.5%, significantly higher than synthetic 2D MG (75.6%, p < 0.0001), DBT alone (82.8%, p < 0.0001) and DBT + ultrasound (88.5%, p = 0.0057); specificity of CEDM was 81%, significantly higher than s2D MG (63.3%, p = 0.0002) and comparable to DBT alone (84.4%, p = 0.3586) and DBT + ultrasound (79.7%, p = 0.4135). In receiver operating characteristic curve analysis, the area under the curve was of 0.896 for CEDM, 0.841 for DBT + ultrasound, 0.769 for DBT alone and 0.729 for s2D MG. CEDM is an accurate diagnostic technique for cancer detection in dense breast. CEDM allowed a significantly higher number of breast cancer detection than the s2D MG, DBT alone and DBT supplemented with ultrasonography in females with dense breast. CEDM is a promising novel technology with higher sensitivity and negative predictive value for breast cancer detection in females with dense breast in comparison to DBT alone or DBT supplemented with ultrasound.


GABA-B receptors in the PNS have a role in Schwann cells differentiation?
γ-aminobutyric acid type B (GABA-B) receptor mediates the inhibitory transmission of γ-aminobutyric acid in the mammalian nervous system, being present in neurons and also in glial cells. Recently the presence of GABA-B has been demonstrated in Schwann cells (SC) suggesting its contribution in regulating the cell fate, maturation, and plasticity. Here, we further support the functional presence of GABA-B receptor in SC plasma membrane. By confocal microscopy immunofluorescence we provide evidences that GABA-B localization on the cell elongated processes correlates with the morphological changes occurring in the differentiated SC. In vivo most of the GABA-B receptors seem to be present in non-myelinating SC, which are committed to ensheath the nociceptive fibers. Therefore, we argue that GABA-B receptors do not control exclusively the in vivo differentiation yielding the myelinating SC, but are also fundamental in regulating the SC plasticity versus the non-myelinating state. Data from the literature and our recent findings corroborate the role of the GABAergic system and GABA-B receptors in the peripheral nervous system, opening new perspectives on the mechanisms controlling the differentiation of SC.


Heat preadaptation improved the ability of Zygosaccharomyces rouxii to salt stress: a combined physiological and transcriptomic analysis.
Zygosaccharomyces rouxii plays important roles in the brewing process of fermented foods such as soy sauce, where salt stress is a frequently encountered condition. In this study, effect of heat preadaptation on salt tolerance of Z. rouxii and the protective mechanisms underlying heat preadaptation were investigated based on physiological and transcriptomic analyses. Results showed that cells subjected to heat preadaptation (37 °C, 90 min) prior to salt stress aroused many physiological responses, including maintaining cell surface smooth and intracellular pH level, increasing Na+/K+-ATPase activity. Cells subjected to heat preadaptation increased the amounts of unsaturated fatty acids (palmitoleic C16:1, oleic C18:1, linoleic C18:2) and decreased the amounts of saturated fatty acids (palmitic C16:0, stearic C18:0) which caused the unsaturation degree (unsaturated/saturated = U/S ratio) increased by 2.4 times when compared with cells without preadaptation under salt stress. Besides, salt stress led to increase in contents of 5 amino acids (valine, proline, threonine, glycine, and tyrosine) and decrease of 2 amino acids (serine and lysine). When comparing the cells pre-exposed to heat preadaptation followed by challenged with salt stress and the cells without preadaptation under salt stress, the serine, threonine, and lysine contents increased significantly. RNA sequencing revealed that the metabolic level of glycolysis by Z. rouxii was weakened, while the metabolic levels of the pentose phosphate pathway and the riboflavin were enhanced in cells during heat preadaptation. Results presented in this study may contribute to understand the bases of adaptive responses in Z. rouxii and rationalize its exploitation in industrial processes.Key points• Heat preadaptation can improve high salinity tolerance of Z. rouxii.• Combined physiological and transcriptomic analyses of heat preadaptation mechanisms.• Provide theoretical support for the application of Z. rouxii.


Increased glutamate uptake and GLAST expression by cyclic AMP in retinal glial cells.
The aim was to investigate the effect of cyclic adenosine monophosphate (cAMP) on glutamate uptake and glial glutamate aspartate transporter (GLAST) expression in cultured rat retinal glial cells. Retinal glial cell cultures were prepared from 1- to 3-day-old Sprague-Dawley rats. Cultures were treated with dibutyryl-cAMP (dBcAMP) for 24 h. Glutamate uptake was measured as 3H-glutamate content of the lysates as determined by scintillation counting. The expression of GLAST in dBcAMP-treated cells was examined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. Cells were identified by immunocytochemistry using antibodies against vimentin and carbonic anhydrase C. Treatment of cultured cells with dBcAMP significantly increased glutamate uptake after 60 min compared with untreated cells (p < 0.01). Maintenance of cells in medium supplemented with dBcAMP increased GLAST mRNA and protein levels. GLAST mRNA levels were elevated 2.9-fold 24 h after treatment. GLAST protein levels were elevated 2.5-fold 24 h after treatment. These results indicate that treatment with cAMP increases glutamate uptake through upregulated GLAST activity in cultured retinal glial cells. These findings suggest that retinal glial cells may regulate extracellular glutamate concentration and protect retinal neurons against glutamate excitotoxicity.


Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine.
Bile acid concentrations are controlled by a feedback regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examined using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (Fxr DeltaL) or intestine (Fxr DeltaIE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in Fxr DeltaL mice but not Fxr DeltaIE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1.


