Hemostatic imbalances produced by plasma exchange.
Ten patients who underwent intensive therapeutic plasma exchange were studied prospectively to determine the nature and extent of changes induced in their coagulation mechanisms. The patients' plasma was replaced with serum albumin and normal saline. Significant changes were noted acutely in the prothrombin time, activated partial thromboplastin time, plasma fibrinogen, and platelet counts. Chronically, significant decreases were found in plasma fibrinogen concentrations and platelet counts. Intensive plasma exchange with fluids devoid of coagulation factors results in defects in the normal hemostatic mechanism.


The TRIM14 PRYSPRY domain mediates protein interaction via its basic interface.
Tripartite motif (TRIM)14 was recently shown to be an important molecule against pathogens. Its PRYSPRY domain acts as a protein-protein interaction module. TRIM14 exerts distinct functions via its PRYSPRY domain by interacting with different partners. However, the structural basis for its binding specificity remains unknown. Here we solved the crystal structure of the TRIM14 PRYSPRY domain, and found a positively charged surface that may mediate its partner specificity. Isothermal titration calorimetry reveals that the TRIM14 PRYSPRY domain binds to acidic peptides, and the analysis of the reported partners of TRIM14 is consistent with our assumption. Therefore, we demonstrate that the PRYSPRY domain of TRIM14 harbors a putative basic interface that may favorably bind to acidic amino acid residues.


Fibrodysplasia ossificans progressiva (FOP) presenting as a rapidly growing non-calcified neck mass.
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare autosomal dominant inherited disorder leading to mature ossification within soft tissues. We report a 62-year-old female with a 3-week history of a rapidly enlarging left neck mass with no associated symptoms. A neck CT showed a ~10 cm solid-appearing non-calcified left neck mass that markedly decreased in size on a one-month follow-up neck MRI, but with new extensive edema/intense enhancement in floor of the mouth. Prior radiographs documented hallux valgus and heterotopic ossification of the psoas/paraspinal muscles and shoulder girdle. In this case of FOP, no intervention was implemented and the symptoms improved over time and thus paralleled other such cases for flare-ups. Clinicians should be aware of this rare entity, as it is frequently misdiagnosed as cancer or other benign entities such as infection, resulting in biopsies that can often hasten disease progression.


Effects of long-term use of antiretroviral therapy on the prevalence of oral Epstein-Barr virus.
The objectives of this study were to determine (i) the prevalence of oral Epstein-Barr virus (EBV) in HIV-infected subjects compared to non-HIV controls and (ii) the effects of long-term use of antiretroviral therapy (ART) on the prevalence of oral EBV. A cross-sectional study was performed in HIV-infected subjects with and without ART, and non-HIV individuals. DNA in saliva samples was extracted and used as a template to detect EBV BamH1W and EBNA1 by quantitative polymerase chain reaction. Student t-test and ANOVA test were performed to determine the prevalence rates among groups. Forty-nine HIV-infected subjects: 37 on ART (age range 23-54 year, mean 37 year), 12 not on ART (age range 20-40 year, mean 31 year), and 20 non-HIV controls (age range 19-53 year, mean 31 year) were enrolled. The numbers of EBV BamH1W in saliva were found to be significantly higher in HIV-infected subjects than non-HIV controls (80% vs. 20%, mean = 12118 vs. 134 copies/10(5) cells, P < 0.001). HIV-infected subjects who were on ART had significantly lower numbers of EBV BamH1W than those who were not (mean = 4102 vs. 138613 copies/10(5) cells, P = 0.011). The numbers were significantly lower in those who received long-term ART compared with short-term (mean = 1401 vs. 11124 copies/10(5) cells, P = 0.034). No significant difference was observed between the groups when using EBNA1 primers. Prevalence of oral EBV was significantly higher in HIV-infected subjects than non-HIV-controls. The numbers of the virus were significantly decreased by ART. Long-term use of ART did not increase oral EBV.


131I therapy using rhTSH stimulation and dosimetry in metastatic malignant struma ovarii.
A 38-year-old woman with metastatic malignant struma ovarii, including massive liver metastases and retroperitoneal lymphadenopathy, underwent ovarian resection and retroperitoneal lymph nodes excision, partial hepatectomy, and radiofrequency ablation for liver metastases. She underwent thyroidectomy and received three I treatments using recombinant human thyrotropin stimulation and radioiodine dosimetry. posttherapy I imaging, anatomic images, and thyroglobulin levels showed significant diminution in the tumor burdens and remarkable decline in thyroglobulin levels. This case provided valuable information on recombinant human thyrotropin-assisted I ablation in conjunction with dosimetry in an unusual presentation of iodine-avid malignant struma ovarii with bulky metastases.


[Expression of Bcl-2 protein and the amplification of c-myc gene in patients with chronic myeloid leukemia].
Chronic myeloid leukemia (CML) represents a malignant myeloproliferative disease developed out of pluripotent hematopoietic stem cell that contains the fusion bcr-abl gene. Disorders that occur in the process of apoptosis represent one of the possible molecular mechanisms that bring about the disease progress. The aim of our study was to carry out the analysis of the presence of the amplification of the c-myc oncogene, as well as the analysis of the changes in the expression of Bcl-2 in the patients with CML. Our study included 25 patients with CML (18 in chronic phase, 7 in blast transformation). Using an immunohistochemical alkaline phosphatase-anti-alkaline phosphatase (APAAP) method, we analyzed the expression of cell death protein in the mononuclear bone marrow cells of 25 CML patients. By a differential PCR (polymerase chain reaction) method, we followed the presence of amplified c-myc gene in mononuclear peripheral blood cells. The level of the expression of Bcl-2 protein was considerably higher in the bone marrow samples of the patients undergoing blast transformation of the disease. The amplification of c-myc gene was detected in 30% of the patients in blast transformation of the disease. The expression of Bcl-2 protein and the amplification of c-myc gene are in correlation with the disease progression.


Management of Persistent SARS-CoV-2 Infection in Patients with Follicular Lymphoma.
There is no consensus on the management of the coronavirus disease (COVID-19) in patients with secondary immunosuppression due to either an underlying hematological disease or to the effects of immunochemotherapy (ICT). Some of them may present persistent infection with multiple relapses of COVID-19, requiring several admissions. This study evaluated the clinical characteristics and outcomes after treatment of 5 patients with follicular lymphoma (FL), previously treated with ICT, who developed several episodes of COVID-19. We analyzed the clinical evolution and response to treatment with antiviral agent, steroids, and convalescent plasma in 5 patients with FL and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistent infection. Reverse transcriptase polymerase chain reaction tests and peripheral blood immunophenotype were performed for all patients. All patients required hospitalization due to pneumonia with severity criteria and were re-admitted after a median of 22 days (13-42) from the previous discharge. They all showed B-cell depletion by immunophenotyping, and no traces of immunoglobulin antibodies against SARS-CoV-2 were detected in any of the cases. The survival rate was 80%. The combination therapy evidenced clinical benefits, demonstrating its capacity to control infection in immunosuppressed FL patients treated with ICT.


Attention-deficit hyperactivity disorder and the shifting sands of psychiatric nosology.
Larsson et al provide epidemiological evidence for a genetic association between attention-deficit hyperactivity disorder (ADHD) and both bipolar disorder and schizophrenia and Hamshere and colleagues confirm the latter association with genome-wide data. Although a genetic link between ADHD and bipolar disorder has been hypothesised for over a decade, the association with schizophrenia fills a notable gap in the literature. This editorial discusses the implications of these findings for clinicians, who must address psychiatric comorbidity in their treatment formulations, and researchers who are learning that the discrete categorical diagnoses of our diagnostic systems may not be up to the task of clarifying the causes and cures of psychopathology.


Vending machine sales of cigarettes to children: results of compliance checks in Wisconsin, 1992-1995.
The effort to curb youth tobacco use relies increasingly on laws intended to limit youth access to tobacco products. As of 1995, all 50 states prohibit the sale of tobacco products to youth under age 18, while 32 states prohibit the purchase, possession or use by minors. Additionally, 33 states require retail licenses to sell tobacco products and 32 states regulate the sale of tobacco products from vending machines. Wisconsin law makes it illegal for a vendor to sell or give cigarettes and other tobacco products to persons under age 18 (Wisconsin Statute 134.66). In a previous issue of the WMJ, we reported the results of community-based assessments of merchant compliance with youth access laws conducted in Wisconsin from 1992-1995. This article focuses on the sale of tobacco products through vending machines.


Investigation of Surface Acoustic Wave Propagation Characteristics in New Multilayer Structure: SiO2/IDT/LiNbO3/Diamond/Si.
Surface acoustic wave (SAW) devices are widely used in many fields such as mobile communication, phased array radar, and wireless passive sensor systems. With the upgrade of mobile networks, the requirements for the performance of SAW devices have also increased, and high-frequency wideband SAW devices have become an important research topic in communication systems and other application fields. In this paper, a theoretical study for the realization of a layered SAW filter based on a new SiO2/IDT/128°YX-LiNbO3/diamond/silicon layered structure using the modeling software COMSOL Multiphysics is presented. The effects of lithium niobate (LiNbO3), an interdigital transducer (IDT), and SiO2 thin films on the evolution of the phase velocity, electromechanical coupling coefficient (k2), and temperature coefficient of frequency were studied by employing a finite element method simulation. Furthermore, a longitudinal coupling resonator filter was designed. To investigate the SAW characteristics of the filter, a transient analysis was conducted to calculate the electrical potential and particle displacement under the resonance condition and to analyze the frequency response. The study concluded that this new multilayer structure can be applied to design and manufacture a variety of high-frequency and wideband SAW filters with a temperature compensation function, for operation above the GHz range.


