The α-barrel tip region of Escherichia coli TolC homologs of Vibrio vulnificus interacts with the MacA protein to form the functional macrolide-specific efflux pump MacAB-TolC.
TolC and its homologous family of proteins are outer membrane factors that are essential for exporting small molecules and toxins across the outer membrane in Gram-negative bacteria. Two open reading frames in the Vibrio vulnificus genome that encode proteins homologous to Escherichia coli TolC, designated TolCV1 and TolCV2, have 51.3% and 29.6% amino acid identity to TolC, respectively. In this study, we show that TolCV1 and TolCV2 functionally and physically interacted with the membrane fusion protein, MacA, a component of the macrolide-specific MacAB-TolC pump of E. coli. We further show that the conserved residues located at the aperture tip region of the α-hairpin of TolCV1 and TolCV2 played an essential role in the formation of the functional MacAB-TolC pump using site-directed mutational analyses. Our findings suggest that these outer membrane factors have conserved tip-to-tip interaction with the MacA membrane fusion protein for action of the drug efflux pump in Gram-negative bacteria.


Long-term outcomes for heart failure patients with and without diabetes: From the Get With The Guidelines-Heart Failure Registry.
Diabetes mellitus is an increasingly prevalent condition among heart failure (HF) patients. The long-term morbidity and mortality among patients with and without diabetes with HF with reduced (HFrEF), borderline (HFbEF), and preserved ejection fraction (HFpEF) are not well described. Using the Get With The Guidelines (GWTG)-HF Registry linked to Centers for Medicare & Medicaid Services claims data, we evaluated differences between HF patients with and without diabetes. Adjusted Cox proportional-hazard models controlling for patient and hospital characteristics were used to evaluate mortality and readmission outcomes. A cohort of 86,659 HF patients aged ≥65 years was followed for 3 years from discharge. Unadjusted all-cause mortality was between 4.4% and 5.5% and all-cause hospitalization was between 19.4% and 22.6% for all groups at 30 days. For all-cause mortality at 3 years from hospital discharge, diabetes was associated with an adjusted hazard ratio of 1.27 (95% CI 1.07-1.49, P = .0051) for HFrEF, 0.95 (95% CI 0.55-1.65, P = .8536) for HFbEF, 1.02 (95% CI 0.87-1.19, P = .8551) for HFpEF. For all-cause readmission, diabetes was associated with an adjusted hazard ratio of 1.06 (95% CI 0.87-1.29, P = .5585) for HFrEF, 1.48 (95% CI 1.15-1.90, P = .0023) for HFbEF, and 1.06 (95% CI 0.91-1.22, P = .4747) for HFpEF. HFrEF and HFbEF patients with diabetes are at increased risk for mortality and rehospitalization after hospitalization for HF, independent of other patient and hospital characteristics. Among HFpEF patients, diabetes does not appear to be independently associated with significant additional risks.


Nychthemeral variations of plasma corticosteroids in captive female Lacerta vivipara Jacquin: influence of stress and reproductive state.
This work was designed to study nychthemeral variations of plasma corticosterone and aldosterone in captive female lizards Lacerta vivipara. In preliminary experiments, the possible alterations of plasma corticosteroids by various stress factors were researched. A prolonged blood sampling (up to 8 min) did not alter plasma corticosterone levels but a significant increase of plasma aldosterone levels was observed. Confinement (1 or 18 hr) in small individual cages before blood collection resulted in a significant increase of both corticosterone and aldosterone. Whatever the period investigated (vitellogenesis, gestation, 2 months after parturition), plasma corticosterone levels showed a unimodal daily rhythm correlated with the activity of the females in the laboratory. No shift of the peak was observed according to season but the mean minimal and maximal levels were lower during vitellogenesis than during the other periods tested. Nychthemeral variations of plasma aldosterone levels were similar to those of corticosterone but of lower amplitude. Adrenal response to a short confinement (less than 1 hr) before blood sampling varied during a 24-hr period (period tested: vitellogenesis). Only minimal levels of corticosteroids were significantly increased. The possible effects of a long duration of captivity under optimal thermal conditions are discussed.


Review of Oribotritia (Acari, Oribatida, Oribotritiidae) with a world checklist and description of a new species from China.
The oribatid mite genus Oribotritia Jacot, 1924 (Oribotritiidae) is reviewed. A new species of Oribotritia collected from litter in Hunchun, China, Oribotritia hunchunensis sp. nov., is described and figured. Four species, Oribotritia angusta Mahunka, 1982, Oribotritia asiatica Hammer, 1977, Oribotritia chichijimensis Aoki, 1980, Oribotritia gigas Bayoumi & Mahunka, 1979, are redescribed based on Chinese specimens. Oribotritia nepalensis Niedbała, 2000 is considered as a new junior subjective synonym of Oribotritia gigas Bayoumi & Mahunka, 1979. A comprehensive, fully annotated and referenced checklist of all known species and a key to known Chinese species of this genus are provided to facilitate to the further research.


ADAM12 overexpression does not improve outcome in mice with laminin alpha2-deficient muscular dystrophy.
We have recently shown that overexpression of ADAM12 results in increased muscle regeneration and significantly reduced pathology in mdx, dystrophin deficient mice. In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe clinical phenotype and would be expected to benefit greatly from enhanced regeneration. We found that dy(W) mice overexpressing ADAM12 indeed have increased muscle regeneration, as evidenced by increased numbers of muscle fibers expressing fetal myosin. However, overexpression of ADAM12 had no significant effect on overall health, as evidenced by body weight, and did not improve muscle pathology.


Treatment of nocturnal asthma in children with a single dose of sustained-release theophylline taken after supper.
In a placebo-controlled, double-blind cross-over study of 2 X 3 weeks' duration, twenty-four children with stable asthma who were wheezing during the night, were treated with a single dose of sustained-release theophylline (SRT) taken after supper. The mean serum theophylline levels 4 and 12 hr after dosing were 7.7 and 11.2 mg/l, respectively. Few side-effects were seen. The mean morning peak expiratory flow (PEF) was significantly higher during SRT treatment (244 +/- 11 1/min) than during placebo treatment (207 +/- 121/min) (P less than 0.001). The mean difference between morning and evening PEF was reduced from 20.7 to 8.6% by treatment with SRT (P less than 0.001). Theophylline significantly reduced the severity of attacks of bronchoconstriction during the night as judged by PEF measurement and use of extra bronchodilator treatment per attack. The response to inhaled terbutaline was increased during SRT treatment compared with that in the placebo period, however pre-treatment PEF did differ significantly between the two periods. The number of acute asthma attacks during the night, the number of symptom-free nights and the use of extra bronchodilators during the night were all significantly improved by SRT treatment (P less than 0.001). Seventeen children correctly identified the SRT period whilst six children showed no preference for either period. A single dose of SRT taken after supper is an effective treatment for nocturnal asthma in children.


Cognitive-behavioral stress management and psychological well-being in HIV+ racial/ethnic minority women with human papillomavirus.
This study is a secondary analysis examining the effects of a cognitive-behavioral stress management (CBSM) intervention on indicators of positive psychological well-being and negative psychological well-being in HIV-positive racial/ethnic minority women at risk for cervical cancer due to human papillomavirus (HPV) infection and/or cervical intraepithelial lesions (CIN). Racial/ethnic minority women with HIV and HPV and/or CIN I were randomized to a 10-week CBSM group or a 1-day psychoeducational seminar. Participants completed a battery of measures of positive and negative psychological well-being at 3 time points: preintervention, 3 months postenrollment, and 9 months postenrollment. Women in the CBSM group reported significant increases in domains of positive well-being, with no changes among women in the psychoeducational seminar, F(6, 63) = 2.42, p < .05, η² = .19. There were no significant changes in domains of negative well-being across time for either group, F(2, 65) = 2.60, p = .08, η² = .07. These findings suggest that racial/ethnic minority women with HIV at risk for cervical cancer who were randomized to a 10-week CBSM group experienced enhanced positive well-being. The lack of effects on negative well-being may be due to the relatively low levels of negative well-being present in this sample at study entry. Future research should examine whether these effects are replicated in a randomized controlled trial of women with biopsy-confirmed CIN who present with greater distress levels that also employs a time-equivalent comparison condition.


A Case of Recurrent Insomnia: Extending the Spectrum of Autoimmune Encephalitis.
Recurrent insomnia is an uncommon manifestation that is encountered rarely in a sleep clinic. We report a woman with recurrent insomnia due to an autoimmune process that resolved after a course of immunotherapy.


Quantitative Quadrupolar NMR (qQNMR) via nitrogen-14 for the accurate control of L-carnitine in food supplements.
A qQNMR methodology using nitrogen-14 as the quadrupolar nucleus of choice has been introduced for the first time as a robust and validated method to determine and quantify L-carnitine in food supplements. The quantification has been carried out by the alternative use of a calibration curve or by addition of ammonium chloride as internal standard. The method was validated at seven concentration levels in the range of 5.58-99.26 mM, affording intra- and inter day accuracies lower than 6.84% (expressed in CV), robustness towards temperature and recycle delay, limit of detection (LOD) of 2.48 mM, limit of quantification (LOQ) of 5.58 mM and remarkably with absence of matrix effect.


Potential for retroposition by old Alu subfamilies.
Alu elements sharing sequence characteristics of the "old" subfamilies are thought to currently be retrotranspositionally inactive. We analyzed one of these old subfamilies of Alu elements, Sx, for sequence conservation relative to the consensus and the length of the "A-tail" as parameters to define the presence of potential Alu Sx source genes in the human genome. Sequence identity to the left half or the right half of the Alu Sx consensus sequence was evaluated for 4424 complete elements obtained from the human genome draft sequence. A small subset of Alu Sx left halves were found to be more conserved than any of the Alu Sx right halves. Selection for promoter function in active elements may explain the slightly higher conservation of the left half. In order to determine whether this sequence identity was the result of recent activity, or simply sequence conservation for older elements, PCR amplification of some of the loci containing Sx elements with conserved left/right halves from different primate genomes was carried out. Several of these Sx Alus were found to have amplified at a later evolutionary period (<35 mya) than expected based on previous studies of Sx elements. Analysis of "A-tail" length, a feature correlated with current retroposition activity, varied between Alu Sx element loci in different primates, where the length increased in specific Alu elements in the human genome. The presence of few conserved Alu Sx elements and the dynamic expansion/contraction of the A-tail suggests that some of these older subfamilies may still be active at very low levels or in a few individuals.


