Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors.
The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABAAR) and increased N-methyl-d-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). We hypothesized that trafficking of synaptic GABAAR and glutamate receptors is maladaptive and contributes to the pharmacoresistance to antiseizure drugs; targeting these components should ameliorate the pathophysiological consequences of refractory SE (RSE). We review studies of rodent models of cholinergic-induced SE, in which we used a benzodiazepine allosteric GABAAR modulator to correct loss of inhibition, concurrent with the NMDA antagonist ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDAR-dependent. Models included lithium/pilocarpine-induced SE in rats and soman-induced SE in rats and in Es1-/- mice, which similar to humans lack plasma carboxylesterase, and may better model soman toxicity. These model human soman toxicity and are refractory to benzodiazepines administered at 40 min after seizure onset, when enough synaptic GABAAR may not be available to restore inhibition. Ketamine-midazolam combination reduces seizure severity, epileptogenesis, performance deficits and neuropathology following cholinergic-induced SE. Supplementing that treatment with valproate, which targets a non-benzodiazepine site, effectively terminates RSE, providing further benefit against cholinergic-induced SE. The therapeutic index of drug combinations is also reviewed and we show the improved efficacy of simultaneous administration of midazolam, ketamine and valproate compared to sequential drug administration. These data suggest that future clinical trials should treat both the lack of sufficient inhibition and the excess excitation that characterize RSE, and include early combination drug therapies. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.


A novel anti-inflammatory activity of lysozyme: modulation of serum complement activation.
Lysozyme is an ubiquitous enzyme found in most biological secretions and leukocytes. This study was aimed at investigating its interaction with other inflammatory mediators on mucosa surfaces, particularly the complement system. Lysozyme has been shown in our present study, to inhibit the haemolytic activity of serum complement in a dose-dependent fashion, when tested within the levels present in normal and inflamed breast-milk samples, and other mucosal secretions. This represents a new anti-inflammatory action of lysozyme in relation to the serum complement, and the exact mode of the interaction need further studies.


Pie-like electrode design for high-energy density lithium-sulfur batteries.
Owing to the overwhelming advantage in energy density, lithium-sulfur (Li-S) battery is a promising next-generation electrochemical energy storage system. Despite many efforts in pursuing long cycle life, relatively little emphasis has been placed on increasing the areal energy density. Herein, we have designed and developed a 'pie' structured electrode, which provides an excellent balance between gravimetric and areal energy densities. Combining lotus root-like multichannel carbon nanofibers 'filling' and amino-functionalized graphene 'crust', the free-standing paper electrode (S mass loading: 3.6 mg cm(-2)) delivers high specific capacity of 1,314 mAh g(-1) (4.7 mAh cm(-2)) at 0.1 C (0.6 mA cm(-2)) accompanied with good cycling stability. Moreover, the areal capacity can be further boosted to more than 8 mAh cm(-2) by stacking three layers of paper electrodes with S mass loading of 10.8 mg cm(-2).


Different perspectives on communication quality and emotional functioning during routine oncology consultations.
To determine quality of communication in routine oncology consultations from patient, physician, and observer perspectives, and to determine agreement of emotional function content in consultations from these three perspectives. In total, 69 consultations were included. Perceived quality of communication and whether or not emotional functioning had been discussed was evaluated with patient- and physician-reported questionnaires. Observer perspective was evaluated by content analysis of audio records of the consultations. Agreement between perspectives was analyzed and means compared using linear mixed models. The patients' ratings of communication quality differed significantly from those of both the physician and observer. Observer and physician scores did not differ significantly. Physicians rated emotional functioning as discussed more often than was reported from patient and observer perspectives. The patients' view of the quality of communication differed from that of the physician and observer. Whether emotional functioning was discussed or not was also perceived differently by patients, physicians, and observer. The underpinnings and implications of these results need to be further explored regarding how to move toward a higher degree of shared understanding, where different perspectives are more in alignment, and how to develop more valid methods for evaluating communication.


Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine.
Galactose-targeted delivery of macromolecules and drug conjugates to asialoglycoprotein receptor (ASGPR) positive cells has been widely documented in animals, although targeting in humans has never been demonstrated. In this study we report the pharmacokinetics and imaging determined in the first patient enrolled in a phase I clinical study of the poly[N-(2-hydroxypropyl)methacrylamide] copolymer bearing doxorubicin and galactosamine, known as PK2. Gradient high performance liquid chromatography (HPLC) evaluation of plasma and urine has been combined with 123I-based imaging to show biphasic clearance of the drug from the plasma (half-lives of 78+/-1 and 990+/-15), and approximately 30% delivery of the drug to the hepatic region, as determined by planar whole body imaging at 24 h. This patient has a multifocal hepatoma, and single photon emission computed tomography (SPECT) analysis showed a ratio of tumour tissue to normal liver uptake of approximately 1:3, at 24 h. On the basis of this patient, effective hepatic targeting can be achieved following an intravenous dose of 20 mg/m2 doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established.


Optimization of methyl jasmonate and β-cyclodextrin for enhanced production of taraxerol and taraxasterol in (Taraxacum officinale Weber) cultures.
Taraxacum officinale Weber (TO) commonly known as "dandelion", is a tropical Asian medicinal plant which contains taraxasterol (TX) and taraxerol (TA) in its roots, which are reported to be commercially important anticancer compounds. The main objective of the present study was to evaluate the increase in yield of TX and TA through elicitation by addition of abiotic elictors like methyl jasmonate (MJ) and β-cyclodextrin (CD), to the root callus suspension cultures of TO. The root callus suspension was maintained on Murashige and Skoog's (MS) medium MS + IAA + BA + 2, 4-D (0.5 ppm + 1 ppm + 0.5 ppm). The concentrations of the abiotic elicitors MJ and CD were optimized using central composite design (CCD) and quantification of TA and TX in elicited cultures was done by High Performance Liquid Chromatography (HPLC) analysis. It was observed that MJ at a concentration of 0.2 mM showed good increase in content of TX to 0.032% w/w and at concentrations 0.05 mM, 0.1 mM and 0.2 mM showed similar increase in TA content to 0.018% w/w, whereas CD at the concentration of 25 mM showed highest increase in TX content to 0.036% w/w and at the concentrations of 25 mM, 50 mM showed increase in TA content to 0.023% w/w as compared to the plant root (PR) which showed content of TX as 0.0299% w/w and TA as 0.0169% w/w. From the present investigation it was concluded that out of the two abiotic elicitors MJ and CD, CD was found to be more effective to increase TA and TX content in Dandelion cell cultures.


New effective method for analysis of the component composition of enzyme complexes from Trichoderma reesei.
A method for analysis of the component composition of multienzyme complexes secreted by the filamentous fungus Trichoderma reesei was developed. The method is based on chromatofocusing followed by further identification of protein fractions according to their substrate specificity and molecular characteristics of the proteins. The method allows identifying practically all known cellulases and hemicellulases of T. reesei: endoglucanase I (EG I), EG II, EG III, cellobiohydrolase I (CBH I), CBH II, xylanase I (XYL I), XYL II, beta-xylosidase, alpha-L-arabinofuranosidase, acetyl xylan esterase, mannanase, alpha-galactosidase, xyloglucanase, polygalacturonase, and exo-beta-1,3-glucosidase. The component composition of several laboratory and commercial T. reesei preparations was studied and the content of the individual enzymes in these preparations was quantified. The influence of fermentation conditions on the component composition of secreted enzyme complexes was revealed. The characteristic features of enzyme preparations obtained in "cellulase" and "xylanase" fermentation conditions are shown.


Intrathecal therapy for tuberculous meningitis: propensity-matched cohort study.
The study aimed to determine the safety and efficacy of intrathecally administered isoniazid (INH) and prednisolone in addition to systemic anti-TB therapy and compare it with systemic anti-TB therapy alone in adult patients with tuberculous meningitis (TBM). In this retrospective study, patients were categorized into two groups: Group A patients received systematic anti-TB therapy alone, Group B patients received IT INH (50 mg) and prednisolone (25 mg) twice a week together with the same standard systemic anti-TB therapy as Group A, in addition to the standard systemic anti-TB therapy. Functional outcomes were compared between the two groups in a prosperity-matched cohort using propensity score matching (PSM) method. A total of 198 patients with TBM were enrolled. After PSM, 30 patients from each group were analyzed, so that there was no significant difference in the characteristics of the two groups. Mortality at follow-up was significantly lower among patients receiving additional IT therapy (4/30, 13.3%) compared with matched patients receiving systemic anti-TB therapy alone (11/30, 36.7%, P value = 0.037). In this propensity score-matched cohort, the addition of IT INH and prednisolone to systemic anti-TB therapy could be effective for the better outcome among adult TBM patients. Further large-scale, prospective, and randomized controlled trials are warranted to the best timing and indication of IT therapy.


Are there characteristic motion patterns in the lumbar spine during flexion?
Flexion is the main motion of the lumbar spine. While in vitro tests with pure moments suggest larger intra-segmental rotations for the more caudal segments, in vivo results show diverging motion distributions. The present study analysed the motion distribution in vivo of 320 asymptomatic subjects. The change of the back curvature between standing and upper body flexion was determined using a non-invasive measurement device. Linear, bilinear, trilinear, quadratic, and cubic regression models were fitted to the segmental motion distribution over the lengths of the lordosis to categorise characteristic motion patterns. Simplicity and approximation quality were used to assign the motion distributions to the regression models. Seventy-seven percent of the motion distributions could be explained by a bilinear model. A further 12% and 11% could be represented by a trilinear and linear model, respectively. Less than 1% of the distributions could not satisfactorily be represented by the models. All of the bilinear models displayed maximum flexion in approximately the middle of lordosis. All linear models showed a decreasing rotation from caudal to cranial. Most of the trilinear models displayed a distribution similar to the bilinear. Age, sex, body height, and weight did not significantly affect these distributions. This in vivo study identified characteristic motion patterns in the lumbar spine during flexion. The quantitative results provide a clear description of the healthy condition and may serve to identify spinal motion abnormalities.


