Elevated plasma TFPI activity causes attenuated TF-dependent thrombin generation in early onset preeclampsia.
Early onset preeclampsia (EOP) is a pregnancy-specific proinflammatory disorder that is characterised by competing thrombotic and bleeding risks. It was the aim of this study to characterise thrombin generation, a major determinant of thrombotic and bleeding risk, in order to better understand the haemostatic balance in patients with EOP. Patients with EOP were recruited at the Rotunda Hospital, Dublin. Twenty-six cases of EOP were recruited over a 21-month period, out of 15,299 deliveries at the Rotunda. Blood samples were collected into sodium citrate plus corn trypsin inhibitor anticoagulated vacutainers, platelet-poor plasma was prepared, and calibrated automated thrombography was used to assess thrombin generation. Results were compared to age and sex-matched non-pregnant controls (n=13) and age- and gestation-matched pregnant controls (n=20). The rate and extent of thrombin generation triggered by low-dose tissue factor (TF) was significantly reduced in patients with EOP compared to pregnant controls, most significantly in cases of severe EOP. EOP patients displayed a trend towards an increased response to endogenous activated protein C and thrombomodulin relative to pregnant controls. Plasma tissue factor pathway inhibitor (TFPI) activity was increased in EOP patients. Inhibition of TFPI abolished the attenuation of thrombin generation stimulated by low-dose TF. In conclusion, patients with EOP are characterised by an attenuated coagulation response characterised by reduced thrombin generation stimulated by low-dose TF and elevated plasma TFPI activity. These changes in coagulation may modulate thrombotic risk and bleeding risk in patients with EOP.


Prognostic impact of incomplete hematologic count recovery and minimal residual disease on outcome in adult acute lymphoblastic leukemia at the time of second complete response.
Outcomes of relapsed adult acute lymphoblastic leukemia (ALL) have improved over time with the introduction of new therapies as well as better supportive care. However, there is still a need for easy-to-use and accurate prognostic tools for patients in first relapse. Whether complete response (CR) with incomplete count recovery (CRh) can be grouped with CR in relapsed ALL trials has not been formally studied. We analyzed 106 ALL patients at first relapse who were treated at three academic centers and achieved CR/CRh. White blood cell count at initial diagnosis and receiving hematopoietic cell transplant (HCT) were independent predictors of overall survival after relapse, while minimal residual disease (MRD) positivity and performance of HCT were predictors of relapse free survival (RFS). Patients who achieved MRD negativity and underwent HCT had the best outcomes. Our results suggest that MRD is a more powerful predictor of outcome than CRh.


A novel low density metal-organic framework with pcu topology by dendritic ligand.
A novel low density two-fold interpenetrated MOF-5 analogue with pcu topology, JUC-100, was designed and prepared successfully. It can be regarded as MOF-5 in which half of the Zn(4)O(CO(2))(6) units are replaced by organic 1,3,5-triphenylbenzene segments. JUC-100 exhibits H(2) uptake ability comparable to interpenetrated MOF-5, but relatively low initial isosteric heat of adsorption.


High-Quality Indigo Naturalis Obtained with Automatic Foam Separation.
Indigo Naturalis is not only an ancient plant dye but also a famous herbal medicine with antibacterial, anti-inflammatory, and anticancer properties. In traditional processes, thousands of manual stirring separate the high-quality Indigo Naturalis from the crude pulp system. However, this method is time-consuming and labor-intensive, resulting in an unstable quality and low yield, which cannot meet the requirements of modern industrial production. In this study, foam-separation technology was used to increase the industrial applicability of high-quality Indigo Naturalis. The process parameters were optimized based on the content of active ingredients, skin irritation effects, and antioxidative stress activity. The results showed that the optimal process of the foam separation achieved the liquid level difference of 40 cm and the foaming intensity of 0.35 MPa. Compared with the original sample, the indigo and indirubin contents in purified Indigo Naturalis were 1.6 and 3 times higher, the total ash content decreased from 86 to 70%, the pH value decreased from 12.18 to 9.71, and the leachate doubled. Animal experiments suggested the significantly reduced irritation (p < 0.01) and enhanced antioxidative stress activity (p < 0.01) of Indigo Naturalis after foam separation. Therefore, the foam-separation equipment developed in this study enabled the refinement of active ingredients in Indigo Naturalis, which greatly improved the production efficiency and quality.


Design and methods of a national, multicenter, randomized and controlled trial to assess the efficacy of a physical activity program to improve health-related quality of life and reduce fatigue in women with metastatic breast cancer: ABLE02 trial.
Patients with a metastatic breast cancer suffer from a deteriorated health-related quality of life and numerous symptoms such as pain, severe fatigue and a decrease of their physical fitness. As the feasibility of a physical activity program has been demonstrated in this population, ABLE02 aims to assess the efficacy of a 6 month-physical activity program using connected devices to improve health-related quality of life and to reduce fatigue in women with metastatic breast cancer. ABLE02 is a prospective, national, multicenter, randomized, controlled and open-label study. A total of 244 patients with a metastatic breast cancer, with at least one positive hormone receptor and a first-line chemotherapy planned, will be randomly assigned (1:1 ratio) to: (i) the intervention arm to receive physical activity recommendations, an activity tracker to wear 24 h a day during the whole intervention (6 months) with at least three weekly walking sessions and quizzes each week on physical activity and nutrition (ii) the control arm to receive physical activity recommendations only. Health-related quality of life will be assessed every 6 weeks and main assessments will be conducted at baseline, M3, M6, M12 and M18 to evaluate the clinical, physical, biological and psychological parameters and survival of participants. All questionnaires will be completed on a dedicated application. An activity program based on a smartphone application linked to an activity tracker may help to improve quality of life and reduce fatigue of patients with a metastatic breast cancer. The growth of e-health offers the opportunity to get real-time data as well as improving patient empowerment in order to change long-term behaviors. NCT number: NCT04354233 .


Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis.
Dupilumab, the first biologic approved for treatment of atopic dermatitis, has demonstrated significant clinical effect and quality of life-enhancing capacity in clinical trials. In these, dupilumab-associated conjunctivitis where reported in a minority of patients. The present case series describe 10 patients treated with dupilumab where eye complications were very common. We have described patient characteristics, including FLG mutations, atopic history and clinical effect of dupilumab. Nine of 10 developed eye-complications, most commonly conjunctivitis (in 7/10). Other adverse events were herpes simplex virus uveitis and varicella-zoster virus meningitis. Although our case series is small, we conclude that dupilumab is an effective treatment option in severe atopic dermatitis, but that the risk of adverse events from the eyes and recurrence of herpes virus infections should be kept in mind. Close collaboration with an ophthalmologist is recommended, especially among patients with severe, long-lasting atopic dermatitis and/or previous eye disease.


Clinical Algorithms with Race: An Online Database.
Some clinical algorithms incorporate a person's race, ethnicity, or both as an input variable or predictor in determining diagnoses, prognoses, treatment plans, or risk assessments. Inappropriate use of race and ethnicity in clinical algorithms at the point of care may exacerbate health disparities and promote harmful practices of race-based medicine. This article describes a comprehensive search of online resources, the scientific literature, and the FDA Drug Label Information that uncovered 39 race-based risk calculators, six laboratory test results with race-based reference ranges, one race-based therapy recommendation, and 15 medications with race-based recommendations. These clinical algorithms based on race are freely accessible through an online database. This resource aims to raise awareness about the use of race-based clinical algorithms and track the progress made toward eradicating the inappropriate use of race. The database will be actively updated to include clinical algorithms based on race that were previously omitted, along with additional characteristics of these algorithms.


Relativistic corrections to electrical first-order properties using direct perturbation theory.
Direct perturbation theory (DPT) is applied to compute relativistic corrections to electrical properties such as dipole moment, quadrupole moment, and electric-field gradient. The corrections are obtained as second derivatives of the energy and are given via method-independent expressions that involve the first derivative of the density matrix with respect to the relativistic perturbation as well as property integrals with additional momentum operators. Computational results obtained using Hartree-Fock (HF), second-order Moller-Plesset (MP2) perturbation theory, and the coupled-cluster singles and doubles approach augmented by a perturbative treatment of triple excitations are presented for the hydrogen halides HX with X=F, Cl, Br, (I, At) and the magnitude of relativistic effects, their basis-set dependence, and the limitations of DPT are discussed. We compare our results to those obtained using the second-order Douglas-Kroll method and benchmark them using four-component HF (Dirac-HF) and MP2 calculations. Relativistic effects are shown to be already important for elements of the third row (Na-Ar) when aiming at a high-accuracy quantum-chemical treatment. DPT provides reliable results for compounds containing elements up to the fourth period (K-Kr) and only breaks down when applied in lowest order to heavier elements. As a first application of the present DPT treatment for electrical properties, we report calculations for bromofluoromethane (CH(2)FBr) which was investigated using rotational spectroscopy by Cazzoli et al. [Mol. Phys. 106, 1181 (2008)] and for which consideration of relativistic effects turns out to be essential for good agreement between theory and experiment in the case of the bromine quadrupole-coupling constant.


Treating tachyarrhythmias with radiofrequency catheter ablation.
Fast, safe, and effective, radiofrequency catheter ablation is becoming more common as a treatment for tachyarrhythmias. This article describes the procedure, which patients are eligible for it, and nursing considerations before, during, and after the procedure.


[The effect of the antigenic fractions of the outer membrane of Francisella tularensis on the T-cell immunity indices].
The immunological evaluation of the influence of individual gel-chromatographic antigenic fractions (GAF) of F. tularensis outer membrane on different forms of T-cell reactiveness, such as delayed hypersensitivity (DH), proliferation of lymphocytes in the reaction of blast transformation (RBT) and mixed lymphocyte culture (MLC), has been made. As revealed in this study, GAF isolated from F. tularensis produce a pronounced immunomodulating effect on the processes linked with polyclonal activation of T-lymphocytes. Thus, GAF II with a molecular weight of 85-200 kD inhibits the maturation and activity of T-effectors of DH, the proliferation of lymphocytes in RBT and MLC. On the contrary, GAF IV with a molecular weight of 15-35 kD produces a stimulating effect on T-cells in the immune system in all the parameters under study.


The Complete Genome Sequences of Iris sibirica and Iris virginica (Iridaceae, Asparagales).
We present the complete genome sequences of Iris sibirica and Iris virginica. Illumina sequencing was performed on genetic material from individual cultivated specimens. The reads were assembled using a de novo method followed by a finishing step. The raw and assembled data are publicly available via Genbank.


