Is there a time window for MRI in Wernicke encephalopathy - a decade of experience from a tertiary hospital.
Wernicke encephalopathy (WE) is a neuropsychiatric syndrome caused by thiamine deficiency. Despite its low sensitivity, brain magnetic resonance imaging (MRI) is the most useful diagnostic technique. Our aim was to investigate whether the timing of the imaging study, and thiamine replacement can influence brain MRI findings in these patients. Retrospective observational study of hospitalized patients between January/2008 and December/2020 with a clinical diagnosis of WE. Data from clinical presentation, diagnostic features, therapeutic approach, and outcomes were collected. We identified 41 patients (55 ± 13.3 years) with WE. Brain MRI was performed in 36 patients, and one third had T2/FLAIR hyperintensities suggestive of WE. We found an association between a history of poor diet and periventricular hyperintensities (p = 0.023), especially on the ventral surface of the thalamus and the periaqueductal region. It was found that the odds of having a typical imaging of WE decreased by 5.3% for each additional unit (100 mg) of thiamine administered (p = 0.046) (95% CI [0.89, 0.99]). On the other hand, the number of days from clinical presentation was not found to be a viable predictor (p = 0.254) (95% CI [0.88, 1.03]) Recovery was positively correlated with the total dose of thiamine received until discharge (p = 0.020). MRI hyperintensities seem to be dependent on the timing of thiamine correction and, particularly, on the thiamine dosage prescribed at admission. Nevertheless, thiamine replacement should not be delayed, as its timely prescription is associated with a better prognosis at discharge.


Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus.
A peptide toxin, ShK, that blocks voltage-dependent potassium channels was isolated from the whole body extract of the Caribbean sea anemone Stichodactyla helianthus. It competes with dendrotoxin I and alpha-dendrotoxin for binding to synaptosomal membranes of rat brain, facilities acetylcholine release at an avian neuromuscular junction and suppresses K+ currents in rat dorsal root ganglion neurones in culture. Its amino acid sequence is R1SCIDTIPKS10RCTAFQCKHS20MKYRLSFCRK30TCGTC35. There is no homology with other K+ channel-blocking peptides, except for BgK from the sea anemone Bunodosoma granulifera. ShK and BgK appear to be in a different structural class from other toxins affecting K+ channels.


Effects of Pyridostigmine bromide on SH-SY5Y cells: An in vitro neuroblastoma neurotoxicity model.
Pyridostigmine bromide (PB) is a reversible acetylcholinesterase (AChE) inhibitor and the first-choice for the treatment of symptoms associated with myasthenia gravis and other neuromuscular junction disorders. However, evidence suggested that PB could be associated with the Gulf War Illness characterised by the presence of fatigue, headaches, cognitive dysfunction, and musculoskeletal respiratory and gastrointestinal disturbances. Given that a potential neurotoxic effect of PB has not yet been completely elucidated, the present investigation used neural SH-SY5Y cells to evaluate the effect of PB on the cellular viability, cell apoptosis, modulation of the cell cycle, oxidative stress, and genotoxicity variables, which indicate neurodegeneration. As expected, a PB concentration curve based on the therapeutic dose of the drug showed an inhibition of the AChE activity. However, this effect was transient and did not involve differential AChE gene regulation by PB. These results confirmed that undifferentiated SH-SY5Y cells can be used as a cholinergic in vitro model. In general, PB did not trigger oxidative stress, and at a slightly higher PB concentration (80ng/mL), higher levels of protein carbonylation and DNA damage were detected, as determined by the marker 8-deoxyguanosine. The PB genotoxic effects at 80ng/mL were confirmed by the upregulation of the p53 and DNA methyltransferase 1 (DNMT1) genes, which are associated with cellular DNA repair. PB at 40ng/mL, which is the minimal therapeutic dose, led to higher cell proliferation and mitochondrial activity compared with the control group. The effects of PB were corroborated by the upregulation of the telomerase gene. In summary, despite the methodological constrains related to the in vitro protocols, our results suggested that exposure of neural cells to PB, without other chemical and physical stressors did not cause extensive toxicity or indicate any neurodegeneration patterns.


Analysis for the Association Between Corpus Callosum Thickness and Corpus Callosotomy Outcomes for Patients With Epileptic Spasms or Tonic Spasms.
This retrospective study is designed to determine whether the thickness of the corpus callosum can predict corpus callosotomy outcome in pediatric patients with epileptic or tonic spasms. We retrospectively studied 25 patients (18 boys) with intractable childhood-onset epileptic or tonic spasms who underwent corpus callosotomy between March 2008 and January 2017. Seizure outcomes were classified as favorable (class I and II of Engel's outcome classification) or unfavorable (class III and IV of Engel's outcome classification) at 12 months postoperatively. We measured the corpus callosum area on the midline and maximum cerebral area on the para-midline in sagittal magnetic resonance images just before surgery. We statistically analyzed the associations between surgical outcomes and corpus callosum area, corpus callosum area/maximum cerebral area (corpus callosum/cerebrum ratio), or age at magnetic resonance imaging just before surgery, using univariate and multivariate logistic regression analyses. Age at surgery ranged from six to 237 months (mean: 119). Main seizure types were epileptic spasms in 17 patients and tonic spasms in eight. Favorable outcomes occurred in 10 (40%) patients and unfavorable outcomes in 15 (60%). Both corpus callosum area and corpus callosum/cerebrum ratio did not show significant associations with the outcomes in the univariate and multivariate analyses. The 95% confidence intervals of corpus callosum/cerebrum ratio strongly overlapped between the favorable and unfavorable outcome groups. Our data failed to support that corpus callosum thickness on the sagittal image is associated with corpus callosotomy outcomes in pediatric patients with epileptic spasms or tonic spasms.


Clinical Value of Surveillance 18F-fluorodeoxyglucose PET/CT for Detecting Unsuspected Recurrence or Second Primary Cancer in Non-Small Cell Lung Cancer after Curative Therapy.
We evaluated the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT surveillance for detecting clinically unsuspected recurrence or second primary cancer (SPC) in patients with non-small cell lung cancer (NSCLC) after curative therapy. A total of 4478 surveillance FDG PET/CT scans from 2864 NSCLC patients without suspicion of recurrence after curative therapy were reviewed retrospectively. In 274 of 2864 (9.6%) patients, recurrent NSCLC or SPC was found by surveillance PET/CT during clinical follow-up. Surveillance PET/CT scans showed sensitivity of 98.9% (274/277), specificity of 98.1% (4122/4201), accuracy of 98.2% (4396/4478), positive predictive value (PPV) of 77.6% (274/353), and negative predictive value of 99.9% (4122/4125). The specificity and accuracy in the curative surgery group were significantly higher than those in the curative radiotherapy group. PPV was significantly improved in subgroups of patients with advanced stage prior to curative therapy, PET/CT scans performed within 3 years after curative-intent therapy, and curative surgery. FDG PET/CT surveillance showed good diagnostic efficacy for detecting clinically unexpected recurrence or SPC in NSCLC patients after curative therapy. It can be more useful when performed soon after therapy in curative surgery recipients and those with an advanced disease stage considering its diagnostic efficacy and yield.


May one-stage exchange for Candida albicans peri-prosthetic infection be successful?
Fungal infection of a total joint arthroplasty has a low incidence but is generally considered as more difficult to cure than bacterial infection. As for bacterial infection, two-stage exchange is considered as the gold standard of treatment. We report two cases of one-stage total joint exchange for fungal peri-prosthetic infection with Candida albicans, where the responsible pathogens was only identified on intraoperative samples. This situation can be considered as a one-stage exchange for fungal peri-prosthetic infection without preoperative identification of the responsible organism, which is considered as having a poor prognosis. Both cases were free of infection after two years. One-stage revision has several potential advantages over two-stage revision, including shorter hospital stay and rehabilitation, no interim period with significant functional impairment, shorter antibiotic treatment, better functional outcome and probably lower costs. We suggest that one-stage revision for C. albicans peri-prosthetic infection may be successful even without preoperative fungal identification. Level IV-Historical cases.


Thromboxane A2 and the development of hypertension in spontaneously hypertensive rats.
Osmotic minipumps containing OKY-046 (15-20 mg/kg per day), to inhibit thromboxane (TX) A2 synthase, were implanted into 43-day-old SHR and age-matched Wistar-Kyoto rats (WKY) to study the role of TXA2 in the development of hypertension in SHR. Inhibition of TXA2 synthase with OKY-046 did not affect urine volume, sodium excretion, potassium excretion, food and water intake or body weight in either WKY or SHR during the two weeks of study. In the first week systolic blood pressure (SBP) was significantly lower in SHR receiving OKY-046 in comparison to SHR which received no OKY-046 (127 +/- 3 vs. 110 +/- 4 mm Hg, P less than 0.01). OKY-046 did not affect SBP in WKY. By the second week SBP in SHR and WKY receiving OKY-046 did not differ from their respective controls despite an 85% reduction in serum immunoreactive TXB2 (iTXB2; the stable hydrolysis product of TXA2) and a 45% reduction in urinary iTXB2 excretion. These results support a possible role for TXA2 in the developmental stage of hypertension in SHR and other factors in the sustained elevation of blood pressure.


Home-based management of children hospitalized with acute gastroenteritis.
To determine the source of medical advice to parents and treatment administered at home for children admitted to hospital with acute gastroenteritis. A questionnaire was completed by the parents of 231 children admitted during a 12 month period. The majority of children had seen their family doctor or an after-hours doctor prior to admission. Clear fluids were used for two-thirds but an oral rehydration solution (ORS) was used in only one-third of children. Medications were used for half, including antibiotics (19%), antidiarrhoeals (9%), antiemetics (7%) and paracetamol (27%). Inpatient assessment suggested that the majority of children had no or mild dehydration. Appropriate oral rehydration is underutilized and medications are overprescribed for the treatment of acute gastroenteritis. Family doctors continue to be the major source of advice for parents. Increased use of ORS at home may reduce hospitalization rates but attempts to change these practices should be directed at parents and family doctors.


N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool.
MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3' UTRmRNA duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).