Retinal artery occlusion does not act as an independent marker of upcoming dementia: results from a Danish 20-year cohort study.
Retinal artery occlusion (RAO) is a vision threatening disease associated with cerebral vascular dysfunction, which may reflect initial signs of cerebral pathology. Early detection of patients in risk of dementia could allow for preventative treatment. Hence, this study aimed to investigate RAO as an independent biomarker of incident dementia. This study was a nationwide, 20-year longitudinal cohort study in Denmark with inclusion from 1998 to 2020 and follow up until the end of 2022. We identified 2 205 159 individuals aged 65 or older through the Danish national health registers and monitored RAO (exposure) and dementia (outcome) status. We calculated incidence rate and performed a Cox regression analysis with hazard ratio (HR) and 95% confidence interval (CI) for RAO as a marker of dementia in a crude, a semi-adjusted (age and sex), and a fully adjusted model (furthermore adjusted for marital status and systemic comorbidity.) RESULTS: We identified 8 863 individuals with RAO. Incidence rates were higher among exposed compared to unexposed individuals (12.28 and 8.18 per 1000 person-years at risk, respectively). Individuals with RAO were more likely to be male and older at inclusion, to have hypertension, dyslipidaemia, cardiovascular disease, chronic kidney disease, and diabetes (p < 0.001). RAO was not associated with all-cause dementia in the crude analysis (HR 1.07 CI [1.00-1.17]) or in the fully adjusted analysis (HR 0.98 CI [0.91-1.06]. Although individuals with RAO had a higher incidence of dementia compared to unexposed individuals, these associations were lost when confounders were taken into account.


The ocular surface epithelial barrier and other mechanisms of mucosal protection: from allergy to infectious diseases.
Studies completed in the last decade provide new insights into the role of the epithelial glycocalyx in maintaining ocular surface barrier function. This review summarizes these findings, their relevance to allergic and infectious disease, and highlights the potential benefits of exploiting the modulation of barrier integrity for therapeutic gain. The molecular components sealing the space between adjacent ocular surface epithelial cells, such as tight junctions, have been extensively characterized, and their contribution to the paracellular barrier established. A second layer of protection - the transcellular barrier - is provided by transmembrane mucins and their O-glycans on the glycocalyx. Cell surface glycans bind carbohydrate-binding proteins to promote formation of complexes that are no longer thought to be a static structure, but, instead, a dynamic system that responds to extrinsic signals and modulates pathogenic responses. Although functioning as a protective mechanism to maintain homeostasis, the glycocalyx also restricts drug targeting of epithelial cells. The traditional model of intercellular junctions protecting the ocular surface epithelia has recently been expanded to include an additional glycan shield that lines apical membranes on the ocular surface. A better understanding of this apical barrier may lead to better management of ocular surface disease.


Immediate activation of stereotypical gender information.
This article reports six experiments in which we explored whether gender stereotype information is typically invoked when certain role and profession terms are read and the extent to which the use of such information is under the reader's strategic control. All of the experiments used a design in which subjects had to decide whether two terms (one an occupation and one a kinship term) could refer to the same person (e.g., surgeon-brother or surgeon-sister). The presentation conditions and the instructions were varied from experiment to experiment, to try to encourage the subjects to respond strategically and to suppress their use of gender stereotypes when responding. The results support not only the hypothesis that information about the stereotypical gender associated with occupations and roles is typically incorporated into the reader's representation immediately, but also the hypothesis that such information is difficult or impossible to suppress. The implications of these findings for current theories of text processing and text representation are discussed.


Modulation of E-Cadherin and N-Cadherin by ovarian steroids and embryonic stimuli.
Endometrium is a dynamic tissue that undergoes extensive remodelling to attain a receptive state which is further modulated in presence of an embryo for successful initiation of pregnancy. Cadherins are the proteins of the junctional complex of which E-cadherin (E-Cad) is crucial for maintaining epithelial cell state and integrity of the epithelial barrier; gain of N-cadherin (N-Cad) in epithelial cells leads to epithelial to mesenchymal transition (EMT). In the present study, we investigated the expression of E-Cad and N-Cad in the mouse endometrial luminal epithelium and its modulation by estrogen, progesterone, and embryonic stimuli. We observed that E-Cad is diffusely expressed in the luminal epithelium of mouse endometrium during the estrus stage and upon estrogen treatment. It is apico-laterally and basolaterally sorted at the diestrus stage and in response to the combined treatment of estrogen and progesterone. In 3D spheroids of human endometrial epithelial cells, combined treatment with estrogen and progesterone led to lateral sorting of E-Cad without any effects on its mRNA levels. at the time of embryo implantation, there is loss of E-Cad along with the gain of N-Cad and SNAIL expression suggestive of EMT in the luminal epithelium. This EMT is possibly driven by embryonic stimuli as treatment with estrogen and progesterone did not lead to the gain of N-Cad expression in the mouse endometrium in vivo or in human endometrial epithelial cells in vitro. In conclusion, the present study demonstrates that steroid hormones directly affect E-Cad sorting in the endometrial epithelium which undergo EMT in response to embryonic stimuli.


Steric requirements for the stimulation of glycosyltransferase activity by lysophosphatidylcholine.
1-Palmitoyl-sn-glycerol-3-phosphocholine and 3-palmitoyl-sn-glycerol-1-phosphocholine have been found to be equipotent in the stimulation of membrane-bound glycosyltransferases in microsomes of rat intestinal villus cells. This indicates that the stimulatory effect of lysophosphatidylcholine is not stereospecific, but that it may be related to a specific detergent property dependent upon the peculiar balance of hydrophilic and hydrophobic components in the molecule.


Topological and causal structure of the yeast transcriptional regulatory network.
Interpretation of high-throughput biological data requires a knowledge of the design principles underlying the networks that sustain cellular functions. Of particular importance is the genetic network, a set of genes that interact through directed transcriptional regulation. Genes that exert a regulatory role encode dedicated transcription factors (hereafter referred to as regulating proteins) that can bind to specific DNA control regions of regulated genes to activate or inhibit their transcription. Regulated genes may themselves act in a regulatory manner, in which case they participate in a causal pathway. Looping pathways form feedback circuits. Because a gene can have several connections, circuits and pathways may crosslink and thus represent connected components. We have created a graph of 909 genetically or biochemically established interactions among 491 yeast genes. The number of regulating proteins per regulated gene has a narrow distribution with an exponential decay. The number of regulated genes per regulating protein has a broader distribution with a decay resembling a power law. Assuming in computer-generated graphs that gene connections fulfill these distributions but are otherwise random, the local clustering of connections and the number of short feedback circuits are largely underestimated. This deviation from randomness probably reflects functional constraints that include biosynthetic cost, response delay and differentiative and homeostatic regulation.


From rat sexual behavior to schizophrenia: a tribute to Professor Emeritus Knut Larsson.
In July of 2002 Knut Larsson celebrated his 80th birthday. He could by then have looked back at a long and distingusihed career in the field of biological psychology. His research on sexual behavior had contributed to a basic understanding of many behavioral, endocrine and neural phenomena associated with or underlying sexual activity. Instead of looking back at his past achievements, Knut has preferred to look forward, constantly trying to find ways to stimulate interest in his own field and in biological psychology in general. This issue is a humble contribution to the noble end of enhancing the standing of biological psychology, particularly in Scandinavia. Foremost, however, it is a homage to a man of outstanding vision and intellectual integrity: Knut Larsson.


New insights into the interplay between miRNAs and autophagy in the aging of intervertebral discs.
Intervertebral disc degeneration (IDD) has been widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in the ageing process of intervertebral disc. Autophagy is an evolutionarily conserved process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic organelles. Autophagy has been proposed as a "double-edged sword" and autophagy dysfunction of IVD cells is considered as a crucial reason of IDD. A rapidly growing number of recent studies demonstrate that both miRNAs and autophagy play important roles in the progression of IDD. Furthermore, accumulated research has indicated that miRNAs target autophagy-related genes and influence the onset and development of IDD. Hence, this review focuses mainly on the current findings regarding the correlations between miRNA, autophagy, and IDD and provides new insights into the role of miRNA-autophagy pathway involved in IDD pathophysiology.


Association of uric acid with progression to preeclampsia and development of adverse conditions in gestational hypertensive pregnancies.
Preeclampsia is a serious pregnancy complication. Gestational hypertension is a common first clinical presentation of preeclampsia. Little is known about which clinical risk factors are associated with the progression from gestational hypertension to preeclampsia. In a retrospective cohort study of 249 singleton pregnant women with an initial presentation of gestational hypertension in an obstetric hospital, we assessed which routinely available clinical risk factors are associated with the progression to preeclampsia and the development of adverse maternal or infant conditions. The mean serum uric acid level at the initial presentation of gestational hypertension was significantly higher comparing patients who later progressed to preeclampsia to those who did not (5.06 vs. 4.59 mg/dl, P < 0.01). Lower gestational age and higher serum uric acid level at the initial presentation of gestational hypertension and subsequent need for antihypertensive drug treatment for blood pressure (BP) control were associated with significantly increased risks of progression to preeclampsia, and development of adverse maternal or infant conditions. One standard deviation (s.d.) increase in serum uric acid level was associated with 2.3-fold increased odds of progression to preeclampsia (adjusted odds ratio (aORs) 2.33 (95% confidence interval (CI) 1.45-3.74)), and 1.5-fold increased odds of developing clinically significant adverse maternal or infant conditions (aOR 1.49 (1.03-2.17)) irrespective of the progression to preeclampsia. Higher serum uric acid levels at the initial presentation of gestational hypertension may indicate heightened risk of progression to preeclampsia and development of adverse maternal/infant conditions.