A dual-channel colorimetric and fluorescent sensor for the rapid and ultrasensitive detection of kanamycin based on gold nanoparticles-copper nanoclusters.
In this work, a dual-channel assay was constructed for the colorimetric and fluorescent detection of kanamycin (KAN) based on gold nanoparticles (Au NPs) and copper nanoclusters (Cu NCs). Initially, the fluorescence of Cu NCs was quenched by 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (AHMT)-functionalized Au NPs due to the inner filter effect (IFE). The existence of KAN acted as a molecular bridge to interact with AHMT via hydrogen bonds and induced the aggregation of AHMT-Au NPs, leading to a change in the color of the gold colloidal solution from reddish-violet to blue within 2 min. Moreover, the aggregated AHMT-Au NPs can weaken its IFE toward Cu NCs and result in fluorescence restoration. With the sensor employed here, the concentration of KAN can be quantitatively analyzed through double channels, and a low LOD (limit of detection) of 1.9 nM and 1.2 nM was realized by the colorimetric and fluorescent method, respectively. Benefitting from the short response time, high sensitivity, and good reliability, the established assay offered great opportunities for the on-site monitoring of antibiotics in environmental samples.


Coronary artery bypass grafting in patients with dialysis-dependent renal failure: ten-year results.
Coronary artery disease has been reported to be accelerated in patients with chronic renal failure on maintenance dialysis. Coronary artery bypass grafting (CABG) in patients on long-term dialysis is still a debated issue. We retrospectively reviewed 19 patients (12 men, 7 women, mean age 64 +/- 11.2 years) with end-stage renal disease who underwent CABG between 1990 and 2000. Operative procedures were CABG alone in 15 (78.9%) patients and CABG associated with valve procedures in 4 (21.1%) patients. The early (30-day) mortality rate was 10.5% (2 of 19 patients). Non-fatal complications occurred in 6 patients (31.5%). Four delayed deaths occurred; the actuarial survivals at 1, 2, 5 and 10 years were 0.86 +/- 0.14, 0.78 +/- 0.10, 0.68 +/- 0.13 and 0.54 +/- 0.15 respectively. Among 13 survivors the mean Canadian Cardiovascular Society class was 1.3 +/- 0.3 (p < 0.001 vs preoperatively). ANOVA procedures showed age (p = 0.01), Canadian Cardiovascular Society class > or = III (p < 0.001), urgent/emergency operation (p < 0.001), left ventricular ejection fraction < 0.50 (p < 0.001), a prior myocardial infarction (p = 0.01), a preoperative mean creatinine level > or = 5 mg/dl (p = 0.02) and a duration of dialysis > or = 60 months (p = 0.03) to be strongly related to early and delayed mortality. CABG in patients with dialysis-dependent chronic renal failure is associated with acceptable results. Accurate patient selection, early referral to surgery, and adequate perioperative management are advisable.


High-resolution genomic profiling of pediatric lymphoblastic lymphomas reveals subtle differences with pediatric acute lymphoblastic leukemias in the B-lineage.
Lymphoblastic lymphoma (LBL) is one of the most frequent occurring pediatric non-Hodgkin lymphomas. In the WHO classification scheme, pediatric LBL is considered to be the same disease entity as pediatric acute lymphoblastic leukemia (ALL). However, it is unclear whether the genetic basis of pediatric LBL development is similar to that of pediatric ALL. We performed genome-wide analyses of copy number aberrations in 12 T-LBL and 7 precursor B-cell LBL pediatric cases using high-resolution SNP-based array CGH. Similar to what previously has been found in T-ALL, T-LBL exhibited recurrent deletions of the CDKN2A locus, occurring in 92% of the cases. Additionally, we detected deletions of RB1 (16%), duplications of MYB (16%), and an amplification of ABL1 in one case. These results show that, similar to T-ALL, the genomic alterations in T-LBL predominantly target genes involved in cell cycle progression. The majority of precursor B-cell LBL was characterized by high-hyperdiploidy (71%), and showed high resemblance with high-hyperdiploid precursor B-cell ALL. Taken together, our data suggest that pediatric LBL and ALL exhibit similar genomic abnormalities within confined immunophenotypic and cytogenetic subgroups, but that the representations of these subgroups differs between the two entities.


Gastric mucosal expression and luminal release of growth factors in gastric carcinoma and duodenal ulcer patients before and after eradication of Helicobacter pylori.
Epidemiological studies have consistently shown an association between infection of Helicobacter pylori (Hp) and duodenal ulcer (DU) and gastric cancer. The mechanism of the ulcerogenic effect of Hp has been related to excessive gastrin release, gastric acid hypersecretion and gastric metaplasia in duodenum. The implication of Hp in gastric carcinogenesis has not been explained. In this study, mucosal expression of EGF and TGF alpha and luminal release of EGF as well as basal and pentagastrin-stimulated acid secretion and plasma gastrin levels have been determined in healthy subjects, gastric carcinoma and DU patients. It was found that Hp positive DU patients show excessive gastrin release and gastric acid secretion combined with increased expression and luminal release of EGF and TGF alpha. These changes returned to normal values two years after the eradication of Hp. Gastric cancer patients also showed increased expression of EGF and TGF alpha and highly increased plasma gastrin but their gastric acid secretion was markedly reduced possibly due to atrophy of oxyntic mucosa. This study indicates that overexpression of growth factors in gastric mucosa may be implicated in the pathogenesis of both duodenal ulcer and gastric cancer and that Hp positive hypochlorhydric and hypergastrinemic patients may be predisposed to development of gastric cancer.


Erythropoiesis: Comparison of Cytotoxic Aldehyde Generation in Beta-Thalassemia Patients Chelated with Deferoxamine or Deferiprone (L1) Versus NO Chelation.
The mechanism of iron-induced organ failure in iron overload disorders is not known, but it is conjectured that excess iron-catalyzed free radical generation contributes to organ damage. We hypothesized that free radical generation, quantified by the presence of 20 separate cytotoxic aldehydes in plasma, would be significantly increased in non-chelated beta-thalassemia major patients, in comparison to those chelated with either deferiprone (L1) or deferoxamine (desferal). We also report on red cell glutathione peroxidase activity in these patient groups, an enzyme involved in averting the damaging effects of free radicals. Ten patients were chelated with nightly subcutaneous infusions of desferal and 10 received the experimental oral chelator L1. Body iron burden was assessed by serum ferritin and hepatic iron concentrations. In comparison to non-chelated controls, significant decreases of 62% and 64% in total cytotoxic aldehyde concentrations were observed in patients chelated with desferal and L1, respectively (p < 0.001). Significantly lower red cell glutathione peroxidase activity was also observed in non-chelated controls, in comparison to those chelated with either desferal or L1 (p < 0.001). This is the first report on the concentrations of cytotoxic aldehydes in non-chelated beta-thalassemia major patients, and the first to report on the effects of L1 against cytotoxic aldehyde formation in plasma of patients with iron-overload.


Engineering a synthetic pathway for maleate in Escherichia coli.
Maleate is one of the most important dicarboxylic acids and is used to produce various polymer compounds and pharmaceuticals. Herein, microbial production of maleate is successfully achieved, to our knowledge for the first time, using genetically modified Escherichia coli. A synthetic pathway of maleate is constructed in E. coli by combining the polyketide biosynthesis pathway and benzene ring cleavage pathway. The metabolic engineering approach used to fine-tune the synthetic pathway drastically improves maleate production and demonstrates that one of the rate limiting steps exists in the conversion of chorismate to gentisate. In a batch culture of the optimised transformant, grown in a 1-L jar fermentor, the amount of produced maleate reaches 7.1 g L-1, and the yield is 0.221 mol mol-1. Our results suggest that the construction of synthetic pathways by combining a secondary metabolite pathway and the benzene ring cleavage pathway is a powerful tool for producing various valuable chemicals.


Compact and accurate ab initio valence bond wave functions for electron transfer: The classic but challenging covalent-ionic interaction in LiF.
This paper combines the valence bond block diabatization approach with the idea of orbital breathing. With highly compact wave functions, the breathing orbital valence bond (BOVB) method is applied to investigate several atomic and molecular properties, including the electron affinity of F, the adiabatic and diabatic potential energy curves and the dipole moment curves of the two lowest-lying 1Σ+ states, the electronic coupling curve and the crossing distance of the two diabatic states, and the spectroscopic constants of the ground states for LiF. The configuration selection scheme proposed in this work is quite general, requiring only the selection of several de-excitation and excitation orbitals in a sense like the restricted active space self-consistent field method. Practically, this is also the first time that BOVB results are extrapolated to complete basis set limit. Armed with the chemical intuition provided by valence bond theory, the classic but challenging covalent-ionic interaction in the title molecule is not only conceptually interpreted but also accurately computed.