Effect of Ixekizumab Treatment on Work Productivity for Patients With Moderate-to-Severe Plaque Psoriasis: Analysis of Results From 3 Randomized Phase 3 Clinical Trials.
Therapies that reduce psoriasis symptoms may improve work productivity. To assess the effect of ixekizumab therapy on work productivity, measured by the Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO). Three multicenter, randomized double-blind phase 3 trials conducted during the following periods: December 2011 through August 2014 (UNCOVER-1), May 2012 through April 2015 (UNCOVER-2), and August 2012 through July 2014 (UNCOVER-3). Adult outpatients with moderate-to-severe chronic plaque psoriasis were included. In UNCOVER-1, patients were randomized 1:1:1 to subcutaneous placebo or 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 12 weeks; UNCOVER-2 and UNCOVER-3 also had an etanercept arm (50 mg twice weekly). Maintenance of initial ixekizumab response was evaluated in UNCOVER-1 and UNCOVER-2 during a randomized withdrawal period following week 12 through week 60. The WPAI-PSO questionnaire was administered at baseline and week 12 for all patients and at weeks 24, 36, 52, and 60 for patients in UNCOVER-1 and UNCOVER-2. Change in work productivity from baseline as measured by WPAI-PSO scores. Across trials, 5101 patients consented; 3866 were randomized (mean [SD] age, UNCOVER-1, 45.7 [12.9] y, 68.1% male; UNCOVER-2: 45.0 [13.0] y, 67.1% male; UNCOVER-3: 45.8 [13.1] y, 68.2% male). At week 12 in UNCOVER-1, the ixekizumab Q4W and ixekizumab Q2W groups showed significantly greater improvements in WPAI-PSO scores (least squares mean change from baseline [SE]) relative to placebo: absenteeism (-3.5 [0.87], P < .001; -2.6 [0.84], P = .003, respectively, vs 0.2 [0.88]), presenteeism (-18.8 [1.28], P < .001; -18.3 [1.24], P < .001, vs 0.5 [1.30]), work productivity loss (-20.6 [1.38], P < .001; -19.8 [1.33], P < .001, vs -0.8 [1.40]), and activity impairment (-24.5 [1.18], P < .001; -25.2 [1.15], P < .001, vs 0.8 [1.18]). Similar results were obtained for UNCOVER-2 and UNCOVER-3, with the exception of absenteeism with ixekizumab Q4W in UNCOVER-2. Additionally, ixekizumab-treated patients showed significantly greater improvements in WPAI-PSO scores vs etanercept-treated patients: UNCOVER-2: presenteeism, work productivity loss, activity impairment (P < .001 both doses), UNCOVER-3: activity impairment (ie, regular activities outside of work) (ixekizumab Q2W; P = .009). Improvements in WPAI-PSO scores at week 12 were sustained to at least week 60. Ixekizumab-treated patients reported short- and long-term improvements in work productivity, which could lead to reduced productivity-related cost burden in patients with psoriasis. clinicaltrials.gov Identifiers: NCT01474512, NCT01597245, NCT01646177.


Unrestored dentin caries and deep dentin restorations in Swedish adolescents.
The objectives of this longitudinal study were to assess: (a) the prevalence of unrestored dentin caries among 15-year-olds, (b) the proportion of these lesions that had progressed to deep dentin lesions (inner half of dentin) since the immediately preceding examination at the age of 14 and (c) the frequency of deep restorations (extending into the inner half of the dentin). The sample consisted of all 15-year-olds (n = 2,487) born in 1990 and included in the Public Dental Service in Malmo, Sweden. Bitewing radiographs taken during 2005-2007 and the immediately preceding radiographs were analysed and scored by two examiners. The main radiographic scores were: sound; radiolucency in the outer or inner half of dentin; restored surface. The results showed that 22% of the individuals had 1 or more dentin lesions left unrestored from the time of the examination at the age of 14 until the next recall examination at the age of 15. During the observation period (median time 1.2 years), 9% of the unrestored outer dentin lesions progressed to deep dentin lesions. The majority of these (93%) were in molars. One or more deep restorations were found in 22% of the 15-year-olds; the majority involved occlusal surfaces of first molars. In conclusion, unrestored dentin lesions were common in 15-year-olds. Progression to deep dentin lesions occurred in 9% of these lesions and was most common in first molars. Occlusal surfaces of first molars had the highest frequency of deep restorations.


Connectivity of mouse somatosensory and prefrontal cortex examined with trans-synaptic tracing.
Information processing in neocortical circuits requires integrating inputs over a wide range of spatial scales, from local microcircuits to long-range cortical and subcortical connections. We used rabies virus-based trans-synaptic tracing to analyze the laminar distribution of local and long-range inputs to pyramidal neurons in the mouse barrel cortex and medial prefrontal cortex (mPFC). In barrel cortex, we found substantial inputs from layer 3 (L3) to L6, prevalent translaminar inhibitory inputs, and long-range inputs to L2/3 or L5/6 preferentially from L2/3 or L5/6 of input cortical areas, respectively. These layer-specific input patterns were largely independent of NMDA receptor function in the recipient neurons. mPFC L5 received proportionally more long-range inputs and more local inhibitory inputs than barrel cortex L5. Our results provide new insight into the organization and development of neocortical networks and identify important differences in the circuit organization in sensory and association cortices.


Depression and neurocognitive functioning in mild traumatic brain injury patients referred for assessment.
The relationship between depression and performance on selected neurocognitive tests was examined in two mild head injury samples (n1 = 72, n2 = 50). A series of hierarchical regression analyses showed that scores on depression-related scales of both the MCMI-II (Millon Clinical Multi-Axial Inventory; Millon, 1987) and MMPI-2 (Minnesota Multiphasic Personality Inventory; Hathaway & McKinley, 1989) were largely independent of cognitive performance. Depression may be prevalent in mild injury, but it is unlikely to mediate deficits observed on commonly used measures of problem solving, visual-motor speed, prose and figural recall.


Partnering with patients using social media to develop a hypertension management instrument.
Hypertension is a lifelong condition; thus, long-term adherence to lifestyle modification, self-monitoring, and medication regimens remains a challenge for patients. The aim of this study was to develop a patient-reported hypertension instrument that measured attitudes, lifestyle behaviors, adherence, and barriers to hypertension management using patient-reported outcome data. The study was conducted using the Open Research Exchange software platform created by PatientsLikeMe. A total of 360 participants completed the psychometric phase of the study; incomplete responses were obtained from 147 patients, and 150 patients opted out. Principal component analysis with orthogonal (varimax) rotation was executed on a data set with all completed responses (N = 249) and applied to 43 items. Based on the review of the factor solution, eigenvalues, and item loadings, 16 items were eliminated and model with 29 items was tested. The process was repeated two more times until final model with 14 items was established. In interpreting the rotated factor pattern, an item was said to load on any given component if the factor loading was ≥0.40 for that component and was <0.40 for the other. In addition to the newly generated instrument, demographic and self-reported clinical characteristics of the study participants such as the type of prescribed hypertension medications, frequency of blood pressure monitoring, and comorbid conditions were examined. The Open Research Exchange platform allowed for ongoing input from patients through each stage of the 14-item instrument development.