Re-examining the significance of surgical volume to breast cancer survival and recurrence versus process quality of care in Taiwan.
This study explored the association of surgical volume versus process quality with breast cancer survival and recurrence. Population-based cancer registration data and National Health Insurance claim data. This population-based study linked Taiwan's Cancer Database with Taiwan's National Health Insurance Database to collect data on all patients diagnosed with breast cancer in 2003-2004 who received surgical treatment. This study included 6,396 female breast cancer patients, reported by 26 hospitals. After controlling for patient and provider characteristics, Cox's regression models did not reveal any association between a physician's surgical volume and breast cancer recurrence or survival, although hospital volume was marginally associated with positive 5-year recurrence (HR: 1.001, 95%CI: 1.000, 1.001). After controlling for hospital or physician volume of surgery, we found a significant association between quality of care and both 5-year survival and recurrence. Random effects were also identified between patients and providers based on 5-year survival and 5-year recurrence. Process quality of care was significantly more related to survival or recurrence than to surgical volume. The random effects found within hospital-patient clustered data indicated that the effect of the clustered feature of this data should be considered when performing volume-outcome related studies.


Chiral gem-difluoroalkyl reagents: gem-difluoroalkyl propargylic borons and gem-difluoroalkyl α-allenols.
Chiral fluorinated reagents provide new opportunities for the discovery of drugs and functional materials because the introduction of a fluorinated group significantly alters a molecule's physicochemical properties. Chiral gem-difluoroalkyl fragments (R-CF2-C*) are key motifs in many drugs. However, the scarcity of synthetic methods and types of chiral gem-difluoroalkyl reagents limits the applications of these compounds. Herein, we report two types of chiral gem-difluoroalkyl reagents chiral gem-difluoroalkyl propargylic borons and gem-difluoroalkyl α-allenols and their synthesis by means of methods involving rhodium-catalyzed enantioselective B-H bond insertion reactions of carbenes and Lewis acid-promoted allenylation reactions. The mild, operationally simple method features a broad substrate scope and good functional group tolerance. These two types of reagents contain easily transformable boron and alkynyl or allenyl moieties and thus might facilitate rapid modular construction of chiral molecules containing chiral gem-difluoroalkyl fragments and might provide new opportunities for the discovery of chiral gem-difluoroalkyl drugs and other functional molecules.


[Identification of molecular markers associated with rice root traits by correlation coefficient analysis].
After growing in nutrient solution for 10 days, 84 rice varieties were harvested and measured in maximum root length (MRL) and root dry weight (RDW) separately. Twenty-seven of them were selected as representative variety for correlated fragments screening with amplified fragment length polymorphism (AFLP) technique. After surveying with 15 pairs of AFLP primers, 7 fragments from 4 pairs of primers were identified having significant correlation with MRL or/and RDW based on correlation coefficient analysis. One of them, "T3P3f", was cloned and sequenced, and its specific primers (Z336) were designed for the regular PCR amplication. Further analysis in 84 rice varieties revealed that correlation coefficient between Z336 and MRL was -0.193, much closer to the significant level of 5%; as between Z336 and RDW was -0.391, over the significant level of 1%. For the trait expression, Z336 could explain the root trait difference of 3.7% for MRL and 15.3% for RDW, respectively. The result shows the marker Z336 might tightly link with a QTL that has the negative relation with RDW expression. With a double haploid (DH) population from a cross of ZYQ8 and JX17, Z336 was finally anchored on rice chromosome 11 with a linked marker of 9.4 cM.


A single-base insertion in BoDFR1 results in loss of anthocyanins in green-leaved ornamental kale.
A CRISPR/Cas9-based knockout assay verified that BoDFR1 drives anthocyanin accumulation in ornamental kale and that BoDFR2, an ortholog of BoDFR1, is redundant. Anthocyanins are widely distributed in nature and give plants their brilliant colors. Leaf color is an important trait for ornamental kale. In this study, we measured anthocyanin contents and performed transcriptome deep sequencing (RNA-seq) of leaves from pink and green ornamental kale. We observed substantial differences in the expression levels of the two DIHYDROFLAVONOL 4-REDUCTASE-encoding genes BoDFR1 (Bo9g058630) and its ortholog BoDFR2 (Bo2g116380) between green-leaved and pink-leaved kale by RNA-seq and RT-qPCR. We cloned and sequenced BoDFR1 and BoDFR2 from both types of kale. We identified a 1-bp insertion in BoDFR1 and a 2-bp insertion in BoDFR2 in green-leaved kale compared to the sequences obtained from pink-leaved kale, both mapping to the second exon of their corresponding gene and leading to premature termination of translation. To confirm the genetic basis of the absence of anthocyanins in green kale, we used CRISPR/Cas9 genome editing to separately knock out BoDFR1 or BoDFR2 in the pink-leaved ornamental kale inbred line P23. We detected very low accumulation of anthocyanins in the resulting mutants Bodfr1-1 and Bodfr1-2, while Bodfr2-1 and Bodfr2-2 had anthocyanin levels comparable to those of the wild-type. We conclude that the insertion in BoDFR1, rather than that in BoDFR2, underlies the lack of anthocyanins in green-leaved ornamental kale. This work provides insight into the function of DFR and will contribute to germplasm improvement of ornamental plants.


A diamond anvil cell with resistive heating for high pressure and high temperature x-ray diffraction and absorption studies.
In this paper we describe a prototype of a diamond anvil cell (DAC) for high pressure/high temperature studies. This DAC combines the use of a resistive oven of 250 W power in a very small volume, associated with special conical seats for Boehler-type diamond anvils in order to have a large angular acceptance. To protect the diamond anvils from burning and to avoid the oven oxidation, the heated DAC is enclosed in a vacuum chamber. The assemblage was used to study the melting curve of germanium at high pressure (up to 20 GPa) and high temperature (up to 1200 K) using x-ray diffraction and x-ray absorption spectroscopy.


Design and experimental demonstration of a silicon five-mode (de)multiplexer based on multi-phase matching condition.
A compact 5-mode (de)multiplexer [(De)MUX] is proposed and experimentally demonstrated based on the principle of multi-phase matching. The proposed device comprises a cascaded asymmetric directional coupler (ADC) based on 3-mode phase-matching, a polarization beam combiner, and a taper waveguide connecting them. The multiple modes in the access waveguides are matched to different modes in the same bus waveguide, which eliminates the need for additional taper structures and results in a total coupling length of only 18.9 µm. Experimental results exhibit that the insertion losses of the five modes are below 3.4 dB, and the mode crosstalks are below -15 dB at the central wavelength. The 3-dB bandwidths of TM0, TM1, TE0, TE1, and TE2 modes are greater than 100 nm, 46 nm, 100 nm, 28 nm, and 37 nm, respectively. The proposed device can serve as a key functional component in highly integrated on-chip mode-division multiplexing systems.


Evaluation and Management of Achalasia Cardia in Children: A Retrospective Observational Study.
Achalasia cardia is a neuromuscular disorder of unknown etiology characterized by aperistalsis of the body of the esophagus and failure of relaxation of the lower esophageal sphincter. The diagnosis of achalasia cardia is delayed due to the rarity and the ability to mimic other common conditions in children. Hence, a study was conducted to evaluate the clinical presentation and the management of achalasia cardia in children. A retrospective observational study was conducted in the department of pediatric surgery at a tertiary center. The children with achalasia cardia who presented between January 2014 and December 2021 were included. A total of 12 patients were treated for achalasia cardia during the study period. All children presented with recurrent episodes of vomiting, whereas dysphagia was seen in six (50%) children. Eighty-three percent of the children presented with a history of weight loss, whereas failure to thrive was seen in nine (75%) children. Five (42%) children were managed as gastroesophageal reflux disease (GERD) for more than a year before presenting to us. Three (25%) children underwent open cardiomyotomy with Thal fundoplication and the rest nine (75%) underwent laparoscopic cardiomyotomy. All are thriving well. Achalasia is an important differential diagnosis in children with suspected GERD. The most common symptom of achalasia cardia is vomiting followed by dysphagia. Weight loss and failure to thrive are important presenting features in children with achalasia which are uncommon in adults. Cardiomyotomy without fundoplication is safe and effective to treat achalasia cardia in children without having any extra complications.


Metformin: A promising option for the management of gestational diabetes mellitus - Exploring the benefits, challenges and clinical needs in the current management of gestational diabetes mellitus.
The incidence of gestational diabetes mellitus (GDM) is increasing. One in three women require insulin to achieve glycaemic targets in GDM. However, it is unclear whether insulin therapy alone is the most effective treatment for all women in achieving glycaemic control and preventing adverse pregnancy outcomes. Although no oral hypoglycaemic agents are approved for pregnancy in Australia, recent research indicates that metformin is effective in preventing adverse perinatal outcomes and may even have possible benefits in the long term. Furthermore, there appears to be a specific role for both metformin and insulin among the GDM population. Metformin provides an option to offer an individualised approach to treat GDM.


Evaluating the Efficacy of the Family Check-Up Online to Improve Parent Mental Health and Family Functioning in Response to the COVID-19 Pandemic: A Randomized Clinical Trial.
This study evaluated the effects of an enhanced version of the Family Check-Up Online (FCU-O), adapted to address parent and family functioning in response to the COVID-19 pandemic. In order to increase accessibility, the FCU-O was delivered as a web-based application coupled with online coaching support, a service delivery model that is consistent with pandemic-related limitations for in-person intervention, as well as the limited staffing and resources available in many schools and health care settings despite the increased need for mental health services driven by the pandemic. This registered clinical trial (blinded) tested the effects of the intervention on parental mental health, parenting behaviors, and family functioning from pre-treatment to 2-month follow-up. Families were randomly assigned to receive the FCU-O (N = 74) or to a wait-list control condition (N = 87). Random assignment to the FCU-O was associated with significant improvements in parental well-being, including reduced anxiety, depression, and perceived stress. Further, the FCU-O predicted significant improvements in adaptive parenting skills (e.g. less negative/coercive parenting, greater proactive parenting), and enhancements in family-relational functioning (e.g. improved coparenting). Effect sizes were small to moderate in magnitude (partial eta squared values between 0.03 and 0.11). The results indicate that online delivery of a family-centered intervention may represent a promising approach for addressing pandemic-related impacts on parent and family functioning.