Small RNA-seq and hormones in the testes of dwarf hamsters (Cricetulus barabensis) reveal the potential pathways in photoperiod regulated reproduction.
Photoperiod regulates the functions and development of gonadal organs of seasonally breeding animals, resulting in breeding peaks in specific seasons. miRNA plays an important role in the regulation of testicular physiological functions. However, the relationship between photoperiods and miRNA levels in testes has yet to be conclusively determined. We investigated testicular miRNA of striped dwarf hamster (Cricetulus barabensis) responses to different photoperiods (long daylength [LD], moderate daylength [MD], and short daylength [SD]) and the potential pathways involved in photoperiod regulated reproduction. Testicular weights and reproductive hormone levels were measured in each of photoperiod treatments after 30 days. The concentrations of testosterone (T) and dihydrogen testosterone (DHT) in testes and Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in serum were higher in MD than in the other two groups. Testicular weights were heaviest in MD. Small RNA-seq was performed for the testes of hamsters in three groups. A total of 769 miRNAs were identified, of which 83 were differentially expressed between LD, MD, and SD. GO and KEGG analysis of target genes revealed that some miRNAs influence testicular activities by regulating the pathways related to cell apoptosis and metabolism. Gene expression pattern analysis showed that the MAPK signaling pathway may be the core pathway for photoperiodic regulation of reproduction. These results suggest that moderate daylength is more suitable for hamster reproduction while long daylength and short daylength may regulate reproduction through different molecular pathways.


A SNP in the Immunoregulatory Molecule CTLA-4 Controls mRNA Splicing In Vivo but Does Not Alter Diabetes Susceptibility in the NOD Mouse.
CTLA-4 is a critical "checkpoint" regulator in autoimmunity. Variation in CTLA-4 isoform expression has been linked to type 1 diabetes development in human and NOD mouse studies. In the NOD mouse, a causative link between increased expression of the minor isoform ligand-independent CTLA-4 and a reduction in diabetes has become widely accepted. Altered splicing of CTLA-4 has been attributed to a single nucleotide polymorphism (SNP) in Ctla4 exon2 (e2_77A/G). To investigate this link, we have used NOD embryonic stem (ES) cells to generate a novel NOD transgenic line with the 77A/G SNP. This strain phenocopies the increase in splicing toward the liCTLA4 isoform seen in B10 Idd5.1 mice. Crucially, the SNP does not alter the spontaneous incidence of diabetes, the incidence of cyclophosphamide-induced diabetes, or the activation of diabetogenic T-cell receptor transgenic CD4(+) T cells after adoptive transfer. Our results show that one or more of the many other linked genetic variants between the B10 and NOD genome are required for the diabetes protection conferred by Idd5.1. With the NOD mouse model closely mimicking the human disease, our data demonstrate that knock-in transgenic mice on the NOD background can test causative mutations relevant in human diabetes.


Molecular analysis of drought tolerance in tea by cDNA-AFLP based transcript profiling.
A cDNA-AFLP approach was used to identify transcript and/or genes specifically expressed in response to drought in tea. Drought was artificially induced and whole genome transcript profiling was done at three different stages-6 days before wilting, 3 days before wilting and at wilting stage of both tolerant and susceptible cultivars, and genetic differences was thus visualized as polymorphisms in the transcriptome. The cDNA-AFLP technique allowed genes and transcripts to be identified in the tolerant genotype (TV-23) whose expression is responsive to drought stress. The cluster analysis revealed two types of clustering-type I separated the tolerant and susceptible cultivar, whereas type II separated the time point of sample and this may be grouped as early and late responsive transcripts. 108 transcript derived fragments were identified as differentially expressed in tolerant genotypes of which 89 sequences could be obtained. Fifty-nine of them showed homology in the public databases. Functional ontology showed genes related to carbohydrate metabolism, response to stress, protein modification process and translation. Cluster I includes five fragments and cluster II includes 25 fragments. Other genes strongly expressed in response to drought in tolerant genotype would help us in identifying and determining the genetic basis of mechanisms involved in conferring drought tolerance in tea.


Simultaneous pattern electroretinogram and visual evoked potential recordings in dyslexic children.
To help clarify the conflicting evidence of neurophysiologic abnormalities in children with reading problems (dyslexia), we examined pattern electroretinograms and visual evoked potentials to stimulation with checks of 24', 49' and 180', each at 5%, 42% and 100% contrast, in a group of dyslexic children and a group of normal (i.e., normally reading) children. Neurophysiologic difference between the groups was restricted to the visual evoked potential, which showed a significant prolongation of the P100 wave in dyslexic children at the highest contrast (100%) and the smallest checks (24'). There was no significant difference between normal and dyslexic children in the P50 and N95 pattern electroretinogram waves. These results support the assumption of a visual deficit in dyslexic children. However, they are not consistent with the evidence of an isolated deficit of the magnocellular function, which, theoretically, would cause more prominent visual evoked potential changes to lower contrast and the largest check stimuli.


Probabilistic mapping of deep brain stimulation in childhood dystonia.
In adults with dystonia Probabilistic Stimulation Mapping (PSM) has identified putative "sweet spots" for stimulation. We aimed to apply PSM to a cohort of Children and Young People (CYP) following DBS surgery. Pre-operative MRI and post-operative CT images were co-registered for 52 CYP undergoing bilateral pallidal DBS (n = 31 genetic/idiopathic dystonia, and n = 21 Cerebral Palsy (CP)). DBS electrodes (n = 104) were automatically detected, and Volumes of Tissue Activation (VTA) derived from individual patient stimulation settings. VTAs were normalised to the MNI105 space, weighted by percentage improvement in Burke-Fahn-Marsden Dystonia Rating scale (BFMDRS) at one-year post surgery and mean improvement was calculated for each voxel. For the genetic/idiopathic dystonia group, BFMDRS improvement was associated with stimulation across a broad volume of the GPi. A spatial clustering of the upper 25th percentile of voxels corresponded with a more delineated volume within the posterior ventrolateral GPi. The MNI coordinates of the centroid of this volume (X = -23.0, Y = -10.5 and Z = -3.5) were posterior and superior to the typical target for electrode placement. Volume of VTA overlap with a previously published "sweet spots" correlated with improvement following surgery. In contrast, there was minimal BFMDRS improvement for the CP group, no spatial clustering of efficacious clusters and a correlation between established "sweet spots" could not be established. PSM in CYP with genetic/idiopathic dystonia suggests the presence of a "sweet spot" for electrode placement within the GPi, consistent with previous studies. Further work is required to identify and validate putative "sweet spots" across different cohorts of patients.


The learning curve of laparoendoscopic single-site (LESS) cholecystectomy: definable, short, and safe.
The applications of laparoendoscopic single-site (LESS) surgery, including cholecystectomy, are occurring quickly, although little is generally known about issues associated with the learning curve of this new technique including operative time, conversion rates, and safety. We prospectively followed all patients undergoing LESS cholecystectomy, and compared operations undertaken at our institutions in cohorts of 25 patients with respect to operative times, conversion rates, and complications. One-hundred fifty patients of mean age 46 years underwent LESS cholecystectomy. No significant differences in operative times were demonstrable between any of the 25-patient cohorts operated on at our institution. A significant reduction in operative times (p < 0.001) after completion of 75 LESS procedures was, however, identified with the experience of a single surgeon. No significant reduction in the number of procedures requiring an additional trocar(s) or conversion to open operations was observed after completion of 25 LESS cholecystectomies. Complication rates were low, and not significantly different between any 25-patient cohorts. For surgeons proficient with multi-incision laparoscopic cholecystectomy, the learning curve for LESS cholecystectomy begins near proficiency. Operative complications and conversions were infrequent and unchanged across successive 25-patient cohorts, and were similar to those reported for multi-incision laparoscopic cholecystectomy after the learning curve.


Artificial nucleases.
The oxidation of DNA and RNA provides a facile approach for investigating the interaction of nucleic acids with proteins and oligonucleotides. In this article, we have outlined our understanding of the mechanism of DNA scission by 1,10-phenanthroline-copper(I) in the presence of hydrogen peroxide. We also discuss results obtained by using 1,10-phenanthroline-oligonucleotide conjugates in probing the size of the transcriptionally active open complex. Finally, we outline an effective method for converting DNA-binding proteins into site-specific modification agents by using 1,10-phenanthroline-copper(I).


Regulation of initiation factors during translational repression caused by serum depletion. Covalent modification.
One to 2 h after transfer of HeLa cells into fresh serum-containing medium, when translation rates are maximal, the initiation factor proteins were examined on immunoblots of two-dimensional gels. Eukaryotic initiation factor (eIF)-2 alpha, eIF-2 beta, and eIF-4A each formed a single immunoreactive spot; eIF-2 gamma formed 2 spots; and eIF-4B formed a complex array of 12-20 spots. After 4 days of growth in unreplenished medium, when translation rates have dropped 4-6-fold, several alterations in the isoelectric forms were observed: eIF-2 alpha now occurred in 2 forms, eIF-2 beta was present in 3-4 forms, and the most acidic cluster of eIF-4B variants was decreased or absent while a new isoelectric variant appeared at the basic end of the array. No changes were observed for eIF-2 gamma or eIF-4A. The 35-50-kDa subunits of the multiprotein initiation factor eIF-3 also showed no changes when the aforementioned growth states were compared. Resolution of 32P-labeled lysates by isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that the eIF-2 alpha modification and the loss of eIF-4B variants reflected changes in phosphorylation states. Stimulation of 4-day grown cells with fresh serum-containing medium caused a reversal of the initiation factor modifications back to the forms prevailing shortly after replating. This analysis indicates that covalent modifications appear concurrently with decreasing initiation rates and suggests that they may be causative.


Biosensing strategies for diagnosis of prostate specific antigen.
Almost from the time of its discovery, the prostate specific antigen (PSA) has been one of the most accurate and most extensively studied indicators of prostate cancer (PC). Because of advancements in biosensing systems and technology, PSA analysis methods have been substantially updated and enhanced as compared to their first instances. With the development of techniques in biosensor technology, the number of PSA biosensors that can be used in the biomedical sector is increasing year by year. Many different recognition elements and transducers have been used in the development of biosensor systems that exhibit high sensitivity, selectivity, and specificity. Here in this review, we provide a current overview of the different approaches to PSA detection.