A soft coordination polymer derived from container molecule ligands.
Partial collapse of the ladder-shaped tunnels of a crystalline cryptophane derived coordination polymer is monitored by single crystal X-ray diffraction.


Stress-Induced (Not Diabetic) Hyperglycemia Is Associated With Mortality in Geriatric Trauma Patients.
Stress-induced hyperglycemia (SIH) is associated with worse outcomes among trauma patients. It is also known that injured geriatric patients have higher mortality when compared to younger patients. We sought to investigate the association of all levels of SIH with mortality among geriatric trauma patients at a level 1 academic trauma center. We hypothesized that SIH in the geriatric trauma population would be associated with increased mortality. A retrospective review of all geriatric patients admitted to our level 1 trauma center over a 3-year period (January 2018-December 2020) was performed using the institutional trauma database. Data collected included demographics, injury severity score (ISS), emergency department (ED) blood glucose level, ED systolic blood pressure (SBP), and mortality. Patients were divided into 4 groups based on emergency room blood glucose level, as follows: normoglycemic (<120 mg/dL), mild hyperglycemia (120-150 mg/dL), moderate hyperglycemia (151-199 mg/dL), and severe hyperglycemia (≥200 mg/dL). Multivariable logistic regression analysis was performed to evaluate the association of SIH and in-hospital mortality adjusting for ISS, age, comorbidities, and ED SBP. A total of 4432 geriatric trauma patients were admitted during the study period, of which 3358 patients (75.8%) were not diabetic. There were 2206 females (65.7%), 2993 were White (89.2%), with a mean age of 81.5 y. There were 114 deaths (3.4%). Univariate results showed that there was a statistically significant association between mortality and glucose groups (P < 0.01). The number of deaths in the four glucose groups were, as follows: 30 (2.0%), 32 (3.8%), 20 (6.2%), and 10 (12.2%), respectively. Multivariable logistic regression analysis results showed that compared to the normoglycemic group, the risk of death was higher in the mild, moderate, and severe glucose groups, as follows: mild group (OR 1.80, 95% confidence interval [CI] 1.04-3.13, P 0.04), moderate group (OR 2.53, 95% CI 1.34-4.80, P < 0.01), and severe group (OR 5.04, 95% CI 2.18-11.67, P < 0.01). Mild, moderate, and severe SIH are statistically significant predictors of death among geriatric trauma patients independently of ISS, age, comorbidities, and SBP.


[Blood lipids in juvenile diabetes mellitus in respect to sex, age, body weight, duration of illness, quality of control and amount of insulin required (author's transl)].
Postprandial lipoproteins, serumcholesterol and serum triglycerides were measured in 76 patients with juvenile diabetes mellitus. The lipoprotein pattern was pathological in 37% [type II (Frederickson) 20%; type IV 17%]. Serum cholesterol was not significantly elevated when compared with normals, but was positively correlated with the duration of the disease. Serum triglycerides were significantly elevated compared with normals.


Endovascular repair of a primary iliac-cecal fistula presenting with gastrointestinal hemorrhage.
We report a case of an arterio-enteric fistula between an external iliac artery aneurysm and otherwise healthy cecum, presenting with torrential hemorrhage per rectum in an 85-year-old patient. Whilst fistulization to the aorta and common iliac arteries has been reported, to our knowledge no previous cases of primary fistulization between an external iliac aneurysm and normal cecum have been. Successful endovascular exclusion of the aneurysm was undertaken with a Wallgraft covered stent and the patient remains well at 1 year.


Vibrio cholera and V. parahaemolyticus coinfection in an oncology patient with gastroenteritis.
Vibrio-related gastroenteritis in the United States is mostly associated with the consumption of raw or improperly cooked seafood. We describe a case of a stage IV lung adenocarcinoma patient who became ill after eating crab while visiting Upstate New York. Molecular testing and culture confirmed a coinfection with V. parahaemolyticus and a nontoxigenic strain V. cholera.


The Caulobacter NtrB-NtrC two-component system bridges nitrogen assimilation and cell development.
A suite of molecular sensory systems enables Caulobacter to control growth, development, and reproduction in response to levels of essential elements. The bacterial enhancer binding protein (bEBP) NtrC, and its cognate sensor histidine kinase NtrB, are key regulators of nitrogen assimilation in many bacteria, but their roles in Caulobacter metabolism and development are not well defined. Notably, Caulobacter NtrC is an unconventional bEBP that lacks the σ54-interacting loop commonly known as the GAFTGA motif. Here we show that deletion of C. crescentus ntrC slows cell growth in complex medium, and that ntrB and ntrC are essential when ammonium is the sole nitrogen source due to their requirement for glutamine synthetase (glnA) expression. Random transposition of a conserved IS3-family mobile genetic element frequently rescued the growth defect of ntrC mutant strains by restoring transcription of the glnBA operon, revealing a possible role for IS3 transposition in shaping the evolution of Caulobacter populations during nutrient limitation. We further identified dozens of direct NtrC binding sites on the C. crescentus chromosome, with a large fraction located near genes involved in polysaccharide biosynthesis. The majority of binding sites align with those of the essential nucleoid associated protein, GapR, or the cell cycle regulator, MucR1. NtrC is therefore predicted to directly impact the regulation of cell cycle and cell development. Indeed, loss of NtrC function led to elongated polar stalks and elevated synthesis of cell envelope polysaccharides. This study establishes regulatory connections between NtrC, nitrogen metabolism, polar morphogenesis, and envelope polysaccharide synthesis in Caulobacter .