Postoperative borderline elevated CEA predicts for earlier relapse in patients with rectal cancer receiving adjuvant postoperative therapy.
The purpose of this study was to determine the impact of a borderline elevated postoperative carcinoembryonic antigen (CEA) on the duration of disease-free survival in patients with rectal cancer treated with postoperative adjuvant radiotherapy and chemotherapy. A retrospective review was undertaken of 145 patients undergoing curative surgery for rectal adenocarcinoma (American Joint Committee on Cancer stages II and III) and treated with postoperative radiotherapy and chemotherapy from January 1994 to February 1997. Patients with known metastatic disease, with gross residual disease after surgery, or without an available postoperative CEA level before adjuvant therapy were not included. All patients were monitored for a minimum of 1 year or until death. The rates of relapse, disease-free survival and overall survival were estimated according to the Kaplan-Meier method. Univariate analyses for the endpoint time to relapse was carried out for the following potential prognostic factors: age, gender, American Joint Committee on Cancer stage, number of lymph nodes, perineural invasion, capillary-like space invasion, margin status, and postoperative CEA level (< or = 4.0 microg/L vs > 4.0 microg/L). A mulitvariate regression analyses was conducted with the Cox proportional hazards model. With a median follow-up of 45 months, the disease-free and overall survival rates at 2 years were 78% and 90% respectively. Eight patients were identified who expressed an elevated postoperative CEA (4.1-10.2 microg/L). Two patients had T3N0 tumors; one tumor was T4N0, four tumors were T3N1, and one was T4N1. The median time to first relapse in these eight patients was 26 months, compared with 69 months for the 137 patients with a postoperative CEA in the normal range (0-4.0 microg/L), (log-rank Chi-squared test = 4.92). As determined by a proportional hazards model, an elevated CEA remained an independent predictor (along with number of positive nodes) for early relapse. Postoperative CEA in patients undergoing curative surgery for rectal cancer provides additional prognostic information in those patients embarking on adjuvant postoperative therapy. An elevated CEA predicts for early relapse and may help define a high-risk subset of patients in whom more aggressive adjuvant therapies should be considered.


Economic Evaluation of Complementary and Alternative Medicine in Oncology: Is There a Difference Compared to Conventional Medicine?
To analyze the financial burden of complementary and alternative medicine (CAM) in cancer treatment. Based on a systematic search of the literature (Medline and the Cochrane Library, combining the MeSH terms 'complementary therapies', 'neoplasms', 'costs', 'cost analysis', and 'cost-benefit analysis'), an expert panel discussed different types of analyses and their significance for CAM in oncology. Of 755 publications, 43 met our criteria. The types of economic analyses and their parameters discussed for CAM in oncology were cost, cost-benefit, cost-effectiveness, and cost-utility analyses. Only a few articles included arguments in favor of or against these different methods, and only a few arguments were specific for CAM because most CAM methods address a broad range of treatment aim parameters to assess effectiveness and are hard to define. Additionally, the choice of comparative treatments is difficult. To evaluate utility, healthy subjects may not be adequate as patients with a life-threatening disease and may be judged differently, especially with respect to a holistic treatment approach. We did not find any arguments in the literature that were directed at the economic analysis of CAM in oncology. Therefore, a comprehensive approach assessment based on criteria from evidence-based medicine evaluating direct and indirect costs is recommended. The usual approaches to conventional medicine to assess costs, benefits, and effectiveness seem adequate in the field of CAM in oncology. Additionally, a thorough deliberation on the comparator, endpoints, and instruments is mandatory for designing studies.


Synthesis and characterization of glycolide, L-lactide, and PDMS-based terpolymers as a support for cell cultures.
Poly(lactic acid)/poly(glycolic acid)/poly(dimethylsiloxane) (PLGA/TEGOMER) terpolymers have been synthesized by the ring-opening polymerization of L-lactide and glycolide with alpha,omega-amine-terminated poly(dimethylsiloxane) prepolymer, using stannous octoate as a catalyst. The resulting terpolymers were characterized by various analytical techniques including size exclusion chromatography, 1H-nuclear magnetic resonance (1H-NMR), Fourier transform infrared spectroscopy, and differential scanning calorimetry. The data showed that the terpolymers presented an amorphous structure. The glass transition temperature decreased with increasing TEGOMER unit content. For in vitro degradation studies, porous films were fabricated using a solvent-casting, particulate leaching technique. Degradation of the PLGA/TEGOMER terpolymer was studied in phosphate-buffered saline at pH 7.4 and 37 degrees C. The degradation was followed by intrinsic viscosity, mass loss, and molecular weight measurements, and 1H-NMR spectroscopy. The mass loss after 55 days was 76% for the PLGA/TEGOMER (71/24/5) sample. Cell growth experiments using Swiss 3T3 fibroblasts demonstrated that PLGA/TEGOMER terpolymer matrices allow the attachment and growth of cells.


Metabolization of elemental sulfur in wheat leaves consecutive to its foliar application.
The qualitative and quantitative aspects of elemental sulfur metabolization in wheat leaves and its effect upon photosynthetic metabolism were studied through the application of micronized sulfur upon the third leaf. Energy-dispersive x-ray analysis combined with scanning electron microscopy emphasized the existence of a sulfur peak associated with a strong potassium peak in the spectra of different tissue regions for treated leaves only, supplying an original evidence of sulfur uptake. Experiments with(35)S-labeled micronized sulfur showed that about 2% of the labeled S was absorbed and metabolized into cystine, methionine, glutathione, and sulfate. The close correlation between the excess of oxygen uptake and oxygen needs for sulfur oxidation in conjunction with the absence of hydrogen sulfide released by treated leaves support direct and fast oxidation of sulfur into sulfate according to a pathway still unclear but independent of photosynthetic CO(2) metabolism in treated leaf. The mechanisms involved in the primary metabolism of element sulfur in wheat therefore appear to be different from those in fungi.


Integrating immunotherapy in the (neo)adjuvant setting of early breast cancer.
Breast cancer is a relative latecomer in the success story of immuno-oncology. In this review, we focus on the preclinical and clinical lines of evidence to justify the evaluation of immune checkpoint inhibition (ICI) for the curative-intent treatment of breast cancer, the latest and ongoing trials of (neo)adjuvant immunotherapy, and practical considerations in clinical practice associated with this new treatment paradigm. Insights from the immunobiology of breast cancer have paved the way for the new frontier of immunotherapy in this malignancy, starting from advanced stages and moving onto curable cases. Tumor-infiltrating lymphocyte quantification and PD-L1 immunohistochemistry are forerunners of predictive biomarkers for sensitivity to ICI in breast cancers. Preliminary results from phase III trials of combinatorial immunochemotherapy to treat early high-risk or locally advanced triple-negative breast cancer are encouraging for pathological complete response. Additional efficacy and patient-reported outcomes of (neo)adjuvant immunochemotherapy trials are awaited. The prospect of integrating ICI in the treatment of early-stage breast cancer is promising. Questions regarding patient selection, the choice of ICI agent and combination partner in escalation strategies, sequencing and duration of treatments, cost-effectiveness and mechanisms of resistance remain to be answered by future research.


Rapid automatized naming as an index of genetic liability to autism.
This study investigated rapid automatized naming (RAN) ability in high functioning individuals with autism and parents of individuals with autism. Findings revealed parallel patterns of performance in parents and individuals with autism, where both groups had longer naming times than controls. Significant parent-child correlations were also detected, along with associations with language and personality features of the broad autism phenotype (retrospective reports of early language delay, socially reticent personality). Together, findings point towards RAN as a potential marker of genetic liability to autism.


Comparative analysis of the daily brain transcriptomes of Asian particolored bat.
Daily rhythms are found in almost all organisms, and they comprise one of the most basic characteristics of living things. Daily rhythms are generated and mainly regulated by circadian clock. Bats have attracted interest from researchers because of their unique biological characteristics. However, little is known about the molecular underpinnings of daily rhythms in bats. In this study, we used RNA-Seq to uncover the daily rhythms of gene expression in the brains of Asian particolored bats over the 24-h day. Accordingly, four collected time points corresponding to four biological states, rest, sleep, wakefulness, and active, were selected. Several groups of genes with different expression levels in these four states were obtained suggested that different physiological processes were active at various biological states, including drug metabolism, signaling pathways, and the circadian rhythm. Furthermore, downstream analysis of all differentially expressed genes in these four states suggested that groups of genes showed daily rhythms in the bat brain. Especially for Per1, an important circadian clock gene was identified with rhythmic expression in the brain of Asian particolored bat. In summary, our study provides an overview of the brain transcriptomic differences in different physiological states over a 24-h cycle.