[Assessment of myocardial viability by thallium-201 reinjection imaging with sublingual nitroglycerin].
Although thallium-201 (201Tl) reinjection imaging improves the detection of myocardial viability compared to standard 3-4-hr redistribution (RD) imaging, it still underestimates the extent of viable myocardium. We examined whether 201Tl reinjection SPECT with sublingual nitroglycerin (NTG) had a higher sensitivity for viability detection than reinjection alone. Eighty patients with coronary artery disease were studied, 38 of them with an old myocardial infarction. At the peak of exercise, 111 MBq 201Tl was injected and the initial and the delayed SPECT images were obtained. Then, all patients were divided randomly into two groups, and in each group, SPECT data were obtained again after the injection of 37 MBq 201Tl with (NTG(+) group) or without 0.6 mg of sublingual NTG (NTG(-) group). Among 50 segments showing fixed defects on the delayed image in the NTG(+) group, 21 (42%) were found to be reversible on the reinjection image, as compared to 16 of 51 (31%) in the NTG(-) group. Twenty-two of 44 (50%) segments showing incomplete RD were found to be reversible in the NTG(+) group, while 17 of 42 (41%) segments in the NTG(-) group. Moreover, the ratio of reversible segments seen in the reinjection images was significantly higher in the collateralized regions of the NTG(+) group than in those of the NTG(-) group (20/26 vs. 14/28, p < 0.05). Thus, 201Tl reinjection SPECT with sublingual NTG improves the detection of ischemic but viable myocardium as compared to SPECT with reinjection alone.


Failure to Find Altruistic Food Sharing in Rats.
Prior research has found that one rat will release a second rat from a restraint in the presence of food, thereby allowing that second rat access to food. Such behavior, clearly beneficial to the second rat and costly to the first, has been interpreted as altruistic. Because clear demonstrations of altruism in rats are rare, such findings deserve a careful look. The present study aimed to replicate this finding, but with more systematic methods to examine whether, and under what conditions, a rat might share food with its cagemate partner. Rats were given repeated choices between high-valued food (sucrose pellets) and 30-s social access to a familiar rat, with the (a) food size (number of food pellets per response), and (b) food motivation (extra-session access to food) varied across conditions. Rats responded consistently for both food and social interaction, but at different levels and with different sensitivity to the food-access manipulations. Food production and consumption was high when food motivation was also high (food restriction) but substantially lower when food motivation was low (unlimited food access). Social release occurred at moderate levels, unaffected by the food-based manipulations. When food was abundant and food motivation low, the rats chose food and social options about equally often, but sharing (food left unconsumed prior to social release) occurred at low levels across sessions and conditions. Even under conditions of low food motivation, sharing occurred on only 1% of the sharing opportunities. The results are therefore inconsistent with claims in the literature that rats are altruistically motivated to share food with other rats.


Application of RNA Interference in the Pinewood Nematode, Bursaphelenchus xylophilus.
The pinewood nematode, Bursaphelenchus xylophilus, is one of the most destructive invasive species worldwide, causing the wilting and eventual death of pine trees. Despite the recognition of their economic and environmental significance, it has thus far been impossible to study the detailed gene functions of plant-parasitic nematodes (PPNs) using conventional forward genetics and transgenic methods. However, as a reverse genetics technology, RNA interference (RNAi) facilitates the study of the functional genes of nematodes, including B. xylophilus. This paper outlines a new protocol for RNAi of the ppm-1 gene in B. xylophilus, which has been reported to play crucial roles in the development and reproduction of other pathogenic nematodes. For RNAi, the T7 promoter was linked to the 5'-terminal of the target fragment by polymerase chain reaction (PCR), and double-stranded RNA (dsRNA) was synthesized by in vitro transcription. Subsequently, dsRNA delivery was accomplished by soaking the nematodes in a dsRNA solution mixed with synthetic neurostimulants. Synchronized juveniles of B. xylophilus (approximately 20,000 individuals) were washed and soaked in dsRNA (0.8 µg/mL) in the soaking buffer for 24 h in the dark at 25 °C. The same quantity of nematodes was placed in a soaking buffer without dsRNA as a control. Meanwhile, another identical quantity of nematodes was placed in a soaking buffer with green fluorescent protein (gfp) gene dsRNA as a control. After soaking, the expression level of the target transcripts was determined using real-time quantitative PCR. The effects of RNAi were then confirmed using microscopic observation of the phenotypes and a comparison of the body size of the adults among the groups. The current protocol can help advance research to better understand the functions of the genes of B. xylophilus and other parasitic nematodes toward developing control strategies through genetic engineering.


Transgenesis in parasitic helminths: a brief history and prospects for the future.
Helminth infections impact the health of hundreds of millions of persons globally and also cause important economic losses in livestock farming. Methodological limitations as well as the low attention given to the study of helminths have impacted biological research and, thus, the procurement of accurate diagnosis and effective treatments. Understanding the biology of helminths using genomic and proteomic approaches could contribute to advances in understanding host-helminth interactions and lead to new vaccines, drugs and diagnostics. Despite the significant advances in genomics in the last decade, the lack of methodological adaptation of current transgenesis techniques has hampered the progression of post-genomic research in helminthology. However, the application of new techniques, such as CRISPR, to the study of trematodes and nematodes has opened new avenues for genome editing-powered functional genomics for these pathogens. This review summarises the historical advances in functional genomics in parasitic helminths and highlights pending limitations that will need to be overcome to deploy transgenesis tools.


EspB and EspD require a specific chaperone for proper secretion from enteropathogenic Escherichia coli.
Enteropathogenic Escherichia coli uses a type III secretion apparatus to deliver proteins essential for pathogenesis to the host epithelium. Several proteins have been detected in culture supernatants of the prototype EPEC strain E2348/69 and three of these, EspA, EspB, and EspD, use type III machinery for export. Here, we report the identification and characterization of CesD, a protein required for proper EspB and EspD secretion. CesD shows sequence homology to chaperone proteins from other type III secretion pathways. Based on this, we hypothesize that CesD may function as a secretion chaperone in EPEC. A mutation in cesD abolished EspD secretion into culture supernatants and reduced the amount of secreted EspB, but had little effect on the amount of secreted EspA. The mutant strain was negative for both FAS and Tir phosphorylation, consistent with the previously described roles for EspB and EspD in EPEC pathogenesis. CesD was shown to interact with EspD but not EspB or EspA. CesD was detected in the bacterial cytosol, and, surprisingly, a substantial amount of the protein was also found to be associated with the inner membrane. Thus, although CesD has some attributes that are similar to other type III secretion chaperones, its membrane localization separates it from previously described members of this family.


Proteasome inhibition induces nuclear translocation of the dioxin receptor through an Sp1 and protein kinase C-dependent pathway.
The dioxin receptor (AhR), in addition to its role in xenobiotic-induced carcinogenesis, appears to participate in cell proliferation, differentiation and organ homeostasis. Understanding potential mechanisms of activation of this receptor in the absence of exogenous ligands is therefore important to study its contribution to endogenous cellular functions. Using mouse embryo primary fibroblasts, we have previously shown that proteasome inhibition increased AhR transcriptional activity in the absence of xenobiotics. We suggested that proteasome inhibition-dependent AhR activation could involve an increase in the expression of the partner protein dioxin receptor nuclear translocator (ARNT). Since ARNT over-expression induced nuclear translocation of the AhR, and ARNT-deficient cells were unable to translocate this receptor to the nucleus upon proteasome inhibition, we have analyzed the effect of proteasome inhibition on the expression of regulatory proteins controlling ARNT levels. Treatment with the proteasome inhibitor MG132 increased endogenous Sp1 phosphorylation and its DNA-binding activity to the ARNT promoter. Sp1 phosphorylation and binding to the ARNT promoter, ARNT over-expression and AhR nuclear translocation were inhibited by GF109203X, a protein kinase C-specific inhibitor. In addition, MG132 stimulated protein kinase C activity in MEF cells with a pattern similar to that observed for ARNT expression. These data suggest that cellular control of protein kinase C activity, through Sp1 and ARNT, could regulate AhR transcriptional activity in the absence of xenobiotics.


[Basis of intravital bone imaging.]
In bone tissues, there are various kinds of cell types, such as osteoclasts, osteoblasts, monocytes, granulocyte, lymphocytes, mesenchymal cells and hematopoietic stem cells. They form a network with each other, and play critical roles in our life activities. The recent development of intravital two-photon imaging has enabled us to visualize the in vivo behavior of bone marrow cells in living bone tissues. This technique facilitates investigation of cellular dynamics in the physiology and pathogenesis of bone disorders in vivo, and would thus be useful for evaluating the efficacy of novel drugs. In this review, we summarize the basis of intravital bone imaging, and also discuss its further application.


Circulating S100B and Adiponectin in Children Who Underwent Open Heart Surgery and Cardiopulmonary Bypass.
S100B protein, previously proposed as a consolidated marker of brain damage in congenital heart disease (CHD) newborns who underwent cardiac surgery and cardiopulmonary bypass (CPB), has been progressively abandoned due to S100B CNS extra-source such as adipose tissue. The present study investigated CHD newborns, if adipose tissue contributes significantly to S100B serum levels. We conducted a prospective study in 26 CHD infants, without preexisting neurological disorders, who underwent cardiac surgery and CPB in whom blood samples for S100B and adiponectin (ADN) measurement were drawn at five perioperative time-points. S100B showed a significant increase from hospital admission up to 24 h after procedure reaching its maximum peak (P < 0.01) during CPB and at the end of the surgical procedure. Moreover, ADN showed a flat pattern and no significant differences (P > 0.05) have been found all along perioperative monitoring. ADN/S100B ratio pattern was identical to S100B alone with the higher peak at the end of CPB and remained higher up to 24 h from surgery. The present study provides evidence that, in CHD infants, S100B protein is not affected by an extra-source adipose tissue release as suggested by no changes in circulating ADN concentrations.


Ciliary dynein arms: Cytoplasmic preassembly, intraflagellar transport, and axonemal docking.
The microtubular scaffold of motile cilia-the axoneme, is decorated with dynein arms, which are large multiprotein complexes essential for ciliary motility. Dynein arms are arranged along the length of the axoneme in a precise repeating pattern, converting chemical energy from ATP hydrolysis into ciliary mechanical movement. How these complicated molecular machines are assembled coordinately and accurately, starting from mere polypeptide chains in the cytoplasm, remains a fascinating yet perplexing question. Rapidly emerging evidence, from multiple studies carried out with different model organisms and with various methodologies, has highlighted the existence of a dedicated assembly pathway. Here, we summarize recent progress made in clarifying the axonemal dynein arm assembly process, focusing on individual assembly steps, including cytoplasmic preassembly, intraflagellar transport, and axonemal docking.