Purine nucleoside and purine base concentrations in bovine thyroid and plasma.
Concentrations of eight purine nucleosides and bases in bovine thyroid and plasma were determined by high pressure liquid chromatography. Plasma purines were metabolized to uric acid in the absence of inhibitors. The concentrations of these purines were 10-100 times greater in thyroid tissue than in plasma.


Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: a pilot study.
The wasting syndrome (cachexia) characterized by anorexia, malaise, and weight loss is observed in many patients with cancer or chronic infection. The excessive levels of tumor necrosis factor-alpha (TNF)/cachectin reported in 50% of cancer patients exhibiting clinically active disease may therefore mediate, at least in part, the cachexia associated with malignancy. Pentoxifylline, a substituted methylxanthine approved for treatment of intermittent claudication, has been shown in preclinical studies to down-regulate TNF RNA expression as well as TNF activity. We report that pentoxifylline suppressed TNF RNA levels on all three occasions in patients with initially elevated levels of TNF RNA. Pentoxifylline did not suppress TNF RNA to subnormal levels in all five patients with initially normal TNF RNA levels. Four patients reported an increased sense of well-being, improved appetite and ability to perform the activities of daily living. Two of these five patients with normal TNF levels each had a weight gain of more than 5% after 3 weeks of pentoxifylline therapy suggesting that, although TNF may be important in the pathogenesis of cancer cachexia, other anorexia-producing cytokines that are potentially affected by pentoxifylline may also be involved. No severe adverse effects were observed. Taken together these findings suggest that pentoxifylline can down-regulate TNF expression and improve the sense of well-being in cancer patients. A larger study with a randomized, double-blind, placebo-controlled design and more sophisticated estimates of quality of life will be needed to confirm these observations.


Improved outcomes after low-concentration hypochlorous acid nasal irrigation in pediatric chronic sinusitis.
We aimed to evaluate the effectiveness of low-concentration hypochlorous acid (HOCl) nasal irrigation compared to isotonic normal saline for pediatric chronic rhinosinusitis. This was a randomized, prospective, active-controlled study. This study investigated the effectiveness of 4 weeks of low-concentration hypochlorous irrigation by analyzing five categorized subjective symptoms and x-ray findings in pediatric patients with rhinosinusitis. Thirty-seven patients were enrolled, and 26 patients successfully completed the study. Total symptom scores significantly improved with both HOCl and normal saline nasal irrigation, but there was no difference between the two groups. X-ray scores also improved in both groups; improvement was much greater in the HOCl group than the placebo group. Nasal irrigation with HOCl is an effective adjuvant treatment compared to isotonic normal saline for pediatric sinusitis. 1b.


Percutaneous Biopsy of Retrobulbar Masses: Anatomical Considerations and MRI Guidance.
Obtaining adequate tissue from retrobulbar masses remains a challenge. To this end, a new method of retrobulbar mass biopsy using MRI guidance is presented. Two patients (7- and 71-year-old male) with indeterminate retrobulbar masses underwent bioptic and cytological samplings using MR-compatible 18G and 20-22G needles, and multi-planar MR fluoroscopy. An inferior approach was taken to avoid injury to the optic nerve and ophthalmic arteries. The two biopsies were completed without complication. The core biopsy resulted in a final diagnosis, whereas the cytological sampling was non-diagnostic. Percutaneous MR-guided retrobulbar mass biopsy proved to be feasible and safe in the two cases described in this report.


Mutations in the gyrA and parC genes in ciprofloxacin-resistant clinical isolates of Acinetobacter baumannii in Korea.
Mutation with Ser-83-->Leu in gyrA gene was associated with the principal mutation for ciprofloxacin resistance in clinical isolates of Acinetobacter baumannii. Double mutation, Ser-83-->Leu in gyrA gene and Ser-80-->Leu in parC gene, was the most frequently detected among ciprofloxacin-resistant isolates. A novel mutation with Ser-80-->Trp in parC gene, in addition to mutation in gyrA gene, was associated with a high-level ciprofloxacin resistance. These results suggested that the presence of an additional mutation in the parC gene contributed to a higher-level of ciprofloxacin resistance than a single mutation in the gyrA gene (geometric mean MICs of ciprofloxacin, 44.1 versus 16 microg/ml, P < 0.05).


Synthetic interaction between the TipN polarity factor and an AcrAB-family efflux pump implicates cell polarity in bacterial drug resistance.
Quinolone antibiotics are clinically important drugs that target bacterial DNA replication and chromosome segregation. Although the AcrAB-family efflux pumps generally protect bacteria from such drugs, the physiological role of these efflux systems and their interplay with other cellular events are poorly explored. Here, we report an intricate relationship between antibiotic resistance and cell polarity in the model bacterium Caulobacter crescentus. We show that a polarity landmark protein, TipN, identified by virtue of its ability to direct flagellum placement to the new cell pole, protects cells from toxic misregulation of an AcrAB efflux pump through a cis-encoded nalidixic acid-responsive transcriptional repressor. Alongside the importance of polarity in promoting the inheritance and activity of virulence functions including motility, we can now ascribe to it an additional role in drug resistance that is distinct from classical efflux mechanisms.


Characterization of JEOL 2100F Lorentz-TEM for low-magnification electron holography and magnetic imaging.
We present results that characterize the performance and capabilities of the JEOL 2100F-LM electron microscope to carry out holography and quantitative magnetic imaging. We find the microscope is well-suited for studies of magnetic materials, or for semi-conductor dopant profiling, where a large hologram width ( approximately 1 microm) and fine fringe spacing ( approximately 1.5 nm) are obtained with good contrast ( approximately 20%). We present, as well, measurements of the spherical aberration coefficient Cs=(108.7+/-9.6)mm and minimum achievable focal step delta f=(87.6+/-1.4)nm for the specially designed long-focal-length objective lens of this microscope. Further, we detail experiments to accurately measure the optical parameters of the imaging system typical of conventional holography setup in a transmission electron microscope. The role played by astigmatic illumination in the hologram formation is also assessed with a wave-optical model, which we present and discuss. The measurements obtained for our microscope are used to simulate realistic holograms, which we compare directly to experimental holograms finding good agreement. These results indicate the usefulness of measuring these optical parameters to guide the optimization of the experimental setup for a given microscope, and to provide an additional degree of practical experimental possibility.


Radioiodinated Rhodamine-123: a potential cationic hepatobiliary imaging agent.
The labelling of the cationic dye Rhodamine-123 with 125I is described. The biodistribution of the iodinated Rhodamine-123 has been determined at different time intervals after intravenous injection into fasted rats. It turned out that the dye is predominantly cleared by the liver and discharged into the bile. The bile acid taurocholate did not enhance the rate of excretion of 125I-Rhodamine-123.


Fast excitatory postsynaptic currents in voltage-clamped mammalian sympathetic ganglion neurones.
Fast excitatory postsynaptic currents (EPSCs) were recorded in voltage-clamped neurones of isolated superior cervical ganglion of the rabbit. The rise time, decay time and whole duration of EPSC, as well as miniature EPSC, were shorter than those of corresponding postsynaptic potentials. Characteristic impedance for EPSC was 5.5 +/- 1.1 M omega, and was a few times lower than for current evoked by iontophoretic application of ACh. The rise time of EPSC was 2.0 +/- 0.2 msec, the time constant of decay was 3.6 +/- 0.5 msec, and the mean amplitude of EPSC was -5.5 +/- 1.0 nA at the resting potential level (-53.8 +/- 1.4 mV) and at 36 degrees C. Amplitude of EPSC varied with membrane potential almost linearly at negative potentials, non-linearly at positive potentials, and nullified at -8.9 +/- 1.8 mV. The decay of EPSC was exponential over the most of its time course and the rate constant of decay (alpha) varied exponentially with membrane potential according to the relationship alpha(V) = B exp(AV), with A = 0.00716 +/- 0.00101 mV-1 and B = 0.46 +/- 0.07 msec-1. The voltage sensitivity of EPSC decay is interpreted in terms of voltage sensitivity in ionic channel lifetimes.


A generalist nematode destabilises plant competition: no evidence for direct effects, but strong evidence for indirect effects on rhizobium abundance.
Difficulties quantifying pathogen load and mutualist abundance limit our ability to connect disease dynamics to host community ecology. For example, specific predictions about how differential pathogen load is hypothesised to drive host competitive outcomes are rarely tested. Additionally, although infection is known to affect mutualists, we rarely measure the magnitude of pathogen effects on mutualist abundance across host competitive contexts. We tested for both mechanisms in a plant-rhizobia-nematode system. We paired the legume Medicago lupulina with intraspecific and interspecific plant competitors, with and without a generalist nematode parasite Meloidogyne sp. Relative change in plant biomass was used to determine how nematode inoculation affected plant competitive outcomes. We counted nematode galls to test for direct effects of parasitism on plant competition and rhizobia nodules to test for indirect effects of nematode presence on rhizobium abundance. Parasites were destabilising despite similar nematode load across competition treatments. During interspecific compared with intraspecific competition, nematode inoculation decreased nodulation on M. lupulina, increased nodulation on Trifolium repens and had no effect on nodulation on Chamaecrista fasciculata. We found no support for hypothesised direct effects of nematode load on competitive outcomes and strong but idiosyncratic indirect effects of nematode inoculation on rhizobium abundance.