Modeling of geochemical processes related to uranium mobilization in the groundwater of a uranium mine.
This paper describes the processes leading to uranium distribution in the groundwater of five boreholes near a restored uranium mine (dug in granite), and the environmental impact of restoration work in the discharge area. The groundwater uranium content varied from <1 microg/L in reduced water far from the area of influence of the uranium ore-containing dyke, to 104 microg/L in a borehole hydraulically connected to the mine. These values, however, fail to reflect a chemical equilibrium between the water and the pure mineral phases. A model for the mobilization of uranium in this groundwater is therefore proposed. This involves the percolation of oxidized waters through the fractured granite, leading to the oxidation of pyrite and arsenopyrite and the precipitation of iron oxyhydroxides. This in turn leads to the dissolution of the primary pitchblende and, subsequently, the release of U(VI) species to the groundwater. These U(VI) species are retained by iron hydroxides. Secondary uranium species are eventually formed as reducing conditions are re-established due to water-rock interactions.


Improving management of tuberculosis in people living with HIV in South Africa through integration of HIV and tuberculosis services: a proof of concept study.
South Africa's tuberculosis burden is the third highest globally and is closely associated with the country's devastating HIV epidemic. The separation of HIV and TB services in primary healthcare services in South Africa hampers TB case finding in patients who are co-infected with HIV and TB. This operational proof of concept study assessed an approach to improving tuberculosis detection and treatment by integrating tuberculosis management into HIV care. The intervention involved workforce re-engineering accompanied by changes to the physical environment in three primary healthcare facilities in Gert Sibande district, Mpumalanga Province, that allowed HIV providers to test their HIV patients for TB and initiate and monitor TB treatment when indicated. To assess the proof of concept we compared the management of TB patients by HIV and TB providers, by reviewing the records of all facility patients who tested positive for tuberculosis between July 2015 and February 2016. We also considered the perceptions of healthcare providers and facility managers about the intervention through structured interviews. Approximately 30% of the 1855 patients with presumed TB in the three clinics had been identified by HIV providers. The percentage of patients consecutively tested for TB was 81.0% and 85.0% (p = 0.0551) for HIV and TB providers, respectively. Of the patients identified with TB by HIV and TB providers, 75.4% and 79.2% (p = 0.2876), respectively, were initiated on treatment. The defaulter rate was higher among HIV, compared to TB, providers (12.8% versus 4.2%). Overall, healthcare providers and facility managers had positive views of the intervention but raised concerns regarding potential increase in workload and administrative issues, as well as infection control. The results of this proof-of-concept study indicate that the full spectrum of TB services can be easily and effectively integrated into existing HIV care programs. However, a possible shift in the service providers' workload, including administrative tasks, must be tackled and effective infection control must be ensured. Further research is needed to assess the impact of TB service integration into the scope of HIV care (or other chronic care programs) on patient outcomes, including analysis of routine data.


Preclinical studies with the Faure high energy neutron facility: response of pig skin to fractionated doses of fast neutrons (66 MeVp----Be).
The early and late responses of pig skin to fractionated doses of both unfiltered and filtered (i.e. hardened) neutrons using the Faure neutron therapy facility (66 MeVp----Be) were determined and compared with those following fractionated doses with 60Co gamma-rays. Dose-effect curves for the quantal responses of moist desquamation (early epithelial response) and dermal necrosis (late response) were fitted by probit analysis and ED50 values obtained. For a neutron fractionation scheme comprised of 12 fractions in 26 days, and using an unfiltered beam, the ED50 values for moist desquamation and dermal necrosis were 18.67 +/- 2.22 and 22.25 +/- 0.48 Gy, respectively, whereas in the case of the filtered beam, the corresponding ED50 values were 24.78 +/- 1.44 and 23.30 +/- 0.47 Gy. In order to provide a comparison, the values for 24 fractions of 60Co gamma-rays given in 39 days (a clinical protocol used in the Groote Schuur Hospital) were 74.02 +/- 2.92 and 66.72 +/- 1.93 Gy for moist desquamation and dermal necrosis, respectively. For the unfiltered beam, values for the comparative biological effectiveness (CBE) were 3.96 and 3.00 for the early and late skin response, respectively. The corresponding CBE values were for the filtered beam 2.99 and 2.86. These results for the Faure neutron therapy facility can be extrapolated to the human situation with a high degree of confidence, so that the neutron dose which would yield acceptable skin damage in patients may be determined using the data presented here.


[Difficulties in extubation--example of an extubation hindrance caused by a stomach tube].
Difficulties in effecting extubation are rare incidents that are difficult to assess systematically, the reasons being often of a rather odd nature. In the example reported here a stomach tube had been responsible for extubation problems. The authors review the literature published so far on this subject.


Polyhydroxyalkanoate biosynthesis and optimisation of thermophilic Geobacillus stearothermophilus strain K4E3_SPR_NPP.
Polyhydroxyalkanoates (PHA) can be used to combat the challenges associated with plastic because it is biodegradable and can be produced from renewable resources. Extremophiles are considered to be potential PHA producers. An initial screening for the PHA synthesizing ability of a thermophilic bacteria Geobacillus stearothermophilus strain K4E3_SPR_NPP was carried out using Sudan black B staining. Nile red viable colony staining was used to further verify that the isolates produced PHA. Crotonic acid assays were used to determine the concentrations of PHA. The bacteria showed 31% PHA accumulation per dry cell weight (PHA/DCW) when glucose was used as a carbon source for growth. The molecule was identified to be medium chain length PHA, A copolymer of PHA containing poly(3-hydroxybutyrate)-poly(3-hydroxyvalerate)-poly(3-hydroxyhexanoate) (PHB-PHV-PHHX) using 1H-NMR. Six carbon sources and four nitrogen sources were screened for the synthesis of maximum PHA content, of which lactose and ammonium nitrate showed 45% and 53% PHA/DCW respectively. The important factors in the experiment are identified using the Plackett-Burman design, and optimization is performed using the response surface method. Response surface methodology was used to optimize the three important factors, and the maximum biomass and PHA productions were discovered. Optimal concentrations yielded a maximum of 0.48 g/l biomass and 0.32 g/l PHA, measuring 66.66% PHA accumulation. Dairy industry effluent was employed for the synthesis of PHA, yielding 0.73 g/l biomass and 0.33 g/l PHA, measuring 45% PHA accumulation. These findings add credibility to the possibility of adopting thermophilic isolates for PHA production using low-cost substrates.