Identification of the chemical form of sulfur compounds in the Japanese pink coral (Corallium elatius) skeleton using μ-XRF/XAS speciation mapping.
The distributions and chemical forms of sulfur compounds in the skeleton of Japanese pink coral (Corallium elatius) were investigated using X-ray spectroscopic techniques combined with micro-focused soft X-ray radiation. Microscopic X-ray fluorescence/soft X-ray photoabsorption (μ-XRF/XAS) speciation mapping clarified that sulfate is the primary species in the coral skeleton, with minor amounts of organic sulfur, whereas both sulfate and organic sulfur coexist in coenenchyme. Analysis of the post-edge region of the XAS spectra confirmed that sulfate ions in the coral skeleton are mainly in the form of gypsum-like inorganic sulfate substituting for the carbonate ions in the calcite skeleton. The sulfate concentration was negatively correlated with the magnesium concentration and positively correlated with that of phosphorus. Speciation mapping of sulfate in the coral skeleton showed clear fluctuations with sulfate concentrations being higher at dark bands, whereas the small amount of organic sulfur had unclear dark/bright bands. These results suggest that the little organic sulfur that is present is contained in the organic matter embedded in the biocrystal of coral skeleton.


Specific cerebral perfusion patterns in three schizophrenia symptom dimensions.
Dimensional concepts such as the Research Domain Criteria initiative have been proposed to disentangle the heterogeneity of schizophrenia. One model introduced three neurobiologically informed behavioral dimensions: language, affectivity and motor behavior. To study the brain-behavior associations of these three dimensions, we investigated whether current behavioral alterations were linked to resting state perfusion in distinct brain circuits in schizophrenia. In total, 47 patients with schizophrenia spectrum disorders and 44 healthy controls were included. Psychopathology was assessed with the Positive And Negative Syndrome Scale and the Bern Psychopathology scale (BPS). The BPS provides severity ratings of three behavioral dimensions (language, affectivity and motor). Patients were classified according to the severity of alterations (severe, mild, no) in each dimension. Whole brain resting state cerebral blood flow (CBF) was compared between patient subgroups and controls. Two symptom dimensions were associated with distinct CBF changes. Behavioral alterations in the language dimension were linked to increased CBF in Heschl's gyrus. Altered affectivity was related to increased CBF in amygdala. The ratings of motor behavior instead were not specifically associated with CBF. Investigating behavioral alterations in three schizophrenia symptom dimensions identified distinct regional CBF changes in the language and limbic brain circuits. The results demonstrate a hitherto unknown segregation of pathophysiological pathways underlying a limited number of specific symptom dimensions in schizophrenia.


Clinical characteristics, treatment and prognosis of infants with retinoblastoma: a multicenter, 10-year retrospective analysis.
To summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis. The data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan-Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants. A total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02-122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan-Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (all P < 0.05). Multivariate Cox regression analyses for OS showed recurrence (HR = 1.376, 95% CI: 0.878-2.156, P = 0.048) was an independent factor for prognosis of infants with RB. The median survival time of infants underwent chemotherapy + intra-arterial chemotherapy (IAC) + enucleation + vitrectomy was the longest than other treatments (n = 9, 47.64 months, OS = 100%, all P < 0.05). There was a history of RB in 17 infants' lineal relatives. Kaplan-merier survival analysis indicated 1 case died and the median survival time was not reached. Recurrence is an independent factor for prognosis of RB infants, which still needs attention after treatment. Early screening, comprehensive treatments and follow-up of patients may lead to improvements of prognosis of RB infants.


Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial networks are incompletely understood and it is unclear how they might affect contractile fiber-type. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated differentially. Proteomic analyses of indirect flight, jump, and leg muscles, together with muscles misexpressing known fiber-type specification factor salm, identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization through evolutionarily conserved transcription factors cut, salm, and H15.


Mosaicism for an additional partial chromosome 8: 46,XX/47,XX+der(8)(p21 leads to qter).
Report on mosaicism of an additional deleted chromosome 8 in a 12-year-old girl. She exhibits several typical but minor features of the trisomy-8 syndrome. Her IQ is 77 (Hawik).


Evaluating the Calibration and Power of Three Gene-Based Association Tests of Rare Variants for the X Chromosome.
Although genome-wide association studies (GWAS) have identified thousands of trait-associated genetic variants, there are relatively few findings on the X chromosome. For analysis of low-frequency variants (minor allele frequency <5%), investigators can use region- or gene-based tests where multiple variants are analyzed jointly to increase power. To date, there are no gene-based tests designed for association testing of low-frequency variants on the X chromosome. Here we propose three gene-based tests for the X chromosome: burden, sequence kernel association test (SKAT), and optimal unified SKAT (SKAT-O). Using simulated case-control and quantitative trait (QT) data, we evaluate the calibration and power of these tests as a function of (1) male:female sample size ratio; and (2) coding of haploid male genotypes for variants under X-inactivation. For case-control studies, all three tests are reasonably well-calibrated for all scenarios we evaluated. As expected, power for gene-based tests depends on the underlying genetic architecture of the genomic region analyzed. Studies with more (haploid) males are generally less powerful due to decreased number of chromosomes. Power generally is slightly greater when the coding scheme for male genotypes matches the true underlying model, but the power loss for misspecifying the (generally unknown) model is small. For QT studies, type I error and power results largely mirror those for binary traits. We demonstrate the use of these three gene-based tests for X-chromosome association analysis in simulated data and sequencing data from the Genetics of Type 2 Diabetes (GoT2D) study.


Amniotic fluid concentrations of fibronectin and intra-amniotic infection.
A cohort study with four groups of pregnant women was designed to evaluate if a decrease in the concentration of fibronectin (FN) in amniotic fluid plays a role in the genesis of premature rupture of the membranes (PROM) and/or intra-amniotic infection: group 1, 15 patients with PROM and intra-amniotic infection; group 2, 15 patients with PROM but without intra-amniotic infection; group 3, 15 patients with preterm labor without PROM or intra-amniotic infection; and group 4, 15 patients who underwent elective amniocentesis for fetal lung maturity studies. No significant differences in amniotic fluid concentrations of FN among any of the four groups was observed (F = 0.146; P = 0.931). These results suggest that a deficiency of FN in amniotic fluid is not a critical factor in determining which patients may be affected by PROM or which of them will develop an intra-amniotic infection.


Polyhydroxyalkanoates (PHAs) synthesis and degradation by microbes and applications towards a circular economy.
Overusing non-degradable plastics causes a series of environmental issues, inferring a switch to biodegradable plastics. Polyhydroxyalkanoates (PHAs) are promising biodegradable plastics that can be produced by many microbes using various substrates from waste feedstock. However, the cost of PHAs production is higher compared to fossil-based plastics, impeding further industrial production and applications. To provide a guideline for reducing costs, the potential cheap waste feedstock for PHAs production have been summarized in this work. Besides, to increase the competitiveness of PHAs in the mainstream plastics economy, the influencing parameters of PHAs production have been discussed. The PHAs degradation has been reviewed related to the type of bacteria, their metabolic pathways/enzymes, and environmental conditions. Finally, the applications of PHAs in different fields have been presented and discussed to induce comprehension on the practical potentials of PHAs.


Failure to induce long-term depression by an anti-correlation procedure in area CA1 of the rat hippocampal slice.
We have independently in our two laboratories re-examined the report by Stanton and Sejnowski (Nature, 339, 215-218, 1989) that single stimuli to a test pathway in area CA1 of the hippocampal slice, when delivered between short bursts of stimuli to a second, convergent pathway, produce an associative long-term depression (LTD) in the test pathway. While robust associative LTP was observed when stimuli to the two inputs were correlated in time, the anti-correlation procedure failed to induce LTD; rather, a trend towards potentiation was observed. This result was obtained using both submerged and interface chambers, and in two different strains of rat. A transient depression lasting for a few minutes could usually be elicited by strong tetanic stimulation; this depression was not restricted to activated pathways.


Congenital malformations of the ear.
Either CT or pluridirectional tomography is capable of demonstrating bony anomalies of the ear. For a variety of reasons, high-resolution "bone algorithm" CT is used as the first imaging procedure at our institution, and pluridirectional tomography is done only on rare occasion, usually when there is an ambiguity on the CT images.


Clinical experience using the Wolf Piezolith device at 2 British stone centers.
Machines using the principle of piezoelectric extracorporeal shock wave lithotripsy have been developed. This has allowed the prospect of painless treatment for renal and ureteral calculi. The experience with use of 2 Wolf Piezolith machines for 1 year is presented. Different second generation lithotriptors have varying techniques of production of shock waves and different imaging methods. The Wolf Piezolith device uses ultrasound imaging and piezoelectric crystals for shock wave generation. Between June 1987 and May 1988, 545 patients 5 to 84 years old were treated with the Wolf Piezolith device. Of these patients 2-month followup data are available for 367 (398 renal units). Outpatient treatment was used routinely. For renal calculi complete fragmentation (into particles less than 2 mm. in size) was achieved in 94 per cent of the patients, with 53 per cent being completely free of stone at 2 months. For ureteral stones treated in situ the best results were obtained in the upper and lower ureter. Over-all, 62 per cent of the patients required more than 1 treatment, with the number of treatment sessions required increasing with the size of the stone treated. Morbidity was low. Ultrasound imaging has proved to be as effective as x-ray imaging. Compared to Dornier HM-3 lithotripsy, installation and running costs were low. The machine offers a favorable alternative to first generation lithotriptors.