Microbial transformation of a beta- and gamma-eudesmols mixture.
Beta- and gamma-eudesmols mixture was microbiologically transformed by Gibberella suabinetti ATCC 20193. Seven different eudesmanoidal metabolites (3-9) were isolated and their structures were elucidated by the different spectroscopic techniques. These metabolites are: eudesma-4-en-11-ol-3-one (carissone), eudesma-3-en-2beta, 11-diol, eudesma-4-en-3beta,11-diol, eudesma-4(15)-en-8,11-diol, eudesma-4(15)-en-2a,11-diol (pterocarpol), 1(3)cyclo-eudesma-4(15)-en-11,12-diol and eudesma-4-en-11,15-diol.


Quantitative analysis of HCV RNA and genotype in patients with chronic hepatitis C accompanied by oral lichen planus.
Lichen planus (LP) is a common oral disorder that may represent a mucosal reaction to a variety of factors, including hepatitis C virus (HCV). To determine whether viral factors play a role in oral lichen planus (OLP) pathogenesis, we measured serum HCV RNA and determined HCV genotype in patients with chronic hepatitis C accompanied by OLP. The subjects included 43 patients with chronic hepatitis C: 23 with OLP (group 1) and 20 without OLP (group 2). Serum was collected from all subjects and used to quantify HCV RNA by the branched DNA signal amplification assay; HCV genotypes were classified by the reverse transcription-polymerase chain reaction (RT-PCR) method into types I, II, III and IV. Comparison of patient characteristics disclosed that the mean age of group 1, 60.7 years, was significantly higher (P = 0.001) than that of group 2 (46.4 years). No significant differences were seen between sexes in values of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein (T protein), albumin and gamma-globulin. There were also no significant differences in HCV RNA levels or HCV genotypes between groups. The findings suggested that OLP pathogenesis was a result of host factors rather than viral factors.


Contextualising sexual health practices among lesbian and bisexual women in Jamaica: a multi-methods study.
Limited research has examined lesbian and bisexual women's sexual health practices in the Caribbean, where lesbian and bisexual women experience sexual stigma that may reduce sexual healthcare utilisation. We conducted a sequential multi-method research study, including semi-structured individual interviews (n = 20) and a focus group (n = 5) followed by a cross-sectional survey (n = 205) with lesbian and bisexual women in Kingston, Montego Bay, and Ocho Rios, Jamaica. Binary logistic analyses and ordinal logistic regression were conducted to estimate the odds ratios for social-ecological factors associated with lifetime STI testing, sex work involvement, and the last time of STI testing. Over half of participants reported a lifetime STI test and of these, 6.1% reported an STI diagnosis. One-fifth of the sample reported ever selling sex. Directed content analysis of women's narratives highlighted that stigma and discrimination from healthcare providers, in combination with low perceived STI risk, limited STI testing access and safer sex practices. Participants described how safer sex self-efficacy increased their safer sex practices. Quantitative results revealed that a longer time since last STI test was positively associated with depression, sexual stigma, and forced sex, and negatively associated with residential location, perceived STI risk, safer sex self-efficacy, and LGBT connectedness. Selling sex was associated with perceived STI risk, relationship status, sexual stigma, food insecurity, and forced sex. Sexual health practices among lesbian and bisexual women in Jamaica are associated with intrapersonal, interpersonal, and structural factors, underscoring the urgent need for multi-level interventions to improve sexual health and advance sexual rights among lesbian and bisexual women in Jamaica.


Copper and manganese co-mediated cascade aza-Michael addition/cyclization and azidation of 1,3-enynes: regioselective synthesis of fully substituted azido pyrroles.
An efficient Cu and Mn co-mediated aerobic oxidative cyclization and azidation reaction of 1,3-enynes with amines and trimethylsilyl azide (TMSN3) for the synthesis of fully substituted azido pyrroles has been developed. The three-component reaction has the characteristics of high regioselectivity, wide substrate scope, and mild reaction conditions. A preliminary mechanism for this transformation is proposed.


Orientational order of near D(3h) solutes in nematic liquid crystals.
Solutes that are similar in size, have a shape that is close to D(3h) symmetry but contain dissimilar substituent groups (methyl versus chloro, contributing different electrostatic interactions to the anisotropic intermolecular potential), are used to delineate the short- and long-range anisotropic intermolecular interactions that lead to solute orientational order in nematic liquid crystals. The short-range interactions should be similar for all solutes and for D(3h) symmetry should yield a single independent order parameter, whereas the long-range interactions are expected to differ with solute. Short-range size and shape mechanisms account for solute orientational order measured in magic mixtures (e.g., 55 wt % ZLI-1132/N-p-ethoxybenzylidene-p(')-n-butylaniline), whereas additional mechanisms are required in other nematic liquid-crystal solvents. The results obtained for long-range interactions cannot be rationalized in detail using simple mean-field models that incorporate solute dipoles, quadrupoles, or polarizabilities. The results suggest that details of the solute electrostatics may need to be incorporated into the description of the anisotropic intermolecular potential.


A US Retrospective Claims Analysis Comparing Healthcare Costs of Patients Transitioning from Immediate-Release Oxycodone to Two Different Formulations of Extended-Release Oxycodone: Xtampza ER or OxyContin.
Opioid therapy for managing chronic pain remains a challenge, as providers must weigh the medical benefit to the patient with the risk of adverse events. Manipulation of many extended-release (ER) opioid formulations may lead to increased serious medical outcomes or death. The economic burden of opioid use disorders due to opioid misuse and abuse may vary depending on which abuse deterrent opioid formulation is prescribed. The study aimed to compare demographic and clinical characteristics and healthcare costs of chronic pain patients treated with two different abuse-deterrent opioid formulations, Xtampza ER and reformulated OxyContin. The source of data was IBM® MarketScan® Commercial Claims and Encounters Medicare Supplemental database, from January 2016 through February 2020. Patients with chronic pain were assigned to either the Xtampza ER or the OxyContin cohort based on the initial ER opioid prescription set as the index date. Continuous healthcare coverage was required during a minimum 3-month pre-index and 9-month post-index periods. Pre-index patients' characteristics were analyzed. Healthcare costs of Xtampza ER vs OxyContin were assessed in the post-index period. After applying selection criteria, 464 patients were observed in the Xtampza ER cohort versus 1927 patients in the OxyContin cohort. In unmatched patients, ER opioid costs were lower for Xtampza ER than OxyContin ($2645 vs $3141; p<0.001), which ultimately led to lower total prescription costs for the Xtampza ER cohort compared to the OxyContin cohort ($7492 vs $8754; p=0.016). In matched patients, the total healthcare costs were significantly lower in the Xtampza ER cohort than in the OxyContin cohort, $22,630 vs $28,386 (p=0.005), respectively. This study suggests that Xtampza ER may result in lower healthcare costs than OxyContin for a population of chronic pain patients switching from immediate release oxycodone based on real-world data.


Muscarinic Acetylcholine Receptor Localization on Distinct Excitatory and Inhibitory Neurons Within the ACC and LPFC of the Rhesus Monkey.
Acetylcholine (ACh) can act on pre- and post-synaptic muscarinic receptors (mAChR) in the cortex to influence a myriad of cognitive processes. Two functionally-distinct regions of the prefrontal cortex-the lateral prefrontal cortex (LPFC) and the anterior cingulate cortex (ACC)-are differentially innervated by ascending cholinergic pathways yet, the nature and organization of prefrontal-cholinergic circuitry in primates are not well understood. Using multi-channel immunohistochemical labeling and high-resolution microscopy, we found regional and laminar differences in the subcellular localization and the densities of excitatory and inhibitory subpopulations expressing m1 and m2 muscarinic receptors, the two predominant cortical mAChR subtypes, in the supragranular layers of LPFC and ACC in rhesus monkeys (Macaca mulatta). The subset of m1+/m2+ expressing SMI-32+ pyramidal neurons labeled in layer 3 (L3) was denser in LPFC than in ACC, while m1+/m2+ SMI-32+ neurons co-expressing the calcium-binding protein, calbindin (CB) was greater in ACC. Further, we found between-area differences in laminar m1+ dendritic expression, and m2+ presynaptic localization on cortico-cortical (VGLUT1+) and sub-cortical inputs (VGLUT2+), suggesting differential cholinergic modulation of top-down vs. bottom-up inputs in the two areas. While almost all inhibitory interneurons-identified by their expression of parvalbumin (PV+), CB+, and calretinin (CR+)-expressed m1+, the localization of m2+ differed by subtype and area. The ACC exhibited a greater proportion of m2+ inhibitory neurons compared to the LPFC and had a greater density of presynaptic m2+ localized on inhibitory (VGAT+) inputs targeting proximal somatodendritic compartments and axon initial segments of L3 pyramidal neurons. These data suggest a greater capacity for m2+-mediated cholinergic suppression of inhibition in the ACC compared to the LPFC. The anatomical localization of muscarinic receptors on ACC and LPFC micro-circuits shown here contributes to our understanding of diverse cholinergic neuromodulation of functionally-distinct prefrontal areas involved in goal-directed behavior, and how these interactions maybe disrupted in neuropsychiatric and neurological conditions.