Dynamics of ramping bursts in a respiratory neuron model.
Intensive computational and theoretical work has led to the development of multiple mathematical models for bursting in respiratory neurons in the pre-Bötzinger Complex (pre-BötC) of the mammalian brainstem. Nonetheless, these previous models have not captured the pre-inspiratory ramping aspects of these neurons' activity patterns, in which relatively slow tonic spiking gradually progresses to faster spiking and a full-blown burst, with a corresponding gradual development of an underlying plateau potential. In this work, we show that the incorporation of the dynamics of the extracellular potassium ion concentration into an existing model for pre-BötC neuron bursting, along with some parameter adjustments, suffices to induce this ramping behavior. Using fast-slow decomposition, we show that this activity can be considered as a form of parabolic bursting, but with burst termination at a homoclinic bifurcation rather than as a SNIC bifurcation. We also investigate the parameter-dependence of these solutions and show that the proposed model yields a greater dynamic range of burst frequencies, durations, and duty cycles than those produced by other models in the literature.


Yomogin, an inhibitor of nitric oxide production in LPS-activated macrophages.
In activated macrophages the inducible form of nitric oxide synthase (i-NOS) generates high amounts of toxic mediator, nitric oxide (NO) which contributes to the circulatory failure associated with septic shock. A sesquiterpene lactone compound (yomogin) isolated from medicinal plant Artemisia princeps Pampan inhibited the production of NO in LPS-activated RAW 264.7 cells by suppressing i-NOS enzyme expression. Thus, yomogin may be a useful candidate for the development of new drugs to treat endotoxemia and inflammation accompanied by the overproduction of NO.


On the anthropological foundation of bioethics: a critique of the work of J.-F. Malherbe.
In this article, I critically analyze the anthropological foundation of the bioethics of philosopher Jean-François Malherbe, particularly as presented in his book, Pour une Éthique de la Médecine. Malherbe argues that such practices as organ donation and transplants, assisted reproduction, resuscitation, and other uses of biotechnologies in contemporary medicine are unethical because they go against essential human nature. Furthermore, he uses this position as a basis to prescribe public policy and institutional practice. In contrast, I argue not only that 'human nature' is much more malleable and adaptive to changes in technology and society than Malherbe allows, but also that his criticisms of medicine and technoscientific development overstep the bounds of the social function of philosophical ethics, which is to inform and clarify public debate. Public policy and institutional practice is thus best left to the democratic political process under the parameters of the just rule of law.


New spectral resolution techniques for resolving and determining the components in binary fixed-dose combinations.
Four spectrophotometric approaches were performed to determine a binary combination of Phenazone and Benzocaine in pure powder form and in pharmaceutical formations. This investigation submits the application of four techniques contingent on the presence of the extended area of the spectra of one compound in the binary mixture, these methods include Absorptivity Centering (a-centering), Absorbance Subtraction (AS), Amplitude Modulation (AM) and Concentration Value (CV). The linearity range for the above-mentioned approaches was found to be 3.0-15.0 μg/mL for Benzocaine in a-centering method and 3.0-30.0 μg/mL for Benzocaine and Phenazone in other advanced methods. The four techniques were evaluated as per ICH criteria and were successfully utilized for the determination of Phenazone and Benzocaine existing in pharmaceutical formulations. All results gained by the submitted approaches were statistically compared with a previously published method, and no important differences were detected.


Measure of microhardness, fracture toughness and flexural strength of N-vinylcaprolactam (NVC)-containing glass-ionomer dental cements.
To investigate the effects of N-vinylcaprolactam (NVC)-containing terpolymers on the fracture toughness, microhardness, and flexural strength of conventional glass-ionomer cements (GIC). The terpolymer of acrylic acid (AA)-itaconic acid (IA)-N-vinylcaprolactam (NVC) with 8:1:1 (AA:IA:NVC) molar ratio was synthesized by free radical polymerization and characterized using (1)H NMR and FTIR. Experimental GIC samples were made from a 50% solution of the synthesized terpolymer with Fuji IX powder in a 3.6:1 P/L ratio. Specimens were mixed and fabricated at room temperature. Plane strain fracture toughness (K(Ic)) was measured in accordance with ASTM Standard 399-05. Vickers hardness was determined using a microhardness tester. Flexural strength was measured using samples with dimensions of 2 mm×2 mm×20 mm. For all mechanical property tests, specimens were first conditioned in distilled water at 37°C for 1 day or 1 week. Fracture toughness and flexural strength tests were conducted on a screw-driven universal testing machine using a crosshead speed of 0.5mm/min. Values of mechanical properties for the experimental GIC were compared with the control group (Fuji IX GIC), using one-way ANOVA and the Tukey multiple range test at α=0.05. The NVC-modified GIC exhibited significantly higher fracture toughness compared to the commercially available Fuji IX GIC, along with higher mean values of flexural strength and Vickers hardness, which were not significantly different. It was concluded that NVC-containing polymers are capable of enhancing clinically relevant properties for GICs. This new modified glass-ionomer is a promising restorative dental material.


The reception of Darwin in late nineteenth-century German paleontology as a case of pyrrhic victory.
This paper investigates German-speaking paleontologists' reception of Darwin's thought and the ways in which they negotiated their space of knowledge production accordingly. In German-speaking regions, the majority of paleontologists welcomed Darwin's magnum opus, since it granted paleontology an independent voice within biology, and thus a new institutional setting. However, in the process of negotiating the features of paleontology within the Darwinian framework, German paleontologists constrained their practices too narrowly, for fear of leaving open possible results at odds with the burgeoning Darwinian biological community. In doing so, they also limited the further development of German paleontology. In other words, paleontologists Karl Alfred von Zittel (1839-1904) and Melchior Neumayr (1845-1890) advocated for a handmaid's role for paleontology, which increased biologists' dependence on paleontologists for empirical evidence, but which limited paleontologists' theoretical autonomy. By analyzing both the institutional strategies and the methodology of German-speaking paleontology at the end of the nineteenth century, this paper shows the importance of scientists' ability to enter into and negotiate their place within the broader biological community.


Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury.
We have determined whether lowering brain temperature during the acute recirculation period following transient cerebral ischemia would influence the extent of ischemic neuronal injury. Anesthetized rats underwent 10 min of bilateral carotid artery occlusion combined with systemic hypotension (50 mmHg). Four animal subgroups were investigated, including non-ischemic controls; rats whose postischemic brain temperature was maintained at 36 or 30 degrees C starting 5 min into the recirculation period; and rats in which postischemic hypothermia was begun 30 min into the recirculation period. In all cases, intra-ischemic brain temperature was 36 degrees C and body temperature was held at 36-37 degrees C throughout. Three days following the ischemic insult, the CA1 sector of the hippocampus was severely damaged in normothermic rats (36 degrees C). In contrast, when postischemic brain temperature was decreased to 30 degrees C starting 5 min into the recirculation period, normal-appearing pyramidal neurons were present throughout the CA1 hippocampus. A beneficial effect of postischemic hypothermia was not demonstrated when brain cooling was initiated 30 min into the recirculation period. These results demonstrate that postischemic hypothermia can markedly protect CA1 pyramidal neurons from injury following transient ischemia. The 'therapeutic window' for postischemic hypothermia was found to be narrow under the present experimental conditions.


Use of an AC induction motor system for producing finger movements in human subjects.
This report describes the set-up and evaluation of a novel system for producing precise finger movements, for tests of movement perception. The specifications were to construct a system using commercially available components that were easy to use but which offered both flexibility and also high precision control. The system was constructed around an industrial AC induction motor with an optical encoder, controlled by an AC servo digital control module that could be programmed using a simple, high-level language. This set-up fulfilled the requirements regarding position and velocity control for a range of movements and also the facility for the subject to move the joint voluntarily while still attached to the motor. However a number of problems were encountered, the most serious being the level of vibration and the inability to vary the torque during movements. The vibration was reduced to the point where it did not affect the subject, by the introduction of mechanical dampening using an anti-vibration coupling and a pneumatic splint. The torque control could not be modified during rotation and so the system could only be operated using constant torque for any given movement.


Suboptimal response to clopidogrel: a genetic risk factor for recurrent ischaemic stroke.
Anti-platelet agents (APA) are widely used in the secondary prevention of ischaemic stroke but about 30% of patients derive suboptimal platelet inhibition from APA. An underlying cause for suboptimal platelet inhibition is varying response to clopidogrel, which is linked to polymorphisms in the CYP2C19 gene responsible for the metabolism and activation of clopidogrel. CYP2C19 polymorphism influences clinical outcomes in patients with coronary artery disease, particularly among those treated with percutaneous transluminal coronary artery stenting. Randomized controlled trials have shown that high doses of clopidogrel can overcome suboptimal platelet response in carriers of the CYP2C19(∗)2 allele. The United States Food and Drug Administration has issued a boxed warning advising clinicians to consider genotyping patients prior to prescribing clopidogrel. There are ongoing studies investigating the clinical utility of genotyping to inform management decisions in stroke prevention.


Membrane-associated 41-kDa GTP-binding protein in collagen-induced platelet activation.
Initially we established that the binding of collagen to human blood platelets stimulates both the rapid loss of PIP2 and the generation of inositol-4,5-bisphosphate (IP2) and inositol-1,4,5-triphosphate (IP3). These results indicate that the binding of collagen stimulates inositol phospholipid-specific phospholipase C during platelet activation. The fact that GTP or GTP-gamma-S augments, and pertussis toxin inhibits, collagen-induced IP3 formation suggests that a GTP-binding protein (or (or proteins) may be directly involved in the regulation of phospholipase C-mediated phosphoinositide turnover in human platelets. We have used several complementary techniques to isolate and characterize a platelet 41-kDa polypeptide (or polypeptides) that has a number of structural and functional similarities to the regulatory alpha i subunit of the GTP-binding proteins isolated from bovine brain. This 41-kDa polypeptide (or polypeptides) is found to be closely associated with at least four membrane glycoproteins (e.g., gp180, gp110, gp95, and gp75) in a 330-kDa complex that can be dissociated by treatment with high salt plus urea. Most important, we have demonstrated that antilymphoma 41-kDa (alpha i subunit of GTP-binding proteins) antibody cross-reacts with the platelet 41-kDa protein (or proteins) and the alpha i subunit of bovine brain Gi alpha proteins, and blocks GTP/collagen-induced IP3 formation. These data provide strong evidence that the 41-kDa platelet GTP-binding protein (or proteins) is directly involved in collagen-induced signal transduction during platelet activation.


Allergenic and antigenic relationship between three species of storage mite and the house dust mite, Dermatophagoides pteronyssinus.
We have explored the antigenic and allergenic relationship between the house dust mite Dermatophagoides pteronyssinus and three species of storage mite, Glycyphagus destructor, Acarus siro, and Tyrophagus longior. Crossed immunoelectrophoresis demonstrated that all the mite extracts contained multiple antigens but that there was only limited cross-reactivity between the different species. Six sera were obtained from workers exposed to storage mites and with occupationally related lower respiratory tract symptoms. All workers had specific IgE to D. pteronyssinus and to one or more of the storage mites. The pattern of reactivity varied between the different sera, two responded primarily to D. pteronyssinus and A. siro and four sera to D. pteronyssinus and G. destructor. Only weak responses were observed to T. longior. RAST-inhibition and affinity-absorption experiments demonstrated that D. pteronyssinus had at least three groups of distinct allergenic determinants, determinants specific to D. pteronyssinus, determinants shared with A. siro, and determinants shared with G. destructor. Similarly, both A. siro and G. destructor have specific allergenic determinants and determinants shared with D. pteronyssinus. The findings demonstrate the complexity of the immunologic responses to the different mite species.


Structural Biology of the Zika Virus.
Zika virus (ZIKV), a Flaviviridae family member transmitted to humans by mosquitoes, has emerged as a major health concern. ZIKV infections can cause serious neurological complications in adults, and infection in pregnant women can cause congenital malformations, including fetal and newborn microcephaly. In response to this emerging concern, the structural virology field was quick to explore the features of ZIKV. These efforts have provided significant insights into ZIKV pathogenesis, and have identified targets for drug design. Here, we review the remarkable progress in structure-based ZIKV research and discuss the current challenges and future opportunities.