Cochlear implant performance and electrically-evoked auditory brain-stem response characteristics.
The purpose of this study was to find a correlation between cochlear implant performances in phoneme discrimination and activity of the brain-stem. Electrically-evoked auditory brain-stem responses (EABRs) and speech recognition performances were measured in 17 patients implanted with an MXM Digisonic DX10 cochlear implant. Speech recognition performances without lip-reading were tested using lists of isolated French words containing 3 phonemes. The results indicated statistically significant correlations between phoneme correct-identification scores and the following EABR variables: wave V latency, wave II-V latency interval and wave III-V latency interval. These results, indicate that up to about 48% of the variance in isolated word recognition without lip-reading can be accounted for by EABR variables. The quality of brain-stem functioning influences central processes in phoneme discrimination.


Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery.
Nanoparticles have offered a unique set of properties for drug delivery including high drug loading capacity, combinatorial delivery, controlled and sustained drug release, prolonged stability and lifetime, and targeted delivery. To further enhance therapeutic index, especially for localized application, nanoparticles have been increasingly combined with hydrogels to form a hybrid biomaterial system for controlled drug delivery. Herein, we review recent progresses in engineering such nanoparticle-hydrogel hybrid system (namely 'NP-gel') with a particular focus on its application for localized drug delivery. Specifically, we highlight four research areas where NP-gel has shown great promises, including (1) passively controlled drug release, (2) stimuli-responsive drug delivery, (3) site-specific drug delivery, and (4) detoxification. Overall, integrating therapeutic nanoparticles with hydrogel technologies creates a unique and robust hybrid biomaterial system that enables effective localized drug delivery.


Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I): 2-Year Clinical and Imaging Results.
This is the first-in-human study of a drug-eluting bioresorbable vascular scaffold (BVS) for treatment of peripheral artery disease (PAD) involving the external iliac artery (EIA) and superficial femoral artery (SFA). Drug-eluting BVS has shown promise in coronary arteries. The ESPRIT BVS system is a device-drug combination consisting of an everolimus-eluting poly-l-lactide scaffold. Safety and performance were evaluated in 35 subjects with symptomatic claudication. Lesions were located in the SFA (88.6%) and EIA (11.4%). Mean lesion length was 35.7 ± 16.0 mm. The study device was successfully deployed in 100% of cases, without recoil. Procedure-related minor complications were observed in 3 patients (groin hematoma, dissection). Within 2 years there was 1 unrelated death, but no patients in this cohort had an amputation. At 1 and 2 years, the binary restenosis rates were 12.1% and 16.1%, respectively, and target lesion revascularization was performed in 3 of 34 patients (8.8%) and 4 of 32 patients (11.8%), respectively. The ankle brachial index 0.75 ± 0.14 improved from pre-procedure to 0.96 ± 0.16 at 2 years' follow-up. At 2 years, 71.0% of the patients were Rutherford-Becker 0, and 93.5% achieved a maximum walking distance of 1,500 feet. The safety of the ESPRIT BVS was demonstrated with no procedure or device-related deaths or amputations within 2 years. The low occurrence of revascularizations was consistent with duplex-ultrasonography showing sustained patency at 2-years. (A Clinical Evaluation of the Abbott Vascular ESPRIT BVS [Bioresorbable Vascular Scaffold] System [ESPRIT I]; NCT01468974).


Synthesis and biological evaluation of dihydroindeno and indeno [1,2-e] [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazines as antimicrobial agents.
Two series of compounds namely, dihydroindeno and indeno [1,2-e] [1,2,4]triazolo [3,4-b] [1,3,4]thiadizines (9a-l & 11a-l) were synthesized by cyclocondensation between α-bromoindanones (7a-b) or/and α,α-dibromoindanones (8a-b) and various 3-alkyl/aryl-4-amino-5-mercapto-1,2,4-s-triazoles (3a-f) in methanol with an aim to explore their effect on in vitro growth of microorganism causing microbial infection. In vitro antibacterial activity was performed against four strains namely, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and antifungal activity against three fungal strains namely, Aspergillus niger, Aspergillus flavus, Penicillium species. Of all the compounds screened for activity some of the compounds were associated with considerably higher antibacterial and antifungal activity than commercial antibiotics.


Traditional drug therapy of hypertension in transplant recipients.
Hypertension is a very common condition among recipients of transplanted organs, and is often related to immunosuppressive therapy. In many transplant centres, calcium antagonists are often used as first-line antihypertensive drug therapy, not only because of efficacy in lowering blood pressure, but also because certain members of the class have a 'beneficial' drug-drug interaction with cyclosporin, which decreases the cost of administering this very expensive immunosuppressant. Diuretics are often used both for blood pressure and volume control, and some centres have used either alpha-beta-blockers, angiotensin-converting enzyme inhibitors, and even beta-blockers with success in certain patients. The high frequency of perceived adverse effects of antihypertensive drugs in transplant recipients and the diversity of training of the specialist physicians involved in their care makes choice of traditional antihypertensive drug therapy in these patients a major challenge.


The role of adjuvants in retroviral vaccines.
The global HIV epidemic continues unchecked. Reports to the World Health Organization's Global Programme on AIDS indicate that more than 14 million persons have become infected with HIV and more than two million have died with AIDS. The spread of AIDS has generated a worldwide mandate for the development of safe and effective vaccines against HIV. Vaccines have been the most effective defense against other viral diseases such as polio and smallpox. However, the development of a vaccine against HIV-1 is a formidable task due to the variation of the virus, inadequate animal models of HIV disease, and the lack of correlates of protective immunity. Several candidate HIV vaccines are composed of synthetic, recombinant, or highly purified subunit antigens. Vaccines composed of subunit antigens generally are considered to be safer than traditional whole-killed or live-attenuated vaccines. However, purified subunit vaccines often are inherently less immunogenic than traditional vaccines. Immunologic adjuvants are agents that act generally to enhance specific immune responses to vaccine antigens. Formulation of experimental HIV vaccines with potent immunologic adjuvants is an attractive approach for amplifying and directing immune responses to highly purified antigens. Alum adjuvants, consisting of aluminum salts, first described in the 1920s, remain the only adjuvants in U.S.-licensed vaccine formulations. Novel adjuvants now undergoing preclinical and clinical testing with experimental subunit vaccine include detoxified lipid A, adjuvant emulsions, liposomes, biodegradable microspheres, muramyl peptides, and saponins. Adjuvants have been shown to elicit cytotoxic T-cell responses as well as antibody to subunit antigens.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of the structure and function of the terminal ileum in Crohn's disease using radiology, the "Dicopac" Schilling test and [14C] G.C.A. breath test.
Twenty patients with Crohn's disease were studied. Thirteen had radiological evidence of involvement of the terminal ileum. None had significant bacterial overgrowth of the small bowel contents and none had had resection of the terminal ileum. In all patients a [14C] glycocholic acid ([14C] G.C.A.) breath test and a "Dicopac" Schilling test were performed to assess terminal ileal function. The data showed poor correlation between the radiological appearance of the terminal ileum and the results of the functional tests. There was also poor correlation between the results of the [14C] G.C.A. breath test and the "Dicopac" Schilling test. Without terminal ileal histology, any assessment of the extent of Crohn's disease of the terminal ileum and of its effect on terminal ileal function, must include the [14C] G.C.A. breath test as well as radiology and the "Dicopac" Schilling test. The limitations of the [14C] G.C.A. breath test as a test of terminal ileal function in Crohn's disease are discussed.


Intramolecular electron transfer and binding constants in iron hexacyanide-cytochrome c complexes as studied by pulse radiolysis.
Internal oxidation and reduction rates of horse cytochrome c in the complexes CII . Fe(III)(CN)6(3)- and CIII . Fe(II)(CN)6(4)-, are 4.6 . 10(4)s-1 and 3.3 . 10(2)s-1, respectively. The binding site of the iron hexacyanide ions on either CII or CIII are kinetically almost indistinguishable; binding constants range from 0.87 . 10(3) to 2 . 10(3)M-1. The present pulse radiolytic kinetic data is compared with that from NMR, T-jump and equilibrium dialysis studies.


Kinetic studies of the interaction of uranyl ions with inorganic pyrophosphatase from baker's yeast.
Kinetic measurements were performed to test the effect of uranyl ions on the enzymatic hydrolysis of pyrophosphate. A strong inhibition of the enzyme was found. From a Dixon-plot an inhibition competitive to the substrate magnesium pyrophosphate and an inhibitory constant of Ki = 3 . 10(-7) M was deduced.


MAP65-1 is required for the depolymerization and reorganization of cortical microtubules in the response to salt stress in Arabidopsis.
Microtubules (MTs) are highly dynamical structures that play crucial roles in plant development and in response to environmental signals and stress conditions. MT-associated proteins (MAPs) play important roles in regulating the organization of MT arrays. MAP65 is a family of plant MT-bundling proteins. Here, we determined the role of MAP65-1 in the response to salt stress. MAP65-1 is involved not only in regulating the depolymerization, but also in the following reorganization of cortical MTs in salt stress responses. In addition, the depolymerization of the cortical MTs affected the survival of seedlings during salt stress, and map65-1 mutants had enhanced salt hypersensitivity levels. MAP65-1 interacted with mitogen-activated protein kinase (MPK) 3 and 6; however, only the mpk6 mutant exhibited hypersensitivity to salt stress, and MPK6 was involved in regulating the salt stress-induced depolymerization of cortical MTs. Thus, MAP65-1 plays a critical role in the response to salt stress and is required for regulating the rapid depolymerization and reorganization of cortical MTs. MAP65-1 interacts with MPK6, not MPK3, affecting the MT's dynamic instability which is critical for plant salt-stress tolerance.


Multivalent nanomedicines to treat COVID-19: A slow train coming.
The high transmission rate and serious consequences of the unprecedented COVID-19 pandemic make it challenging and urgent to identify viral pathogens and understand their intrinsic resistance mechanisms, to pave the way for new approaches to combat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multivalent interactions are responsible for performing a broad range of biological functions in normal cells, such as cell-cell communication and adhesion. Multivalency underlies the reversibility of ligand-receptor interactions during infections. Previous studies into multivalent nanomedicines used against viruses, have revealed their ability, not only to probe the molecular processes of viral infections, but also to target pathogen-host cell binding with minimal collateral damage to normal cells. Nanomedicines are comparable in size to viruses and to cell receptor complexes (that mediate viral uptake), and can function as safe and accurate armoured vehicles to facilitate the transport of anti-viral drugs. Multivalent nanomedicines can be designed to avoid binding to extracellular serum proteins, and ultimately lead to destruction of the viruses. This brief perspective highlights the potential of innovative smart and safe multivalent nanomedicines that could target multiple viral factors involved in infections at cellular levels. For instance it is possible to target viral spike protein mediated entry pathways, as well as viral replication and cell lysis. Nanomedicine-based approaches could open new opportunities for anti-coronavirus therapies.