Clinical Significance of Receptor-Interacting Protein 3 and Parkin, Essential Molecules for Necroptosis, in Breast Cancer.
Receptor-interacting protein 3 (RIP3) is the main initiator of necroptosis. Parkin prevents the formation of the RIP1-RIP3 complex by promoting polyubiquitination of RIP3. However, the mechanism by which necroptosis affects the clinical features of breast cancer and prognosis is not known. Here, we aimed to study the effect of necroptosis on the clinical features and prognosis of breast cancer by assessing the expression of RIP3 and Parkin. Tissue microarrays (TMAs) were constructed from 257 cases of breast cancer. Immunohistochemistry was performed on 4-μm tissue sections from each TMA block. The χ² test, Kaplan-Meier survival analysis with log-rank test, and Cox regression proportional hazard model were used for statistical analysis. Low RIP3 expression resulted in a large tumor size and high nuclear grade. Low RIP3 expression was correlated with human epidermal growth factor receptor 2 positivity, short overall survival (OS), and short disease-free survival (DFS). The triple negative breast cancer group with low RIP3 expression and lymph node (LN) positive group with low RIP3 expression had the shortest OS. High Parkin expression was associated with high histological grade, estrogen and/or progesterone receptor negativity, and lymphatic emboli, but was not correlated with OS and DFS. OS was correlated with LN metastasis and RIP3 loss and DFS with large tumor size, LN metastasis, and RIP3 loss. Low RIP3 and high Parkin expression are associated with aggressive clinical features in breast cancer. RIP3, a molecular marker of necroptosis, is an independent factor associated with survival in breast cancer. Further in-depth studies are needed to investigate the role of necroptosis in breast cancer development, metastasis, and treatment in the future.


Feasibility and outcome of concurrent chemoradiotherapy for recurrent cervical carcinoma after initial surgery.
The prognosis for recurrent cervical carcinoma following initial surgery is dismal even when aggressive radiotherapy or salvage surgery is used. We retrospectively reviewed hospital records to evaluate the efficacy and feasibility of concurrent chemoradiotherapy as a salvage treatment. From 1999 to 2007, 47 patients received salvage chemoradiotherapy. Involved-field irradiation was delivered at a median dose of 64.8 Gy (range, 36-100.2), including brachytherapy boost in 10 patients. Pelvic re-irradiation was performed in 4 of the 12 women who had a previous history of pelvic radiotherapy. All but one patient received cisplatin-based concomitant chemotherapy during radiotherapy. The median overall follow-up period was 27 months and for surviving patients was 57 months. The interval between initial surgery and recurrence was 22 months (range, 4-203), and the median recurrent mass size was 4 cm (range, 0.5-11). In 34 patients, recurrent tumors were confined to the pelvis (21 central and 13 peripheral). Grade 3-4 acute hematologic toxicity was the most frequent toxicity and was observed in 29 (62%) women. Five-year actuarial cumulative incidence of severe gastrointestinal and genitourinary toxicity was 13% and 7%, respectively. Thirty-three patients (70%) showed a complete response and 9 (19%) a partial response following salvage chemoradiation. Five-year overall and disease-free survival rates were 44% and 41%, respectively. Salvage chemoradiotherapy appears to be a feasible treatment option for women with recurrent cervical carcinoma following surgery. The treatment had a high salvage rate and acceptable late complication rate, despite being associated with substantial acute toxicity.


Gallium Components-Based Drug Delivery: A Potential Treatment for COVID-19.
With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showing new characteristics and manifesting new variants, the efficacy of vaccination can be reduced. In the meanwhile, no SARS-CoV-2-specific drug has been introduced in the fight against coronavirus disease 2019 (COVID-19) yet, and currently used drugs have also shown serious side effects in patients under treatment. Thus, it is pivotal to continue researching potential therapeutics to treat COVID-19. Recently, studies have shown that Gallium maltolate disrupts the replication of SARS-CoV-2 and therefore has antiviral activity against this virus. Nevertheless, as Gallium compounds have manifested serious side effects in the human body (e.g., hemoglobin synthesis dysfunction and pulmonary complications), drug delivery methods should be recruited to minimize the possible side effects and to optimize the efficacy of the drug in the fight against COVID-19. Liposomes, as nanocarriers, not only increase the half-life of the conjugated compound but also have shown promising features in the delivery of COVID-19-specific drugs to the target tissue. Herein, we propose that conjugation of Gallium maltolate with liposome nanocarriers can be beneficial to target tissues infected with SARS-CoV-2.


Efficient harvest of in vivo IL-2-activated CD3+ lymphocytes for adoptive immunotherapy by selective leukapheresis (lymphocytapheresis).
Autologous activated lymphocytes are an alternative to tumor-infiltrating lymphocytes for adoptive immunotherapy. We developed a method of selective lymphocytapheresis that harvests large numbers of interleukin-2 (IL-2)-activated autologous T lymphocytes. Five patients with metastatic malignant melanoma received 2.4 x 10(6) IU/m2 IL-2 sc. once a day 5 days a week for 3 weeks before lymphocytapheresis. Four patients went through lymphocytapheresis without IL-2 pretreatment. After IL-2 pretreatment, activated memory T cells increased significantly. Increasing CD3+ cells paralleled the significant enhancement of the cytotoxic activity against an HLA-A2-matched allogeneic melanoma cell line during the 3 weeks of IL-2 pretreatment. Lymphocytapheresis was performed 72 h after the last IL-2 injection to obtain the maximum recovery of activated lymphocytes at the peak of the rebound phenomenon. IL-2 pretreatment resulted in many more lymphocytes in the harvest than without pretreatment. The percentage, number, and lytic units of CD3+ cells harvested by the differential apheresis were significantly higher than were present in peripheral blood before lymphocytapheresis. These results show that pretreatment of melanoma patients with low-dose IL-2 before lymphocytapheresis allows the selective harvest of large numbers of activated T lymphocytes for adoptive immunotherapy.


Inferring false beliefs from actions and reactions.
Current evidence suggests that young children have little understanding of false belief. Standard false belief tasks, however, may underestimate children's ability for 2 reasons. First, the only cue to belief in these tasks is a protagonist's lack of perceptual access to some critical event, and this may not be a very salient cue for young children. Second, the standard tasks require children to make forward-looking predictions from the causes of a belief (e.g., from what a protagonist has or has not perceived) to either the protagonist's belief or the protagonist's action, and children may not be very skilled at making such predictions. In 2 experiments we investigated whether 3-year-olds would do better on tasks in which the belief cues were stronger, and in which they could reason backward to the belief from its effects (e.g., from a protagonist's actions and reactions). Even on these easy tasks, however, they did not perform well. These findings provide strong support for the view that children of this age do not fully understand the representational nature of belief.


Detection of differentially expressed genes in HeLa x fibroblast hybrids using subtractive suppression hybridization.
To understand genetic differences and similarities between tumorigenic and nontumorigenic HeLa x fibroblast hybrid cells, subtractive suppression hybridization (SSH), based on suppression PCR and a combination of normalization and subtraction in a single procedure, was used. Using the nontumorigenic CGL1 and tumorigenic CGL3, forward (CGL1-CGL3) and reverse (CGL3-CGL1) subtracted libraries were constructed. Among 192 clones, seven were identified as differentially expressed genes specific for either CGL1 or CGL3. All seven were not reported previously as differentially expressed genes in this hybrid system. In the forward subtraction, p16 was isolated, indicating the involvement of the loss of tumorigenic phenotype. Subsequent transfection of wild-type p16 to the tumorigenic CGL3 showed growth suppression in colony formation assay; however, no tumor suppression was observed when the transfectant was inoculated into nude mice. These results indicate that: (a) SSH is a suitable method to identify differentially expressed genes in two types of cells; and (b) although p16 plays some roles in growth suppression, the p16-transfected CGL3 is still capable to proliferate in vivo.


Establishment and analysis of biological characteristics of a human duodenal carcinoma cell line, WDC-1.
Duodenal carcinoma is very rare and its culture cell lines have rarely been established. Tumor cells separated from a surgically resected primary tumor of duodenal carcinoma were put into culture. The patient was an 81-year-old female and had metastatic lymph nodes. We investigated the biological characteristics of the culture cells including in vitro cell kinetics, karyotype, expression of tumor markers and integrins and tumorigenicity and histology in nude mice. A new cell line, designated WDC-1, was established. This duodenal carcinoma cell line proliferated in a monolayered sheet with a doubling time of 50 h. The histological findings of the xenograft in nude mice were similar to those of the primary tumor. WDC-1 cells produced carcinoembryonic antigen and expressed 1 integrin and very late antigen (VLA)-4d in vitro. A duodenal carcinoma cell line was established, which is rare and may contribute to progress in understanding the biological features of duodenal cancer.