Verification of the relationship between the sequential organ failure assessment score and the length of intensive care unit and hospital stay in terms of medical resources input.
This study aimed to clarify the relationship between the sequential organ failure assessment (SOFA) score and the length of intensive care unit (ICU) and hospital stays and verify whether the SOFA score can indicate the optimal length of ICU stay. Medical resource input was evaluated as the medical treatment score, converted by volume, within 2 days after ICU admission. After classifying emergency patients into surgical and nonsurgical categories, the relationship between medical resources, SOFA score, and ICU and hospital stay lengths was analyzed. Medical resource input was high when the SOFA score was high after ICU admission. A positive correlation was confirmed between the SOFA score and length of ICU stay in surgical and nonsurgical patients. Nonsurgical patients are more likely to be discharged within the diagnosis procedure combination hospital stages I and II if medical resources are high in the initial stages of ICU admission. The SOFA score affects medical resource input and the length of ICU stay. The early input of medical resources after ICU admission reduces the length of hospital stay in the diagnosis procedure combination, suggesting that the SOFA score is a valuable indicator of the optimal length of ICU stay.


Purification and characterization of a novel chlorpyrifos hydrolase from Cladosporium cladosporioides Hu-01.
Chlorpyrifos is of great environmental concern due to its widespread use in the past several decades and its potential toxic effects on human health. Thus, the degradation study of chlorpyrifos has become increasing important in recent years. A fungus capable of using chlorpyrifos as the sole carbon source was isolated from organophosphate-contaminated soil and characterized as Cladosporium cladosporioides Hu-01 (collection number: CCTCC M 20711). A novel chlorpyrifos hydrolase from cell extract was purified 35.6-fold to apparent homogeneity with 38.5% overall recovery by ammoniumsulfate precipitation, gel filtration chromatography and anion-exchange chromatography. It is a monomeric structure with a molecular mass of 38.3 kDa. The pI value was estimated to be 5.2. The optimal pH and temperature of the purified enzyme were 6.5 and 40°C, respectively. No cofactors were required for the chlorpyrifos-hydrolysis activity. The enzyme was strongly inhibited by Hg²⁺, Fe³⁺, DTT, β-mercaptoethanol and SDS, whereas slight inhibitory effects (5-10% inhibition) were observed in the presence of Mn²⁺, Zn²⁺, Cu²⁺, Mg²⁺, and EDTA. The purified enzyme hydrolyzed various organophosphorus insecticides with P-O and P-S bond. Chlorpyrifos was the preferred substrate. The Km and Vmax values of the enzyme for chlorpyrifos were 6.7974 μM and 2.6473 μmol·min⁻¹, respectively. Both NH2-terminal sequencing and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometer (MALDI-TOF-MS) identified an amino acid sequence MEPDGELSALTQGANS, which shared no similarity with any reported organophosphate-hydrolyzing enzymes. These results suggested that the purified enzyme was a novel hydrolase and might conceivably be developed to fulfill the practical requirements to enable its use in situ for detoxification of chlorpyrifos. Finally, this is the first described chlorpyrifos hydrolase from fungus.


Serum levels of rapid turnover proteins are decreased and related to systemic inflammation in patients with ovarian cancer.
Poor nutritional status is common in ovarian cancer. It is well known that the nutritional status of a patient with malignant disease is associated with survival, and that it can be assessed by serum levels of rapid turnover proteins (RTPs), such as retinol binding protein, prealbumin and transferrin. Systemic inflammation, usually observed in the form of elevated C-reactive protein (CRP) or neutrophil/lymphocyte ratio (NLR), occurs by various mechanisms involving numerous pro-inflammatory cytokines. These include interleukin (IL)-17 and other soluble protein mediators, such as soluble IL-2 receptor (sIL-2R) and vascular endothelial growth factor (VEGF). In this study, circulating levels of RTP were decreased in advanced stages of ovarian cancer, and significant inverse correlations were found between RTP levels and serum levels of CRP or NLR. CRP levels were also correlated with serum levels of VEGF and sIL-2R. Moreover, NLR, VEGF and sIL-2R levels, and IL-17 production, were all inversely correlated with RTP levels. These findings indicate that chronic inflammation may be associated with compromised immune function, such as an impaired T-cell response, via various inflammatory proteins, including sIL-2R, VEGF and IL-17. The key mechanisms leading to cancer cachexia, in which nutritional impairment is a major clinical issue, appear to be primarily immune reactions caused by chronic inflammation. Anti-inflammatory treatments may be effective in clinically improving various symptoms associated with these mechanisms.


Asymptomatic adnexal masses: correlation of FDG PET and histopathologic findings.
To analyze asymptomatic adnexal masses at positron emission tomography (PET) with fluorodeoxyglucose (FDG) in correlation with histopathologic findings and evaluate FDG PET for assessing malignancy in comparison with transvaginal B-mode and Doppler ultrasonography (US) and magnetic resonance (MR) imaging. Ninety-nine patients underwent static FDG PET of the abdomen. US scans were evaluated according to sonomorphologic scoring systems. Resistance index of tumor blood vessels was calculated. Transverse and sagittal T1-weighted MR images obtained before and after intravenous administration of gadopentetate dimeglumine with a fat-saturation technique and T2-weighted MR images were acquired at 1.5 T. Adnexal mass malignancy was first assessed with each modality and then with a combination of the three techniques. Final diagnosis was made with histopathologic evaluation. FDG PET depicted seven of 12 malignant and 66 of 87 benign asymptomatic adnexal tumors. False-negative PET results were obtained in five of seven stage pT1a cystadenocarcinomas and tumors of low malignant potential but not in advanced-stage ovarian carcinomas. Small moderately intense FDG accumulations in the lower pelvis were caused by benign adnexal tumors or gastrointestinal activity in 21 of 27 cases. The overall sensitivities and specificities were 58% (95% CI: 27.7, 84.8) and 76% (95% CI: 65.5, 84.4), respectively, for FDG PET; 92% (95% CI: 61.5, 99.8) and 60% (95% CI: 48.7, 70.1), respectively, for US; 83% (95% CI: 51.6, 97.7) and 84% (95% CI: 74.5, 90.9), respectively, for MR imaging; and 92% (95% CI: 61.5, 99.8) and 85% (95% CI: 75.8, 91.8), respectively, for the combination of three modalities. Since the sensitivity of US is as high as that of PET, MR imaging, and the combination of three modalities, it remains the method of choice for diagnosis and assessment of asymptomatic adnexal masses.


Postembryonic changes in the structure of the olfactory bulb of the chinook salmon (Oncorhynchus tshawytscha) across its life history.
Juvenile chinook salmon (Oncorhynchus tshawytscha) memorize odors characteristic of their natal stream, then use these imprinted olfactory cues to return to that same stream years later as sexually mature adults. In a preliminary effort to identify neuroanatomical changes in the salmon olfactory system that may underlie these behavioral capabilities, the structure of the olfactory bulb (OB) was studied at three developmental periods across the life history: in early juvenile development (0.1-4 months of age), in late juvenile development (11-16 months), and as spawning adults (48 months). Using antibodies that selectively label primary olfactory afferents (anti-keyhole limpet hemocyanin), combined with a thionin counterstain, the telencephalon (TEL), OB, and two of the bulb's laminar components, the olfactory nerve-glomerular layer (ONL-GL) and inner cell layer (ICL), could be easily identified. Laminar organization and relative volume (i.e. percent of OB comprised by ONL-GL or ICL) were then compared across groups, and absolute volumes of the OB, ONL-GL, and ICL were compared to that of the TEL at each stage. Three age-related processes were observed across the life history. First, a rapid increase in organizational and structural maturity of the OB was found to be confined to early juvenile life. Second, an increase in OB, ONL-GL, and ICL volume, relative to TEL volume, was found to occur across the entire life history. Lastly, the composition of the OB itself changed, in that an increase in the relative volume of the ONL-GL, and a decrease in that of the ICL, were observed across the life history. Taken together, these results indicate that the OB of young salmon matures dramatically while the fish is still in the freshwater phase of its life history. Then, during migration to the ocean and growth to the adult stage, the volume of the OB, relative to that of the telencephalon, and the relative volume of the input layer of the bulb, both undergo a marked, continuous increase. These changes in the structure, and presumably the function, of the olfactory bulb of salmon may be important in the behavioral phenomena of olfactory imprinting as juveniles and homing as adults.


Modified Bondy's technique: refinements of the surgical technique and long-term results.
To evaluate the short- (6 mo) and long-term (5 yr) outcomes of modified Bondy technique, with particular reference to hearing results. Retrospective study. Quaternary referral otology and cranial base center. Two hundred thirty ears of 222 patients were operated on, using a modified Bondy technique between 1983 and 2005. All patients had primary acquired epitympanic cholesteatomas with intact pars tensa and intact ossicular chain in normal or good-hearing ear. Preoperative audiometric results revealed a mean air conduction pure-tone average of 27.7 +/- 9.6 dB (range, 10-65 dB) and a mean bone conduction pure-tone average of 14.2 +/- 6.4 dB (range, 5-50 dB). The mean preoperative air-bone gap was 13.5 +/- 6.7 dB (range, 0-25 dB). The average length of follow-up was 7.8 years (range, 5-16 yr). There was no recurrent cholesteatoma in the present series. A pearl-like residual cholesteatoma was found in the cavity in 7.4% of ears. Two patients (0.8%) developed stenosis of meatoplasty. Three ears (1.3%) exhibited retraction pockets extending to the attic. Postoperative discharging ear was observed in 3% of cases and was successfully treated with topical drops. At the long-term follow-up, the air-bone gap was unchanged or improved from the preoperative level in 88% of cases. The mean postoperative short- and long-term air-bone gaps were 14.6 +/- 8.5 dB (range, 0-55 dB) and 14.1 +/- 8.2 dB (range, 0-50 dB), respectively. Postoperative high-frequency sensorineural hearing loss with bone conduction worsening between 20 and 30 dB at 4 kHz was observed in 4 cases (1.7%). No dead ears were encountered postoperatively. A modified Bondy operation is recommended in selected cases of epitympanic cholesteatoma in normal or good-hearing ear with an intact pars tensa and ossicular chain. Modified Bondy technique ensures complete eradication of disease while preserving a good preoperative hearing in 1-stage operation.