Are Bethesda III Thyroid Nodules More Aggressive than Bethesda IV Thyroid Nodules When Found to Be Malignant?
The Bethesda classification system for thyroid fine needle aspirate (FNA) is used to predict the risk of malignancy and to guide the management of thyroid nodules. We postulated that thyroid malignancies characterized as Bethesda III on FNA have more aggressive features than those classified as Bethesda IV. A retrospective chart review was performed to identify those who underwent thyroid surgery at a single tertiary hospital setting between 2015 and 2020. Associations between Bethesda category, molecular genetic test results, and histopathologic findings were examined. Out of 628 surgeries that were performed, 199 (54.2%) Bethesda III nodules and 216 (82.8%) Bethesda IV nodules were malignant. Of those that were malignant, 37 (18.6%) and 22 (10.2%) Bethesda III and Bethesda IV nodules showed aggressive features, respectively (p value = 0.014). There was a proportionally increased number of aggressive features in extra-thyroidal extension, lymph nodes metastasis, and all aggressive subtypes of papillary thyroid cancer in the Bethesda III category. Although Bethesda IV nodules are much more likely to be malignant (p value = 0.002), our study suggests that Bethesda III nodules that are resected are more likely to have aggressive features than Bethesda IV nodules, with a statistically significant increase in the solid variant of papillary thyroid cancer and lymph node metastasis.


Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3.
To investigate whether coadministration of vindesine is a risk factor for acute kidney injury caused by high-dose methotrexate in patients with hematologic malignancies and identify its mechanism. A retrospective analysis was conducted on 211 cycles of HD-MTX therapy in 178 patients with hematological malignancies. Multivariate logistic regression analysis was performed to evaluate whether VDS coadministration was a risk factor for AKI and the inhibitory effect of VDS on MTX was studied in cell models in vitro. The occurrence of AKI was significantly higher in the MTX + VDS group than in the MTX group. Multivariate logistic regression analysis showed that VDS coadministration was an important risk factor for the occurrence of AKI [odds ratio (OR) = 2.62, 95% confidence interval (CI) 1.03-6.66]. After coadministration of VDS, serum MTX concentrations at 24 h, 48 h, and 72 h increased from 0.42 ± 0.46 μmol/L, 0.07 ± 0.01 μmol/L, and 0.03 ± 0.01 μmol/L to 0.98 ± 2.73 μmol/L, 0.18 ± 0.42 μmol/L, and 0.09 ± 0.21 μmol/L (p < 0.05, p < 0.01, and p < 0.01), respectively. Delayed elimination was closely related to AKI (p < 0.001). The transfected cell model results showed that VDS is an inhibitor of the transporters BCRP, MRP2, and OAT1/OAT3. VDS inhibited BCRP and MRP2-mediated transport of MTX with IC50 values of 17.91 µM and 34.73 µM, respectively. Coadministration of VDS increases HD-MTX-induced AKI in patients with hematologic malignancies, which may be explained by the fact that VDS increases the exposure to and decreases the excretion of MTX by inhibiting OAT1/OAT3, BCRP, and MRP2.


alpha-Adrenergic agents modulate the activity of the spinal pattern generator for ejaculation.
Spinal cord transection at a thoracic level activates fictive ejaculation (FE) in the male rat. It has earlier been demonstrated that fictive motor patterns may be activated by pharmacological means and that the noradrenergic system seems to be particularly efficient in triggering locomotor fictive patterns in spinal animals. In the present study, the hypothesis was tested that the spinal noradrenergic system participates in the activation of the spinal generator for ejaculation (SGE). To this aim, the effect of the adrenergic agents, methoxamine, prazosin, clonidine, and yohimbine, upon FE was evaluated in spinal male rats using electromyographic techniques. The results obtained show that ejaculatory rhythmic patterns, accompanied by the expulsion of urethral contents and phasic penile movements, can be elicited by the intravenous (i.v.) injection of methoxamine or yohimbine. These drug-induced motor sequences appear superimposed to the intrinsic ejaculatory spinal rhythm. By contrast, i.v. injection of prazosin or clonidine blocked the expression of the spontaneous ejaculatory rhythmic pattern without inducing any other genital response. These data suggest that an increased noradrenergic tone, either by blockade of presynaptic alpha2-adrenoceptors or by stimulation of postsynaptic alpha1-adrenoceptors, results in the activation of the SGE. Present findings provide the evidence that the SGE might be importantly influenced by the noradrenergic system, which exerts a facilitatory control on the expression of the genital motor pattern of ejaculation.


Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.
Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.


Qualitative and quantitative contrasts in the mechanisms of lumen enlargement by coronary balloon angioplasty and directional coronary atherectomy.
This study was designed to define and contrast the mechanisms of lumen enlargement from coronary balloon angioplasty and directional coronary atherectomy using intracoronary ultrasound imaging in vivo. The mechanisms of lumen enlargement produced by percutaneous transluminal coronary balloon angioplasty and directional coronary atherectomy are not known because the coronary artery wall has not previously been studied both before and after dilation. We used intracoronary ultrasound to quantitate coronary lumen, vessel and plaque area both before and immediately after successful coronary angioplasty (n = 30) and directional coronary atherectomy (n = 25) at the site of most severe stenosis. Angioplasty increased lumen area by 2.80 +/- 0.25 mm2 (mean +/- SE, p < 0.0001). Eighty-one percent of this lumen gain resulted from an increase in vessel area and the remaining 19% from a reduction in plaque area. Lumen gain of individual lesions was separated into three groups: 67% had an increase in vessel area (vessel expansion), 13% had a decrease in plaque area and 20% had a combination of both. In contrast, vessel expansion contributed only 22% of the lumen gain with directional coronary atherectomy, with the majority (78%) of increase in lumen size coming from a reduction in plaque area. Directional coronary atherectomy increased lumen area from 2.36 +/- 0.05 to 7.00 +/- 0.28 mm2 (p < 0.0001). Plaque reduction was the sole mechanism in 60% of lesions, vessel expansion was the sole mechanism in 12% and a combination of both mechanisms occurred in 28%. Lumen enlargement of eccentric lesions treated with directional coronary atherectomy was more commonly associated with plaque reduction (p < 0.02), whereas eccentricity did not affect the mechanism of lumen enlargement with coronary angioplasty. This is the first study to systematically examine the coronary artery wall in vivo at the site of a severe stenosis both before and after catheter-based interventions in humans. Lumen enlargement from coronary angioplasty occurs predominantly from vessel expansion or stretching, although a reduction in plaque area contributes to the lumen gain in many patients and is the sole mechanism in a few. Lumen gain from directional coronary atherectomy is predominantly from reduction in plaque area (probably owing to tissue removal), although vessel stretching (balloon effect) occurs and is the sole mechanism in a small minority of vessels. Plaque reduction is more common in directional coronary atherectomy of eccentric lesions.


Complete nucleotide sequence of the Marek's disease virus ICP4 gene.
The Marek's disease virus (MDV) gene encoding a homologue to the ICP4 protein of herpes simplex virus has been mapped to BamHl fragment A based on the physical map of the MDV genome (Fukuchi et al., 1984). The gene lies completely within the inverted repeat flanking the unique short region of the genome. The complete nucleotide sequence of the MDV ICP4 gene has been determined. The coding region is 4245 nucleotides long and has an overall G+C content of 52%. The MDV ICP4 protein is predicted to have a structure similar to that of ICP4-like proteins of other herpesviruses in that it has five distinct regions, the second and fourth of which are highly conserved. In addition, the protein contains the characteristic run of serine residues located toward its amino terminus. The MDV ICP4 gene is expressed in MDV-infected chicken embryo fibroblasts.


Construction of wire leads and electrodes for use in slow wave recording in small animals.
Techniques are described for the construction of wire electrodes and leads for use in recording slow wave activity in chronic animal preparations. Advantages of the technique include durability, lightness and absence of significant interference with animal movement.


Configuration variability of the six-minute walk test among licensed physical therapists working with neurologic conditions: a pilot survey.
The six-minute walk test (6MWT) is considered reliable and valid for assessing walking capacity in people with neurologic conditions. However, the consistency in the test length and configuration used is unclear. To determine how the 6MWT was configured by licensed physical therapists working with patients with neurologic conditions in clinical practice, identify their knowledge of the American Thoracic Society (ATS) and Academy of Neurologic Physical Therapy (ANPT) guidelines for the 6MWT and assess relationships between therapist demographic characteristics and knowledge of the 6MWT guidelines. One hundred forty-six therapists completed a survey related to the configuration they used for the 6MWT. Configuration of the 6MWT varied widely. Space limitation was the most frequently selected reason for reported configurations. Over half had available the standardized 100-feet straight walkway but fewer than one-third used this configuration of the ATS guidelines. Fewer than half knew of the ATS guidelines and nearly three-fourths knew of the ANPT guidelines. American Physical Therapy Association membership and having a higher percentage of neurologic patients were associated with knowledge of both guidelines. The 6MWT must be completed within the constraints of the working environment, and this requirement is clinically relevant when comparing patient results to normative values and measurements across clinics. Our results suggest a need for updated norms that are more congruent with space constraints in current practice settings.