Interactive effects of nitrogen deposition and fire on plant and soil chemistry in an alpine heathland.
The response of alpine heathland vegetation and soil chemistry to N additions of 0, 10, 20 and 50 kg N ha(-1) year(-1) in combination with simulated accidental fire (+/-) was monitored over a 5-year period. N addition caused rapid and significant increases in plant tissue N content and N:P and N:K of Calluna vulgaris, suggesting increasing phosphorus and potassium limitation of growth. Soil C:N declined significantly with N addition, indicating N saturation and increasing likelihood of N leakage. Fire further decreased soil C:N and reduced potential for sequestration of additional N. This study shows that alpine heathlands, which occupy the headwaters of many rivers, have limited potential to retain deposited N and may rapidly become N saturated, leaking N into downstream communities and surface waters.


A novel internet sampling for HIV surveillance: feasibility of self-sampling and preparation of DBS for delivery detection of HIV total nucleic acid and complementarity to sentinel surveillance.
To propose a new mode of HIV test and surveillance among population of men who have sex with men (MSM): Internet-based Self-sampling at home plus Laboratory testing of HIV total nucleic acid (TNA) in dried blood spot (DBS) (ISL of DBS TNA). Feasibility of ISL of DBS TNA was studied. Characteristics of the new mode and that of conventional surveillance mode at HIV voluntary counseling and testing clinic (VCT) were compared. A non-governmental organization (NGO) published the recruitment information on the WeChat public account. MSM filled in the questionnaire online, applied for self-sampling service package, and mailed the self made DBS to professional laboratory. The laboratory performed HIV TNA test and submitted the test results to online platform. Participants queried test results online with their unique ID. Center for Disease Control and Prevention (CDC) followed up participants with positive nucleic acid results using IDs and contact information. Rates were compared by using the Chi-Square test or Fisher's exact test. Four hundred twenty-three questionnaires were completed. 423 self-sampling service packages were sent out and 340 DBSs were returned to professional laboratory within one month with qualified rate of sampling as high as 95.0% (323/340). Seven samples were found to be TNA positive. Comparing ISL of DBS TNA with sentinel surveillance, it was found that there was a significant difference in the composition ratio of the two modes of surveillance population (P < 0.05). HIV prevalence of ISL of DBS as 2.17% was significantly lower than sentinel site as 8.96% (χ2 = 14.953, P = 0.000 < 0.05). ISL of DBS TNA proposed is feasible and has a high self-sampling qualification rate, good confidentiality. It is an effective supplement to routine sentinel surveillance and has important promotion value.


Analyzing the Local Electronic Structure of Co3O4 Using 2p3d Resonant Inelastic X-ray Scattering.
We present the cobalt 2p3d resonant inelastic X-ray scattering (RIXS) spectra of Co3O4. Guided by multiplet simulation, the excited states at 0.5 and 1.3 eV can be identified as the 4 T 2 excited state of the tetrahedral Co2+ and the 3 T 2g excited state of the octahedral Co3+, respectively. The ground states of Co2+ and Co3+ sites are determined to be high-spin 4 A 2(T d ) and low-spin 1 A 1g (Oh ), respectively. It indicates that the high-spin Co2+ is the magnetically active site in Co3O4. Additionally, the ligand-to-metal charge transfer analysis shows strong orbital hybridization between the cobalt and oxygen ions at the Co3+ site, while the hybridization is weak at the Co2+ site.


A Cohort Study on the Duration of Plasmodium falciparum Infections During the Dry Season in The Gambia.
In areas where Plasmodium falciparum malaria is seasonal, a dry season reservoir of blood-stage infection is essential for initiating transmission during the following wet season. In The Gambia, a cohort of 42 individuals with quantitative polymerase chain reaction-positive P falciparum infections at the end of the transmission season (December) were followed monthly until the end of the dry season (May) to evaluate infection persistence. The influence of human host and parasitological factors was investigated. A large proportion of individuals infected at the end of the wet season had detectable infections until the end of the dry season (40.0%; 16 of 40). At the start of the dry season, the majority of these persistent infections (82%) had parasite densities >10 p/µL compared to only 5.9% of short-lived infections. Persistent infections (59%) were also more likely to be multiclonal than short-lived infections (5.9%) and were associated with individuals having higher levels of P falciparum-specific antibodies (P = .02). Asymptomatic persistent infections were multiclonal with higher parasite densities at the beginning of the dry season. Screening and treating asymptomatic infections during the dry season may reduce the human reservoir of malaria responsible for initiating transmission in the wet season.


Lead contamination in raptors in Europe: A systematic review and meta-analysis.
Lead contamination is a widely recognised conservation problem for raptors worldwide. There are a number of studies in individual raptor species but those data have not been systematically evaluated to understand raptor-wide lead exposure and effects at a pan-European scale. To critically assess the extent of this problem, we performed a systematic review compiling all published data on lead in raptors (1983-2019) and, through a meta-analysis, determined if there was evidence for differences in exposure across feeding traits, geographical regions, between hunting and non-hunting periods, and changes over time. We also reviewed the impact of lead on raptors and the likely main source of exposure. We examined 114 studies that were unevenly distributed in terms of time of publication and the countries in which studies were performed. Peer-reviewed articles reported data for 39 raptor species but very few species were widely monitored across Europe. Obligate (vultures) and facultative scavengers (golden eagle, common buzzard and white-tailed sea eagle) accumulated the highest lead concentrations in tissues and generally were the species most at risk of lead poisoning. We found no evidence of a spatial or decadal trend in lead residues, but we demonstrated that high lead blood levels relate to hunting season. Exposure at levels associated with both subclinical and lethal effects is common and lead from rifle bullets and shot is often the likely source of exposure. Overall, our review illustrates the high incidence and ubiquity of lead contamination in raptors in Europe. However, we did not find studies that related exposure to quantitative impacts on European raptor populations nor detailed studies on the impact of mitigation measures. Such information is urgently needed and requires a more harmonised approach to quantifying lead contamination and effects in raptors across Europe.


The role of echocardiography and CT in the diagnosis of cardiac tumors.
A young male who presented with atypical chest pain was found to have a primary cardiac tumor. Chest X-ray, electrocardiogram, and echocardiographic findings can be nonspecific. Differential diagnosis and the role of different diagnostic modalities including echocardiogram, computerized tomography and magnetic resonance imaging are discussed.


Using DMPP with cattle manure can mitigate yield-scaled global warming potential under low rainfall conditions.
Organic fertilisers can reduce the carbon (C) footprint from croplands, but adequate management strategies such as the use of nitrification inhibitors are required to minimise side-effects on nitrogen (N) losses to the atmosphere or waterbodies. This could be particularly important in a context on changing rainfall patterns due to climate change. A lysimeter experiment with maize (Zea mays L.) was set up on a coarse sandy soil to evaluate the efficacy of 3,4-dimethylpyrazole phosphate (DMPP) to mitigate nitrous oxide (N2O) emissions, nitrate (NO3-) leaching losses and net global warming potential from manure, with (R+) and without (R-) simulated rainfall events. Soil water availability was a limiting factor for plant growth and microbial processes due to low rainfall during the growing season. Nitrification was effectively inhibited by DMPP, decreasing topsoil NO3- concentrations by 28% on average and cumulative N2O losses by 82%. Most of the N2O was emitted during the growing season, with annual emission factors of 0.07% and 0.95% for manure with and without DMPP, respectively. Cumulative N2O emissions were 40% higher in R-compared to R+, possibly because of the higher topsoil NO3- concentrations. There was no effect of DMPP or rainfall amount on annual NO3- leaching losses, which corresponded to 12% of manure-N and were mainly driven by the post-harvest period. DMPP did not affect yield or N use efficiency (NUE) while R-caused severe reductions on biomass and NUE. We conclude that dry growing seasons can jeopardize crop production while concurrently increasing greenhouse gas emissions from a sandy soil. The use of nitrification inhibitors is strongly recommended under these conditions to address the climate change impacts.


Gemcitabine-loaded albumin nanospheres (GEM-ANPs) inhibit PANC-1 cells in vitro and in vivo.
With the development of nanotechnology, special attention has been given to the nanomaterial application in tumor treatment. Here, a modified desolvation-cross-linking method was successfully applied to fabricate gemcitabine-loaded albumin nanospheres (GEM-ANPs), with 110 and 406 nm of mean diameter, respectively. The aim of this study was to assess the drug distribution, side effects, and antitumor activity of GEM-ANPs in vivo. The metabolic viability and flow cytometry analysis revealed that both GEM-ANPs, especially 406-nm GEM-ANPs, could effectively inhibit the metabolism and proliferation and promote the apoptosis of human pancreatic carcinoma (PANC-1) in vitro. Intravenous injection of 406-nm GEM-ANPs exhibited a significant increase of gemcitabine in the pancreas, liver, and spleen of Sprague-Dawley rats (p < 0.05). Moreover, no signs of toxic side effects analyzed by blood parameter changes were observed after 3 weeks of administration although a high dose (200 mg/kg) of GEM-ANPs were used. Additionally, in PANC-1-induced tumor mice, intravenous injection of 406-nm GEM-ANPs also could effectively reduce the tumor volume by comparison with free gemcitabine. With these findings, albumin nanosphere-loading approach might be efficacious to improve the antitumor activity of gemcitabine, and the efficacy is associated with the size of GEM-ANPs.


Case Report: Successful Living Donor Kidney Transplantation in a Highly Human Leukocyte Antigen-Sensitized Recipient With a Positive Cytotoxic Crossmatch Using Bortezomib-Based Desensitization Without Intravenous Immunoglobulin.
Highly sensitized patients, who produce antibodies against multiple anti-human leukocyte antigens, have significantly reduced chances for renal transplantation. Traditionally, desensitization protocols to reduce the levels of antibodies have relied on the use of intravenous immunoglobulin and plasmapheresis. Here we report the case of a patient with a calculated panel-reactive antibody level of 100% who was desensitized using multiple courses of bortezomib, a proteasome inhibitor, in an intravenous immunoglobulin-free regimen. The patient underwent a successful transplantation with an allograft from a living donor and has continued to do well post-transplantation. The expression of anti-human leukocyte antigen antibodies decreases the likelihood of transplantation for patients by restricting the available donor pool. New protocols that reduce antibody expression in these patients and allow for renal transplantation are needed. Bortezomib, as used in the patient reported here, represents a promising new medication for successful desensitization and transplantation.