Metachronous contralateral Leydig-cell tumour in an 8-year-old boy.
Leydig-cell tumours of the testis are rare and usually benign in children. The possibility of metachronous bilateral tumours should be considered not only for testicular teratomas but also in the follow up of a Leydig-cell tumour. Testis-sparing surgery is feasible and safe in prepubertal boys after exclusion of a malignant tumour.


Scintigraphic renal function after unilateral pyeloplasty in children: a systematic review.
To systematically review previous reports and thus determine the functional outcome after pyeloplasty in children with unilateral hydronephrosis due to pelvi-ureteric junction obstruction, and the possible variables that could affect it. We searched Medline/PubMed, Embase, and Web of Science for articles in English published from 1966 to 2007, using both 'medical subject headings' and 'free text' protocols. Abstracts, full texts, and bibliographies of pertinent papers were reviewed to select studies of scintigraphic renal function before and after pyeloplasty. The postoperative change in scintigraphic renal function was assessed in relation to presentation (antenatal vs postnatal), timing of surgery (early vs delayed), age at surgery, and preoperative ultrasonography (US) and scintigraphic findings. Thirty-six studies (2.1% of the initial search) were eventually selected for review. Studies were generally of poor scientific quality and very heterogeneous in their indications for surgery and follow-up protocols. Postoperative function showed a wide variability. Symptomatic patients diagnosed postnatally seemed to have a greater chance of functional improvement after surgery than asymptomatic patients diagnosed antenatally. The chance of improvement seemed also to be greater in patients with moderately rather than severely impaired preoperative function. Otherwise, the improvement seemed unrelated to the age at surgery, the preoperative US findings, or the excretion pattern on renal scintigraphy. Of patients having delayed surgery >97.5% had preserved function afterward. CONCLUSIONS; Patients with moderately impaired preoperative function and those diagnosed postnatally because of symptoms are those with the greatest likelihood of having a functional improvement after surgery.


Tetanus in pediatric patients--predictors affecting mortality and role of immunoglobulin.
Analysis of pediatric tetanus cases was carried out to study the predictors of mortality and role of tetanus immunoglobulin (TIG). Shorter incubation period, onset time and autonomic dysfunction were significantly associated with mortality and may be used to stratify patients requiring intensive care. TIG may not have independent role in decreasing mortality in sick patients.


Generalized Møller-Plesset Multiconfiguration Perturbation Theory Applied to an Open-Shell Antisymmetric Product of Strongly Orthogonal Geminals Reference Wave Function.
The antisymmetric product of strongly orthogonal geminals (APSG) method is a wave function theory that can effectively treat the static electron correlation. Recently, we proposed the open-shell APSG method using one-electron orbitals for open-shell parts. In this paper, we have extended the perturbation correction to the open-shell APSG calculations through Møller-Plesset-type multiconfiguration perturbation theory (MP-MCPT). Numerical applications demonstrate that the present open-shell MP-MCPT can reasonably reproduce the dissociation energies or equilibrium distances for open-shell systems.


Strategies for protein-based nanofabrication: Ni2+-NTA as a chemical mask to control biologically imposed symmetry.
Technologies that improve control of protein orientation on surfaces or in solution, through designed molecular recognition, will expand the range of proteins that are useful for biosensors, molecular devices and biomaterials. A limitation of some proteins is their biologically imposed symmetry, which results in indistinguishable recognition surfaces. Here, we have explored methods for modifying the symmetry of an oligomeric protein that exhibits useful self-assembly properties. Escherichia coli glutamine synthetase (GS) contains 24 solvent-exposed histidines on two symmetry-related surfaces. These histidines drive a metal-dependent self-assembly of GS tubes. Immobilization of GS on the affinity resin Ni2+-NTA followed by on-column modification with diethyl pyrocarbonate affords asymmetrically modified GS that self-assembles only to the extent of 'short' dimeric GS tubes, as demonstrated by electron microscopy, dynamic light scattering and atomic force microscopy. The utility of Ni2+-NTA as a chemical mask was also demonstrated for asymmetric modification of engineered cysteines adjacent to the natural histidines. Current genetic methods do not provide distinguishable recognition elements on symmetry-related surfaces of biologically assembled proteins. Ni2+-NTA serves as a mask to control chemical modification in vitro of residues within symmetry-related pairs, on proteins containing functional His-tags. This strategy may be extended to modification of a wide range of amino acids with a myriad of reagents.


Detection and Characterization of Circulating Tumor Cells by the CellSearch Approach.
Cancer metastasis occurs when cells shed from a primary or metastatic tumor, enter the circulation, and begin to grow in distant locations of the body. With current techniques it is possible to measure the presence of a few circulating tumor cells (CTC) in a blood sample. Detection of even the presence of a very small number (one or more) of these CTC in a 7.5 mL blood sample with the CellSearch system is associated with a significant decrease in survival of patients with metastatic carcinomas. The techniques and definitions used for the detection and enumeration of CTC with the CellSearch system were validated in series of preclinical and prospective multicenter studies. After enumeration of the CTC, the cells can be isolated from the cartridge for the purpose of downstream single-cell analysis. In this chapter, we will describe in detail the sample acquisition, sample preparation, data acquisition, and assignment of CTC used in the CellSearch system.


Risk factors for the development of Tenon's capsule cysts after trabeculectomy.
Tenon's capsule cysts (TCCs) are a complication of glaucoma filtering surgery. They are frequently associated with substantial elevations in intraocular pressure (IOP) beginning 2 to 8 weeks postoperatively. To determine the incidence and possible risk factors for the development of TCCs, case records of all patients who received trabeculectomy over a 4-year period at the Wills Eye Hospital were reviewed. The incidence of TCCs was 28% in those who underwent trabeculectomy. Characteristics of patients after trabeculectomy in whom TCCs developed were compared with patients after trabeculectomy in whom TCCs did not develop. Both univariate and multivariate techniques were used to assess the association of characteristics associated with the development of TCCs. Factors associated with increased risk (P less than 0.05) were: history of prior TCCs, argon laser trabeculoplasty, male gender, and the use of preoperative sympathomimetics. The use of a compression shell was associated with decreased risk (P less than 0.05).


Aerosol lung scintigraphy in the detection of bronchiectasis.
Twenty patients were studied to assess the value of aerosol ventilation scintigraphy, using 99Tcm diethylene triamine penta-acetic acid (DTPA) as a screening test for bronchiectasis. All patients had previously undergone bronchography for suspected bronchiectasis. Nine had cylindrical bronchiectasis and 11 had no demonstrable abnormality. Only two of the 20 patients had features suggestive of bronchiectasis on their chest radiographs. Segmental defects in ventilation were demonstrated by scintigraphy in five of the nine patients with bronchiectasis (56%). Regional ventilation appeared normal in 26 of the 27 lungs which were bronchographically normal (96%). Whilst the sensitivity of aerosol ventilation scintigraphy in detecting bronchiectasis is low (56%), it compares favourably with that of the chest radiograph (22%) in this group of patients with mild disease and non-specific symptoms. Thus, in some, it may obviate the need for bronchography.


Foreign bodies and urinary stones.
Experimental and clinical aspects of calculogenesis about foreign bodies are reviewed. Factors such as infections, urine dilution, urinary pH, and suture materials are discussed from an investigative point of view. The various kinds of clinical foreign body stones reported are categorized according to the manner of introduction into the urinary tract and anatomic locations.


Spatial-dependent quantum dot-photon entanglement via tunneling effect.
Utilizing the vortex beams, we investigate the entanglement between the triple-quantum dot molecule and its spontaneous emission field. We present the spatially dependent quantum dot-photon entanglement created by Laguerre-Gaussian (LG) fields. The degree of position-dependent entanglement (DEM) is controlled by the angular momentum of the LG light and the quantum tunneling effect created by the gate voltage. Various spatial-dependent entanglement distribution is reached just by the magnitude and the sign of the orbital angular momentum (OAM) of the optical vortex beam.


Effect of carboxyl mutations on functional properties of bovine rhodopsin.
Bovine rod rhodopsin and membrane-carboxyl group mutants are expressed using the recombinant baculovirus expression system. Biosynthesis of wild-type and the mutant D83N is normal. The mutations E122L and E134D/R affect glycosylation and translocation. After regeneration, purification and reconstitution in retina lipids a wild-type photosensitive pigment with spectral and photolytic properties identical to native bovine rod rhodopsin is generated. Only the mutations D83N and E122L affect the spectral properties and then only slightly. All mutations induce a shift in the Meta I<==>Meta II equilibrium towards Meta I (E134D/R) or Meta II (D83N, E122L). FT-IR analysis shows that the mutation E134D/R does not significantly affect the carboxyl-vibration region but, in particular in the case of E134R, affects secondary structural changes upon Meta II formation. E122L also has an effect on secondary structural changes and in addition eliminates a negative band at 1728 cm-1. The mutation D83N removes a pair of negative/positive bands from the carboxyl-vibration region, indicating that Asp83 stays protonated upon formation of Meta II but undergoes a change in hydrogen bonding.


Pathogenic selection promotes adaptive immune variations against serious bottlenecks in early invasions of bullfrogs.
Adaptive genetic variations are key for understanding evolutionary processes influencing invasions. However, we have limited knowledge on how adaptive genetic diversity in invasive species responds to new pathogenic environments. Here, we compared variations in immune major histocompatibility complex (MHC) class-II β gene and neutral loci in relation to pathogenic chytrid fungus (Batrachochytrium dendrobatidis, Bd) infection across invasive and native populations of American bullfrog between China and United States (US). Chinese invasive populations show a 60% reduction in neutral cytb variations relative to US native populations, and there were similar MHC variation and functional diversity between them. One MHC allele private to China was under recent positive selection and associated with decreased Bd infection, partly explaining the lower Bd prevalence for Chinese populations than for native US populations. These results suggest that pathogen-mediated selection favors adaptive MHC variations and functional diversity maintenance against serious bottlenecks during the early invasions (within 15 generations) of bullfrogs.