Longitudinal Patterns of Food Procurement Over the Course of the COVID-19 Pandemic: Findings From a Canadian Online Household Survey.
Consumer food procurement during the COVID-19 pandemic has been understudied. This investigation aimed to longitudinally evaluate food procurement patterns, concern of virus exposure in grocery retailers, and food access challenges over the pandemic among a sample of households in Quebec, Canada. Online surveys were collected at three time points of the pandemic: first wave in spring 2020 (lockdown period), summer 2020 (deconfinement period), and second wave in winter 2021 (curfew period). Respondents were the household's primary grocery shopper (n = 491). Non-parametric tests and multivariable logistic regression were conducted to compare responses over time and to evaluate characteristics of respondents who regularly used no-contact grocery methods (store pick-up or home delivery). Frequency of in-store grocery shopping was lowest during the lockdown (once per week or less), and significantly increased over time to resemble pre-pandemic frequency. Concern of virus exposure in grocery retailers and disinfection/discarding of food packaging was highest during the lockdown, but significantly decreased over time. At all time points, use of public transit, walking or cycling for grocery shopping was associated with regular use of no-contact grocery methods (curfew odds ratio (OR): 3.13 (95% confidence interval 1.60, 6.14). Age (60 years+) was associated with regular use during the lockdown [OR: 2.27 (1.13, 4.59)]. Among our sample, frequency of in-store grocery shopping was lowest and concern of virus exposure in stores was highest during the lockdown period. No-contact grocery use was associated with transportation mode and potentially with personal risk perception (age).


In situ formation of phosphorescent molecular gold(I) cluster in a macroporous polymer film to achieve colorimetric cyanide sensing.
A highly phosphorescent molecular Au(I) cluster capable of rapid, sensitive, and selective detection of cyanide has been successfully fabricated. The origin of the outstanding sensing performance of the molecular Au(I) cluster toward cyanide is justified by X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) analyses. The response mechanism employed with the molecular Au(I) cluster and the cost-effectiveness in cyanide detection affords several key sensor features, making this molecular Au(I) cluster-based sensor unique compared to other cyanide sensing schemes. Importantly, by exploring the phosphorescent properties of the molecular Au(I) cluster in solid state, we demonstrate the first example of the molecular gold(I) cluster-based macroporous sensing film for colorimetric detection of cyanide in complex samples, including red wine, coffee, juice, and soil. Remarkably, the as-prepared sensing film inherits the sensing ability of the molecular Au(I) cluster, and offers a high mechanical flexibility and novel opportunities for real-time monitoring cyanide release in cassava manufacturing.


Using Cageside Measures to Evaluate Analgesic Efficacy in Mice (Mus musculus) after Surgery.
Recent studies have revealed some of the most frequently used analgesics in mice are not effectively treating postoperative pain. Our laboratory sought to compare and assess the validity and reliability of 2 cageside pain assessments that we recently developed for use in mice-nesting consolidation and grooming transfer tests. We then applied these tests to compare the efficacy of commonly used analgesics-buprenorphine (0.1 mg/kg SC every 12 h for 48 h) and carprofen (30 mg/kg in drinking water for 72 h)-alone and in multimodal combination as a refinement for treating postoperative pain in mice. Briefly, C57BL/6 and CD1 male and female mice underwent assessment under conditions of baseline, anesthesia-analgesia, and laparotomy. Results showed that multimodal analgesia displayed the greatest analgesic coverage over the postoperative period, whereas buprenorphine showed slightly less coverage, and carprofen and saline groups displayed signs of pain at most postoperative time points. After anesthesia-analgesia, buprenorphine and multimodal mice lost significant body weight in the absence of a painful stimulus and displayed other significant drug-related changes. Animals treated with carprofen showed few drug-related changes after anesthesia-analgesia but also demonstrated minimal benefit from postsurgical analgesia. Overall, multimodal analgesia was more effective for treating postsurgical pain in mice than the single-analgesic protocols we tested; however, effects on weight loss need to be considered during analgesic selection. Nesting consolidation and grooming transfer tests were valid and highly reliable over time, in inbred and outbred mice, in male and female mice, under different housing conditions. In addition, the nesting consolidation test had excellent reliability between observers. These findings can be used in refining the detection and treatment of postoperative pain in mice.


Sympathetic skin response (SSR) in multiple sclerosis.
The function of the autonomic system in multiple sclerosis (MS) is often afflicted. In order to reveal the presence of autonomic disturbances examination of sympathetic skin response (SSR), as a simple non-invasive method of the evaluation of conduction in autonomic nervous system, was performed in 25 patients with clinically defined MS. The diagnosis was confirmed by MRI and evoked potentials studies. Bimodal type of stimulation was used: the median nerve was stimulated, then the auditory stimulus (burst) was presented to the patient. Responses were recorded simultaneously from the palms and soles. SSR was abnormal in 19 patients (76%). Absence of the response from lower limbs and normal response from upper limbs were found in 6 patients (24%), increase in latency and decrease in amplitude from upper and lower limbs were found in 8 patients (32%) and increase in latency, decrease in amplitude of the response from upper limbs with absence of the response from lower limbs were found in 5 patients (20%). SSR appears to be a simple and effective method of assessing sympathetic disturbances in multiple sclerosis.


High prevalence of bacteriuria in pregnancy and its screening methods in north India.
The study aims at finding out the prevalence of bacteruria in pregnancy in an urban setting and ascertaining methods to screen them in primary care clinics. A total of 1 61 pregnant ladies visiting a primary care clinic were screened for bacteriuria based on the symptomatology. Urine culture was done to know the prevalence of bacteriuria. Sensitivities and specificities were calculated for each symptom and risk assessment. A score card was developed based on combination of positive risk assessment and constellation of symptoms. Prevalence of symptomatic and asymptomatic bacteriuria was found to be 19.87% and 4.34% respectively. Prevalence of bacteriuria was significantly high among those who had intercourse more frequently and those with less water intake. Those with a score of more than or equal to 4, as per score card were 60% more likely to suffer from bacteriuria. When combined with microscopic examination for leucocytes on positively screened, the positive predictive value was found to be 89%. It is concluded that prevalence of symptomatic bacteriuria is common among pregnant women. Syndromic management of cases on the basis of score card is helpful in resource constraint areas. This may be combined with microscopic examination of urine to entail rational use of antibiotics.


Bayesian clinical trial design using historical data that inform the treatment effect.
We consider the problem of Bayesian sample size determination for a clinical trial in the presence of historical data that inform the treatment effect. Our broadly applicable, simulation-based methodology provides a framework for calibrating the informativeness of a prior while simultaneously identifying the minimum sample size required for a new trial such that the overall design has appropriate power to detect a non-null treatment effect and reasonable type I error control. We develop a comprehensive strategy for eliciting null and alternative sampling prior distributions which are used to define Bayesian generalizations of the traditional notions of type I error control and power. Bayesian type I error control requires that a weighted-average type I error rate not exceed a prespecified threshold. We develop a procedure for generating an appropriately sized Bayesian hypothesis test using a simple partial-borrowing power prior which summarizes the fraction of information borrowed from the historical trial. We present results from simulation studies that demonstrate that a hypothesis test procedure based on this simple power prior is as efficient as those based on more complicated meta-analytic priors, such as normalized power priors or robust mixture priors, when all are held to precise type I error control requirements. We demonstrate our methodology using a real data set to design a follow-up clinical trial with time-to-event endpoint for an investigational treatment in high-risk melanoma.


Flexible instrument with contact-aided structure and force feedback for endoscopic surgery.
Robot-assisted surgery can effectively reduce the difficulty and improve the success rate of the surgeries. However, currently available flexible instruments have several limitations, such as large size, few degrees of freedom, and lack of contact force perception. This study proposes a master-slave flexible instrument capable of force feedback. The instrument has a maximum outer diameter of 3 mm and an overall length of 1200 mm. With the internal working channel unoccupied, a three-dimensional force sensing unit is designed based on the neural network. The corresponding master-slave control method with proportional force feedback was also designed to effectively control the instrument. To verify the effectiveness of the system, in vitro and in vivo experiments were conducted. The corresponding tasks were successfully completed. The animal trial conducted in the digestive tract of a live swine proved that the system has the potential for clinical use.


Factors influencing morbidity of carotid endarterectomy without a shunt.
A retrospective analysis of 156 unshunted carotid endarterectomies in 124 patients indicates that at least three factors may influence the surgeon to consider using an indwelling shunt. Contralateral internal carotid artery occlusion, prolonged cross-clamp time, and possibly stump pressures less than 25 mm Hg torr were associated with increased rate of permanent neurologic deficit. Selective shunting would not be based on stump pressures less than 50 mm Hg torr, previous ipsilateral stroke, or abnormal intraoperative electroencephalogram.


Sixty Years of Confronting Diabetes and Kidney Disease.
The good old days were not good, at least in terms of treating patients with type 2 diabetes. In the 1960s, the development of a radioimmunoassay for insulin permitted determination of the distinguishing features of type 1 and type 2 diabetes. The latter was treated with sulfonylureas and then phenformin, although the mechanisms of action at the time were unknown. The University Group Diabetes Program was a randomized controlled trial experienced by my medical generation, and the results were dramatic, both medically and legally. Next came the thiazolidinediones. All compounds were associated with weight gain and any end point benefits were uncertain. Nevertheless, basic science explained how glucose is sensed and even found a home for sulfonylureas in some patients. Next came the boom in renin-angiotensin-aldosterone system blockade, sacred ground for many, albeit the benefits were less than astounding. Other wonder drugs came and went. Over the decades, great strides were made in defining the pathology of diabetic renal disease, which is appropriate because the condition has become a primary cause of end-stage renal failure. Nonetheless, recent advances have turned around a depressing situation and are reasons for optimism. We now have compounds that actually could help patients with type 2 diabetes. One hundred years after insulin's introduction, it is high time.