Activation of astrocytes in the basal forebrain in mice facilitates isoflurane-induced loss of consciousness and prolongs recovery.
General anesthesia results in a state of unconsciousness that is similar to sleep. In recent years, increasing evidence has reported that astrocytes play a crucial role in regulating sleep. However, whether astrocytes are involved in general anesthesia is unknown. In the present study, the designer receptors exclusively activated by designer drugs (DREADDs) approach was utilized to specifically activate astrocytes in the basal forebrain (BF) and observed its effect on isoflurane anesthesia. One the other side, L-α-aminoadipic acid was used to selectively inhibit astrocytes in the BF and investigated its influence on isoflurane-induced hypnotic effect. During the anesthesia experiment, cortical electroencephalography (EEG) signals were recorded as well. The chemogenetic activation group had a significantly shorter isoflurane induction time, longer recovery time, and higher delta power of EEG during anesthesia maintenance and recovery periods than the control group. Inhibition of astrocytes in the BF delayed isoflurane-induced loss of consciousness, promoted recovery, decreased delta power and increased beta and gamma power during maintenance and recovery periods. The present study suggests that astrocytes in the BF region are involved in isoflurane anesthesia and may be a potential target for regulating the consciousness state of anesthesia.


The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention.
Salmonella is a facultative intracellular pathogen that causes diseases ranging from self-limiting enteritis to typhoid fever. This bacterium uses two type III secretion systems to deliver effector proteins directly into the host cell to promote infection and disease. Recent characterization of these virulence proteins and their host-cell targets is uncovering the molecular mechanisms of Salmonella pathogenesis and is revealing a picture of the atomic interface between this pathogen and its host. This level of analysis provides the possibility of designing novel therapeutics to disrupt infection and disease processes at the molecular level.


Thyroid gland responses to intermale aggression in an inherently aggressive wild rat.
The aim of the present investigation was to ascertain whether intermale aggression (by fighting) affects thyroid gland activity in wild rat. Following intermale aggression for three hours, thyro-follicular epithelial height was significantly decreased and colloidal content in follicular lumen increased only in the subordinate rats whereas the thyroid gland of the dominant rats was not perceptibly changed. Thus, aggression inhibits thyroid gland activity only in the subordinate rats. It is suggested that this effect may be due to psychosomatic rather than physical stress during aggression.


General procedure to aid the development of continuous pharmaceutical processes using multivariate statistical modeling - an industrial case study.
Streamlining the manufacturing process has been recognized as a key issue to reduce production costs and improve safety in pharmaceutical manufacturing. Although data available from earlier developmental stages are often sparse and unstructured, they can be very useful to improve the understanding about the process under development. In this paper, a general procedure is proposed for the application of latent variable statistical methods to support the development of new continuous processes in the presence of limited experimental data. The proposed procedure is tested on an industrial case study concerning the development of a continuous line for the manufacturing of paracetamol tablets. The main driving forces acting on the process are identified and ranked according to their importance in explaining the variability in the available data. This improves the understanding about the process by elucidating how different active pharmaceutical ingredient pretreatments, different formulation modes and different settings on the processing units affect the overall operation as well as the properties of the intermediate and final products. The results can be used as a starting point to perform a comprehensive and science-based quality risk assessment that help to define a robust control strategy, possibly enhanced with the integration of a design space for the continuous process at a later stage.


Upgrading of sea by-products: potential nutraceutical applications.
Since many years, numerous kinds of processes based on enzymatic hydrolysis at various pH, involving added plant or bacterial enzymes after inactivation by heating of endogenous enzymes present in the raw material or, alternatively, based on the action of endogenous enzymes, have contributed to the degradation of marine by-product proteins in order to produce fractions exerting biological activities. Peptides obtained by enzymatic hydrolysis of fish proteins exhibit not only nutritional but also biological properties of dietary uses, or even therapeutic potential. In this review, we have focused on the different enzymatic processes able to generate bioactive peptides from marine by-products and exerting high potential in nutraceutical applications to fight against important public health issues like obesity, stress, hypertension, and migraine. Beyond the nutraceutical and pharmaceutical aspects, this way of valorization is also included in the necessary development of by-product fishing industries for economic and ecological reasons in the worldwide context of marine resources depletion.


Developmental and behavior problems predict parenting stress in young children with global delay.
To identify parent-reported symptoms that predict parenting stress in preschoolers with global developmental delay, 201 parents/guardians of 142 boys and 59 girls with global delay, mean age 39.1 months (range, 18 to 63 months) were studied retrospectively. Parents completed the following: (a) a semistructured interview; (b) the Child Development Inventory, (c) Child Behavior Checklist 1½-5, and the (d) Parenting Stress Index-Short Form. Forty-two percent of parents described clinically significant parenting stress (≥ 85th percentile). The Parenting Stress Index-Short Form subscales Difficult Child and Parent-Child Dysfunctional Interactions were elevated. Parental stress increased with higher gross motor development and decreased as social and fine-motor ratios increased. Furthermore, stress increased when parents reported higher levels on the Emotionally Reactive and Withdrawn scale scores and when parents reported Pervasive Developmental and Oppositional Defiant Problems. In mobile children with global delay, behavior problems predict parenting stress.


Rapid method development for chiral separation in drug discovery using sample pooling and supercritical fluid chromatography-mass spectrometry.
A novel strategy for rapid chiral method development has been implemented using sample pooling and supercritical fluid chromatography-mass spectrometry (SFC-MS) on four chiral stationary phases, namely Chiralpak AD and AS, and Chiralcel OJ and OD, and eight different modifier concentrations (5 to 40% methanol-0.2% isopropylamine). The screening is performed under an outlet pressure of 110 bar at 35 degrees C, and at a flow-rate of 2.5 ml/min for the initial 20 min and then ramped up to 4 ml/min and held for 4.5 min to elute all solutes from the column. The entire process is fully automated from injection to data processing, and operates unattended for 15 h overnight to obtain optimal chiral separation for multiple compounds. A unique feature of using SFC-MS to monitor chiral synthesis is the negligible interferences from achiral impurities. In addition, with SFC-MS, enantiomeric excess can be determined with much lower detection limits than UV and much shorter analysis times compared to normal-phase/reversed-phase liquid chromatography.


Hepatoprotective phytocompounds from Cryptomeria japonica are potent modulators of inflammatory mediators.
Cryptomeria japonica is an important plantation conifer tree in Asia. This study aimed to characterize the anti-inflammatory and hepatoprotective activities of the phytocompounds from C. japonica wood on LPS- or TPA-induced activation of proinflammatory mediators and CCl(4)-induced acute liver injury in mice. A CJH7-2 fraction was purified from C. japonica extracts following bioactivity-guided fractionation, and it exhibited significant activities on inhibition of NO production and iNOS expression as well as up-regulating HO-1 expression in LPS-stimulated macrophages. CJH7-2 also potently inhibits COX-2 enzymatic activity (IC(50)=5 microg/mL) and TPA-induced COX-2 protein expression in mouse skin (1mg/200 microL/site). CJH7-2 (10 mg/kg BW) can prevent CCl(4)-induced liver injury and aminotransferases activities in mice. Chemical fingerprinting analysis showed that terpenes are the major bioactive compounds in the CJH7-2 fraction. This is the first study to demonstrate that chemical constituents from the wood extract of C. japonica possess anti-inflammatory activities in vitro and in vivo that may play a role in hepatoprotection.


Allogeneic transplantation for ALL in adults.
Allogeneic transplantation is an effective treatment for adult patients with high-risk ALL, including patients in first or second remission. Although only a few studies have evaluated the optimal transplant regimens, the data would suggest that a TBI-based regimen results in better disease control. Although not as potent as it is in other hematologic malignancies, the GVL effect is an important component of achieving cure of ALL. Because of the toxicity of the fully ablative regimen, reduced-intensity transplants are being explored in older patients with ALL when the prognosis is especially poor with standard chemotherapy.


Enriched sewage sludge from anaerobic pre-treatment in spurring valorization potential of black soldier fly larvae.
The valorization of sewage sludge by black soldier fly larvae (BSFL) has gained attentions for sewage sludge management since the sludge can be reduced securely as well as larval biomass can be used for biorefineries application. Nevertheless, the BSFL growth was impeded while assimilating nutrition from sewage sludge due to the presence of extracellular polymeric substances (EPS) that had entrapped the essential nutrients inside. Accordingly, the pre-treatment of sewage sludge via anaerobic digestion at different pH was employed in this work to rupture the EPS structure and release more nutrients for larval growth. The results showed that larvae fed with raw sewage sludge had attained the lowest final larval weight (2.05 ± 0.38 mg/larva) as opposed to batches fed with pre-treated sewage sludges. This was because the soluble carbohydrate (more than 6.81 ± 1.31 mg of glucose/g sewage sludge) in EPS was released after anaerobic pre-treatment, facilitating larval assimilation for growth. Furthermore, it was observed that further increasing of pH for sewage sludge pre-treatment had led to lower final larval weight gained due to the inhibitory effect stemming from ammonia production at higher pH. The anaerobic pre-treatment of sewage sludge being executed at pH 3 for 8 days had achieved the highest final larval weight at 7.34 ± 0.97 mg/larva. The still low quality of sewage sludges after the pre-treatment also offered benefit, where high sewage sludge reduction and waste reduction index were recorded due to the necessity of BSFL to consume more sewage sludge in compensating the nutrients destitution in sludge. Lastly, the possibility of predicting final larval weight was successfully materialized via a statistical model derived from the multiple linear regression method. The derived model incorporated the interactive parameters of anaerobic pre-treated pH and durations at various combinations could predict the final larval weight.


Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial.
Cerebral vasospasm remains a major source of morbidity after aneurysmal subarachnoid hemorrhage (SAH). We demonstrate that simvastatin reduces serum markers of brain injury and attenuates vasospasm after SAH. Patients with angiographically documented aneurysmal SAH were randomized within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n=19) or placebo (n=20) for 14 days. Plasma alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase were recorded weekly to evaluate laboratory evidence of hepatitis or myositis. Serum markers of brain injury were recorded daily. The primary end point of vasospasm was defined as clinical impression (delayed ischemic deficit not associated with rebleed, infection, or hydrocephalus) in the presence of > or =1 confirmatory radiographic test (angiography or transcranial Doppler demonstrating mean V(MCA) >160 m/sec). There were no significant differences in laboratory-defined transaminitis or myositis between groups. No patients developed clinical symptoms of myopathy or hepatitis. Plasma von Willebrand factor and S100beta were decreased 3 to 10 days after SAH (P<0.05) in patients receiving simvastatin versus placebo. Highest mean middle cerebral artery transcranial Doppler velocities were significantly lower in the simvastatin-treated group (103+/-41 versus 149+/-47; P<0.01). In addition, vasospasm was significantly reduced (P<0.05) in the simvastatin-treated group (5 of 19) compared with those who received placebo (12 of 20). The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit.


Synthesis and helical structure of lactam bridged BH3 peptides derived from pro-apoptotic Bcl-2 family proteins.
Protein-protein interactions within the Bcl-2 family are mediated by the helical BH3 domains of pro-apoptotic family members. To study the mechanism of this BH3 domain-protein interaction, a series of cyclic lactam bridged BH3 peptide analogues were synthesized by a novel combined Fmoc/tBu/Bzl protections strategy. These peptide analogues were studied by circular dichroism spectroscopy and found to adopt highly helical structure. These helical peptides stabilized by a lactam bridge serve as useful models to analyze the structure-function relationship of the pro-apoptotic BH3 domains. Furthermore, the synthetic method for lactam bridge incorporation reported here may find application in studies of other helical structures and development of helix mimics.


Algorithm for the diagnosis and management of asthma: a practice parameter update: Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology.
This algorithm on the diagnosis and treatment of asthma is intended to complement and update the previously published Practice Parameters for the Diagnosis and Treatment of Asthma. Both documents were developed by the Joint Task Force on Practice Parameters, representing the AAAAI, ACAAI, and the JCAAI. The authors of this asthma algorithm have attempted to include all the elements essential for the diagnosis and care of patients with asthma. Every effort was made to keep the algorithm clear and concise, yet thorough and complete (Fig 1). Each component of the algorithm is elaborated further in a brief annotation. For further discussion, the reader is referred to the more extensive Practice Parameters for the Diagnosis and Treatment of Asthma.


A comparison of blood, crystalloid and oxygenated crystalloid cardioplegia solutions on myoglobin and creatine kinase release following cardiac surgery.
Oxygenated crystalloid cardioplegia was found not to produce better cardioprotection than blood or crystalloid cardioplegia, as assessed by myoglobin and creatine kinase MB (CPK-MB) isoenzyme, in patients undergoing coronary artery surgery. Myoglobin and CPK-MB levels were found to peak at 1 and 3 h, respectively, following release of the aortic cross-clamp. There was a good correlation between peak myoglobin and CPK-MB levels. CPK-MB of non-cardiac origin was found to represent a substantial proportion of total CPK-MB 4 h after the release of the aortic cross-clamp.


Role of nuclear receptors in lung tumourigenesis.
Nuclear receptors are a family of ligand dependent transcription factors which have important roles in control of growth and differentiation in many cell types. This review will focus on the role of two members of this family (estrogen receptors and PPARgamma) in the initiation and progression of lung cancer. These receptors have been studied in other types of cancer, and the differences between findings in lung cancer and other malignancies will be discussed. We will also describe recent studies on the basic mechanisms of action of these receptors and suggest novel therapeutic targets. Specifically, there is emerging evidence that these receptors can induce gene expression through both ligand-dependent and ligand-independent pathways, and distinct families of genes are likely to be regulated depending on the mechanism of nuclear receptor signalling. These data suggest that a greater understanding of the basic biology and mechanisms of these receptors is required to develop specific pharmacological agents as therapeutics for cancer. Specifically, the development of selective agonists for these receptors, such as tamoxifen, may lead to more selective engagement of anti-tumourigenic pathways. In addition, combinatorial therapy using selective nuclear receptor activators in conjunction with the recently developed EGF receptor inhibitors (gefitinib, erlotinib) may sensitise cells which are unresponsive to the effects of EGF receptor inhibitors alone, providing powerful new therapeutic strategies.


Amplified effect of social vulnerability on health inequality regarding COVID-19 mortality in the USA: the mediating role of vaccination allocation.
Vaccination reduces the overall burden of COVID-19, while its allocation procedure may introduce additional health inequality, since populations characterized with certain social vulnerabilities have received less vaccination and been affected more by COVID-19. We used structural equation modeling to quantitatively evaluate the extent to which vaccination disparity would amplify health inequality, where it functioned as a mediator in the effect pathways from social vulnerabilities to COVID-19 mortality. We used USA nationwide county (n = 3112, 99% of the total) level data during 2021 in an ecological study design. Theme-specific rankings of social vulnerability index published by CDC (latest data of 2018, including socioeconomic status, household composition & disability, minority status & language, and housing type & transportation) were the exposure variables. Vaccination coverage rate (VCR) during 2021 published by CDC was the mediator variable, while COVID-19 case fatality rate (CFR) during 2021 published by John Hopkinson University, the outcome variable. Greater vulnerabilities in socioeconomic status, household composition & disability, and minority status & language were inversely associated with VCR, together explaining 11.3% of the variance of VCR. Greater vulnerabilities in socioeconomic status and household composition & disability were positively associated with CFR, while VCR was inversely associated with CFR, together explaining 10.4% of the variance of CFR. Our mediation analysis, based on the mid-year data (30th June 2021), found that 37.6% (mediation/total effect, 0.0014/0.0037), 10% (0.0003/0.0030) and 100% (0.0005/0.0005) of the effects in the pathways involving socioeconomic status, household composition & disability and minority status & language, respectively, were mediated by VCR. As a whole, the mediation effect significantly counted for 30.6% of COVID-19 CFR disparity. Such a mediation effect was seen throughout 2021, with proportions ranging from 12 to 32%. Allocation of COVID-19 vaccination in the USA during 2021 led to additional inequality with respect to COVID-19 mortality. Viable public health interventions should be taken to guarantee an equitable deployment of healthcare recourses across different population groups.


Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis.
Successful treatment of melanoma is still challenging, because metastasis remain chemoresistant and radioresistant. Accordingly, combinational treatments involving death ligands are mandatory. In a recent study from our lab, the majority out of 18 melanoma cell lines remained resistant against treatment with the death ligand TRAIL (tumor necrosis factor related apoptosis inducing ligand). Resistance was shown to be mainly due to incomplete processing of caspase-3 into catalytically inactive p21 by binding of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP). Co-irradiation with sub-lethal ultraviolet (UV) B caused depletion of XIAP resulting in synergistic sensitization of all but two melanoma cell lines to TRAIL. We show here the XIAP depletion to essentially require initial caspase-mediated cleavage, which promotes proteasomal degradation of XIAP. Utilizing specific caspase inhibitors and small interfering RNA-mediated knockdown, we further identified caspase-3 to be responsible for performing the initial cleavage of XIAP after UVB treatment. Additional evidence suggests an accelerated mitochondrial outer membrane permeabilization in response to co-treatment with TRAIL and UVB, which directs the release of XIAP antagonizing factors including Smac. Distraction of XIAP consequently liberates caspase-3 to autocatalytically process into active p17. Activated caspase-3 cleaves XIAP and further enhances its activation in a positive regulatory feedback loop. The molecular mechanism discovered here appears to have broader implications, because cleavage of XIAP was also shown to accompany cisplatin-induced sensitization of melanoma cells to TRAIL.


Amyloid deposition in immunoblastic lymphadenopathy.
Two cases of immunoblastic lymphadenopathy are reported that in addition to having the usual histologic and electron microscopic appearance previously described exhibit perivascular and intersitial green polarization when stained with Congo red, indicating amyloid deposition. Electron microscopic examination confirmed the light microscopic findings. This finding may have significance in regard to etiology, progression, and treatment of this disease entity.


Delamination cysts: a predictor of acetabular cartilage delamination in hips with a labral tear.
The treatment and prognosis of labral tears of the hip depend primarily on whether there is concomitant injury of the adjacent acetabular articular cartilage. We asked whether a delamination cyst on the preoperative plain radiographs correlated with delamination of the acetabular articular cartilage at the time of hip arthroscopy. We reviewed the preoperative radiographs of 125 consecutive hips that had a labral tear at hip arthroscopy for the presence of a delamination cyst. A delamination cyst was defined as an acetabular subchondral cyst either directly adjacent to a lateral acetabular cyst or in relation to a subchondral crack in the anterosuperior portion of the acetabulum. All patients with acetabular cartilage delamination at arthroscopy were identified. There were 16 patients with delamination cysts on radiographs and 15 patients with cartilage delamination at arthroscopy. A delamination cyst on the preoperative anteroposterior and/or frog lateral radiographs of the hip accurately predicted acetabular cartilage delamination, especially in hips with labral tears not caused by a major trauma. A delamination cyst is a previously unrecognized and novel radiographic sign that can preoperatively identify acetabular cartilage delamination in patients with labral tears, thereby facilitating the selection of the appropriate surgery and determining prognosis. Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.


Music therapy to promote movement from isolation to community in homeless veterans.
The U.S. Department of Veterans Affairs' Operation Stand Down has done much to address homeless needs among veterans. Gaining client trust is central to the effectiveness of the program. Music therapy has been found beneficial in moving individuals from isolation to community. We report our experience with participatory music therapy in Operation Stand Down and offer this as a legitimate intervention to enhance client participation.