Layered double hydroxide eliminate embryotoxicity of chemotherapeutic drug through BMP-SMAD signaling pathway.
Recent studies indicate that exogenous chemotherapy agents can cross the placenta barrier and cause fetal toxicity, while there exists barely alternative therapy for pregnant cancer patients. Here, we show a robust protective effect of layered double hydroxide (LDH) against etoposide (VP16) induced in vitro mouse embryonic stem cells (mESCs) toxicity and in vivo embryo developmental disorders. The nano-composite system (L-V) abrogated the original VP16 generated mitochondrial mediated mESCs toxicity totally, surprisingly maintained the pluripotency without leukemia inhibitory factor (LIF) and prevented the down-regulation of ectoderm marker expression during spontaneous embryoid bodies differentiation. Fetal growth retardation, the related placenta and skeletal structural abnormalities and long-term toxicity in the offspring were generated when pregnant mice exposed to VP16, while these detrimental effects were abolished when substituted with L-V. The different uterine drug accumulation of VP16 and L-V contributed to partly cause for the functional variation. And further transcriptome analysis confirmed developmental related BMP4-SMAD6 signaling pathway is of crucial importance. Our study revealed the devastating effects of VP16 on embryonic development and the toxicity-relieve method using nano-carrier system, which will provide important guidance for clinical application of LDH as alternative therapeutic system with minimal side effects for pregnant women diagnosed with cancer.


A Systematic Review on Cannabis Hyperemesis Syndrome and Its Management Options.
Several forms of cannabinoids are currently being used to manage nausea and vomiting (N/V). Emerging cases of refractory N/V associated with chronic cannabis use among adults and older patients have been reported named cannabis hyperemesis syndrome (CHS). CHS is a condition that leads to repeated and severe N/V in long-term users of cannabinoids. The aim of this study was to outline current treatments for the management of CHS. A systematic review was conducted using PubMed, Ovid MEDLINE, Cochrane Central, EMBASE, and Google Scholar. Databases were used to search for articles on CHS published from January 2009 to June 2021, yielding 225 results of which 17 were deemed relevant and underwent review by 2 separate reviewers. The duration of cannabis administration ranged between 6 months to 11 years may precipitate symptoms of CHS. The Rome IV diagnostic criteria of CHS require cannabinoid use and persistence of N/V symptoms for at least the past 6 months. Cannabis cessation is noted to be the most successful management, but other treatments also demonstrated symptom relief; these include hot water hydrotherapy, topical capsaicin cream, haloperidol, droperidol, benzodiazepines, propranolol, and aprepitant administration. More research on CHS is needed to enhance knowledge translation, education, and create awareness in the medical community on the side effects of cannabinoids and to propose the best treatment options.


Essential barriers and considerations for the implementation of electronic patient-reported outcome (ePRO) measures in oncological practice: contextualizing the results of a feasibility study with existing literature.
Monitoring electronic patient-reported outcomes (ePRO) can provide various benefits to cancer patients, such as enhanced quality of life, reduction of hospital admissions, and even prolonged survival. Furthermore, ePRO might offer significant benefits to patients under antineoplastic treatment in the context of the current COVID-19 pandemic. However, evidence on feasibility of ePRO in routine cancer care and barriers met in a real-life setting remains limited. We conducted a feasibility study among patients diagnosed with multiple myeloma currently under antineoplastic treatment. Patients filled out weekly ePRO questionnaires and were followed up for 6 months. In case of adverse events, an alert was sent to the clinic. We assessed uptake and adherence, as well as subjective perceptions of patients and clinic staff. A semi-structured literature review was conducted to contextualize results. Eleven patients were recruited and followed up for 6 months. Overall adherence was found at a high level and remained stable throughout the study period. Feedback from patients was positive; however, clinic staff expressed disappointment and frustration, criticising an increase of workload while not perceiving any benefit to the oncological treatment. Both findings were backed by evidence we found in literature. Implementation of ePRO monitoring to routine cancer treatment seems to be feasible regarding patients' acceptance and compliance. However, integration of the tool into clinical workflow without increasing workload and deterring clinicians proves to be a major challenge. The online version contains supplementary material available at 10.1007/s10389-022-01767-3.


Validity of the Brazilian pediatric triage system CLARIPED at a secondary level of emergency care.
To evaluate the validity of the triage system CLARIPED in a pediatric population in the city of São Paulo, Brazil. Prospective, observational study in a secondary-level pediatric emergency service from Sep-2018 to Ago-2019. A convenience sample of all patients aged 0-18 years triaged by the computerized CLARIPED system was selected. Associations between urgency levels and patient outcomes were analyzed to assess construct validity. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) to identify the most urgent patients were estimated, as well as under-triage and over-triage rates. The distribution of 24,338 visits was: RED 0.02%, ORANGE 0.9%, YELLOW 23.5%, GREEN 47.9%, and BLUE 27.7% (highest to the lowest level of urgency). The frequency of the following outcomes increased with increasing urgency: hospital admission (0.0%, 0.02%, 0.1%, 7.1% and 20%); stay in ED observation room (1.9%, 2,4%, 4.8%, 24.1%, 60%); use of ≥ 2 diagnostic/therapeutic resources (2.3%, 3.0%, 5.9%, 28.8%, 40%); ED length of stay (12, 12, 15, 99.5, 362 min). The most urgent patients (RED, ORANGE, and YELLOW) exhibited higher chances of using ≥ 2 resources (OR 2.55; 95%CI: 2.23-2.92) or of being hospitalized (OR 23.9; 95%CI: 7.17-79.62), compared to the least urgent (GREEN and BLUE). The sensitivity to identify urgency was 0.88 (95%CI: 0.70-0.98); specificity, 0.76 (95%CI: 0.75-0.76); NPV, 0.99 (95%CI: 0.99-1.00); overtriage rate, 23.0%, and undertriage, 11.5%. This study corroborates the validity and safety of CLARIPED, demonstrating significant correlations with clinical outcomes, good sensitivity, and low undertriage rate in a secondary-level Brazilian pediatric emergency service.


Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer.
Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%. Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer. Prostate cancer was found in 55 patients (40%); the volume of the largest cancer in each specimen was determined using histologic morphometry. The authors identified the 8% of these 139 cytoprostatectomy specimens with the largest volume of prostate cancer. The largest 11 of the 55 cancers represented 7.9% of the total 139 samples. These cancers ranged in volume from 0.5-6.1 ml, representing only 20% of all patients with prostate cancer. If the strong evidence is accepted that cancer progression is proportional to cancer volume, it was concluded that prostate cancers larger than 0.5 ml appear to correspond to the 8% of men who will be diagnosed with a clinically significant carcinoma, as derived previously. Conversely, those 80% of prostate cancers smaller than 0.5 ml probably are not likely to reach a clinically significant size in view of the long doubling time of this cancer.


Impact of immunosuppressive drugs on circulating Tfh cells in kidney transplant recipients: A pilot study.
T follicular helper cells (Tfh) are recently revealed to be vital in antibody-mediated rejection (AMR) in kidney transplant recipients (KTRs). However, the impact of immunosuppressive drugs on Tfh cells is not fully understood. The purpose of this study was to investigate the variation of Tfh cells phenotypically and functionally in KTRs treated with different immunosuppression regimens. We recruited 26 KTRs treated with tacrolimus (TAC) -based regimen, 13 with sirolimus (SRL) -based regimen and 10 healthy controls (HC) in this study. The percentage and absolute number of circulating Tfh cells and the co-expression of Tfh related molecules including inducible costimulatory molecule (ICOS), programmed cell death protein 1 (PD-1), interleukin-21 (IL-21) and signal transducer and activator of transcription 3 (STAT3) were analyzed by flow cytometry, while serum IL-6 was detected by electrochemiluminescence immunoassay. The percentage and absolute number of Tfh cells and the co-expression of PD-1, STAT3 in Tfh cells were significantly higher in TAC group than that in SRL group. While no difference was found in regard to IL-21 and ICOS co-expressed with Tfh cells among three groups. Multiple linear regression analysis results showed that pre-transplant PRA level was the significant confounder affecting the absolute numbers of Tfh and CD4+CXCR5+PD-1+ T cells. In addition, correlation analysis showed that CD4+CXCR5+STAT3+ T cells were positively correlated to Tfh cells. Our study indicates that sirolimus can suppress the quantity of Tfh cells more significantly than tacrolimus. The higher level of circulating Tfh cells in tacrolimus group might be related to STAT3 signaling.


[Indocyanine green kinetics in newborns with non-hemolytic hyperbilirubinemia (author's transl)].
The kinetic parameters of indocyanine green elimination from blood were determined after an intravenous load of the dye in a dosage of 2-4 mg per kg body weight in 22 newborns with a non-hemolytic hyperbilirubinemia. Since the uptake of indocyanine green by liver is selectively carried out and the dye is not further metabolised, these kinetic parameters serve as measures for the performance of hepatocellular elimination. 11 of these newborns were treated 5 days previously with 7.5 mg phenobarbital per kg body weight. Compared to the untreated group, the serum bilirubin concentration significantly decreased after treatment with phenobarbital and the parameters of elimination of the dye from blood changed as described by saturation-kinetics. The maximal elimination-rate Vmax and the Michaelis-Menten-constant Km were significantly higher in newborns treated with phenobarbital (71.1 muMol/l-min and 356.4 muMol/l) than in the untreated ones (23.4 muMol/l-min and 100.0 mutmol/l). Kinetic data of indocyanine green elimination gathered in newborns treated with and without phenobarbital support the hypothesis that cytoplasmatic proteins oliver should facilitate the uptake of organic anions inclusively bilirubin into the liver cell. A defiency of such transport proteins may be one of the causes of non-hemolytic hyperbilirubinemia in newborns.