Effects of adenosine and its analogues on isolated intracerebral arterioles. Extraluminal and intraluminal application.
We evaluated the responses of brain parenchymal arterioles to intraluminal and extraluminal application of adenosine and its analogues. Intracerebral arterioles (28.4- to 60.3-microns diameter) were isolated from Sprague-Dawley rats, cannulated with micropipettes, and perfused in vitro. Both extraluminal and intraluminal adenosine, 5'-(N-ethylcarboxamido)adenosine (NECA), R-N6-(phenylisopropyl)adenosine (R-PIA), and S-N6-(phenylisopropyl)adenosine (S-PIA) elicited concentration-dependent dilation of these arterioles, but intraluminal application was less potent and efficacious than extraluminal application. Inosine was not vasoactive. A common order of agonist potency (NECA > adenosine > R-PIA > or = S-PIA) was determined for both extraluminal and intraluminal application. Theophylline (10 microM) caused a rightward shift of the adenosine concentration-response curve and a 50-fold reduction in potency. Intraluminal theophylline was one sixth as effective as extraluminal theophylline in antagonizing the extraluminal adenosine response, whereas intraluminal 8-sulfophenyltheophylline, a polar theophylline derivative, was ineffective. Polyadenylic acid (PolyA, 1 microM), an adenosine polymer that does not penetrate the endothelium, induced a dilation of 44.2 +/- 5.3% when applied extraluminally but had no effect when infused intraluminally. The dilator effect of PolyA was antagonized by theophylline. We conclude that: (1) intraluminal adenosine and its analogues are effective dilators of intracerebral arterioles, (2) the dilator effects of both intraluminally and extraluminally applied adenosine are predominantly mediated by A2-type receptors, and (3) adenosine receptors mediating vasodilation are not present on the luminal surface of the endothelium.


Salvage and palliation of patients with metastatic colorectal cancer.
The natural history of colorectal cancer is briefly discussed. A review of the literature shows that survival figures have not improved significantly in the past three decades. The results of chemotherapy and surgery in advanced disease are presented. It is concluded from these data that hepatic artery ligation and infusion chemotherapy or, in selected cases, resection with adjuvant chemotherapy may improve palliation and survival in patients with hepatic metastases from colorectal cancer.


The development of stimulus control over tics: a potential explanation for contextually-based variability in the symptoms of Tourette syndrome.
Research has demonstrated that providing reinforcement for tic-free intervals can decrease tic frequency in controlled analogue settings. The aim of the current study was to determine whether reinforcement could be used to create stimulus control over tic expression. Ten children with chronic tic disorders (including Tourette syndrome) completed four discrimination training sessions. Each session consisted of three exposures to each of three, 5 min. conditions presented in a random order. In one condition, participants were reinforced for tic absence on a 10-s fixed interval schedule in the presence of a purple light. In a second condition, participants were instructed to suppress their tics, but were not reinforced for doing so in the presence of an orange light. In a third condition, participants were instructed not to suppress their tics in the presence of two non-illuminated lights. Confirming findings from other studies, results showed that reinforcing tic suppression reduced tic frequency to a greater extent than only providing instructions to suppress. To test for stimulus control, a fifth session was conducted following the aforementioned discrimination training sessions. The fifth session consisted of three exposures to each of three 5 min. conditions presented in a random order. In one condition, a purple light was illuminated. In a second condition, an orange light was illuminated. In a third condition, neither light was illuminated. Across all three conditions, instructions to suppress (or not suppress) tics were not provided, and reinforcers for successful suppression were not delivered. Results indicated that in the presence of the purple light, tics were significantly lower than when neither light was illuminated. These findings provide preliminary support for the idea that a history of differential reinforcement in various contexts may play a role explaining variability in tic symptom expression.


Finding the Spatial Co-Variation of Brain Deformation With Principal Component Analysis.
Strain and strain rate are effective traumatic brain injury metrics. In finite element (FE) head model, thousands of elements were used to represent the spatial distribution of these metrics. Owing that these metrics are resulted from brain inertia, their spatial distribution can be represented in more concise pattern. Since head kinematic features and brain deformation vary largely across head impact types (Zhan et al., 2021), we applied principal component analysis (PCA) to find the spatial co-variation of injury metrics (maximum principal strain (MPS), MPS rate (MPSR) and MPS × MPSR) in four impact types: simulation, football, mixed martial arts and car crashes, and used the PCA to find patterns in these metrics and improve the machine learning head model (MLHM). We applied PCA to decompose the injury metrics for all impacts in each impact type, and investigate the spatial co-variation using the first principal component (PC1). Furthermore, we developed a MLHM to predict PC1 and then inverse-transform to predict for all brain elements. The accuracy, the model complexity and the size of training dataset of PCA-MLHM are compared with previous MLHM (Zhan et al., 2021). PC1 explained variance on the datasets. Based on PC1 coefficients, the corpus callosum and midbrain exhibit high variance on all datasets. Finally, the PCA-MLHM reduced model parameters by 74% with a similar MPS estimation accuracy. The brain injury metric in a dataset can be decomposed into mean components and PC1 with high explained variance. The spatial co-variation analysis enables better interpretation of the patterns in brain injury metrics. It also improves the efficiency of MLHM.


Asymmetric allylboration of ketones catalyzed by chiral diols.
Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of ketones. The reaction requires 15 mol % of 3,3'-Br2-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in good yields (76-93%) and high enantiomeric ratios (95:5-99.5:0.5). High diastereoselectivities (dr >/= 98:2) and enantioselectivities (er >/= 98:2) are obtained in the reactions of acetophenone with crotyldiisopropoxyboranes.


Memory traces compete under regimes of limited Arc protein synthesis: implications for memory interference.
Recently encoded information can be lost in the presence of new information, a process called 'retrograde interference'. Retrograde interference has been extensively described for more than a century; however, little is known about its underlying mechanisms. Different approaches agree on the need of the synthesis of plasticity related proteins (PRPs) to consolidate a long-term memory (LTM). Our hypothesis is that when PRPs are limited, interference of a task over LTM formation of another may be due to the utilization of protein resources common to both tasks. Here, by combining the tasks of inhibitory avoidance (IA) and open field (OF) exploration in rats, we show that memory traces compete for their stabilization if PRPs are limited. As a result, LTM is formed for only one of the tasks with a consequent decrease in the memory for the other. Furthermore, infusing Arc antisense oligonucleotide into the dorsal hippocampus, we found that Arc is necessary for LTM formation of these two types of learning tasks and is one of the PRPs that can be shared between them when animals are trained in both OF and IA. In sum, these findings suggest that under conditions of reduced protein availability, a learning task interferes with LTM formation of another by using the available PRPs.


Descending necrotizing mediastinitis in the elderly patients.
Descending Necrotizing Mediastinitis (DNM) is a polymicrobic, dangerous and often fatal process, arising from head or neck infections and spreading along the deep fascial cervical planes, descending into the mediastinum. It can rapidly progress to sepsis and can frequently lead to death. It has a high mortality rate, up to 40% in the different series, as described in the literature. Surgical and therapeutic management has been discussed for long time especially in an elderly patient population. The literature has been reviewed in order to evaluate different pathogenesis and evolution and to recognise a correct therapeutic management.


Adult-to-adult right lobe living donor liver transplantation: comparison of endoscopic retrograde cholangiography with standard T2-weighted magnetic resonance cholangiography for evaluation of donor biliary anatomy.
To compare the value of endoscopic retrograde cholangiography (ERC) and standard T2-weighted magnetic resonance cholangiography (MRC) in the evaluation process as adult-to-adult right lobe living donor liver transplantation (LDLTx) demands a successful outcome, and exact knowledge of the biliary tree is implicated to avoid biliary complications, postoperatively. After starting the LDLTx program, 18 liver transplant candidates were selected for LDLTx by a stepwise evaluation process. ERC and standard T2-weighted MRC were performed to evaluate the biliary system of the donor liver. The anatomical findings of ERC and MRC mapping were compared using the Ohkubo classification. ERC allowed mapping of the whole biliary system in 15/15 (100%) cases, including 14/15 (93.3%) with biliary variants while routine MRC was only accurate in 2/13 (15.4%) cases. MRC was limited in depicting the biliary system proximal of the hepatic bifurcation. Postoperative biliary complications occurred in 2 donors and 8 recipients. Biliary complications were associated with Ohkubo type C, E or G in 6/8 recipients, and 2/3 recipients with biliary leak received a graft with multiple (>=2) bile ducts. Pretransplant ERC is safe and superior over standard MRC for detection of biliary variations that occur with a high frequency. However, precise knowledge of biliary variants did not reduce the incidence of postoperative biliary complications.


Analytic and Clinical Validation of an Ultrasensitive, Quantitative Polymerase Chain Reaction Assay for EGFR Mutation Analysis With Circulating Tumor DNA.
- The mutation analysis of epidermal growth factor receptor (EGFR) has become a common test to guide therapeutic decision making for lung cancer. Molecular testing with circulating tumor DNA in plasma allows diagnosis of mutations when tumor tissue is not available as well as monitoring treatment response with repeat biopsies. - To develop a timely and cost-effective assay that can accurately detect EGFR mutations in circulating tumor DNA and to evaluate the analytic and clinical performance of the assay. - Analytic assessment was conducted with a set of reference materials carrying classic EGFR mutations. A recently developed Poisson distribution-based approach was employed to understand the assay sensitivity. Clinical evaluation was performed with 224 pairs of plasma and matched tissues from patients with stage I to IV disease. EGFR mutation rates of 390 consecutive plasma samples processed in the central service laboratory were compared with previously reported prevalence in an Asian population. - Our results suggested that limit of detection for the EGFR quantitative polymerase chain reaction assay was 10 mutation copies, and the lowest detectable copy numbers could be extended to a single-digit level. The clinical sensitivity was 53.3% for all stages combined and 81.4% for late stages, with a high specificity of 100%. Clinical observations showed an overall positive finding rate of 32.5% and 41.4% for stage IV disease, which is consistent with previously reported EGFR mutation prevalence in an Asian population. - Our results supported the clinical utility of the ultrasensitive, quantitative polymerase chain reaction assay for EGFR mutation analysis with circulating tumor DNA.