QSPR-based prediction of air-water interfacial adsorption coefficients for nonionic PFAS with large headgroups.
Air-water interfacial adsorption has been demonstrated to be an important process affecting the retention and distribution of PFAS in soil, surface waters, and the atmosphere, as well as being central to certain remediation methods. Measured or estimated air-water interfacial adsorption coefficients are needed for quantifying and modeling the interfacial adsorption of PFAS. A single-descriptor QSPR model developed in prior work for predicting air-water interfacial adsorption coefficients of PFAS was demonstrated to successfully represent more than 60 different PFAS, comprising all headgroup types and a wide variety of tail structures. However, the model overpredicted values for nonionic PFAS with very large headgroups. A revised QSPR model was developed in the present study to predict air-water interfacial adsorption coefficients for nonionic PFAS with large headgroups. A two-descriptor QSPR model employing molar volume and headgroup-to-tail molar-volume ratio successfully represented measured data for both nonionic PFAS and nonionic hydrocarbon surfactants. This new model provides a means to produce estimates of air-water interfacial adsorption coefficients for nonionic PFAS for which measured values are typically not available.


Activation of the innate signaling molecule MAVS by bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death.
La Crosse virus (LACV), a zoonotic Bunyavirus, is a major cause of pediatric viral encephalitis in the United States. A hallmark of neurological diseases caused by LACV and other encephalitic viruses is the induction of neuronal cell death. Innate immune responses have been implicated in neuronal damage, but no mechanism has been elucidated. By using in vitro studies in primary neurons and in vivo studies in mice, we have shown that LACV infection induced the RNA helicase, RIG-I, and mitochondrial antiviral signaling protein (MAVS) signaling pathway, resulting in upregulation of the sterile alpha and TIR-containing motif 1 (SARM1), an adaptor molecule that we found to be directly involved in neuronal damage. SARM1-mediated cell death was associated with induced oxidative stress response and mitochondrial damage. These studies provide an innate-immune signaling mechanism for virus-induced neuronal death and reveal potential targets for development of therapeutics to treat encephalitic viral infections.


Phenolic content, antioxidant activity and effective compounds of kumquat extracted by different solvents.
The total phenolic and flavonoid content of extracts from peel of kumquat were higher than those from pulp, and those extracted from immature kumquat were higher than those from mature kumquat. The highest levels of phenolic and flavonoid content were obtained in hot water extracts. The flavonoids of kumquat extracted from hot water were mainly soluble conjugated compounds, including C-glycosides, such as 3',5'-di-C-β-glucopyranosylphloretin (DGPP), acacetin 8-C-neohesperidoside (margaritene), acacetin 6-C-neohesperidoside (isomargaritene), apigenin 8-C-neohesperidoside, and O-glycosides, such as acacetin 7-O-neohesperidoside (fortunellin), isosakuranetin 7-O-neohesperidoside (poncirin) and apigenin 7-O-neohesperidoside (rhoifolin). A positive relationship existed between total phenolic content and DPPH scavenging potency (p<0.001). Total flavonoid content showed a similar correlation (p<0.001) to DPPH scavenging potency. The effective flavonoids contributing to antioxidant activity were DGPP and apigenin 8-C-neohesperidoside, which could be extracted in high amounts, by hot water at 90°C, from immature kumquat peel.


Current Therapeutic Management of Perinatal Stroke with a Focus on the Upper Limb: A Cross-Sectional Survey of UK Physiotherapists and Occupational Therapists.
To determine current UK pediatric physiotherapist (PT) and occupational therapist (OT) management of perinatal stroke. Web-based cross-sectional survey. Participants were members of the Association of Paediatric Chartered Physiotherapists and Occupational Therapists specialist section: children young people and families working with infants. Items covered prioritization of referrals, assessments, therapy approaches aimed at the upper limb, and parental support. 179 therapists responded. 87.2% of PTs and 63.0% of OTs managed infants with perinatal stroke. Infants with clinical signs of motor dysfunction at referral were prioritized for early initial assessment. The most frequently used assessments were the Alberta Infant Motor Scale (AIMS) and Bayley Scales of Infant Development (BSID). Of PTs and OTs, 41.9 and 40.0% used no standardized assessments. Frequently used therapy interventions were Bobath/Neurodevelopmental Therapy (NDT), positioning aids and passive movements. 88.1% of therapists would choose a bilateral rather than unilateral (affected side) therapy approach for infants with perinatal stroke aged up to 6 months. Of PTs and OTs, 56.9 and 57.1% provided psychological support to families. Assessment and provision of therapy services following perinatal stroke is variable. Increased use of standardized assessments and centralized data collection regarding service provision for high-risk infants is recommended.


The predictive value of global longitudinal strain in patients with heart failure mid-range ejection fraction.
Heart failure (HF) with mid-range ejection fraction (HFmrEF) is defined as HF with a left ventricular (LV) ejection fraction (LVEF) of 41-49%. However, the change in LV function and the subsequent prognosis in these patients remain unclear. We aimed to investigate whether LV global longitudinal strain (LV GLS) could differentiate the changes in LVEF and predict the clinical outcomes in patients with HFmrEF. According to the changes in LVEF on follow-up echocardiography, 273 outpatients with HFmrEF were divided into 3 groups: HFwEF (HF with worse EF: <40%), HFsEF (HF with similar EF: 40-49%), and HFrecEF (HF with recovered EF: >50%). Further, the LV GLS at diagnosis was evaluated. The average follow-up duration was 31 months. Among patients with HFmrEF, the more impaired the LV GLS at baseline, the higher probability of HFwEF development. In comparison with patients with HFwEF and HFsEF, those with HFrecEF had a lower risk of hospitalization for HF. At a cut-off value of -11%, LV GLS differentiated the subsequent risk of cardiovascular death in patients with HFmrEF. In Cox regression, patients with LV GLS >-11% had a high risk of cardiovascular death. In patients with HFmrEF, LV GLS is associated with LVEF changes and subsequent cardiovascular death. Patients with HFrecEF had a lower risk of hospitalization for HF.


FKBP5 risk alleles and the development of intrusive memories.
Intrusive memories are unwanted recollections that maintain distress and are central to numerous psychological disorders, including posttraumatic stress disorder (PTSD). Convergent evidence suggests that glucocorticoid increases enhance the strength of emotional memories. The FKBP5 polymorphism modulates glucocorticoid receptor sensitivity, and has been shown to increase risk for PTSD. Healthy high and low risk FKBP5 allele carriers (N=46) underwent a cold pressor task, and then viewed negative and neutral images. Two days later participants were given a surprise recall test and measure of intrusive memories of the images. Following the cold pressor task, high-risk allele participants had a higher cortisol response than low-risk participants. High-risk carriers also reported more intrusive memories of the negative and neutral images than low-risk carriers. These findings point to the minor alleles of the FKBP5 polymorphism being a risk factor for development of intrusive memories, possibly as a result of impaired glucocorticoid receptor sensitivity. This may explain one mechanism for FKBP5 being a risk factor for PTSD following traumatic events.


An unusual form of spondyloepiphyseal dysplasia, with advanced carpal and spinal end-plate ossification mimicking COMP-mutation-like multiple epiphyseal dysplasia.
We present a child with irregular ossification of tubular bone epiphyses, short bones, and spine. The radiographic evolution of bones undergoing endochondral ossification was followed from the age of 1 year 9 months to 6 years. The unusual features demonstrated in this child made classification difficult: pseudoachondroplasia was excluded because no mutations of the COMP gene were found. Considering the evolution of the radiographic appearances, the most likely diagnosis would seem to be an unusual form of spondyloepiphyseal dysplasia, mimicking some aspects of multiple epiphyseal dysplasia. Endochondral ossification was diffusely altered with a mixture of epiphyseal ossification delay associated with acceleration and early fusion. This case was a unique presentation within the family, suggesting a mutation in the affected child.


A Case of Spontaneous Intracranial Hypotension: The Role of Dynamic CT Myelography and Epidural Blood Patch in Diagnosis and Treatment.
Spontaneous intracranial hypotension (SIH) most commonly results from cerebrospinal fluid (CSF) leaks in the upper spinal canal. Alterations in the equilibrium between the volumes of intracranial blood and CSF lead to compensatory dilatation of the vascular spaces, mostly on the venous side. Dynamic computerized tomogram (CT) myelography can be very helpful in diagnosing the site of a CSF leak in the spinal canal. Subsequently, the site of the leak can be sealed with epidural blood patch (EBP).


A Convoluted Picture of Diabetic Myonecrosis.
A patient with well-controlled type 2 diabetes was found to have diabetic myonecrosis, a rare condition associated with poorly controlled type 2 diabetes. Diagnosis was masked by concern for lumbosacral plexopathy from a history of spinal cord infarct. A 49-year-old African American woman with type 2 diabetes and paraplegia secondary to spinal cord infarct presented to the emergency department with left leg swelling and weakness from her hip to toes. Hemoglobin A1c was 6.0%, and there was no leukocytosis or elevated inflammatory markers. Computed tomography showed evidence of infectious process or possible diabetic myonecrosis. Recent reviews show fewer than 200 reports of diabetic myonecrosis since first described in 1965. It typically is seen in poorly controlled types 1 and 2 diabetes, with average hemoglobin A1c of 9.34% at time of diagnosis. Diabetic myonecrosis should be considered in diabetic patients with unexplained swelling and pain - particularly in the thigh - even with unremarkable lab values.


Role of long-term stenting in treatment of pediatric subglottic stenosis.
Twelve cases of childhood subglottic stenosis diagnosed either acquired or congenital were treated using an endolaryngotracheal Montgomery T-tube. Stenting lasted on average 5.6 months. Tracheotomy closure was possible in 75% of cases on average 15.3 months after diagnosis. Tube-linked complications involved the child pulling out, forward migration of the tube out, lower tracheal migration of the tube, clogging and the formation of granulation tissue at its superior extremity. Comparison of outcomes with those for laryngeal surgery (cricoid split, laryngotracheal reconstruction) found in the literature, suggests that long-term T-tube stenting is the optimal treatment for subglottic stenosis where tracheomalacia precludes laryngeal surgery.