Seasonal changes in gonadal hormone levels of adult male canaries and their relation to song.
Samples of song and blood levels of three gonadal hormones, T, DHT, and E2, were taken at monthly intervals from six adult male canaries over a period of 1 year, as these birds went from 12 to 24 months of age. Song variability and addition of new syllable types were maximal during the summer and early fall, with a peak in September. A secondary peak in new syllable acquisition occurred in March. Blood T levels were particularly low during July-August and during February. Thus, a lowering of blood T levels preceded by about 1 month the two marked peaks in new syllable acquisition. Blood levels of the two other hormones were related less obviously to song learning peaks. It is hypothesized that a concurrence of hormonal, neural, and behavioral changes facilitates song learning in adulthood.


Relevance of experimental allergic encephalomyelitis to multiple sclerosis.
What the study of EAE has taught us that has relevance to human demyelinating diseases is discussed.


Effect of pinealectomy on arterial blood pressure and food and water intake in the rat.
Pinealectomy in the rat induces a significant increase of the arterial blood pressure within 15 days from the surgical procedure; this hypertension is still present 30 and 60 days after pinealectomy while after 90 days it returns to the normal range. Histological examination of the kidneys of pinealectomized hypertensive rats shows wall thickening and lumen narrowing of the arterioles, adventitial and periadventitial fibrosis, dense glomeruli. The vascular lesions are not diffuse but patchily distributed. Body weight is higher in pinealectomized rats compared with normal and sham-operated animals: this difference becomes significant about 40 days after pinealectomy and gradually decreases until it disappears at the end of the third month. Food and water intake is higher in pinealectomized rats up to the 7th week; during the 8th week they return to the normal range.


High-quality genome sequence and description of Bacillus ndiopicus strain FF3(T) sp. nov.
Strain FF3(T) was isolated from the skin-flora of a 39-year-old healthy Senegalese man. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry did not allow any identification. This strain exhibited a 16S rRNA sequence similarity of 96.8% with Bacillus massiliensis, the phylogenetically closest species with standing nomenclature. Using a polyphasic study made of phenotypic and genomic analyses, strain FF3(T) was Gram-positive, aeroanaerobic and rod shaped and exhibited a genome of 4 068 720 bp with a G+C content of 37.03% that coded 3982 protein-coding and 67 RNA genes (including four rRNA operons). On the basis of these data, we propose the creation of Bacillus ndiopicus sp. nov.


How many Na+-dependent carriers for L-alanine and L-proline in the eel intestine? Studies with brush-border membrane vesicles.
Using brush-border membrane (BBM) vesicles prepared from the intestine of the European eel, the specificity of L-alanine and L-proline Na+-dependent transport was investigated by measuring the uptake of isotopically labelled substrates. In the presence of Na+ ions, cross-inhibition between alanine and proline transports was observed; in addition alpha-(methylamino)isobutyric acid (MeAIB) inhibited proline but had no effect on alanine uptake. These results can be explained by the presence, in eel intestinal BBM vesicles, of at least two distinct agencies for Na+-dependent proline and alanine translocation. The first system is specific for alanine and short-chain neutral amino acids; the second system, specific for imino acids and the N-methylated analogues, is regulated by alanine concentration.


Are psychiatrists trained to be leaders in mental health? A survey of early career psychiatrists.
The aim of this study was to investigate how early career psychiatrists in 2014 valued the leadership skill education in their training to become psychiatrists. All psychiatrists who gained Fellowship since 2009 after training in New Zealand or Australia were invited to take part in a survey. Respondents considered themselves not adequately prepared for the leadership, management and administrative tasks and roles they have as psychiatrists, with preparedness for management tasks scoring the lowest. They valued as most useful to have opportunity to practice with a leadership role, to be able to observe 'leaders at work', to have a supervisor with special interests and skills in leadership and management and to have a formal teaching program on leadership and management. They advised teaching to be given throughout the entire 5 years of the training program by experienced leaders. Leadership skills training in the education of psychiatrists should contain both practical experience with leadership and management roles and formal teaching sessions on leadership and management skills development. Suggestions for improvement of the leadership and management skills education in the training of psychiatrists have been formulated.


Administration of the p38 MAPK inhibitor SB203580 affords brain protection with a wide therapeutic window against focal ischemic insult.
We have reported previously the delayed and differential induction of p38alpha and p38beta mitogen-activated protein kinases (MAPKs) in microglia and astrocytes, respectively, in brain after transient global ischemia. We report here the sustained induction and activation of p38alpha MAPK in activating microglia in rat brain after transient middle cerebral artery occlusion (MCAO). The intraventricular administration of SB203580, a p38 MAPK inhibitor, 30 min before MCAO reduced the infarct volume to 50% of the control, which was accompanied by the significant improvement of neurological deficits. More interestingly, the infarct volume was reduced to 72% and 77% when SB203580 was administered 6 hr and 12 hr after MCAO, respectively. The induction of various factors involved in inflammatory processes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and cyclooxygenase-2 (COX-2), was suppressed by the administration of SB203580 at 6 hr after MCAO. These results suggest that sustained activation of p38 MAPK pathway and p38 MAPK-associated inflammatory processes play a crucial role in postischemic brain.


Dimethyl sulfoxide for cryopreservation of alginate encapsulated liver cell spheroids in bioartificial liver support; assessments of cryoprotectant toxicity tolerance and dilution strategies.
The Bioartificial Liver (BAL) is an extra-corporeal liver support designed to support the function of the Liver in patients with impaired liver function. The BAL biomass consists of alginate encapsulated liver spheroids (AELS). To facilitate rapid delivery of a BAL to patients the AELS are cryopreserved using a DMSO-containing cryoprotectant solution. This study assesses toxicity of DMSO in AELS at concentrations and temperatures relevant to the cryopreservation and recovery process of a cellular biomass. Additionally, it develops a process to remove DMSO from AELS before delivery of cell product to patients. Exposure of AELS to DMSO, at a concentration of 12% (v/v) for 10 min did not have a negative effect on the viability of the AELS up to 24 h after exposure, irrespective of the exposure temperature between 37 C and 0 C. Evidence of toxicity was only seen with exposure to 40% (v/v) DMSO, which was more notable at warm temperatures. Post-Thaw removal of DMSO was measured by determining the DMSO concentration of the post-thaw washes using refractometry. Washing AELS 3 times in tapering concentrations of Glucose supplemented DMEM at an AELS:wash ratio of 1:2 was sufficient to reduce DMSO to undetectable levels (<1%). The study demonstrated that the thawing method minimised DMSO toxicity to the BAL biomass, and the post-thaw washing protocol successfully removed all the DMSO present in the cryopreserved BAL. Thereby enabling effective cryopreservation of the BAL for future clinical translation.


Comparative effects of dopamine D(1) and D(2) receptor antagonists on nerve growth factor protein induction.
We previously reported that following acute administration of haloperidol or (-)-sulpiride, both dopamine D(2)-receptor antagonists, to mice induced nerve growth factor (NGF) gene expression, mediated by the interaction of c-fos with the AP-1 binding site present in the first intron on the NGF gene. In contrast, the D(1)-receptor antagonist R-(-)-8-chloro-2,3,4, 5-tetrahydro-3,1-methyl-5-phenyl-11-3-benzyoepine-7-ol (SCH23390) did not induce NGF mRNA expression. We report here immunohistochemical and Western blot analyses showing that following injection of these drugs for 14 consecutive days, the amount of NGF protein increased gradually and was induced significantly in the hippocampus, piriform cortex, amygdala, dorsal striatum, and nucleus accumbens neurons. NGF enhances the release of acetylcholine from these regions. Cholinergic innervation in the striatum and nucleus accumbens neurons is believed to be related to late-onset extrapyramidal symptoms, while in the hippocampus and piriform cortex it is involved in enhancing cognition. Thus, our data suggest that haloperidol- and (-)-sulpiride-induced NGF expression may be associated with both beneficial and adverse effects.


Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage in Drosophila.
Optimal mitochondrial function determined by mitochondrial dynamics, morphology and activity is coupled to stem cell differentiation and organism development. However, the mechanisms of interaction of signaling pathways with mitochondrial morphology and activity are not completely understood. We assessed the role of mitochondrial fusion and fission in the differentiation of neural stem cells called neuroblasts (NB) in the Drosophila brain. Depleting mitochondrial inner membrane fusion protein Opa1 and mitochondrial outer membrane fusion protein Marf in the Drosophila type II NB lineage led to mitochondrial fragmentation and loss of activity. Opa1 and Marf depletion did not affect the numbers of type II NBs but led to a decrease in differentiated progeny. Opa1 depletion decreased the mature intermediate precursor cells (INPs), ganglion mother cells (GMCs) and neurons by the decreased proliferation of the type II NBs and mature INPs. Marf depletion led to a decrease in neurons by a depletion of proliferation of GMCs. On the contrary, loss of mitochondrial fission protein Drp1 led to mitochondrial clustering but did not show defects in differentiation. Depletion of Drp1 along with Opa1 or Marf also led to mitochondrial clustering and suppressed the loss of mitochondrial activity and defects in proliferation and differentiation in the type II NB lineage. Opa1 depletion led to decreased Notch signaling in the type II NB lineage. Further, Notch signaling depletion via the canonical pathway showed mitochondrial fragmentation and loss of differentiation similar to Opa1 depletion. An increase in Notch signaling showed mitochondrial clustering similar to Drp1 mutants. Further, Drp1 mutant overexpression combined with Notch depletion showed mitochondrial fusion and drove differentiation in the lineage, suggesting that fused mitochondria can influence differentiation in the type II NB lineage. Our results implicate crosstalk between proliferation, Notch signaling, mitochondrial activity and fusion as an essential step in differentiation in the type II NB lineage.