On the Edge of Dispensability, the Chloroplast ndh Genes.
The polypeptides encoded by the chloroplast ndh genes and some nuclear genes form the thylakoid NADH dehydrogenase (Ndh) complex, homologous to the mitochondrial complex I. Except for Charophyceae (algae related to higher plants) and a few Prasinophyceae, all eukaryotic algae lack ndh genes. Among vascular plants, the ndh genes are absent in epiphytic and in some species scattered among different genera, families, and orders. The recent identification of many plants lacking plastid ndh genes allows comparison on phylogenetic trees and functional investigations of the ndh genes. The ndh genes protect Angiosperms under various terrestrial stresses, maintaining efficient photosynthesis. On the edge of dispensability, ndh genes provide a test for the natural selection of photosynthesis-related genes in evolution. Variable evolutionary environments place Angiosperms without ndh genes at risk of extinction and, probably, most extant ones may have lost ndh genes recently. Therefore, they are evolutionary endpoints in phylogenetic trees. The low number of sequenced plastid DNA and the long lifespan of some Gymnosperms lacking ndh genes challenge models about the role of ndh genes protecting against stress and promoting leaf senescence. Additional DNA sequencing in Gymnosperms and investigations into the molecular mechanisms of their response to stress will provide a unified model of the evolutionary and functional consequences of the lack of ndh genes.


Primary Leiomyosarcoma of the Ovarian Vein Causing Obstructive Uropathy: A Case Report.
Retroperitoneal vascular leiomyosarcoma (RVLMS) are rare soft-tissue sarcomas that most commonly arise from large blood vessels and have a poor prognosis. We present the case of a 61-year-old woman who presented with isolated left flank pain. Abdominal computed tomography and magnetic resonance imaging revealed a 5 cm retroperitoneal soft-tissue mass that was contiguous with the left ovarian vein and connected to the proximal ureter, causing hydronephrosis. As ureteroscopy suggested extrinsic compression of the ureter, a percutaneous biopsy of the mass was obtained, whereupon diagnosis of leiomyosarcoma was made. Radical en-bloc excision of the tumor, including the involved upper urinary tract and the gonadal vein, was performed. The tumor proved to be a leiomyosarcoma arising from the ovarian vein wall. No adjuvant therapy was planned, and no recurrence was noticed at her 24-month follow-up. Primary RVLMS of the ovarian vein is an uncommon condition. To date, only a few sporadic cases have been reported in the literature. What makes the present case further interesting is the unusual tumor's relationship with the patient's ureter, raising both diagnostic and management challenges. To our best knowledge, this is so far the fourth reported case of its kind to cause ureteral obstruction.


[Comparisons of histological grading between biopsy and radical prostatectomy specimens in prostatic adenocarcinoma].
To examine how accurately biopsy specimens reflect the corresponding excised specimens in terms of histologic grades of prostatic adenocarcinoma, histologic grades of biopsy specimens were compared to those of radical prostatectomy specimen in 29 patients who underwent radical prostatectomy without any prior treatment. For the assessment of histological grading, Japanese General Rule for Prostatic Cancer (JGRPC), in which adenocarcinoma was graded as being either well, moderately or poorly differentiated, and Gleason's system were applied. According to JGRPC, histologic grades of biopsy specimens were identical to those of the prostatectomy specimens in 83% of cases, with biopsy specimens given higher grades than those of the prostatectomy specimen in 4 (14%), and lower grades in 1 (3%). According to Gleason score histological grade of biopsy specimens were identical to those of the prostatectomy specimens in only 52%. However, the grouping category of Gleason score (2 to 5, 6, 7 and 8 to 10) assigned to the biopsy was lower than that of prostatectomy specimen in only 3 cases (10%) and was greater than that of prostatectomy specimen in 5 cases (17%). These results suggest that histological grades based upon biopsy specimens will predict those of the corresponding prostatectomy specimens in the majority (72% to 83%) but not all of the cases.


Fifteen-Year Prevalence, Trajectories, and Predictors of Body Dissatisfaction From Adolescence to Middle Adulthood.
Body dissatisfaction is common in adolescence and associated with negative outcomes (e.g., eating disorders). We identified common individual trajectories of body dissatisfaction from mid-adolescence to adulthood, and predictors of divergent patterns. Participants were 1,455 individuals from four waves of Project EAT (Eating and Activity in Teens and Young Adults), a population-based, 15-year longitudinal study. Aggregate body dissatisfaction increased over 15 years, which was largely attributable to increases in weight. Growth mixture modeling identified four common patterns of body dissatisfaction, revealing nearly 95% of individuals experienced relatively stable body dissatisfaction from adolescence through adulthood. Baseline depression, self-esteem, parent communication/caring, peer dieting, and weight-based teasing predicted differing trajectories. Body dissatisfaction appears largely stable from mid-adolescence onward. There may be a critical period for body image development during childhood/early adolescence. Clinicians should intervene upon body dissatisfaction before it becomes chronic, and target depression, self-esteem, parent/child connectedness, and responses to teasing and peer dieting.


Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer.
Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption.


Dynamical decoupling in water-glycerol glasses: a comparison of nitroxides, trityl radicals and gadolinium complexes.
Our previous study on nitroxides in o-terphenyl (OTP) revealed two separable decoherence processes at low temperatures, best captured by the sum of two stretched exponentials (SSE) model. Dynamical decoupling (DD) extends both associated dephasing times linearly for 1 to 5 refocusing pulses [Soetbeer et al., Phys. Chem. Chem. Phys., 2018, 20, 1615]. Here we demonstrate an analogous DD behavior of water-soluble nitroxides in water-glycerol glass by using nitroxide and/or solvent deuteration for component assignment. Compared to the conventional Hahn experiment, we show that Carr-Purcell and Uhrig DD schemes are superior in resolving and identifying active dephasing mechanisms. Thereby, we observe a partial coherence loss to intramolecular nitroxide and trityl nuclei that can be alleviated, while the zero field splitting-induced losses for gadolinium labels cannot be refocused and contribute even at the central transition of this spin-7/2 system. Independent of the studied spin system, Uhrig DD leads to a characteristic convex dephasing envelope in both protonated water-glycerol and OTP glass, thus outperforming the Carr-Purcell scheme.


High detectivity graphene/si heterostructure photodetector with a single hydrogenated graphene atomic interlayer for passivation and carrier tunneling.
Hydrogenated graphene is easy to prepare and chemically stable. Besides, hydrogenation of graphene can open the band gap, which is vital for electronic and optoelectronic applications. Graphene/Si photodetector (PD) has been widely studied in imaging, telecommunications, and other fields. The direct contact between graphene and Si can form a Schottky junction. However, it suffers from poor interface state, where the carrier recombination at the interface causes serious leakage current, which in turn leads to a decrease in the detectivity. Hence, in this study, hydrogenated graphene is used as an interfacial layer, which passivates the interface of graphene/Si (Gr/Si) heterostructure. Besides, the single atomic layer thickness of hydrogenated graphene is also crucial for the tunneling transport of charge carriers and its suitable energy band position reduces the recombination of carrier. The fabricated graphene/hydrogenated-graphene/Si (Gr/H-Gr/Si) heterostructure PD showed an extremely low dark current about 10-7A. As a result, it had low noise current and exhibited a high specific detectivity of ∼2.3 × 1011Jones at 0 V bias with 532 nm laser illumination. Moreover, the responsivity of the fabricated PD was found to be 0.245 A W-1at 532 nm illumination with 10μW power. These promising results show a great potential of hydrogenated graphene to be used as an interface passivation and carrier tunneling layer for the fabrication of high-performance Gr/Si heterostructure PDs.


Autonomic nervous activities assessed by heart rate variability in pre- and post-adolescent Japanese.
There are many studies with respect to the age-related change of the characteristics of beat-to-beat heart rate variability (HRV), reflected by cardiac autonomic control, especially focusing on adulthood (i.e., aging related to the incidence of metabolic syndrome) in Japanese individuals. However, it is not still clear how basic control matures during childhood. This study was, therefore, designed to explore the HRV characteristics of pre- and post-adolescent Japanese, in a cross-sectional manner. Resting HRV data was recorded in a relaxing supine position from 136 healthy individuals between 8 and 20 years (48 boys between 8 and 14 years; 88 girls between 8 and 20 years) who were instructed to breathe periodically (0.25 Hz). Frequency-domain analysis (i.e., the spectral analysis based on an autoregressive model) of short-term, stationary R-R intervals was performed to evaluate the low- (LF; below 0.15 Hz) and high- (HF; 0.15-0.40 Hz) frequency powers. The HF to total power represents the vagal control of heart rate (PNS indicator), and the ratio of LF to HF (LF/HF) is considered to relate to the sympathetic modulations (SNS indicator). Both PNS and SNS indices had substantially no effect from age and/or gender in the range between 8 and 20 years. In conclusion, the control of the cardiac autonomic nervous system in Japanese seems already to be compatible with that in adulthood before approximately 10 years. In other word, the cardiac autonomic modulation would presumably be maturated before the age of approximately 7-8 years, though further research is awaited.


How predictable is the postoperative work resumption after aortocoronary bypass surgery?
The number of aortocoronary bypass procedures increased at the Cardiovascular Surgery Department of the University Hospital in Leuven (Belgium) from 12 patients in 1971 to 650 patients in 1983. A similar evolution took place in the other existing Belgian cardiovascular centers and new departments were created to fill this need. The financial burden of the direct hospital costs of these procedures on the National Health Care program is considerable. The postoperative work-resumption will restore the patient's social dignity, it can increase the patient's personal income and thus decrease the indirect costs such as workmen's compensation; it will therefore improve the cost effectiveness of coronary surgery so that it can be offered to the numerous patients who need it for their survival or for the improvement of their quality of life. Studies about the employment status before and after aortocoronary surgery, as published from other centers, can not be projected on the Belgian situation due to the difference in population cohorts, laws regulating the working conditions, the national unemployment ratio and disability compensations. With this in mind, a study of the preoperative and postoperative employment and its predictability was undertaken.