Dielectric response and transport properties of alkylammonium formate ionic liquids.
Dielectric relaxation spectra of three members of the alkylammonium formate family of protic ionic liquids (PILs), namely, ethylammonium formate (EAF), n-butylammonium formate (BuAF), and n-pentylammonium formate (PeAF), as well as the pseudo-PIL triethylamine + formic acid (molar ratio 1:2; TEAF) have been studied over a wide frequency (50 MHz to 89 GHz) and temperature range (5-65 °C), complemented by measurements of their density, viscosity, and conductivity. It turned out that the dominating relaxation of EAF, BuAF, and PeAF arises from both cation and anion reorientations which are synchronized in their dynamics due to hydrogen bonding. Amplitudes and relaxation times of this mode reflect the-compared to nitrate-different nature of H bonding between the formate anion and ethylammonium cation, as well as increasing segregation of the PIL structure into polar and non-polar domains. The TEAF data suggest that its dominating relaxation is due to the rotation of the complex triethylamine⋅(formic acid)2 in which no significant proton transfer to an ion pair occurred. Weak dissociation of this complex into ions was postulated to account for the high conductivity of TEAF.


Redox Status and Neuro Inflammation Indexes in Cerebellum and Motor Cortex of Wistar Rats Supplemented with Natural Sources of Omega-3 Fatty Acids and Astaxanthin: Fish Oil, Krill Oil, and Algal Biomass.
Health authorities worldwide have consistently recommended the regular consumption of marine fishes and seafood to preserve memory, sustain cognitive functions, and prevent neurodegenerative processes in humans. Shrimp, crabs, lobster, and salmon are of particular interest in the human diet due to their substantial provision of omega-3 fatty acids (n-3/PUFAs) and the antioxidant carotenoid astaxanthin (ASTA). However, the optimal ratio between these nutraceuticals in natural sources is apparently the key factor for maximum protection against most neuro-motor disorders. Therefore, we aimed here to investigate the effects of a long-term supplementation with (n-3)/PUFAs-rich fish oil, ASTA-rich algal biomass, the combination of them, or krill oil (a natural combination of both nutrients) on baseline redox balance and neuro-inflammation indexes in cerebellum and motor cortex of Wistar rats. Significant changes in redox metabolism were only observed upon ASTA supplementation, which reinforce its antioxidant properties with a putative mitochondrial-centered action in rat brain. Krill oil imposed mild astrocyte activation in motor cortex of Wistar rats, although no redox or inflammatory index was concomitantly altered. In summary, there is no experimental evidence that krill oil, fish oil, oralgal biomass (minor variation), drastically change the baseline oxidative conditions or the neuro-inflammatory scenario in neuromotor-associated rat brain regions.


Changes in pancreatic glutathione peroxidase and superoxide dismutase activities in the prediabetic diabetes-prone BB rat.
Pancreatic superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) activities were measured during the development of diabetes in diabetes-prone BB rats (BBdp) prior to insulin dependence. The pancreata from seven to eight BBdp rats of each sex were examined at ages 5, 7, 10, and 18 weeks and compared with age-matched control BB rats (BBc). At Week 18, BBdp rats had moderate to high insulitis but normal levels of blood glucose and insulin. Pancreatic CuZnSOD activity in BBdp rats was two times higher than the activity seen in BBc rats at age 5-10 weeks but then declined to the same level as seen in BBc rats at 18 weeks of age. MnSOD activity increased over time in the BBdp rats but remained very low in BBc rats. These changes in CuZnSOD and MnSOD activity resulted in BBdp rats having twice the pancreatic total SOD activity compared with BBc rats (P < 0.0001). Total GSHPx activity was significantly reduced in the pancreata from both male and female BBdp rats compared with their respective controls (P < 0.01 and P < 0.0001, respectively). The lower total GSHPx activity was due to reduced selenium-dependent GSHPx (SeGSHPx) activity. Erythrocyte and plasma activity of these enzymes was not different between rats with or without insulitis, indicating that differences in enzyme activities were confined to the pancreas. Thus, changes in pancreatic antioxidant enzyme activities occur prior to the development of diabetes symptoms in BBdp rats and may be related to the destruction of the pancreatic B cells and ultimate development of diabetes.


Coronary pressure and FFR predict long-term outcome after PTCA.
Although coronary stents have been the most important improvement in percutaneous coronary interventions in the last 10 years, it is well known to interventionalists that many patients after percutaneous transluminal coronary angioplasty (PTCA) have a favourable outcome without stenting. Coronary angiography, however, is not sensitive enough to identify those particular patients and it has been suggested that a combination of angiographic and functional criteria would be more suitable to distinguish patients with a low restenosis chance after plain balloon angioplasty. In the present study, the authors investigated the value of coronary pressure measurement for conditional stenting in 85 patients. It was demonstrated that in patients in whom a high fractional flow reserve (FFR) was present (> 0.90), the incidence of coronary events at two-year follow-up was almost three times lower than in those patients with an FFR below 0.90. Such high FFRs could be obtained in approximately 45% of all patients. In an additional group of patients, it was demonstrated by intravascular ultrasound (IVUS) studies that the mechanism of a high FFR after plain balloon angioplasty is most likely the result of a larger lumen compared with patients with a suboptimal FFR. This means that, in patients in whom both the angiographic and the functional result after PTCA is optimal, a restenosis rate is achieved similar to that achieved by stenting. Obviously, in such patients, additional stenting and a number of problems in the long-term possibly related to stenting can be avoided. Therefore, coronary angiography and coronary pressure measurement have a complementary value in the evaluation of PTCA results and such information can be easily obtained by using a pressure wire instead of a regular guidewire.


Graphdiyne-Related Materials in Biomedical Applications and Their Potential in Peripheral Nerve Tissue Engineering.
Graphdiyne (GDY) is a new member of the family of carbon-based nanomaterials with hybridized carbon atoms of sp and sp2, including α, β, γ, and (6,6,12)-GDY, which differ in their percentage of acetylene bonds. The unique structure of GDY provides many attractive features, such as uniformly distributed pores, highly π-conjugated structure, high thermal stability, low toxicity, biodegradability, large specific surface area, tunable electrical conductivity, and remarkable thermal conductivity. Therefore, GDY is widely used in energy storage, catalysis, and energy fields, in addition to biomedical fields, such as biosensing, cancer therapy, drug delivery, radiation protection, and tissue engineering. In this review, we first discuss the synthesis of GDY with different shapes, including nanotubes, nanowires, nanowalls, and nanosheets. Second, we present the research progress in the biomedical field in recent years, along with the biodegradability and biocompatibility of GDY based on the existing literature. Subsequently, we present recent research results on the use of nanomaterials in peripheral nerve regeneration (PNR). Based on the wide application of nanomaterials in PNR and the remarkable properties of GDY, we predict the prospects and current challenges of GDY-based materials for PNR.


Acoustical properties of selected tissue phantom materials for ultrasound imaging.
This note summarizes the characterization of the acoustic properties of four materials intended for the development of tissue, and especially breast tissue, phantoms for the use in photoacoustic and ultrasound imaging. The materials are agar, silicone, polyvinyl alcohol gel (PVA) and polyacrylamide gel (PAA). The acoustical properties, i.e., the speed of sound, impedance and acoustic attenuation, are determined by transmission measurements of sound waves at room temperature under controlled conditions. Although the materials are tested for application such as photoacoustic phantoms, we focus here on the acoustic properties, while the optical properties will be discussed elsewhere. To obtain the acoustic attenuation in a frequency range from 4 MHz to 14 MHz, two ultrasound sources of 5 MHz and 10 MHz core frequencies are used. For preparation, each sample is cast into blocks of three different thicknesses. Agar, PVA and PAA show similar acoustic properties as water. Within silicone polymer, a significantly lower speed of sound and higher acoustical attenuation than in water and human tissue were found. All materials can be cast into arbitrary shapes and are suitable for tissue-mimicking phantoms. Due to its lower speed of sound, silicone is generally less suitable than the other presented materials.


Oculocardiac reflex during retinal surgery using peribulbar block and nitrous narcotic anesthesia.
This study was designed to examine the effects of local and general anesthesia on the oculocardiac reflex (OCR) in adults during retinal detachment surgery, with an aim of determining the safest type of anesthesia and on which extraocular muscle traction causes a higher incidence of OCR. The study was performed on 30 American Society of Anesthesiologists-I patients (age range 40-60 years) who were undergoing retinal detachment surgery. Fifteen patients underwent surgery with general anesthesia and 15 were given a local peribulbar block. A fixed traction of 400 g was applied to all the extraocular muscles, and the heart rate, rhythm, and electrocardiogram of each patient was monitored. The overall incidence of OCR was higher with general anesthesia (63.3%) than with local anesthesia (14.4%). There was a significant decrease in heart rate for the rectus muscles (P < .0005) as well as the oblique muscles (P < .005) during traction with general anesthesia. All four rectus muscles were equally sensitive in eliciting the reflex. The incidence of dysrhythmias was 20% with general anesthesia and 6.67% with local anesthesia. This study showed that local anesthesia produces less bradycardia and ectopic arrhythmias and, therefore, may be safer and better than general anesthesia for surgeries in which traction of extraocular muscles is required.


Stable isotope tracking of endangered sea turtles: validation with satellite telemetry and δ15N analysis of amino acids.
Effective conservation strategies for highly migratory species must incorporate information about long-distance movements and locations of high-use foraging areas. However, the inherent challenges of directly monitoring these factors call for creative research approaches and innovative application of existing tools. Highly migratory marine species, such as marine turtles, regularly travel hundreds or thousands of kilometers between breeding and feeding areas, but identification of migratory routes and habitat use patterns remains elusive. Here we use satellite telemetry in combination with compound-specific isotope analysis of amino acids to confirm that insights from bulk tissue stable isotope analysis can reveal divergent migratory strategies and within-population segregation of foraging groups of critically endangered leatherback sea turtles (Dermochelys coriacea) across the Pacific Ocean. Among the 78 turtles studied, we found a distinct dichotomy in δ(15)N values of bulk skin, with distinct "low δ(15)N" and "high δ(15)N" groups. δ(15)N analysis of amino acids confirmed that this disparity resulted from isotopic differences at the base of the food chain and not from differences in trophic position between the two groups. Satellite tracking of 13 individuals indicated that their bulk skin δ(15)N value was linked to the particular foraging region of each turtle. These findings confirm that prevailing marine isoscapes of foraging areas can be reflected in the isotopic compositions of marine turtle body tissues sampled at nesting beaches. We use a Bayesian mixture model to show that between 82 and 100% of the 78 skin-sampled turtles could be assigned with confidence to either the eastern Pacific or western Pacific, with 33 to 66% of all turtles foraging in the eastern Pacific. Our forensic approach validates the use of stable isotopes to depict leatherback turtle movements over broad spatial ranges and is timely for establishing wise conservation efforts in light of this species' imminent risk of extinction in the Pacific.