Analysis of the Macular Region Following Panretinal Photocoagulation for the Treatment of Diabetic Retinopathy Using Optical Coherence Tomography.
Diabetic retinopathy (DR) is the most prevalent microvascular complication of diabetes. Panretinal photocoagulation (PRP) is the established treatment for mitigating severe visual impairment resulting from proliferative DR. This study aims to investigate the impact of PRP on the macular region in patients with DR, utilizing optical coherence tomography (OCT) for assessment. An experimental study was meticulously designed, implementing PRP as the primary intervention. The investigation was conducted within the Department of Ophthalmology at the Affiliated Huaian No.1 People's Hospital, Huai'an, Jiangsu, China. A total of 120 participants diagnosed with DR and undergoing treatment at our hospital were enrolled in the study. The participants were randomly assigned to either the control group (CG, n = 60) or the study group (SG, n = 60). The CG received conventional drug treatment involving oral iodized lecithin, while the SG received PRP. OCT was employed to monitor changes in macular fovea volume and macular retinal thickness. Evaluation criteria encompassed clinical efficacy, macular fovea volume, macular retinal thickness, IL-6 and VEGF levels, incidence of adverse reactions, and quality of life in both groups. The study resulted in a higher total effective rate in the SG (96.67%) compared to the CG (80.00%) (χ2 = 8.09, P < .05). Post-treatment, reductions were observed in macular fovea volume and macular retinal thickness, with significantly lower SG values than CG values (P < .05). Both serum IL-6 and VEGF levels exhibited reductions in both groups after treatment, with the SG displaying a more significant decrease compared to the CG (P < .05). The occurrence of adverse reactions significantly decreased in the SG relative to the CG (P < .05). Quality of life scores for the SG was notably elevated compared to the CG (P < .05). PRP emerges as a highly valuable approach in the management of DR. It contributes to retinal thickness improvement within the macular region and inflammation reduction, and also enhances therapeutic outcomes, minimizes adverse reactions, and optimizes patients' quality of life. These findings warrant further clinical adoption and widespread promotion.


Delayed bowel perforation in electrocution: An unpredictable foe.
Electrocution injuries, particularly high voltage, are uncommon, but can be devastating. Thermal burns, arrhythmias and myonecrosis are commonly known and monitored complications of electrical injuries. Direct thermal trauma to internal viscera is also known and almost all internal organs have been reported to be affected, bowel being the most common. However, bowel perforation occurring in a delayed fashion is one rare, dreaded and erratic complication of electrocution, making it a dangerous pitfall if missed. Alimentary tract perforations can present on a delayed basis in high voltage electrocution injuries; advise for clinical follow up must incorporate this possibility at the time of discharge. Presentation of delayed visceral injuries is subtle & atypical, and post burn immunosuppression may play a part for such presentation. We suggest that all victims of high voltage electrocution with abdominal wall burns receive diagnostic laparoscopy and/or CECT abdomen as part of workup of their injuries. Any non-enhancing segment of bowel on CECT, howsoever small, should be prudently evaluated with laparoscopy.


Evidence for synaptic potentiation in a cortical network during learning.
The connections between the lateral olfactory tract (LOT) and layer I of the piriform cortex were used to test the idea that certain forms of learning involve potentiation of cortical synapses. Rats were trained on a series of two-odor discriminations over a period of several days after which patterned electrical stimulation (short, high frequency bursts with 5-6 bursts per second) of the LOT was used as a discriminative cue. The animals reacted to the stimulation as though it were an odor and quickly learned to respond appropriately and to distinguish between 'positive' and 'negative' electrodes. Comparisons of the monosynaptic responses in the piriform cortex evoked by single pulse stimulation of the LOT before and after learning revealed that the population synaptic responses were substantially potentiated by the training. This effect was present in an unchanged form 24 h later. Responses elicited by control stimulating electrodes were slightly or not at all affected by training to stimulation with another electrode. Synaptic potentiation was not found in a small group of rats that did not learn to respond to patterned stimulation and was also absent when the stimulation was applied to naive rats. These results provide evidence that rapid learning of a specific cue potentiates cortical synapses in a defined terminal field.


[Comparative studies on the biochemical properties, phage relationships and antigenic structure of S. aureus strains isolated from sheep].
Defined were the biochemical, phage, and antigenic properties of a total of 104 strains of S. aureus of the udder. It was found that by their biochemical behaviour 85 of the strains corresponded to var. ovis. Phage typing showed that the strains were lyzed in a highest percent by phages of groups IV and M. Dominating were the 42D/78/107/119 and 78 phages. Studies revealed that the strains were antigenically homogenic. Antigens h2 and k1k2 were characteristic of S. aureus var. ovis.


Acute bacterial endophthalmitis after intravitreal bevacizumab injection: Case report and literature review.
A case report of a 52 year old male who received intravitreal bevacizumab and developed culture positive endophthalmitis. Vitreous culture indicated that endophthalmitis was caused by Staphylococcus epidermidis. The patient was initially managed with intravitreal injection of ceftazidime and vancomycin, followed by pars plana lensectomy, pars plana vitrectomy with intravitreal injection of 1 mg/0.1 ml vancomycin, 2.25 mg/0.1 ml ceftazidime, 5 mg/0.1 ml fortified amphotericin-B and 4 mg/0.1 ml dexamethasone. Postoperatively the patient improved significantly. However, vision improved from hand motion to counting fingers secondary to severe retinal ischemia. Acute endophthalmitis can develop after intravitreal bevacizumab injections and cause profound visual loss. A review of literature was also performed for similar cases.


A novel polymorphism near HLA class II region is associated with spontaneous clearance of HCV and response to interferon treatment in Chinese patients.
A recent genome-wide association study (GWAS) has identified the single-nucleotide polymorphism (SNP) rs4273729 in a 100-kbp region comprising human leukocyte antigens (HLAs) class II genes as an important predictor of hepatitis C virus (HCV) clearance in European and African populations. This study was to determine whether this polymorphism is also associated with spontaneous HCV clearance as well as response to interferon treatment in Chinese patients. Thus, 686 chronic HCV carriers, 432 individuals with spontaneous viral clearance and 243 patients with pegylated interferon-α and ribavirin (PEG IFN-α/RBV) treatment were genotyped. The rs4273729 GG genotype was strongly associated with spontaneous HCV clearance as well as better IFN/RBV treatment response compared with the GC/CC genotypes in Chinese Han population (additive model: odds ratio (OR)=0.62, 95% confidence interval (95% CI)=0.51-0.76; OR=0.58, 95% CI=0.38-0.88, respectively). Rs4273729, rs12980275, baseline HCV RNA and platelet level were independent predictors for sustained virological response (SVR). The area under the receiver-operating characteristic curve (AUC) was 0.578 when including rs4273729 alone, but the prediction value was improved significantly (AUC=0.733) when further including rs12980275, baseline viral load and baseline platelet level. In conclusion, the genetic variation of rs4273729 is associated with clearance of HCV in both the natural course and the treatment process in Chinese Han population.


Utility of the Python package Geoweaver_cwl for improving workflow reusability: an illustration with multidisciplinary use cases.
Computational workflows are widely used in data analysis, enabling automated tracking of steps and storage of provenance information, leading to innovation and decision-making in the scientific community. However, the growing popularity of workflows has raised concerns about reproducibility and reusability which can hinder collaboration between institutions and users. In order to address these concerns, it is important to standardize workflows or provide tools that offer a framework for describing workflows and enabling computational reusability. One such set of standards that has recently emerged is the Common Workflow Language (CWL), which offers a robust and flexible framework for data analysis tools and workflows. To promote portability, reproducibility, and interoperability of AI/ML workflows, we developed geoweaver_cwl, a Python package that automatically describes AI/ML workflows from a workflow management system (WfMS) named Geoweaver into CWL. In this paper, we test our Python package on multiple use cases from different domains. Our objective is to demonstrate and verify the utility of this package. We make all the code and dataset open online and briefly describe the experimental implementation of the package in this paper, confirming that geoweaver_cwl can lead to a well-versed AI process while disclosing opportunities for further extensions. The geoweaver_cwl package is publicly released online at https://pypi.org/project/geoweaver-cwl/0.0.1/ and exemplar results are accessible at: https://github.com/amrutakale08/geoweaver_cwl-usecases.


[Facial soft tissue three dimensional morphometry].
The purpose of this article were to assess the reproducibility of the landmark locating, and to obtain some facial soft tissue measurements data of the teenagers. 8 males were selected to refix the black markers by the same operator and remeasure 14 items by the system, then compare both results. Three dimensional facial morphametry was investigated in a sample of 20 teenagers at the early stage of the permanent dentition. No item of the remeasurement test showed statistical difference error. The sexual dimorphism was found in the measurements connecting with lower face height(Sn-Pg). It indicated that the landmarks selected in this study had biologic significance and unique definition. The result of teenager facial measurements is in accordance with growth rule.


Periodic liquid crystalline waveguiding microstructures.
Different methods allowing for creating optical waveguides with liquid-crystal (LC) cores, in which molecules form periodic patterns with precisely controlled periods, are reported. The first one is based on reversible photoalignment with high-resolution selective illumination and allows to control the period of LC molecules inside silica microcapillaries. The second method employs microstructures formed in PDMS, allowing to obtain both: LC-core waveguides and a set of specially designed periodic microelectrodes used for the periodic reorientation of molecules. Using both methods, we successfully controlled the period of the patterned alignment in the range from about 500 µm and scaled it down to as small as 20 µm. We performed experimental studies on waveguiding phenomenon in such structures, in view to obtain transmission spectra typical to optical fiber gratings. Since the results achieved in experimental conditions differed from those expected, the additional numerical simulations were performed to explain the observed effects. Finally, we obtained the waveguiding in a blue phase LC, characterized by naturally created three-dimensional periodicity with periods smaller than one micrometer. In such a structure, we were able to observe first-order bandgap, and moreover, we were able to tune it thermally in nearly the whole visible spectral range.


Alleged resection of the vas deferens: medicolegal implications.
New York state law requires that significant complications be reported by telephone within 24 hours, followed by a full written report within five days with the names of the alleged involved physicians. This case illustrates the potential medicolegal consequences following the mandated immediate nonsubstantiated report of an alleged bilateral vas deferens injury during a bilateral inguinal herniorrhaphy in a 7-month-old male. Review of the surgical pathologic specimen showed that both hernial sacs did indeed contain segments of vas deferens structures, which based on the findings at reexploration, were consistent with duplication or embryonic remnants of the vas deferens. The vas deferens was found to be normal and uninjured bilaterally. The legal ramifications remain unclear. Since there is no clear cut method to retract the allegation, the physician's profile may be permanently damaged.