Medical miracles and the longue durée.
The hematologist-historian author became interested in the nature 'medical miracles', following a request to write a report on a set of bone marrows that was sent to the Vatican as a possible miracle cure in a cause for canonization. She questioned the prevalence of medical miracles, their structure, and relationship to other 'official' miracles that are recognized by the Church. Evidence was drawn from a variety of sources: oral testimony of pilgrims at feast day celebrations, ex voto paintings, and 160 miracle files in 67 canonization records of the Vatican Archives. Some changes can be detected through time, but the results also testify to remarkable longue durée in the healing experience: the patterns of suffering and despair, the gestures of pleading, the presence of beds and dreams, the astonishment of the caregivers, and above all the simultaneous recourse to medicine and religion both.


Phototriggered release of amine from a cucurbituril macrocycle.
A method for the phototriggered release of a biogenic amine from the host-guest complex with the cucurbit[7]uril macrocycle in aqueous solution was devised. The approach exploits a photoinduced pH jump from 8 to 5, combined with the pH-dependent switching of the competitive capacity of a guest dye. The fluorescence fingerprint of the competitor can be used to monitor the amine release in the micromolar concentration regime.


Deaths due to jambia-inflicted lesions in a domestic environment.
Domestic violence is a significant health problem affecting women all around the world by causing a wide range of physical and psychological traumas. Yemen has a very high percentage of women experiencing intimate partner violence (up to 50%) and a high mortality rate. In this article, we are presenting 3 particular cases of domestic violence deaths in which the weapon used was a jambia (jambia, jambiah, jambiya, djambia), a special dagger specific to Yemen and the surrounding areas. We are also summarizing the main characteristics of jambia-inflicted lesions and their thanatology.


Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.
The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.


Missing out on post-acute rehabilitation: a single case example.
Acute care providers may encounter any number of potential traps when providing treatment to individuals with acquired brain injury (ABI) who present behavioral issues. These traps, or faulty ways of viewing the patient's recovery process, may lead to mistakes that significantly impact the likelihood of successful recovery. This article, designed to increase awareness of the possible issues which acute care providers often face, will discuss four such traps, as well as illustrate a treatment approach which utilizes a non-aversive cognitive-behavioral treatment plan through the experience of one individual.


Hard top soft bottom microfluidic devices for cell culture and chemical analysis.
We report fabrication and characterization of microfluidic devices made of thermoplastic and elastomeric polymers. These hard-soft hybrid material devices are motivated by the combined need for large scale manufacturability, enhanced barrier properties to gas permeation and evaporation of aqueous solutions compared to poly(dimethyl siloxane) (PDMS) devices, and compatibility with deformation-based actuation. Channel features are created on rigid polymers such as polyethylene terephthalate glycol (PETG), cyclic olefin copolymer (COC), and polystyrene (PS) by hot embossing. These "hard tops" are bonded to elastomeric "soft bottoms" (polyurethane (PU) or PDMS-parylene C-PDMS) to create devices that can be used for microfluidic cell culture where deformation-based fluid actuation schemes are used to perfuse and recirculate media. The higher barrier properties of this device compared to PDMS devices enable cell culture with less evaporation and creation of hypoxic conditions.


The impact of learning on cost: the case of heart transplantation.
The effect of increased experience on outcomes is evaluated for a heart transplantation program. While previous research on surgical procedures has documented a strong and consistent relationship between experience and quality (mortality and complication rates), little correlation has been found between experience and cost. Most of this research has relied on comparisons between different-sized programs at the same point in time, making it difficult to interpret. The lack of clear financial incentives in the past may also have muted a relationship between cost and experience that has been consistently documented and used in planning the production of almost all other non-health-related goods and services. The traditional operations research or managerial accounting model for projecting the impact of learning on four measures of cumulative average resource consumption (death rates, length of stay, billing units, and charges), modified to include a lower limit, was applied to the experience of a heart transplant program. The data fit the model well. The slope of the learning curve is steepest for death rates and flattest for charges. Possible implications of such learning curves on the strategic thinking of institutions and the planning and management of health services are discussed.


Synchronous double primary malignant lymphoma of low grade malignancy and early cancer (collision tumor) of the stomach.
Collision tumors of the stomach are rare tumors, with about 32 cases reported in the English and German literature. In this report the case of a 65-year-old male with a synchronous primary malignant lymphoma (immunocytoma) and an early cancer of the stomach is presented. A total gastrectomy with esophago-jejunostomy was performed. Postoperatively the affected region was irradiated. 30 months later a re-evaluation did not reveal any recurrence of the disease. The diagnostic and therapeutic problems of collision tumors of the stomach and a possible relationship between the two tumors are discussed against the background of the literature.


Adverse effects of near current-electrode placement in non-invasive bio-impedance measurements.
A major problem confronting application of impedance techniques to studies of disease is the extraction of intrinsic properties of the tissue from the measured impedances, which unavoidably involve geometric factors as well. Amongst the foremost are the sizes and locations of the measuring electrode arrays, and this paper addresses one of these, the location of current injecting electrodes. Tetrapolar impedance measurements on a 17.5 cm segment of the thigh gave R and X values three to four times larger when the current injecting electrodes were placed 2.5 cm from the sensing electrodes than when very distant placement was used. The frequency dependences of R and X were affected as well, though the X versus R plots still showed virtually perfect depressed-center semicircles, as in the Cole model. R(f) and X(f) for the set of contiguous 2.5 cm wide sub-segments show that these behaviors can be explained by a combination of the transverse orientation of current flow lines near the injecting electrodes and the anisotropy of the resistivity associated with the bundled fiber structure of muscle tissue. The measured impedance was found to be a separable function of geometric and intrinsic tissue variables, but far more complicated than is implicit in the usual cylindrical models. The results also suggest that many full and segmental body composition studies in the literature may be prone to substantial errors due to too close placement of the current injecting electrodes.


Exploring the adult sexual wellbeing and behavior during the COVID-19 pandemic. A systematic review and meta-analysis.
Implemented social distancing measures may have forestalled the spread of COVID-19, yet they suppressed the natural human need for contact. The aim of this systematic review was to explore the impact of the COVID-19 pandemic on adult sexual wellbeing and sexual behavior. An extensive search in Pubmed, Scopus, and PsycInfo databases based on PRISMA guidelines was conducted. After applying specific eligibility criteria, screening resulted in 38 studies. Results were drawn from 31,911 subjects and outlined the negative effect of the pandemic in sexual frequency, function, satisfaction, and the behavioral changes regarding masturbation and internet-based practices. Meta-analyses of the drawn data on 1,343 female, and 1,372 male subjects quantified the degree of sexual function change during the COVID-19 pandemic vs. prior the pandemic. A random effects model revealed the significant negative impact of the pandemic on female sexual function (SMD: 0.76, 95% CI:0.74 to 1.59), while no significant change was found for the males (SMD: 0.25, 95% Cl: -0.03 to 0.52). Significant heterogeneity was identified across included studies (p < 0.00001, I2 = 97%, I2 = 90% for females and males, respectively). As part of the global health, sexual wellbeing should be on the focus of clinicians and researchers.


Colchicine attenuates left ventricular hypertrophy but preserves cardiac function of aortic-constricted rats.
To investigate the effects of colchicine on left ventricular (LV) function and hypertrophy (LVH) of rats subjected to constriction of transverse aorta (TAoC), we evaluated SO (sham operated, vehicle; n = 25), SO-T (sham operated, colchicine 0.4 mg/kg body wt ip daily; n = 38), TAoC (vehicle; n = 37), and TAoC-T (TAoC, colchicine; n = 34) on the 2nd, 6th, and 15th day after surgery. Colchicine attenuated LVH of TAoC-T compared with TAoC rats, as evaluated by ratio between LV mass (LV(M)) and right ventricular mass, LV wall thickness, and average diameter of cardiac myocytes. Systolic gradient across TAoC ( approximately 45 mmHg), LV systolic pressure, LV end-diastolic pressure, and rate of LV pressure increase (+dP/dt) were comparable in TAoC-T and TAoC rats. However, the baseline and increases of LV systolic pressure-to-LV(M) and +dP/dt-to-LV(M) ratios induced by phenylephrine infusion were greater in TAoC-T and SO-T compared with SO rats. Baseline and increases of +dP/dt-to-LV(M) ratio were reduced in TAoC compared with SO rats. TAoC rats increased polymerized fraction of tubulin compared with SO, SO-T, and TAoC-T rats. Our results indicate that colchicine treatment reduced LVH to pressure overload but preserved LV function.