Association Between Responsibility for the Death of Others and Postdeployment Mental Health and Functioning in US Soldiers.
Rates of suicidal thoughts and behaviors (STBs) in US soldiers have increased sharply since the terrorist attacks on September 11, 2001, and postdeployment posttraumatic stress disorder (PTSD) remains a concern. Studies show that soldiers with greater combat exposure are at an increased risk for adverse mental health outcomes, but little research has been conducted on the specific exposure of responsibility for the death of others. To examine the association between responsibility for the death of others in combat and mental health outcomes among active-duty US Army personnel at 2 to 3 months and 8 to 9 months postdeployment. This cohort study obtained data from a prospective 4-wave survey study of 3 US Army brigade combat teams that deployed to Afghanistan in 2012. The sample was restricted to soldiers with data at all 4 waves (1-2 months predeployment, and 2-3 weeks, 2-3 months, and 8-9 months postdeployment). Data analysis was performed from December 12, 2020, to April 23, 2021. Primary outcomes were past-30-day PTSD, major depressive episode, STBs, and functional impairment at 2 to 3 vs 8 to 9 months postdeployment. Combat exposures were assessed using a combat stress scale. The association of responsibility for the death of others during combat was tested using separate multivariable logistic regression models per outcome adjusted for age, sex, race and ethnicity, marital status, brigade combat team, predeployment lifetime internalizing and externalizing disorders, and combat stress severity. A total of 4645 US soldiers (mean [SD] age, 26.27 [6.07] years; 4358 men [94.0%]) were included in this study. After returning from Afghanistan, 22.8% of soldiers (n = 1057) reported responsibility for the death of others in combat. This responsibility was not associated with any outcome at 2 to 3 months postdeployment (PTSD odds ratio [OR]: 1.23 [95% CI, 0.93-1.63]; P = .14; STB OR: 1.19 [95% CI, 0.84-1.68]; P = .33; major depressive episode OR: 1.03 [95% CI, 0.73-1.45]; P = .87; and functional impairment OR: 1.12 [95% CI, 0.94-1.34]; P = .19). However, responsibility was associated with increased risk for PTSD (OR, 1.42; 95% CI, 1.09-1.86; P = .01) and STBs (OR, 1.55; 95% CI, 1.03-2.33; P = .04) at 8 to 9 months postdeployment. Responsibility was not associated with major depressive episode (OR, 1.30; 95% CI, 0.93-1.81; P = .13) or functional impairment (OR, 1.13; 95% CI, 0.94-1.36; P = .19). When examining enemy combatant death only, the pattern of results was unchanged for PTSD (OR, 1.44; 95 CI%, 1.10-1.90; P = .009) and attenuated for STBs (OR, 1.46; 95 CI%, 0.97- 2.20; P = .07). This cohort study found an association between being responsible for the death of others in combat and PTSD and STB at 8 to 9 months, but not 2 to 3 months, postdeployment in active-duty soldiers. The results suggest that delivering early intervention to those who report such responsibility may mitigate the subsequent occurrence of PTSD and STBs.


Combined hormone-chemotherapy for metastatic prostatic carcinoma. Eleven-year follow-up.
Thirty-six patients with histology-proved Stage D2 carcinoma of the prostate were treated with a combination of bilateral orchiectomy, diethylstilbestrol 3 mg/day, and chemotherapy (5-fluorouracil and cyclophosphamide) soon after diagnosis was established. The combined therapy was well tolerated by the patients, and complications were not severe and of a transient nature. The majority of patients showed a subjective and objective improvement: 75 per cent of patients had relief of bone pain, and 80 per cent reported relief in urinary symptoms. There was regression or stabilization of the primary tumor in 82.2 per cent. Disappearance or stabilization of osteoclastic lesions on bone scans was noted in 55.5 per cent of patients. The cumulative survival rate at eleven years is 55.5 per cent.


Sequence and transcript analysis of the bovine herpesvirus 1 thymidine kinase locus.
A detailed sequence and transcript analysis of the thymidine kinase (tk) gene of bovine herpesvirus 1 (BHV1, Cooper strain) was carried out. A tk open reading frame (ORF) of 1077 bp was identified and compared with tk ORFs previously published for other strains of BHV1. The Cooper sequence was in good agreement with that of strain Q3932 but differed significantly from strains 6660 and LA. Reanalysis of the LA tk sequence, however, failed to confirm this difference. Except for five single base substitutions, our results indicate that the Cooper, Q3932, and LA strains share the same tk sequence. The size of the tk mRNA was determined by Northern blot analysis. In contrast to the size of other herpesvirus tk mRNAs (approximately 1.5 kb), the BHV1 tk transcript was 4.3 kb. Northern blot analysis indicated that the tk transcript was 3' coterminal with the downstream 3.1-kb transcript which encodes a BHV1 homologue of the HSV1 H glycoprotein (gH). The 5' ends of the tk and gH mRNAs were mapped by S1 analysis to positions 135 and 91 bp upstream of their respective translation start sites. The 5' end of the tk transcript was found to overlap a 5.2-kb transcript with opposite polarity to the tk mRNA.


The first implementation of allele-specific primers for detecting the knockdown and acetylcholinesterase target site mutations in malaria vector, Anopheles sacharovi.
Anopheles sacharovi, a primer malaria vector species of Turkey, have a significant public health importance. It is aimed to determine the insecticide resistance status in Anopheles sacharovi populations in the Aegean and Mediterranean regions of Turkey. A total of 1638 individuals were analysed from 15 populations. Bioassay results indicated all An. sacharovi populations were resistant to DDT, malathion, fenitrothion, bendiocarb, propoxur. Many populations have begun to have resistance against permethrin and deltamethrin. Biochemical analyses results revealed that glutathione-S-transferases and P450 monooxygenases might be responsible from the mechanisms of DDT resistance; esterases and acetylcholinesterase might be responsible for organophosphate and carbamate resistance; P450 monooxygenases and esterases might be responsible for pyrethroid resistance into populations sampled from the study area. Allele-specific primers detected L1014F and L1014S mutations that provide kdr resistance against pyrethroids and DDT. Increased acetylcholinesterase insensitivity was detected while Ace-1 G119S mutations were not detected in An. sacharovi populations by using allele-specific primers. Overall results indicate the presence of multiple resistance mechanisms in Turkish An. sacharovi field populations suggesting that populations might gain resistance against all possible insecticide in the future. Therefore, insecticide resistance management strategies are urgently needed for effective vector control implementation.


Rapid estimation of the duration of gamma-ray-induced proliferation delay in human lymphocytes by the harlequin staining technique.
The duration of gamma-ray-induced proliferation delay in human lymphocyte cultures was measured by a rapid and simple method using fluorescence-plus-Giemsa (harlequin) staining to distinguish between cells that had divided different numbers of times in culture. By this rapid method, irradiation of unstimulated (G0) or stimulated (G1) lymphocytes was shown to result in a proliferation delay of 1.2 h/Gy (1.2 h/100 rad) or 1.4 h/Gy (1.4 h/100 rad), respectively, in 64 h cultures: The duration of delays had a linear relationship with doses from 2 to 8 Gy (200 to 800 rad).


Spatiotemporal analysis and predicting rainfall trends in a tropical monsoon-dominated country using MAKESENS and machine learning techniques.
Spatiotemporal rainfall trend analysis as an indicator of climatic change provides critical information for improved water resource planning. However, the spatiotemporal changing behavior of rainfall is much less understood in a tropical monsoon-dominated country like Bangladesh. To this end, this research aims to analyze spatiotemporal variations in rainfall for the period 1980-2020 over Bangladesh at seasonal and monthly scales using MAKESENS, the Pettitt test, and innovative trend analysis. Multilayer Perception (MLP) neural network was used to predict the next 8 years' rainfall changes nationally in Bangladesh. To investigate the spatial pattern of rainfall trends, the inverse distance weighting model was adopted within the ArcGIS environment. Results show that mean annual rainfall is 2432.6 mm, of which 57.6% was recorded from July to August. The Mann-Kendall trend test reveals that 77% of stations are declining, and 23% have a rising trend in the monthly rainfall. More than 80% of stations face a declining trend from November to March and August. There is a declining trend for seasonal rainfall at 82% of stations during the pre-monsoon, 75% during the monsoon, and 100% during the post-monsoon. A significant decline trend was identified in the north-center during the pre-monsoon, the northern part during the monsoon, and the southern and northwestern portions during the post-monsoon season. Predicted rainfall by MLP till 2030 suggests that there will be little rain from November to February, and the maximum fluctuating rainfall will occur in 2025 and 2027-2029. The ECMWF ERA5 reanalysis data findings suggested that changing rainfall patterns in Bangladesh may have been driven by rising or reducing convective precipitation rates, low cloud cover, and inadequate vertically integrated moisture divergence. Given the shortage of water resources and the anticipated rise in water demand, the study's findings have some implications for managing water resources in Bangladesh.


Availability and utilization of malaria prevention strategies in pregnancy in eastern India.
Malaria in pregnancy in India, as elsewhere, is responsible for maternal anemia and adverse pregnancy outcomes such as low birth weight and preterm birth.It is not known whether prevention and treatment strategies for malaria in pregnancy (case management, insecticide-treated bednets, intermittent preventive therapy) are widely utilized in India. This cross-sectional study was conducted during 2006-2008 in two states of India, Jharkhand and Chhattisgarh, at 7 facilities representing a range of rural and urban populations and areas of more versus less stable malaria transmission. 280 antenatal visits (40/site) were observed by study personnel coupled with exit interviews of pregnant women to assess emphasis upon, availability and utilization of malaria prevention practices by health workers and pregnant women. The facilities were assessed for the availability of antimalarials, lab supplies and bednets. All participating facilities were equipped to perform malaria blood smears; none used rapid diagnostic tests. Chloroquine, endorsed for chemoprophylaxis during pregnancy by the government at the time of the study, was stocked regularly at all facilities although the quantity stocked varied. Availability of alternative antimalarials for use in pregnancy was less consistent. In Jharkhand, no health worker recommended bednet use during the antenatal visit yet over 90% of pregnant women had bednets in their household. In Chhattisgarh, bednets were available at all facilities but only 14.4% of health workers recommended their use. 40% of the pregnant women interviewed had bednets in their household. Only 1.4% of all households owned an insecticide-treated bednet; yet 40% of all women reported their households had been sprayed with insecticide. Antimalarial chemoprophylaxis with chloroquine was prescribed in only 2 (0.7%) and intermittent preventive therapy prescribed in only one (0.4%) of the 280 observed visits. A disconnect remains between routine antenatal practices in India and known strategies to prevent and treat malaria in pregnancy. Prevention strategies, in particular the use of insecticide-treated bednets, are underutilized. Gaps highlighted by this study combined with recent estimates of the prevalence of malaria during pregnancy in these areas should be used to revise governmental policy and target increased educational efforts among health care workers and pregnant women.