Roles and dynamics of 3-methylcytidine in cellular RNAs.
Modified nucleotides within cellular RNAs significantly influence their biogenesis, stability, and function. As reviewed here, 3-methylcytidine (m3C) has recently come to the fore through the identification of the methyltransferases responsible for installing m3C32 in human tRNAs. Mechanistic details of how m3C32 methyltransferases recognize their substrate tRNAs have been uncovered and the biogenetic and functional relevance of interconnections between m3C32 and modified adenosines at position 37 highlighted. Functional insights into the role of m3C32 modifications indicate that they influence tRNA structure and, consistently, lack of m3C32 modifications impairs translation. Development of quantitative, transcriptome-wide m3C mapping approaches and the discovery of an m3C demethylase reveal m3C to be dynamic, raising the possibility that it contributes to fine-tuning gene expression in different conditions.


Vibronic structure of the cyanobutadiyne cation. I. VUV photoionization study of HC5N.
We report the vacuum-ultraviolet threshold-photoelectron spectrum of HC5N recorded over a wide spectral range, from 84 000 to 120 000 cm-1, with a 120 cm-1 spectral resolution, better than what was achieved in previous photoelectron studies, and with mass selectivity. The adiabatic ionization potential of cyanobutadiyne is measured at 85 366 (±40) cm-1. Assignment of the vibrational bands of the four lowest electronic states X+2Π, A+2Π, B+2Σ+, and C+2Π are performed, supported by high level ab initio calculations which are fully detailed in Paper II [B. Gans et al., J. Chem. Phys. 150, 244303 (2019)] and by Franck-Condon simulations. Only vibrational stretching modes are observed in the threshold-photoelectron spectra. The ground state of HC5N+ exhibits a vibrational progression in the ν2 stretching mode involving mainly the elongation of the C≡C triple bonds, whereas the A+ and C+ excited electronic states show a progression in the stretching mode mainly associated with the elongation of the C≡N bond, i.e., ν4 and ν3, respectively. The B+ state appears almost as a vibrationless structure in close vicinity to the A+ state.


Note: tunable notch filter based on liquid crystal technology for microwave applications.
In this work, a compact design of an electrically tunable notch filter, based on liquid crystal (LC) technology, has been designed, manufactured, and characterized. The proposal has been achieved through particular configuration schemes with low cost inverted-microstrip structures and conventional spurlines structures due to its ease of integration. Central frequency tunability has been induced by applying low ac voltages, thus involving low power consumption. For these devices, filter responses have been approached specifically at microwave C-band frequency allocated for many satellite communications applications. Also, it has taken advantage of new highly anisotropic nematic LC mixtures at those frequency ranges.


HLA-DR-expressing Langerhans'-like cells in vaginal and cervical epithelium.
Sections of ethanol-fixed, paraffin-embedded tissue specimens from human vagina and exocervix were stained by an indirect immunofluorescence method with a rabbit antiserum to HLA-DR antigens. A specific staining of cells having a dendritic appearance were seen. The cells were randomly distributed, mainly in the parabasal cell-layer of the stratified squamous epithelium. The number of dendritic cells was 1-3% of all cells in the cervical epithelium and 1-5% of the cells in the vaginal epithelium. Most probably these cells are Langerhans' cells.


Adaptive Landscapes in the Age of Synthetic Biology.
For nearly a century adaptive landscapes have provided overviews of the evolutionary process and yet they remain metaphors. We redefine adaptive landscapes in terms of biological processes rather than descriptive phenomenology. We focus on the underlying mechanisms that generate emergent properties such as epistasis, dominance, trade-offs and adaptive peaks. We illustrate the utility of landscapes in predicting the course of adaptation and the distribution of fitness effects. We abandon aged arguments concerning landscape ruggedness in favor of empirically determining landscape architecture. In so doing, we transform the landscape metaphor into a scientific framework within which causal hypotheses can be tested.


VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells.
Pyruvate dehydrogenase kinase (PDK) is a pivotal enzyme in cellular energy metabolism that has previously been implicated in cancer through both RNAi based studies and clinical correlations with poor prognosis in several cancer types. Here, we report the discovery of a novel and selective ATP competitive pan-isoform inhibitor of PDK, VER-246608. Consistent with a PDK mediated MOA, VER-246608 increased pyruvate dehydrogenase complex (PDC) activity, oxygen consumption and attenuated glycolytic activity. However, these effects were only observed under D-glucose-depleted conditions and required almost complete ablation of PDC E1α subunit phosphorylation. VER-246608 was weakly anti-proliferative to cancer cells in standard culture media; however, depletion of either serum or combined D-glucose/L-glutamine resulted in enhanced cellular potency. Furthermore, this condition-selective cytostatic effect correlated with reduced intracellular pyruvate levels and an attenuated compensatory response involving deamination of L-alanine. In addition, VER-246608 was found to potentiate the activity of doxorubicin. In contrast, the lipoamide site inhibitor, Nov3r, demonstrated sub-maximal inhibition of PDK activity and no evidence of cellular activity. These studies suggest that PDK inhibition may be effective under the nutrient-depleted conditions found in the tumour microenvironment and that combination treatments should be explored to reveal the full potential of this therapeutic strategy.


(-) Epicatechin prevents alterations in lysosomal glycohydrolases, cathepsins and reduces myocardial infarct size in isoproterenol-induced myocardial infarcted rats.
The preventive effects of (-) epicatechin on oxidative stress, cardiac mitochondrial damage, altered membrane bound adenosine triphosphatases and minerals were reported previously in isoproterenol-induced myocardial infarction model. Leakage of lysosomal glycohydrolases and cathepsins play an important role in the pathology of myocardial infarction. This study was aimed to evaluate the preventive effects of (-) epicatechin on alterations in lysosomal glycohydrolases, cathepsins and myocardial infarct size in isoproterenol-induced myocardial infarcted rats. Male albino Wistar rats were pretreated with (-) epicatechin (20mg/kg body weight) daily for a period of 21 days. After the pretreatment period, isoproterenol (100mg/kg body weight) was injected subcutaneously into the rats at an interval of 24h for two days to induce myocardial infarction. The levels of serum cardiac troponin-I and the activities of serum and heart lysosomal enzymes (β-glucuronidase, β-N-acetyl glucosaminidase, β-galactosidase, cathepsin-B and cathepsin-D) were increased significantly (P<0.05) and the activities of β-glucuronidase and cathepsin-D in the heart lysosomal fractions were significantly (P<0.05) decreased in isoproterenol-induced myocardial infarcted rats. The in vitro study revealed the potent antioxidant action of (-) epicatechin. Pretreatment with (-) epicatechin daily for a period of 21 days prevented the leakage of cardiac marker, lysosomal glycohydrolases, cathepsins, and reduced infarct size, thereby protecting the lysosomal membranes in isoproterenol-induced myocardial infarcted rats, by virtue of its membrane stabilizing property.


Light scattering investigation above the nematic-smectic-A phase transition in binary mixtures of calamitic and bent-core mesogens.
Quasielastic light scattering measurements were performed in the nematic phase of mixtures consisting of the calamitic mesogen 8OCB doped with small concentrations of the bent-core molecule P-7PIMB. It was found that the regular part of the bend elastic constant decreases strongly with dopant concentration X. Close to the nematic-smectic-A phase transition temperature, the divergent part of the bend elastic constant, which is proportional to the bare correlation length xi(0)(||) parallel to the layer normal, also decreases rapidly with X. The effect of the dopant on xi(0)(||) is examined in brief theoretically.


Comparative study of polyhydroxyalkanoates production from acidified and anaerobically treated brewery wastewater using enriched mixed microbial culture.
The production of polyhydroxyalkanoates (PHA) from wastewaters using microbial mixed cultures (MMC) has been attracting increased interest because of PHA's biodegradability characteristics. Production of PHA by an MMC enriched with PHA-accumulating bacteria was compared using anaerobically treated and acidified brewery wastewaters under various feeding strategies, namely pulse and batch feed addition. To obtain an enriched MMC, a sequencing batch reactor was inoculated with activated sludge fed with acetate and subjected to aerobic dynamic feeding. The enriched MMC was able to accumulate PHA up to 72.6% of cell dry weight (CDW) with pulse addition of acetate controlled by the dissolved oxygen (DO) concentration in the reactor. In a batch accumulation experiment with acetate, the PHA content achieved (28.5% CDW) was less than that of the pulse feeding strategy with the same amount of acetate (~2000 mg C/L). Using anaerobically treated and acidified brewery wastewater fed in pulses, the maximum PHA accumulated by the enriched MMC was similar for both wastewaters (45% CDW), in spite of the higher volatile fatty acid concentration in acidified brewery wastewater. The pulse feed addition controlled by the DO concentration was difficult to implement for wastewater as compared to acetate because the difference in DO concentration between substrate availability and depletion was low. For the batch addition of acidified wastewater, a slightly lower PHA content (39% CDW) was obtained. These results show that both brewery wastewaters can be utilized for PHA production with a similar maximum PHA storage capacity.


Activation of peripheral CD8+ T lymphocytes via CD28 plus CD2: evidence for IL-2 gene transcription mediated by CD28 activation.
It is well established that peripheral CD8+ and CD4+ T cells display different requirements for in vitro activation by mitogenic mAb. Most CD4+ T cells can be activated by anti-CD3 or mitogenic combinations of anti-CD2. In contrast, CD8+ T cells display minimal responses to CD3 activation, and no proliferation is observed via CD2 activation. Purified peripheral blood CD8+ T cells, stringently depleted of APC, have been studied for their capacity to respond to mAb directed against CD3, CD2 and CD28, used alone or in combination. It is demonstrated that proliferation can be induced by co-stimulation of CD2 and CD28. This does not require autologous APC. CD8+ T cells can also be activated by the combination of anti-CD3 plus anti-CD28 in the presence of APC, but only minimal cell proliferation is obtained in the absence of APC. The response via CD2 plus CD28 is IL-2-dependent, as demonstrated by the ability of mAb against the IL-2 receptor to block proliferation, and is almost completely inhibited by cyclosporine A (CsA). These results suggest that the signal generated by stimulation of CD28 in combination with CD2 differs from that seen with CD28 activation combined with either PMA or CD3. Induction of IL-2 gene activation in CD8+, CD28+ peripheral T cells may therefore require additional "second signals", which are not necessary for activation of CD4+ cells. One such signal might be the interaction between CD28 and its natural ligand.