Effects of diesel exhaust inhalation on heart rate variability in human volunteers.
Particulate matter (PM) air pollution is associated with alterations in cardiac conductance and sudden cardiac death in epidemiological studies. Traffic-related air pollutants, including diesel exhaust (DE) may be at least partly responsible for these effects. In this experimental study we assessed whether short-term exposure to DE would result in alterations in heart rate variability (HRV), a non-invasive measure of autonomic control of the heart. In a double-blind, crossover, controlled-exposure study, 16 adult volunteers were exposed (at rest) in randomized order to filtered air (FA) and two levels of diluted DE (100 or 200 microg/m(3) of fine particulate matter) in 2-h sessions. Before, and at four time points after each exposure we assessed HRV. HRV parameters assessed included both time domain statistics (standard deviation of N-N intervals (SDNN), and the square root of the mean of the sum of squared differences between successive N-N intervals (RMSSD)) and frequency domain statistics (high-frequency (HF) power, low-frequency (LF) power, and the LF/HF ratio). We observed an effect at 3-h after initiation of DE inhalation on the frequency domain statistics of HRV. DE at 200 microg/m(3) elicited an increase in HF power compared to FA (Delta=0.33; 95% CI: 0.01-0.7) and a decrease in LF/HF ratio (Delta=-0.74; 95% CI: -1.2 to -0.2). The effect of DE on HF power was not consistent among study participants. There was no DE effect on time domain statistics and no significant DE effect on HRV in later time points. We did not observe a consistent DE effect on the autonomic control of the heart in a controlled-exposure experiment in young participants. Efforts are warranted to understand discrepancies between epidemiological and experimental studies of air pollution's impact on HRV.


Mass spectrometry based translational proteomics for biomarker discovery and application in colorectal cancer.
Colorectal cancer (CRC) is a leading cause of cancer-related death in the world. Clinically, early detection of the disease is the most effective approach to tackle this tough challenge. Discovery and development of reliable and effective diagnostic tools for the assessment of prognosis and prediction of response to drug therapy are urgently needed for personalized therapies and better treatment outcomes. Among many ongoing efforts in search for potential CRC biomarkers, MS-based translational proteomics provides a unique opportunity for the discovery and application of protein biomarkers toward better CRC early detection and treatment. This review updates most recent studies that use preclinical models and clinical materials for the identification of CRC-related protein markers. Some new advances in the development of CRC protein markers such as CRC stem cell related protein markers, SRM/MRM-MS and MS cytometry approaches are also discussed in order to address future directions and challenges from bench translational research to bedside clinical application of CRC biomarkers.


Demographic and clinical characteristics of a Spanish population of people living with type 1 diabetes who practice nonprofessional sports: The DIABESPORT survey.
To determine the characteristics of people with type 1 diabetes mellitus (T1D) who practice sports, the support they receive, and the way in which they manage their disease during sports. An observational cross-sectional study designed as a web-based survey released through social media was carried out, directed to physically active people with T1D. A total of 342 subjects completed the survey (16 children; 67.5% males). The duration of living with T1D was 18.6 ± 11.4 years. The mean glycosylated hemoglobin concentration (HbA1c) was 6.7 ± 0.8%, and the mean time in range (TIR) was 72.9 ± 15.8%. Only 27.2% started sports activity following the diagnosis of T1D. The most frequently used basal insulin was insulin degludec (38.6%). The usual treatment modification before doing sports consisted of bolus reduction (42.5%) or only the adjustment of nutritional supplements (19.7%). In cases of long-acting insulin users, the basal dose usually remained unchanged during sports. One-quarter of the participants were insulin pump users, and of these, 12.5% always disconnected the pump during physical activities. Severe hypoglycemia on the day of physical activity was experienced by 5% of the participants in the last 6 months. One-third reported a lack of support from their physician, and 61% had learned to manage glycemic control during sports by themselves. This study highlights the adjustments made by people living with T1D during sports practice, and the lack of support received from healthcare professionals.


Facile nitrogen doping in fungal hyphae-derived biochars via cooperation of microbial culture and pyrolysis for efficient catalytic reduction of 4-nitrophenol.
Manipulating the elemental composition is one major strategy to tune the properties of biochars to endow different functions to meet various application requirements. Compared with the widely reported plants- and manure-based precursors for biochars, microbes-based precursors take the lead in regional independency, rapid growth, morphology uniformity and abundant species with different adjustable elemental composition. In this work, fungal hyphae with massive microtubule structure were selected as a typical microbe precursor to prepare biochars whose catalysis capability was further evaluated by a representative reduction reaction of 4-nitrophenol (4-NP) using sodium borohydride as reductant. By simply increasing the nitrogen concentration in the culturing medium, the fungal hyphae derived biochars with increased nitrogen contents (2.1 wt% → 4.3 wt%) were successfully obtained after pyrolysis, showing almost two times higher catalysis ability (4.75 × 10-2 s-1 → 7.26 × 10-2 s-1) towards 4-nitrophenol. The Arrhenius equation calculation further proved that the more doping of nitrogen would increase the active sites rather than altering the reaction pathway. A high surface area of 997 m2 g-1 at pyrolysis temperature of 800 °C was obtained resulting from the fine microstructure of fungal hyphae. Higher pyrolysis temperature derived biochars remarkably promote their catalysis ability. These results indicated that biochars with controllable nitrogen contents can be prepared by cooperating culturing and pyrolysis processes, which pointed out an easy, rapid, scalable, and promising way to synthesis biochars with tunable functions for different applications.


The role of the clinical microbiology laboratory in solid organ transplantation programs.
Infections remain a major complication of solid organ transplantation. For this reason, the clinical microbiology laboratory plays a key role in the success of transplant programs, which must have the support of a qualified laboratory, both technically and professionally. Transplant programs strongly condition the structure and functionality of microbiology laboratories, but at the same time, benefit greatly from the knowledge generated from these programs. The laboratory must make a special effort to implement rapid methods that can respond to the broad spectrum of potential pathogens in solid organ transplant patients. The integration of microbiologists in multidisciplinary teams is highly recommended, as only then can they obtain the highest quality and efficiency in the diagnostic process. This article provides an updated review of the techniques to be used once transplantation has occurred. The role of the microbiologist is also crucial in the pretransplant period, as good microbiological candidate evaluation at this time strongly conditions the success of the transplantation program.


The reinnervation of the tongue and salivary glands after lingual nerve injuries in cats.
The recovery of fibres in the chorda tympani and lingual nerves has been investigated in cats following nerve injury by recording the receptor properties of gustatory, thermosensitive and mechanosensitive units and the return of vasomotor and secretomotor responses. The combined trunk of the chorda tympani and lingual nerves was either crushed (4 animals) or sectioned (3 animals) unilaterally and recovery allowed for 12 weeks. After nerve crush, integrated whole nerve activity recorded from the chorda tympani during stimulation of the tongue with gustatory or thermal stimuli revealed a response profile which was similar to controls. After nerve section little or no activity could be recorded. Recordings made from 52 single units in the chorda tympani after nerve crush revealed that the proportions of gustatory, thermosensitive and mechanosensitive units were similar to those of controls. The units had slower conduction velocities, responded less vigorously and to a narrower range of stimuli. Recordings made from 46 units in the chorda tympani after nerve section revealed very few gustatory or thermosensitive units, the majority were purely mechanosensitive and the decrease in conduction velocity was greater than after nerve crush. Electrical stimulation of efferent vasodilator fibres in both the chorda tympani and lingual nerves, evoked a temperature rise on the dorsal surface of the tongue. This effect was completely restored after nerve crush but was significantly smaller after nerve section. The flow rate of saliva from the submandibular salivary gland was not significantly changed by nerve crush but was significantly smaller after nerve section. There was no evidence for functional reinnervation of gustatory or secretomotor terminals by inappropriate fibre types.


Effect of household size on nutritional patterns among the Dutch elderly.
Elderly persons are vulnerable to nutritional risks. Factors such as living alone make the elderly prone to poor nutritional status as a result of inadequate diets. The results of a Dutch national nutrition survey of food consumption and nutritional status among 539 independently living, apparently healthy elderly persons, aged 65 to 79 years, show that in general the intake of macronutrients deviates from the Dutch recommendations. In particular, saturated fat intake and P:S ratio were unfavorable, especially for the solitary elderly persons (saturated fat intake 19.0 +/- 3.2% and 17.7 +/- 3.3% total energy for men and women, respectively). Except for vitamin B-6 (about 92% of the recommendation on a group level for men and 78% for women), the intake of micronutrients studied is considered to be adequate. Elderly women living alone had a higher calcium:phosphorus ratio (0.76 +/- 0.12), lower meat consumption (90 +/- 31 gm), and a lower mean HDL-cholesterol concentration (1.22 +/- 0.28 mmol/L) in serum than non-solitary elderly women (Ca:P ratio 0.73 +/- 0.12, meat consumption 100 +/- 36 gm, HDL-cholesterol concentration 1.45 +/- 0.38 mmol/L). Potatoes, vegetables, and meat were more often prepared for more than one day at a time by elderly persons living alone than by the non-solitary elderly.


Breast cancer during pregnancy: a mini-review.
As modern women delay childbearing, pregnancy-associated breast cancer (PABC) becomes a more frequent problem faced by oncologists, gynecologists, and obstetricians alike. However, no evidence exists concerning the management of this condition. We summarized the current literature regarding epidemiology, pathology, diagnosis, treatment and prognosis of PABC. Data were collected by searching PubMed and Medline for the period from 1950 to 2007. There are no randomized controlled trials regarding PABC management. Current evidence suggests that diagnosis may be carried out with limitations regarding staging; surgical treatment may be performed as for the non-pregnant women. Radiotherapy and endocrine therapy are contraindicated during pregnancy, while chemotherapy is allowed after the first trimester. Prognosis is considered poor. Subsequent pregnancy is allowed only 2 years after completing treatment. Due to lack of prospective randomized controlled clinical studies, both ongoing studies and future evidence are expected to solve problems related to breast cancer management during pregnancy.


Personality assessment and insurance reimbursement.
A contract between APA and OCHAMPUS has committed APA to developing a national peer review capability for the review of out-patient psychological services. This paper describes the review criteria which apply to personality assessment and psychological testing.