Who's in charge here? Regulating cell cycle regulators.
Recent studies have illuminated key features of the transcriptional and signal transduction networks governing the cell division cycle of Caulobacter crescentus. These mechanisms generate oscillations in the activity of CtrA, a key regulator of DNA replication and transcription of cell cycle regulated genes. ctrA transcription is itself regulated as part of a cascade of transcriptional regulators, each of which drives the synthesis of proteins needed at different stages of the cell cycle. The CtrA protein is post-transcriptionally regulated by an extended network of two-component signaling proteins and by proteolysis. Proteins within these pathways are localized at opposite ends of the cell to generate two progenies in different stages of the cell cycle upon cell division.


Glyceraldehyde-3-phosphate dehydrogenase acts as an adhesin in Erysipelothrix rhusiopathiae adhesion to porcine endothelial cells and as a receptor in recruitment of host fibronectin and plasminogen.
Erysipelothrix rhusiopathiae is the causative agent of animal erysipelas and human erysipeloid. Previous studies suggested glyceraldehyde 3-phosphate dehydrogenase (GAPDH) plays a role in the pathogenesis of E. rhusiopathiae infection. We studied E. rhusiopathiae GAPDH interactions with pig vascular endothelial cells, fibronectin, and plasminogen. Recombinant GAPDH (rGAPDH) was successfully obtained, and it was shown that it plays a role in E. rhusiopathiae adhesion to pig vascular endothelial cells. Moreover, rGAPDH could bind fibronectin and plasminogen in a dose-dependent manner. To our knowledge, this is the first study demonstrating that a moonlighting protein plays a role in pathogenesis of E. rhusiopathiae infections.


[POSSIBILITIES OF THE RAOIOFREQUENCY ABLATION METHOD IN TREATMENT OF PULMONARY AND PLEURAL MALIGNANCIES].
Various methods of radiofrequency ablation, using FOTEK-150 apparatus, were applied in 74 patients for pulmonary and pleural malignancies. Immediate positive effect was achieved in 92% observations, complications have occurred in 13% patients. It is expedient to use the method in patients, suffering pulmonary and pleural malignancies, when radical surgery is impossible. Radiofrequency ablation may be applied as a palliative method of treatment of pulmonary and pleural malignancies.


alpha2 adrenoceptors are involved in the regulation of the gripping-induced immobility episodes in taiep rats.
In 1989 Holmgren et al. (Holmgren et al. 1989 Lab Anim Sci 39:226-228) described a new mutant rat that developed a progressive motor disturbance during its lifespan. The syndrome is characterized by a tremor in the hind limbs followed by ataxia, episodes of tonic immobility, epilepsy, and paralysis. The acronym of these symptoms (taiep) became the name of this autosomic, recessive mutant rat. The taiep rats are neurological mutant animals with a hypomyelination, followed by a progressive demyelination process. At 7-8 months of age, taiep rats develop immobility episodes (IEs) characterized by a cortical desynchronization, associated with the theta rhythm in the hippocampus and changes of the nucal electromyogram (EMG), whose pattern is like rapid-eye-movement (REM) sleep. These rats also show an altered sleep pattern with an equal REM sleep distribution. This study analyzed therole of alpha(2) adrenoceptors in the expression of gripping-induced IEs in 8-month-old male taiep rats. The alpha(2) adrenoceptor agonists clonidine and xylacine increased the frequency of gripping-induced IEs whereas the alpha(2) antagonists yohimbine and idazoxandecreased or prevented such episodes. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which alpha(2) adrenergic mechanisms are involved in the modulation of cataplexy. Unexpectedly, the repetitive administration of clonidine resulted in jumping behavior, indicative of phasic activation of extensor musculature. Taken together, our results show that alpha(2) adrenoceptors are involved in the modulation in gripping-induced IEs and after the administration of several doses of clonidine produced phasic motor activation.


Dependence of cAMP meditated increases in Cl- and HCO(3)- permeability on CFTR in bovine corneal endothelial cells.
The cystic fibrosis transmembrane conductance regulator (CFTR) is present on the apical membrane of corneal endothelial cells. Increasing intracellular [cAMP] with forskolin stimulates an NPPB and glibenclamide-inhibitable apical Cl(-) and HCO(3)(-) permeability [Sun, X.C., Bonanno, J.A., 2002. Expression, localization, and functional evaluation of CFTR in bovine corneal endothelial cells. Am. J. Physiol. Cell Physiol. 282, C673-C683]. To definitively determine that the increased permeability is dependent on CFTR, we used an siRNA knockdown approach. Apical Cl(-) and HCO(3)(-) permeability and steady-state HCO(3)(-) flux were measured in the presence or absence of forskolin using cultured bovine corneal endothelial cells that were transfected with CFTR siRNA or a scrambled sequence control. CFTR protein expression was reduced by approximately 80% in CFTR siRNA treated cultures. Forskolin (10 microM) increased apical chloride permeability by 7-fold, which was reduced to control level in siRNA treated cells. CFTR siRNA treatment had no effect on baseline apical chloride permeability. Apical HCO(3)(-) permeability was increased 2-fold by 10 microM forskolin, which was reduced to control level in siRNA treated cultures. Similarly, there was no effect on baseline apical HCO(3)(-) permeability by knocking down CFTR expression. The steady-state apical-basolateral pH gradient (DeltapH) at 4h in control cultures was increased approximately 2.5-fold by forskolin. In CFTR siRNA treated cells, the baseline DeltapH was similar to control, however forskolin did not have a significant effect. We conclude that forskolin induced increases in apical HCO(3)(-) permeability in bovine corneal endothelium requires CFTR. However, CFTR does not have a major role in determining baseline apical chloride or HCO(3)(-) permeability.


Mystery of PCO2 Gap in Sepsis.
How to cite this article: Patil VP. Mystery of PCO2 Gap in Sepsis. Indian J Crit Care Med 2019;23(10):443-444.