COVID-19 paraclinical diagnostic tools: Updates and future trends.
COVID-19 is one of the most widely affecting pandemics. As for many respiratory viruses-caused diseases, diagnosis of COVID-19 relies on two main compartments: clinical and paraclinical diagnostic criteria. Rapid and accurate diagnosis is vital in such a pandemic. On one side, rapidity may enhance management effectiveness, while on the other, coupling efficiency and less costly procedures may permit more effective community-scale management. In this review, we shed light on the most used and the most validated diagnostic tools. Furthermore, we intend to include few under-development techniques that may be potentially useful in this context. The practical intent of our work is to provide clinicians with a realistic summarized review of the essential elements in the applied paraclinical diagnosis of COVID-19.


Symptoms associated with vaginal colonization with yeast.
We correlated vulvovaginal symptoms with vaginal cultures for yeast in healthy female college students. Yeasts were isolated from 42 (29.2%) of 144 women. Only four (22%) of 18 women with positive fungal cultures had fungal elements visualized microscopically in vaginal material suspended in 10% potassium hydroxide (potassium hydroxide wet preparations). Symptoms, mainly vulvovaginal itching and irritation, were reported by 28 (67%) of 42 women whose cultures contained yeast and by 22 (22%) of 102 women who were not colonized by yeast (p less than 0.01). We conclude that vaginal colonization by yeasts is commonly associated with vulvovaginal symptoms, often in the absence of positive potassium hydroxide wet preparation results. These data suggest that vaginal specimens from women who have vulvovaginal symptoms and negative potassium hydroxide wet preparation results should be cultured for fungi before the diagnosis of fungal vulvovaginitis is excluded.


Competing risk nomogram for predicting cancer-specific mortality in patients with non-melanoma skin cancer.
This study aimed to assess the cumulative incidences of Non-melanoma skin cancer (NMSC)-specific mortality (NMSC-SM) and develop a competing risk nomogram for NMSC-SM. Data on patients diagnosed with NMSC between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. To identify the independent prognostic factors, univariate and multivariate competing risk models were used, and a competing risk model was constructed. Based on the model, we developed a competing risk nomogram to predict the 1-, 3-, 5-, and 8-year cumulative probabilities of NMSC-SM. The precision and ability to discriminate of the nomogram were evaluated through the utilization of metrics, such as receiver-operating characteristic (ROC) area under the curve (AUC), concordance index (C-index), and a calibration curve. Decision curve analysis (DCA) was employed to assess the clinical usefulness of the nomogram. Race, age, the primary site of the tumor, tumor grade, size, histological type, summary stage, stage group, order of radiation and surgery, and bone metastases were identified as independent risk factors. The prediction nomogram was constructed using the variables mentioned above. The ROC curves implied the good discrimination ability of the predictive model. The nomogram's C-index was 0.840 and 0.843 in the training and validation sets, respectively, and the calibration plots were well fitted. In addition, the competing risk nomogram demonstrated good clinical usefulness. The competing risk nomogram displayed excellent discrimination and calibration for predicting NMSC-SM, which can be used in clinical contexts to help guide treatment decisions.


Differences in psychological need hierarchies between black and white drug addicts.
A total of 109 Black and White heroin and cocaine addicts in treatment for drug abuse were compared on the Adjective Checklist (ACL). We found that the White addict had a significantly different pattern of needs than did the Black addict, characterized by more psychological dependence, distress, and maladjustment. Consistent with the MMPI literature in this area, the ACL provides an accurate evaluation of personality dimensions among drug addicts, and White addicts are more psychologically maladjusted than Black addicts.


Acute Coronary Syndrome admissions and outcome during COVID-19 Pandemic-Report from large tertiary centre in India.
Few studies from various countries have reported decline in Acute Coronary Syndrome (ACS) admissions to hospital during COVID-19 pandemic. We studied the impact of COVID-19 strict lockdown on ACS admission in a tertiary referral hospital in India. This showed 43% decline in admissions (n = 104 vs mean n = 183) and even in those who got admitted, there was a delay in presentation compared to previous year, which was reflected in the outcome of patients. Government and health organizations should educate the public early-on during the pandemic about the consequences of ignoring other acute medical problems such as ACS.


Clinicopathological significance of lipid peroxidation in carotid plaques.
Several reports have suggested an association between lipid peroxidation and human carotid atherosclerosis, but few reports have demonstrated a link between lipid peroxidation and carotid plaques in humans. In this study, we investigated the relationship between clinical features, histopathological characteristics and lipid peroxidation in patients undergoing carotid endarterectomy (CEA). Forty-one carotid plaques were obtained. A portion of the most severe lesions was subjected to histopathologic examination, and the remainder of the plaques examined for lipid peroxidation. Thiobarbituric acid-reactive substances (TBARS) values were determined as a marker for lipid peroxidation. The lipid-rich core (LC) and macrophage infiltration (Mphi) component as a percentage of total plaque area were measured morphometrically. Based on the results, all plaques were classified into four groups. Group I (GI): LC <10%; Group IIa (GIIa): LC 10-30%, Mphi <5%; Group IIb (GIIb): LC 10-30%, Mphi < or = 5%, and Group III (GIII): LC < or =30%. The plaque TBARS values of GIII were significantly higher than those of GI, GIIa, and GIIb. The TBARS values of GIIb were one-and-a-half times higher than those of GIIa. Our results show that lipid peroxidation in carotid plaques is significantly associated with carotid atherosclerosis, especially plaque instability. These findings provide direct evidence of an association between lipid peroxidation and human atherosclerosis.


Polymeric siRNA gene delivery - transfection efficiency versus cytotoxicity.
Within the field of gene therapy, there is a considerable need for the development of non-viral vectors that are able to compete with the efficiency obtained by viral vectors, while maintaining a good toxicity profile and not inducing an immune response within the body. While there have been many reports of possible polymeric delivery systems, few of these systems have been successful in the clinical setting due to toxicity, systemic instability or gene regulation inefficiency, predominantly due to poor endosomal escape and cytoplasmic release. The objective of this review is to provide an overview of previously published polymeric non-coding RNA and, to a lesser degree, oligo-DNA delivery systems with emphasis on their positive and negative attributes, in order to provide insight in the numerous hurdles that still limit the success of gene therapy.


A cytotoxic beta-carboline from the bryozoan Catenicella cribraria.
1-Vinyl-8-hydroxy-beta-carboline was identified as the cytotoxic constituent of the bryozoans Catenicella cribraria and Cribricellina cribraria. Literature nmr data for this previously known compound, now reported from a new source, were corrected.


Animal Models of Contact Dermatitis: 2,4-Dinitrofluorobenzene-Induced Contact Hypersensitivity.
Allergic contact dermatitis (ACD) is a common skin disease with high prevalence in work environments. Human allergic contact dermatitis is triggered by the exposure to haptens that leads to an initial phase known as sensitization. During this phase, hapten-protein complexes presented by antigen-presenting cells activate a T-cell-mediated response, leading to the generation of memory cells against the hapten. Upon re-exposure to the same hapten, the elicitation phase is initiated. This phase is characterized by a quicker acute inflammatory response involving activation and/or infiltration of a variety of immune cell populations. Human ACD can be studied through the use of animal models of contact hypersensitivity (CHS). The 2,4-dinitrofluorobenzene (DNFB)-induced CHS model is a commonly used mouse model that has been helpful in the study of the mechanisms as well as potential therapeutic interventions of ACD. In this chapter I will provide a detailed protocol to develop acute DNFB-induced CHS in mice in a period of 7 days. In addition, I will discuss several key considerations for experimental design including best controls, potential expected outcomes, and sample collection.


Large Ankyrin repeat proteins are formed with similar and energetically favorable units.
Ankyrin containing proteins are one of the most abundant repeat protein families present in all extant organisms. They are made with tandem copies of similar amino acid stretches that fold into elongated architectures. Here, we built and curated a dataset of 200 thousand proteins that contain 1.2 million Ankyrin regions and characterize the abundance, structure and energetics of the repetitive regions in natural proteins. We found that there is a continuous roughly exponential variety of array lengths with an exceptional frequency at 24 repeats. We described that individual repeats are seldom interrupted with long insertions and accept few deletions, in line with the known tertiary structures. We found that longer arrays are made up of repeats that are more similar to each other than shorter arrays, and display more favourable folding energy, hinting at their evolutionary origin. The array distributions show that there is a physical upper limit to the size of an array of repeats of about 120 copies, consistent with the limit found in nature. The identity patterns within the arrays suggest that they may have originated by sequential copies of more than one Ankyrin unit.


Problematic eating behaviors in adolescents with low self-esteem and elevated depressive symptoms.
Previous research has indicated that low self-esteem may be an important risk factor for the development of eating disorders. Few longitudinal studies have examined the relationships between low self-esteem, depressive symptoms, and eating disorders in adolescents. The present study investigated whether low self-esteem was associated with depressive symptoms and problematic eating behaviors. Measures of low self-esteem and problematic eating behaviors were administered to a sample of 197 adolescent primary-care patients. Depressive symptoms and problematic eating behaviors were assessed ten months later. Youths with low self-esteem were at greater risk for high levels of depressive symptoms and eating disorder symptoms. In addition, depressive symptoms mediated the association of low self-esteem with problematic eating behaviors.