Similarities between the Yin/Yang Doctrine and Hormesis in Toxicology and Pharmacology.
Hormesis is a generalizable dose-response relationship characterized by low-dose stimulation and high-dose inhibition. Despite debate over this biphasic dose-response curve, hormesis is challenging central beliefs in the evaluation of chemicals or drugs and has influenced biological model selection, concentration range, study design, and hypothesis testing. We integrate the traditional Chinese philosophy - Yin/Yang doctrine - into the representation of the Western hormetic dose-response relationship and review the Yin/Yang historical philosophy contained in the hormesis concept, aiming to promote general acceptance and wider applications of hormesis. We suggest that the Yin/Yang doctrine embodies the hormetic dose-response, including the relationship between the opposing components, curve shape, and time-dependence, and may afford insights that clarify the hormetic dose-response relationship in toxicology and pharmacology.


[Ischemia-reperfusion injury after kidney transplantation].
Ischemia-reperfusion injury is an inescapable phenomenon in kidney transplantation. It combines lesional processes of biochemical origin associated with oxydative stress and of immunological origin in connection with the recruitment and activation of innate immunity cells. Histological lesions associate acute tubular necrosis and interstitial œdema, which can progress to interstitial fibrosis. The extent of these lesions depends on donor characteristics (age, expanded criteria donor, etc.) and cold ischemia time. In the short term, ischemia-reperfusion results in delayed recovery of graft function. Cold ischemia time also impacts long-term graft survival. Preclinical models, such as murine and porcine models, have furthered understanding of the pathophysiological mechanisms of ischemia-reperfusion injury. Due to its renal anatomical proximity to humans, the porcine model is relevant to assessment of the molecules administered to a donor or recipient, and also of additives to preservation solutions. Different donor resuscitation and graft perfusion strategies can be studied. In humans, prevention of ischemia-reperfusion injury is a research subject as concerns donor conditioning, additive molecules in preservation solutions, graft reperfusion modalities and choice of the molecules administered to the recipient. Pending significant advances in research, the goal is to achieve the shortest possible cold ischemia time.


Peripheral Blood Transcriptome in Breast Cancer Patients as a Source of Less Invasive Immune Biomarkers for Personalized Medicine, and Implications for Triple Negative Breast Cancer.
Transcriptome studies of peripheral blood cells can advance our understanding of the systemic immune response to the presence of cancer and the mechanisms underlying cancer onset and progression. This enables the identification of novel minimally invasive immune biomarkers for early cancer detection and personalized cancer management and may bring forward new immunotherapy options. Recent blood gene expression analyses in breast cancer (BC) identified distinct patient subtypes that differed in the immune reaction to cancer and were distinct from the clinical BC subtypes, which are categorized based on expression of specific receptors on tumor cells. Introducing new BC subtypes based on peripheral blood gene expression profiles may be appropriate, since it may assist in BC prognosis, the identification of patients likely to benefit from immunotherapy, and treatment efficacy monitoring. Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous, and difficult-to-treat disease, and identification of novel biomarkers for this BC is crucial for clinical decision-making. A few studies have reported TNBC-enriched blood transcriptional signatures, mostly related to strong inflammation and augmentation of altered immune signaling, that can differentiate TNBC from other classical BC subtypes and facilitate diagnosis. Future research is geared toward transitioning from expression signatures in unfractionated blood cells to those in immune cell subpopulations.


On Laws of Thought-A Quantum-like Machine Learning Approach.
Incorporating insights from quantum theory, we propose a machine learning-based decision-making model, including a logic tree and a value tree; a genetic programming algorithm is applied to optimize both the logic tree and value tree. The logic tree and value tree together depict the entire decision-making process of a decision-maker. We applied this framework to the financial market, and a "machine economist" is developed to study a time series of the Dow Jones index. The "machine economist" will obtain a set of optimized strategies to maximize profits, and discover the efficient market hypothesis (random walk).


The increased risk of bleeding due to drug-drug interactions in patients administered direct oral anticoagulants.
Direct oral anticoagulants (DOACs) have the potential to increase bleeding due to drug-drug interactions (DDIs). In the present study, the risk of bleeding was evaluated when drugs with potential DDIs were simultaneously prescribed with DOACs. The present study included patients with non-valvular atrial fibrillation (AF) and venous thromboembolism (VTE) who were newly prescribed DOACs between January 2014 and December 2016. The study included 115,362 patients with AF or VTE who were newly administered DOACs (median age, 73 years, range, 19-108 years; males, 53.0%; AF, 81.9%). A total of 7001 any bleeding (6.1%) and 2283 major bleeding (2.0%) events occurred with DOAC prescriptions. Based on multiple logistic regression analysis, the number of DDIs was significantly associated with bleeding events independent of CHA2DS2-VASc score and Charlson Comorbidity Index (CCI). The rates of exposure to DDI drugs associated with any bleeding and major bleeding were 56.7% and 66.1%, respectively. The most common DDI drugs showed similar distributions in any or major bleeding; non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, diltiazem, and amiodarone were frequently prescribed. Physicians prescribing DOACs for AF or VTE should be aware of the increasing risk of bleeding associated with drugs having potential DDIs regardless of comorbidities.


Clinical and neuropathologic findings in a case of severe myoclonic epilepsy of infancy.
The autopsy of a 19-month-old boy with severe myoclonic epilepsy of infancy (SMEI) and sudden unexpected death (SUD) revealed several developmental brain abnormalities. The most striking features were microdysgenesis of cerebellum and cerebral cortex and threefold spinal cord channels with surrounding ectopic tissue. Hippocampus and brainstem were normal.


Roux-en-Y gastric bypass stimulates hypothalamic miR-122 and inhibits cardiac and hepatic miR-122 expressions.
MicroRNAs (miRNAs) are endogenous noncoding small ribonucleic acids that have emerged as one of the central players of gene expression regulation. This study was designed to determine and identify miRNAs that are associated with Roux-en-Y gastric bypass (RYGB). Male Sprague-Dawley rats were divided into two groups: sham and RYGB. Changes in food intake and body weight were measured. miRNA microarray analyses on the brain hypothalamus and heart were performed. The expressions of miR-122 were analyzed, and the activities of adenosine monophosphate-activated protein kinase (AMPK) were determined in the hypothalamus, heart, and liver. Antisense oligonucleotide miR-122 was transfected into hepatocellular carcinoma cells to validate in vivo results. Body weights decreased in the RYGB group compared with those in sham group. Food intake was different between sham and RYGB groups. Of 350 miRNAs that were investigated, we observed that miR-122, being predominantly found in the liver, markedly increased (>35-fold) in the hypothalamus and decreased (>4-fold) in the heart. Quantitative polymerase chain reaction analysis revealed that expression of miR-122 was induced in hypothalamus but attenuated in the heart and liver of the RYGB group. Activities of AMPK were decreased in the hypothalamus but increased in the heart and liver. Knockdown of miR-122 in hepatocellular carcinoma cells stimulated phosphorylation levels AMPK. The results in this study suggest that RYGB regulates the expressions of miR-122 in the hypothalamus, heart, and liver, which in turn may modulate the activities of AMPK, the master regulator of metabolism.


Baseline data from the Nyando Integrated Child Health and Education Project--Kenya, 2007.
Approximately 10 million children aged <5 years die each year in developing countries. The leading infectious causes of these deaths include acute respiratory infections, diarrhea, measles, and malaria; malnutrition contributes to approximately 50% of these deaths. To address multiple conditions that contribute to mortality, child-survival programs require effective interventions and implementation strategies. To assess the effectiveness of multiple interventions, CDC has joined with partners to create the Nyando Integrated Child Health and Education (NICHE) project to combine several proven approaches to child survival in an impoverished rural district of western Kenya. During March-April 2007, CDC began the NICHE project with a baseline survey. This report summarizes preliminary data from that survey, which determined that 1) 86.1% of surveyed households were in the poorest Kenya socioeconomic quintile and 2) among children aged 6-35 months, 21.5% had experienced an acute respiratory infection and 9.1% had experienced diarrhea in the preceding 24 hours, 28.0% had chronic malnutrition, 66.2% had anemia, and 19.8% had a positive malaria smear. Comprehensive interventions will be needed to improve living conditions and reduce the risk for death before age 5 years among children in this population.


Adrenalectomy enhances the induction of heme oxygenase and the degradation of cytochrome P-450 in liver.
The induction of hepatic heme oxygenase in response to cobaltous chloride (CoCl2) administration was examined in normal, sham-operated, and adrenalectomized rats. The basal level of heme oxygenase was elevated about 2-fold in adrenalectomized rats as compared to normal controls or sham-operated animals. The extent of heme oxygenase induction by CoCl2 was also increased about 2-fold above normal in adrenalectomized animals and was accompanied by an enhanced breakdown of cytochrome P-450. The initial decline (approximately 2 h) and the late rebound increase (approximately 16 h) of delta-aminolevulinate synthase activity caused by the metal administration were, however, similar for all three groups of animals. Hydrocortisone is known to restore the impaired inducibility of delta-aminolevulinate synthase by allylisopropylacetamide in adrenalectomized rats. In this study, treatment with hydrocortisone prevented the exaggerated metal induction of heme oxygenase but did not affect the associated initial decline or the late rebound of delta-aminolevulinate synthase. These data indicate that hydrocortisone and adrenalectomy can significantly influence the extent of the induction of heme oxygenase produced by CoCl2, but that both the initial decline and the rebound induction of delta-aminolevulinate synthase associated with this metal treatment are apparently independent of these endocrine controls.


Effects of cyclophosphamide on open, granulating skin wounds in rats.
The effect of cyclophosphamide on the healing of open cutaneous wounds was studied in rats. Following intraperitoneal injections of 25 mg/kg body weight every second day for 9 days, only about 7% of the wounds were completely covered by epithelium after 15 days, whereas in the control animals 60% of the wounds were completely epithelialized. Measurements of wound diameters in circular skin wounds revealed unhealed wound areas in the drug treated animals which were significantly larger than those of the control animals. Cyclophosphamide was found to reduce the occurrence of H3-labelled cells in the granulation tissue when evaluated after 11 days. At 15 days there was no difference in the labelling frequency between treated and control animals, indicating reversal of the drug effect.