The effect of FTO gene rs9939609 polymorphism on the association between colorectal cancer and different types of dietary fat intake: a case-control study.
Colorectal cancer (CRC) is one of the most common cancers in the world. Some dietary factors such as fat intake have been identified as the risk factors for CRC. This study aimed to investigate the effect of fat mass and obesity-associated (FTO) gene rs9939609 polymorphism on the association between CRC and different types of dietary fats. This case-control study was performed on 135 CRC cases and 294 healthy controls in Tehran, Iran. Data on demographic factors, anthropometric measurements, physical activity, the intake of different types of dietary fats, and FTO gene rs9939609 polymorphism was collected from all participants. The association between cancer and dietary fat intake in individuals with different FTO genotypes was assessed using different models of logistic regression. Oleic acid intake was higher in the case group compared to the control group in both people with TT (7.2±3.46 vs. 5.83±3.06 g/d, P=0.02) and AA/AT genotypes (8.7±6.23 vs. 5.57 ±3.2 g/d, P<0.001). Among carriers of AA/AT genotypes of FTO rs9939609 polymorphism, a positive association was found between CRC and higher intakes of oleic acid (OR=1.12, CI95% 1.03-1.21, P=0.01) and cholesterol (OR=1.01, CI95% 1.00-1.02; P=0.01) after adjusting for age, sex, physical activity, alcohol use, smoking, calorie intake, and body mass index. Higher intakes of cholesterol and oleic acid were associated with a higher risk of CRC in FTO-risk allele carriers. The association of CRC and dietary fat may be influenced by the FTO genotype. Further longitudinal studies are warranted to confirm these findings.


Patients presenting at the emergency department with acute abdominal pain are less likely to be admitted to inpatient wards at times of access block: a registry study.
Also known as access block, shortage of inpatient beds is a common cause of emergency department (ED) boarding and overcrowding, which are both associated with impaired quality of care. Recent studies have suggested that access block not simply causes boarding in EDs, but may also result in that patients are less likely to be admitted to the hospital from the ED. The present study's aim was to investigate whether this effect remained for patients with acute abdominal pain, for which different management strategies have emerged. Access block was defined in terms of hospital occupancy and the appropriateness of ED discharges addressed as 72 h revisits to the ED. As a registry study of ED administrative data, the study examined a population of patients who presented with acute abdominal pain at the ED of a 420-bed hospital in southern Sweden during 2011-2013. Associations between exposure and outcomes were addressed in contingency tables and by logistic regression models. Crude analysis revealed a negative association between access block and the probability of inpatient admission (38.6 % admitted at 0-95 % occupancy, 37.8 % at 95-100 % occupancy, and 35.0 % at ≥ 100 % occupancy) (p < .001). No significant associations between exposure and 72 h revisits emerged. Multivariable models indicated an odds ratio of inpatient admission of 0.992 (95 % CI: 0.986-0.997) per percentage increase in hospital occupancy. Study findings indicate that patients with acute abdominal pain are less likely to be admitted to the hospital from the ED at times of access block and that other management strategies are employed instead. No association with 72 h revisits was seen, but future studies need to address more granular outcomes in order to clarify the safety aspects of the effect.


Open abdomen and age; results from IROA (International Register of Open Abdomen).
No definitive data exist regarding epidemiology and outcomes of patients treated with open abdomen (OA) linked to age. This is a prospective, observational, cohort study that includes patients treated with OA. Patients were divided into 4 age groups: group 1: 16-40 y.o.; group 2: 41-60 y.o.; group 3:61-80 y.o.; group 4:> 80 y.o. 760 patients were enrolled. Average age was 60 ± 18aa; 57.2% were males. Most frequent indication was peritonitis (50.9%). Mean open duration of open abdomen was8±18 days. Definitive closure was reached in 81.1% of patients. Complications were recorded in 84.8% of patients with significant differences between groups (p = 0.001). Overall mortality was41.2% with significant differences between groups (p < 0.001) (group 1 25.6%, group 2 36.1%, group 3 44.5%, group 4 67.1%) 1 month follow-up mortality post-OA was 9.2% and 1 year follow-up mortality was 11.6%; CONCLUSIONS: Open abdomen treatment is feasible at every age. Diseases requiring treatment with OA are differently distributed in relation to the different age groups. Advanced age has negative effect on complications and mortality rate.


Multiple changes in the sensitivity of cingulate cortical neurones to putative neurotransmitters in ageing rats: substance P, acetylcholine and noradrenaline.
The responsiveness of neurones in the anterior cingulate cortex to iontophoretically applied substance P(SP), acetylcholine (ACh), noradrenaline (NA) and GABA was compared in young (3-4 months) and old (24-30 months) rats. Neurones in the old rats were less sensitive to the depressant effects of NA but not GABA. These cells were also less sensitive to the excitatory actions of ACh but markedly more sensitive to those of SP. Such changes in responsiveness could be involved in the deficits in cerebral function which often occur in old age.


Neuroprotective effect of pharmacological postconditioning on cerebral ischaemia-reperfusion-induced injury in mice.
To investigate the mechanism of neuroprotection rendered via pharmacological postconditioning in cerebral ischaemia-reperfusion-induced injury in mice. Pharmacological postconditioning is strategy which either involves hindering deleterious pathway or inducing modest stress level which triggers intracellular defence pathway to sustain more vigorous insult leading to conditioning. Hence, in current research we explored the potentiality of CGS21680 (0.5 mg/kg; i.p), an adenosine A2 A receptor agonist and PTEN inhibitor, SF1670 (3 mg/kg; i.p.) to trigger postconditioning after inducing cerebral global ischaemia (17 min) and reperfusion (24 h)-induced injury via occlusion of both carotid arteries. Mice were also given treatment with LY294002 (1.5 mg/kg; i.p.), a PI3K inhibitor and adenosine A2 A receptor antagonist, Istradefylline (2 mg/kg; i.p.), to establish the precise mechanism of postconditioning. Various biochemical and behavioural parameters were assessed to examine the effect of pharmacological postconditioning. Pharmacological postconditioning induced with CGS21680 and SF1670 attenuated the infarction along with improved behavioural and biochemical parameters in comparison with ischaemia-reperfusion control group. The outcome of postconditioning with CGS21680 and SF1670 was significantly reversed by LY294002 and Istradefylline, respectively. The neuroprotective effects of CGS21680 and SF1670 postconditioning on cerebral ischaemia-reperfusion injury may be due to PI3K/Akt pathway activation.