Striae distensae after breast augmentation.
One known but not fully understood complication after breast augmentation is the new onset of stretch marks (striae distensae) on the surgically treated breast. To date, all publications on this subject have been case reports. No report has fully described the actual incidence, risk factors, or management of striae distensae after breast surgery. This study prospectively followed patients who underwent primary breast augmentation using silicone implants in a single group practice from 2007 to 2011. New-onset striae distensae were actively investigated. Time from surgery to the moment of striae onset, patient age, nulliparity, use of oral contraceptives, overweight, personal history of stretch marks, and other variables were evaluated. A total of 409 patients were included in the study. In 19 cases (4.6%), new-onset striae distensae after breast augmentation were observed. The population with striae distensae was significantly younger than the total population (29.56 vs 20.91 years; p=0.012). Striae distensae also were more common in nulliparous than in multiparous women (8.29 vs 0.52%; p=0.006), overweight women (17.77 vs 3.02%; p=0.016), women using oral contraceptives (7.89 vs 0.55%; p=0.008), and women with a personal history of stretch marks (8.97 vs 3.36%; p=0.031). No relation was shown regarding implant pocket type, size, or profile. Striae distensae may be a common but underreported complication after breast augmentation. In this series, striae distensae developed in 4.6% of the patients within 1 year after breast augmentation. Severity may vary from inconspicuous small marks (classifications 1 and 2) to wide red and active striae rubra (classifications 3 and 4). Nulliparity, use of oral contraceptives, overweight, personal history of stretch marks, and younger age were related to a higher incidence of striae distensae. The increased rates in these groups may be associated with their exposure to higher estrogen levels and the important role of this hormone in facilitating the formation of striae distensae. Further studies are needed to show whether changes in these risk factors (i.e., weight loss, contraceptive withdrawal) may help to decrease striae distensae rates is these populations. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.


N6-methyladenosine-related non-coding RNAs are potential prognostic and immunotherapeutic responsiveness biomarkers for bladder cancer.
Bladder cancer (BC) is a commonly occurring malignant tumor of the urinary system, demonstrating high global morbidity and mortality rates. BC currently lacks widely accepted biomarkers and its predictive, preventive, and personalized medicine (PPPM) is still unsatisfactory. N6-methyladenosine (m6A) modification and non-coding RNAs (ncRNAs) have been shown to be effective prognostic and immunotherapeutic responsiveness biomarkers and contribute to PPPM for various tumors. However, their role in BC remains unclear. m6A-related ncRNAs (lncRNAs and miRNAs) were identified through a comprehensive analysis of TCGA, starBase, and m6A2Target databases. Using TCGA dataset (training set), univariate and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop an m6A-related ncRNA-based prognostic risk model. Kaplan-Meier analysis of overall survival (OS) and receiver operating characteristic (ROC) curves were used to verify the prognostic evaluation power of the risk model in the GSE154261 dataset (testing set) from Gene Expression Omnibus (GEO). A nomogram containing independent prognostic factors was developed. Differences in BC clinical characteristics, m6A regulators, m6A-related ncRNAs, gene expression patterns, and differentially expressed genes (DEGs)-associated molecular networks between the high- and low-risk groups in TCGA dataset were also analyzed. Additionally, the potential applicability of the risk model in the prediction of immunotherapeutic responsiveness was evaluated based on the "IMvigor210CoreBiologies" data set. We identified 183 m6A-related ncRNAs, of which 14 were related to OS. LASSO regression analysis was further used to develop a prognostic risk model that included 10 m6A-related ncRNAs (BAALC-AS1, MIR324, MIR191, MIR25, AC023509.1, AL021707.1, AC026362.1, GATA2-AS1, AC012065.2, and HCP5). The risk model showed an excellent prognostic evaluation performance in both TCGA and GSE154261 datasets, with ROC curve areas under the curve (AUC) of 0.62 and 0.83, respectively. A nomogram containing 3 independent prognostic factors (risk score, age, and clinical stage) was developed and was found to demonstrate high prognostic prediction accuracy (AUC = 0.83). Moreover, the risk model could also predict BC progression. A higher risk score indicated a higher pathological grade and clinical stage. We identified 1058 DEGs between the high- and low-risk groups in TCGA dataset; these DEGs were involved in 3 molecular network systems, i.e., cellular immune response, cell adhesion, and cellular biological metabolism. Furthermore, the expression levels of 8 m6A regulators and 12 m6A-related ncRNAs were significantly different between the two groups. Finally, this risk model could be used to predict immunotherapeutic responses. Our study is the first to explore the potential application value of m6A-related ncRNAs in BC. The m6A-related ncRNA-based risk model demonstrated excellent performance in predicting prognosis and immunotherapeutic responsiveness. Based on this model, in addition to identifying high-risk patients early to provide them with focused attention and targeted prevention, we can also select beneficiaries of immunotherapy to deliver personalized medical services. Furthermore, the m6A-related ncRNAs could elucidate the molecular mechanisms of BC and lead to a new direction for the improvement of PPPM for BC. The online version contains supplementary material available at 10.1007/s13167-021-00259-w.


Recurrent axon collaterals underlie facilitating synapses between cerebellar Purkinje cells.
Morphological studies have provided ample evidence for synaptic connections between cerebellar Purkinje cells (PCs), but the functional properties of these synapses remain elusive. We report on direct recordings of synaptically connected PCs in mice cerebellar slices. In PCs filled with a fluorescent dye to aid axon visualization and postsynaptic target identification, presynaptic action potentials elicited unitary inhibitory postsynaptic currents in neighboring PCs in 10% of potential connections tested. In 11 pairs, postsynaptic currents had a delay onset of 1.62 +/- 0.16 ms with respect to the presynaptic spike, a 10-90% rise time of 2.20 +/- 0.33 ms, and a monoexponential decay with a time constant of 13.3 +/- 1.7 ms. Average values for peak current and variance-to-mean ratio were 55 +/- 14 and 30 +/- 3 pA, respectively. In contrast to the depressing nature of the synapse between PCs and deep cerebellar nuclei neurons, PC-PC synapses exhibited strong facilitation operating within a time window of a few milliseconds; paired-pulse ratios for 3- and 20-ms intervals were 1.79 +/- 0.18 and 1.01 +/- 0.14, respectively (n = 6). The facilitation is of presynaptic nature because it is accompanied by a decrease in failure rate. Trains of action potentials evoked in presynaptic varicosities volume-averaged calcium transients whose peak increased 1.7-fold as the frequency increased from 50 to 166 Hz. We suggest that PC-PC synapses are tuned for high fidelity of transmission during bursts of PC activity and that their operation in the cerebellar circuit modulates synchronized PC firing.


Hospitalization and death after recovery from acute COVID-19 among renal transplant recipients.
Data on post-COVID-19 in renal transplant recipients (RTR) is scarce. We investigated the rate of hospitalizations, reasons for hospital admission, and mortality rate among RTR who survived acute COVID-19. A multi-center retrospective observational cohort study measured hospital admission and death to 180 days after acute SARS-CoV-2 infection in 308 adult patients. The median age was 57 years, 64.9% were male. All patients had at least one comorbidity, and 26.3% had diabetes. Data on post-COVID-19 course was available for 267 patients, and 49 of them (15.9%) required hospital treatment after recovery from the acute infection. The most common indications included pneumonia (24.5%) and renal allograft dysfunction (22.4%), 7 (14.3%) had sepsis and 5 (10.2%) had thrombotic events. A median duration of the hospital stay was 12 days. Six patients (2.2%) died due to multiorgan failure, respiratory insufficiency or urosepsis. The strongest predictor for hospitalization after acute COVID-19 was hospitalization for acute SARS-CoV-2 infection, while better allograft function decreased the probability of hospitalization. Delayed consequences of acute COVID-19 are highly prevalent and the health care systems should be prepared to respond to the needs of RTR suffering from post-COVID-19 complications.


miR-143 suppresses epithelial-mesenchymal transition and inhibits tumor growth of breast cancer through down-regulation of ERK5.
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer invasion and metastasis. Many studies have significantly enhanced the knowledge on EMT through the characterization of microRNAs (miRNAs) influencing the signaling pathways and downstream events that define EMT on a molecular level. In this study, we found that miR-143 suppressed EMT. Up-regulating miR-143 enhanced E-cadherin-mediated cell-cell adhesion ability, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-143 on tumor growth. Additionally, we demonstrated that up-regulating extracellular signal regulated kinase 5 (ERK5) was associated with poor prognosis of breast cancer patients. Moreover, we observed an inverse correlation between miR-143 and ERK5 in breast cancer tissues. miR-143 directly targeted seed sequences in the 3'-untranslated regions of ERK5. Furthermore, we revealed that the downstream molecules of glycogen synthase kinase 3 beta (GSK-3β)/Snail signaling were involved in EMT and modulated by ERK5. In summary, our findings demonstrated that miR-143 down-regulated its target ERK5, leading to the suppression of EMT induced by GSK-3β/Snail signaling of breast cancer. © 2015 Wiley Periodicals, Inc.


The Impact of Paternal Alcohol Consumption on Offspring Brain and Behavioral Development.
Fetal alcohol spectrum disorders (FASD) describe the wide array of long-lasting developmental abnormalities in offspring due to prenatal alcohol (ethanol [EtOH]) exposure via maternal gestational drinking. Although the teratogenic consequences of prenatal EtOH exposure, are apparent, the effects of preconception paternal EtOH exposure (PatEE) are still unclear. Previous research suggests that PatEE can induce molecular changes and abnormal behavior in the offspring. However, it is not known whether PatEE impacts the development of the neocortex and behavior in offspring as demonstrated in maternal consumption models of FASD (J Neurosci, 33, 2013, 18893). In this study, we utilized a novel mouse model of PatEE where male mice self-administered 25% EtOH for an extended period prior to conception, generating indirect exposure to the offspring through the paternal germline. Following mating, we examined the effects of PatEE on offspring neocortical development at postnatal day (P) 0 and evaluated several aspects of behavior at both P20 and P30 using a battery of behavioral assays. PatEE resulted in significant impact on neocortical development, including abnormal patterns of gene expression within the neocortex at P0 and subtle alterations in patterns of intraneocortical connections. Additionally, PatEE mice exhibited a sex-specific increase in activity and sensorimotor integration deficits at P20, and decreased balance, coordination, and short-term motor learning at P30. This suggests that PatEE may generate long-lasting, sex-specific effects on offspring behavior. These results demonstrate that the developmental impact of preconception PatEE is more harmful than previously thought and provide additional insights into the biological mechanisms that may underlie atypical behavior observed in children of alcoholic fathers.