Green synthesis and optimization of nano-magnetite using Persicaria bistorta root extract and its application for rosewater distillation wastewater treatment.
The aim of this research is to synthesize magnetite nanoparticles, using Persicaria bistorta root extract as the reducing agent, and to test its adsorption properties in the treatment of rosewater distillation wastewater. Taking advantage of Taguchi method, effect of synthesis parameters, including molar concentration of FeCl2, concentration of plant extract, temperature, and pH on crystallite size and magnetization strength is studied. Based on the successful synthesis of magnetite nanoparticles and characterization experiments, Persicaria bistorta root extract can be considered as a proper alternative as the reducing agent. Data analysis shows that crystallite size and magnetization are positively correlated with concentration of FeCl2 and pH, while inversely related to temperature and independent of plant extract concentration. The optimum values achieved for concentration of FeCl2, temperature, and pH are 0.15 M, 70 °C, and 11, respectively, with the production of nanoparticles with magnetite size of 45.5 nm and magnetization value of 62.5 emu/g. In addition, the application of as-synthesized magnetite nanoparticles as an adsorbent for treatment of rosewater distillation wastewater proved its high adsorption capacity for chemical oxygen demand (COD) up to 149 mg/g. Adsorption data also shows a good fitness with Langmuir and Freundlich isotherm models.


Thiadiazine-thione derivatives ameliorate STZ-induced diabetic neuropathy by regulating insulin and neuroinflammatory signaling.
Diabetes Mellitus is accompanied by chronic hyperglycemia, inflammation, and related molecular processes, which leads to diabetic neuropathy. In this work, we tested Thiadiazine-thione (TDT) synthetic derivatives TDT1 and TDT2 against streptozotocin (STZ)-induced diabetic neuropathy. Sprague Dawley's rats, SH-SY5Y neuronal and BV2 microglial cells were employed in this work, followed by behavioral, biochemical, and morphological studies utilizing RT-qPCR, ELISA, Immunoblotting, immunohistochemistry, Immunofluorescence, and in silico analyses. TDT1 and TDT2 abolished STZ-induced allodynia and hyperalgesia. Next, we examined IRS1/PI3K/AKT signaling to assess TDT1 and TDT2's impact on diabetic neuropathy. STZ downregulated IRS1, PI3K, AKT mRNA and protein expression in rat spinal cord and SH-SY5Y neuronal cells. TDT1 and TDT2 improved IRS1, PI3k, and AKT mRNA and protein expression. STZ elevated GSK3β mRNA and protein expression in vivo and in vitro, whereas TDT1 and TDT2 mitigated it. STZ increased the expression of inflammatory mediators such as p-NF-κB, TNF-α, and COX-2 in rat spinal cord lysates. TDT1 and TDT2 co-treatment with STZ decreased inflammatory cytokine expression by ameliorating astrocytosis (revealed by increased GFAP) and microgliosis (indicated by increased Iba1). TDT1 and TDT2 reduced STZ-induced JNK, Iba1, and COX-2 upregulation in BV2 microglial cells validating our in vivo findings. In silico molecular docking and MD simulations analyses suggested that TDT1 and TDT2 have IRS binding affinity, however, both compounds had an identical binding affinity, but distinct interaction pattern with IRS protein residues. Overall, these findings demonstrate that TDT derivatives mitigated STZ-induced neuropathy through modulating the insulin and inflammatory signaling pathways.


The VCS parameters: Potential hematological indicators for predicting antituberculosis drug-induced neutropenia.
The morphological changes in activated neutrophils associated with antituberculosis drugs can be measured by volume, conductivity, and scatter (VCS) technology on the Coulter LH750 hematology analyzer. We conducted the current study to further validate the clinical usefulness of the neutrophil VCS parameters in predicting drug-induced neutropenia. Peripheral blood samples were collected from 52 patients with drug-induced neutropenia, 309 patients without any abnormal CBC, and 237 healthy controls. The mean neutrophil volume (MNV) with its distribution width (NDW) and the mean neutrophil scatter (MNS) were studied. We observed a significant increase in the MNV and NDW as well as a significant decrease in the MNS in neutropenia patients approximately one week prior to development of neutropenia compared to healthy controls as well as to case controls. In addition, the delta MNV and delta MNS were respectively correlated well with delta absolute neutrophil counts when neutropenia occurred. The ROC curve analyses showed that the MNV、NDW and MNS had larger areas under curves compared to conventional parameters. With a cutoff of 150.15 for the MNV, a sensitivity of 84.4% and specificity of 75.7% were achieved prior to neutropenia. The neutrophil VCS parameters may be clinically useful as potential hematological indicators for predicting antituberculosis drug-induced neutropenia.


Psyllium is a natural nonfermented gel-forming fiber that is effective for weight loss: A comprehensive review and meta-analysis.
Psyllium is a natural, predominantly soluble fiber that forms a viscous gel when hydrated and is not digested or fermented. In the small intestine, psyllium gel increases chyme viscosity, slowing the degradation and absorption of nutrients. Psyllium has a significant effect in patients with metabolic syndrome and type-2 diabetes on glycemic control, while lowering serum cholesterol in hypercholesterolemic patients. Some randomized controlled studies have shown that psyllium also facilitates weight loss in overweight and obese participants. A comprehensive review and meta-analysis assessing psyllium's impact on body weight, body mass index (BMI), and waist circumference in overweight and obese participants. A comprehensive search was performed (Medline, Scopus, Cochrane Database) through March 21, 2022, using search terms to identify randomized, controlled, clinical studies designed to assess weight loss in overweight and obese participants over at least 2 months. Data were analyzed using the inverse variance method with random effects models. Six studies meeting inclusion criteria were identified (total n = 354). The meta-analysis showed that psyllium, dosed just before meals (mean dose 10.8 g/day, mean duration 4.8 months), was effective for decreasing body weight (MD = -2.1 kg [95% confidence interval [CI]: -2.6 to -1.6]; p < .001), BMI (MD = -0.8 kg/m 2 [95% CI: -1.0 to -0.6]; p < .001) and waist circumference (MD = -2.2 cm [95% CI: -2.9 to -1.4]; p < .001) in overweight and obese populations. Gel-forming nonfermented psyllium fiber, dosed just before meals, is effective in facilitating weight loss in overweight and obese participants.


Reducing Neuronal Networks to Discrete Dynamics.
We consider a general class of purely inhibitory and excitatory-inhibitory neuronal networks, with a general class of network architectures, and characterize the complex firing patterns that emerge. Our strategy for studying these networks is to first reduce them to a discrete model. In the discrete model, each neuron is represented as a finite number of states and there are rules for how a neuron transitions from one state to another. In this paper, we rigorously demonstrate that the continuous neuronal model can be reduced to the discrete model if the intrinsic and synaptic properties of the cells are chosen appropriately. In a companion paper [1], we analyze the discrete model.


Are noise and air pollution related to the incidence of dementia? A cohort study in London, England.
To investigate whether the incidence of dementia is related to residential levels of air and noise pollution in London. Retrospective cohort study using primary care data. 75 Greater London practices. 130 978 adults aged 50-79 years registered with their general practices on 1 January 2005, with no recorded history of dementia or care home residence. A first recorded diagnosis of dementia and, where specified, subgroups of Alzheimer's disease and vascular dementia during 2005-2013. The average annual concentrations during 2004 of nitrogen dioxide (NO2), particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5) and ozone (O3) were estimated at 20×20 m resolution from dispersion models. Traffic intensity, distance from major road and night-time noise levels (Lnight) were estimated at the postcode level. All exposure measures were linked anonymously to clinical data via residential postcode. HRs from Cox models were adjusted for age, sex, ethnicity, smoking and body mass index, with further adjustments explored for area deprivation and comorbidity. 2181 subjects (1.7%) received an incident diagnosis of dementia (39% mentioning Alzheimer's disease, 29% vascular dementia). There was a positive exposure response relationship between dementia and all measures of air pollution except O3, which was not readily explained by further adjustment. Adults living in areas with the highest fifth of NO2 concentration (>41.5 µg/m3) versus the lowest fifth (<31.9 µg/m3) were at a higher risk of dementia (HR=1.40, 95% CI 1.12 to 1.74). Increases in dementia risk were also observed with PM2.5, PM2.5 specifically from primary traffic sources only and Lnight, but only NO2 and PM2.5 remained statistically significant in multipollutant models. Associations were more consistent for Alzheimer's disease than vascular dementia. We have found evidence of a positive association between residential levels of air pollution across London and being diagnosed with dementia, which is unexplained by known confounding factors.


Classification of Marek's disease viruses according to pathotype: philosophy and methodology.
The concept of pathotype in Marek's disease (MD) probably dates from the recognition of a more virulent form of the disease in the late 1950s (Benton & Cover, 1957). Distinctions between MD virus strains were further expanded with the description of the vv pathotype in the early 1980s and of the vv+ pathotype in the 1990s. Pathotype designations reflect important biological properties that correlate with the break-through of vaccinal immunity in the field. However, pathotyping methods applied by various laboratories have not been uniform, preventing critical comparison of results. Better uniformity of pathotyping procedures is desirable.The Avian Disease and Oncology Laboratory (ADOL) method is based on induction of lymphoproliferative lesions in vaccinated chickens. This method has been used to pathotype more than 45 isolates and is the basis for the current pathotype classification of MD virus strains. Its limitations include requirements for a specific type of chickens (15x7 ab+), large numbers of animals, and a statistical method to compare lesion responses to those of JM/102W and Md5 control strains. Because of these limitations, it has not been and is not likely to be used in other laboratories. Comparability in pathotyping can be improved by the comparison of field isolates with standard prototype strains such as JM/102W, Md5 and 648A (American Type Culture Collection) or their equivalents. Data may be generated by different in vivo procedures that measure tumour induction, neurological disease (both neoplastic and non-neoplastic lesions), or solely non-neoplastic criteria (such as lymphoid organ weights or virus replication). Methods based on neoplastic criteria, especially when generated in MD-immunized chickens, will probably correlate most closely with that of the ADOL method and be most relevant to evolution of MD virus in the field. Based on data from several trials, a modification of the ADOL method that utilizes fewer chickens and can be conducted with commercial specific pathogen free strains is proposed. The modified method is based on "best fit" comparisons with prototype strains, and is expected to provide results generally comparable with the original method. A variety of other alternative criteria (see earlier) are also evaluated both for primary pathotyping and as adjuncts to other pathotyping methods. Advantages and disadvantages of alternative methods are presented.