EG-VEGF and Bv8: a novel family of tissue-restricted angiogenic factors.
A novel family of angiogenic mitogens have been recently characterized. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF), and the mammalian homologue of Bombina variegata peptide 8 (Bv8), are two highly related endothelial cell mitogens and chemotactic factors with restricted expression profiles and selective endothelial cell activity. These peptides share two cognate G-protein coupled receptors. The expression of human EG-VEGF occurs predominantly in steroidogenic glands. Consistent with such an expression pattern, the human EG-VEGF gene promoter has a potential binding site for steroidogenic factor (SF)-1, a pivotal element for steroidogenic-specific transcription. In the human ovary, the expression of EG-VEGF is temporally and spatially complementary to the expression of VEGF-A, both in the follicular and in the luteal phase, suggesting complementary and coordinated roles of these molecules in ovarian angiogenesis. Also, EG-VEGF expression correlates with vascularity in the polycystic ovary syndrome, a leading cause of infertility. Bv8 expression is mainly restricted to the testis. The identification of these tissue-selective angiogenic factors raises the possibility that other secreted molecules with selectivity for the endothelium of other organs exist.


Design, development and usability of an educational AI chatbot for People with Haemophilia in Senegal.
Gaps in the disease knowledge of People with Haemophilia (PWH) in Senegal are important barriers to the effective management of haemophilia. Digital health systems for chronic diseases in low- and middle-income countries are suggested to improve education and self-management. Artificial Intelligence (AI) chatbots could improve knowledge and support symptom monitoring. Development process and usability testing of an AI chatbot to assess its future adoption in Senegal. An AI chatbot prototype was designed based on a multilingual conversational engine using Natural Language Processing. A sequential mixed method was used including a co-creative design process with a task force made up of PWH and medical doctors. Usability was assessed through the System Usability Scale (SUS) questionnaire. An AI chatbot in French and Wolof, named Saytù Hemophilie, was developed for Android and Apple iOS devices. It was assessed as a very usable system with a SUS score of 81.7, above average. 42% would prefer to use the Wolof version even if they were very satisfied with the French version. The level of Wolof in the app did not always correspond to users' levels. Participants praised its accessibility and reliability, and its ability to enhance self-learning. Findings suggest that a culturally adapted digital conversational agent is likely to be used by PWH in Senegal and their families to improve education and self-management of haemophilia. Relevance and impact are foreseen for other communities in Africa and beyond.


Magnetic resonance diffusion tensor imaging of cervical spinal cord and lumbosacral enlargement in patients with cervical spondylotic myelopathy.
To identify the correlations of diffusion tensor imaging (DTI) indices between the cervical spinal cord and lumbosacral enlargement in healthy volunteers and patients with cervical spondylotic myelopathy (CSM). DTI was performed at the cervical spinal cord and lumbosacral enlargement in 10 CSM patients and 10 volunteers at 1.5T. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of were measured and compared between CSM patients and volunteers. DTI indices of different cervical segments in volunteers were compared. DTI indices of the cervical spinal cord were correlated with those of the lumbosacral enlargement. In healthy subjects, DTI indices of different cervical cord sections showed no significant difference (ADC: F = 0.62; P = 0.65; FA: F = 1.228; P = 0.312); there was no correlation between the DTI indices of the cervical spinal cord and those of the lumbosacral enlargement (ADC: r = 0.442, P = 0.201; FA: r = -0.054, P = 0.881). In the CSM patients, the ADC value significantly increased, while the FA value significantly decreased in the cervical spinal cord (ADC: P = 0.002; FA: P < 0.001) and lumbosacral enlargement (ADC: P = 0.003; FA: P < 0.001) compared with the healthy group. Both DTI indices showed no correlation between the cervical spinal cord and those of the lumbosacral enlargement in the CSM group (ADC: r = -0.052, P = 0.887; FA: r = 0.129, P = 0.722). The ADC value of the cervical spinal cord and lumbosacral enlargement in CSM patients showed significant increase compared with healthy volunteers, while the FA value significantly decreased. Both DTI indices of the cervical spinal cord had no linear correlation with those of the lumbosacral enlargement. J. Magn. Reson. Imaging 2016;43:1484-1491.


Comparison of treatment outcome definitions in drug-resistant tuberculosis patients with high incidence of acquired second-line drug resistance.
Simplified drug-resistant tuberculosis (DR-TB) treatment outcome definitions, mostly centred around receipt of treatment and sputum culture status at 6 months after treatment initiation, have been proposed, but have not been widely evaluated in resource-limited settings. To compare DR-TB treatment outcomes, as defined by the World Health Organization (WHO) at the time of treatment, with simplified definitions. We performed retrospective folder reviews of a cohort of 246 South African DR-TB patients, most of whom developed second-line drug resistance. Sequential treatment outcomes were assigned retrospectively using both simplified Tuberculosis Network European Trials Group (TBNET)-based and 2013 WHO-based definitions. Of 246 patients, 40% were HIV-positive, and 88% developed second-line drug resistance. Patients were observed for a median of 38 (interquartile range 24 - 63) months from DR-TB treatment initiation. Using WHO-based definitions, 93% of patients had >1 sequential outcome, whereas with simplified definitions, 25% of patients had >1 outcome. Fewer outcomes of cure (3% v. 9%) and more outcomes of treatment failure (42% v. 22%) were assigned using simplified definitions. Simplified outcome definitions applied to real-world patients with long, often complex treatment histories resulted in underestimating cures and overestimating treatment failures compared with WHO-based definitions. Simplified definitions may identify more individuals at higher risk for treatment failure than WHO-based definitions, but without consistent programmatic follow-up it may be difficult to distinguish cure, failure and loss to follow-up.


Eco-geochemical evaluation of the Leizhou Peninsula (southern China) and the prediction of heavy metal content in soils.
The Leizhou Peninsula is an important base for tropical and subtropical cash crops in China, but still lacks systematic research on regional eco-geochemical characteristics. Here the elemental results show that risk-free soils accounted for 9168 km2 and were mainly concentrated in the northern Leizhou Peninsula, while risk-controllable soils occupied 3318 km2 and were mostly distributed in the southern part. The contributor of the heavy metals in soils was mainly natural rocks, while the road traffic dust and coal combustion were also responsible for the origin of anomalous elements Cd, Cr, and Ni (0.004-1.8, 0.76-590, and 0.14-372 mg/kg, respectively). 90.15 % of the Leizhou Peninsula plants were not obviously contaminated, yet the comparison between the data collected in 1997 and 2018 allows us to speculate that Ni in the studied soils will reach the risk screening value in 7 years, followed by Cr and Cu in 39 and 92 years, respectively.


Quantum-accessible reinforcement learning beyond strictly epochal environments.
In recent years, quantum-enhanced machine learning has emerged as a particularly fruitful application of quantum algorithms, covering aspects of supervised, unsupervised and reinforcement learning. Reinforcement learning offers numerous options of how quantum theory can be applied, and is arguably the least explored, from a quantum perspective. Here, an agent explores an environment and tries to find a behavior optimizing some figure of merit. Some of the first approaches investigated settings where this exploration can be sped-up, by considering quantum analogs of classical environments, which can then be queried in superposition. If the environments have a strict periodic structure in time (i.e. are strictly episodic), such environments can be effectively converted to conventional oracles encountered in quantum information. However, in general environments, we obtain scenarios that generalize standard oracle tasks. In this work, we consider one such generalization, where the environment is not strictly episodic, which is mapped to an oracle identification setting with a changing oracle. We analyze this case and show that standard amplitude-amplification techniques can, with minor modifications, still be applied to achieve quadratic speed-ups. In addition, we prove that an algorithm based on Grover iterations is optimal for oracle identification even if the oracle changes over time in a way that the "rewarded space" is monotonically increasing. This result constitutes one of the first generalizations of quantum-accessible reinforcement learning.


Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy.
The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types. Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors. Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy.


Determinants of birthweight: gender based analysis.
The objective of this cross sectional study is to look at determinants of birth weight and their association with the gender of the baby in 2,795 full term children living in the occupied Palestinian territory, derived from a stratified random sample of 2,994 households in the West Bank and 2,234 households in the Gaza Strip. The response rate was 85%. Multivariable analysis using analysis of variance for mixed models showed that sex and birth order, maternal age and education and to a lesser extent region were determinants of birth weight for all children. The effect of maternal education on birth weight differed for female and male infants, tending to be relatively unchanged for male infants and with mean birth weights increasing with maternal education in female infants. The effect of birth order differed by maternal age, with mean birth weight increasing with maternal age for first and second births; but being unaffected by maternal age for infants of birth order greater than two. We conclude that birth weight is influenced by common biological determinants across cultures, but is also influenced by social, ethnic, and environmental factors that are culture specific, of which some might be gender related.


Visual representation of statistical information improves diagnostic inferences in doctors and their patients.
Doctors and patients have difficulty inferring the predictive value of a medical test from information about the prevalence of a disease and the sensitivity and false-positive rate of the test. Previous research has established that communicating such information in a format the human mind is adapted to-namely natural frequencies-as compared to probabilities, boosts accuracy of diagnostic inferences. In a study, we investigated to what extent these inferences can be improved-beyond the effect of natural frequencies-by providing visual aids. Participants were 81 doctors and 81 patients who made diagnostic inferences about three medical tests on the basis of information about prevalence of a disease, and the sensitivity and false-positive rate of the tests. Half of the participants received the information in natural frequencies, while the other half received the information in probabilities. Half of the participants only received numerical information, while the other half additionally received a visual aid representing the numerical information. In addition, participants completed a numeracy scale. Our study showed three important findings: (1) doctors and patients made more accurate inferences when information was communicated in natural frequencies as compared to probabilities; (2) visual aids boosted accuracy even when the information was provided in natural frequencies; and (3) doctors were more accurate in their diagnostic inferences than patients, though differences in accuracy disappeared when differences in numerical skills were controlled for. Our findings have important implications for medical practice as they suggest suitable ways to communicate quantitative medical data.