Molecular dynamics simulation study explaining inhibitor selectivity in different class of histone deacetylases.
Histone deacetylases (HDACs) are key regulators of gene expression and thereby compelling targets in the treatment of various cancers. Class- and isoform-selective HDAC inhibitors targeting the particular isoform to treat cancers without affecting the normal expression of other isoforms are highly desirable. Molecular dynamics simulations were performed with the set of selective inhibitors and HDAC isoforms of three different classes. The results were compared both within and across the isoforms. The hydrogen bonds between protein and inhibitors are directly correlated with the selective experimental activity. The calculated distances between important amino acids and the metal binding part of inhibitors have disclosed the optimal distance to be maintained by a selective inhibitor. In addition, the calculated non-bonded interaction energies between inhibitor and catalytic residues revealed that the subtle difference in the amino acids at the highly conserved active sites of HDAC isoforms effectively scripts the selectivity story observed experimentally. The results of this study provide valuable information in designing highly selective HDAC inhibitors.


[Reconstruction of large vermilion defects with buccinator myomucosal flap].
To investigate a novel method for the reconstruction of large vermilion defects. Based on the size and shape of the defects, a buccinator myomucosal flap pedicled with the junction of buccinator and orbicularis oris in the oral commisure was designed and rotated to reconstruct the large vermilion defects. The upper bound of the flap is at least 1 cm away from the stensen's duct. The width is about 2.5-3.0 cm, and the length is as far as to arrive the raphe pterygomancibularis. The donate site is directly closed primarily. There is no need for secondary pedicle division. From July 2003 to April 2013, 14 cases with large vermilion defects was reconstructed with this method. No flap necrosis occurred with primary healing. 5 cases were followed up with an average follow up period of 1 year (0.5-3 years). The apprearance and function of the reconstructed vermilion were satisfactory without any apparent donor site defect. The patients were satisfied with both the functional and cosmetic results. The buccinator myomucosal flap is a simple and ideal method for reconstruction of large vermilion defects, especially for the defects closed to the commisure.


Estrogenic activity of isolated compounds and essential oils of Pimpinella species from Turkey, evaluated using a recombinant yeast screen.
Several plants and plant-derived pure compounds, designated as phytoestrogens, have been reported to cause estrogenic effects. They have been used for alleviation of menopausal symptoms, prevention of osteoporosis, heart disease and cancer. There is an increased interest in studying phytoestrogens such as isoflavones and lignans for their use as replacements for synthetic estrogens. In this study, the estrogenic activity of essential oils of eleven Pimpinella species and the compounds isolated from these species were evaluated using the yeast estrogen screen (YES) assay. The essential oils containing (E)-anethole as major compound showed estrogenic activity in the YES assay, except for the aerial parts without fruits of P. anisetum and P. flabellifolia. The percent maximal response produced by most anethole-containing oils was 30-50%. Fruits of P. isaurica and P. peucedanifolia were estrogenic in spite of the absence or trace amount of anethole, respectively. This study indicates that the estrogenic activity of Pimpinella oils is not solely due to the presence of anethole. Components other than anethole may be responsible for contributing towards the estrogenic activity. The essential oils from different species varied in their estrogenic potencies (relative potency from 8.3 x 10(-8) to 1.2 x 10(-6) compared to 17 beta-estradiol) and among the different plant parts, the fruit oils of most species were estrogenic followed by the aerial parts without fruits and the root oils and their EC50 values varied from 45 micrograms/mL to 650 micrograms/mL.


Reactive oxygen as modulator of TNF and fas receptor-mediated apoptosis in vivo: studies with glutathione peroxidase-deficient mice.
Reactive oxygen species (ROS) can directly induce or enhance tumor necrosis factor (TNF)-mediated apoptosis in a number of different cell lines. To test the relevance of intracellular ROS in modulating apoptotic signaling in vivo, we evaluated hepatocellular apoptosis mediated by the TNF or Fas receptor in wild-type and glutathione peroxidase-1 (Gpx1-/-)-deficient mice (129SV/B6 background). Apoptosis developed in livers of wild-type animals 4-6 h after intraperitoneal administration of 700 mg/kg galactosamine/100 micro g/kg endotoxin. Apoptosis was indicated by processing of procaspases-3 (assessed by western blotting), a fivefold increase in caspase-3 activity (DEVD-AMC as substrate), and a 44-fold increase in DNA fragmentation (ELISA). The time course and magnitude of apoptosis were the same in Gpx1-/- mice. In contrast, Gpx1-/- mice had higher plasma alanine aminotransferase (ALT) levels and more severe hemorrhage compared to wild-type animals at 6 h. Treatment of wild-type mice with the anti-Fas antibody Jo-2 (0.6 mg/kg i.v.) resulted in processing of procaspase-3 and a sevenfold increase in caspase-3 activity in both wild-type and Gpx1-/- mice. However, higher plasma ALT values in Gpx1-/- mice at 3 h may reflect a trend to develop more rapidly secondary necrosis. These data suggest that, under our experimental conditions, intracellular ROS did not modulate the death receptor-initiated apoptotic signaling cascade in hepatocytes. As Gpx1 is located in the cytosol and in mitochondria, which are the main cellular compartments involved in apoptotic signaling, our findings indicate that the oxidant stress in vivo was insufficient to modulate these signaling pathways. However, Gpx1 deficiency enhances the susceptibility for secondary necrosis or neutrophil-induced cell injury.


Fracture-separation of the medial humeral epicondyle caused by arm wrestling.
Ten cases with fracture-separation of the medial humeral epicondyle occurring during arm wrestling were studied to clarify the nature of injury and the mechanism involved. Patients were all male, aged 13 to 15 years. The following results were obtained: (1) the injury often occurred in children immediately before closure of the epiphyseal plate, (2) the injury occurred only when the arm wrestler took a posture in which his center of gravity could shift easily, (3) the injury developed only when one wrestler tried to force the end of the match and the other countered that move, and (4) no lateral instability of the elbow was observed in patients with this injury. These results suggest that the injury is caused by muscular violence. When the maximally contracted muscles attaching to the medial humeral epicondyle are suddenly and passively stretched by shifting of the patient's center of gravity and by the opposing wrestler's counterattack, a shift from concentric contraction to eccentric contraction could occur and apply a large muscle force to the medial humeral epicondyle.


Serum hs-CRP as a useful marker for predicting the efficacy of lumbar epidural steroid injections on pain relief in patients with lumbar disc herniations.
We examined systemic inflammatory serum markers and pain responses to image-guided lumbar epidural steroid injections (LESI) both before and after LESI in patients with lumbar disc herniations with various pathological intervertebral disc changes. Sixty male patients were scheduled for LESI every two weeks for three injections. Prior to injection therapy the following laboratory tests were performed: a complete blood count (CBC), high-sensitivity C-reactive protein (hs-CRP), and an erythrocyte sedimentation rate (ESR). Five groups of fifteen patients each were classified according to MRI observation: I) control group, II) disc protrusion, III) disc prolapse, IV) disc extrusion, and V) sequestered disc herniation. LESI were scheduled two weeks apart and were done with fluoroscopy using 40 mg of triamcinolone with 5 ml of preservative-free lidocaine. All patients returned 6 weeks following their initial injection and repeat hs-CRP assays were obtained. No patient in this study had an abnormal CBC or ESR. No patient in the control group had an elevated hs-CRP. The percentage and number of patients in each experimental group with elevated hs-CRP levels were: II) 0% (0/15), III) 20% (3/15), IV) 80% (12/15), and V) 73% (11/15). LESI was more efficacious in the two contained disc herniation groups (II and III). It was found that the higher the hs-CRP levels prior to LESI therapy, the less improvement in pain scores following LESI. The results of this study suggest that elevated hs-CRP levels may be useful for objectively evaluating and predicting responses to LESI in those patients with lumbar disc pathology with lower extremity radiculitis.


Carbon nanotube-chitosan system for electrochemical sensing based on dehydrogenase enzymes.
Multiwalled carbon nanotubes (CNT) were solubilized in aqueous solutions of a biopolymer chitosan (CHIT). The CHIT-induced solubilization of CNT facilitated their manipulations, including the modification of electrode surfaces for sensor and biosensor development. The colloidal solutions of CNT-CHIT were placed on the surface of glassy carbon (GC) electrodes to form robust CNT-CHIT films, which facilitated the electrooxidation of NADH. The GC/CNT-CHIT sensor for NADH required approximately 0.3 V less overpotential than the GC electrode. The susceptibility of CHIT to chemical modifications was explored in order to covalently immobilize glucose dehydrogenase (GDH) in the CNT-CHIT films using glutaric dialdehyde (GDI). The stability and sensitivity of the GC/CNT-CHIT-GDI-GDH biosensor allowed for the interference-free determination of glucose in the physiological matrix (urine). In pH 7.40 phosphate buffer solutions, linear least-squares calibration plots over the range 5-300 microM glucose (10 points) had slopes 80 mA M(-1) cm(-2) and a correlation coefficient 0.996. The detection limit was 3 microM glucose (S/N = 3). The CNT-CHIT system represents a simple and functional approach to the integration of dehydrogenases and electrodes, which can provide analytical access to a large group of enzymes for wide range of bioelectrochemical applications including biosensors and biofuel cells.


The puzzle(s) of pharmacoresistant epilepsy.
Despite the availability of >25 antiepileptic drugs, 30% of people with epilepsy do not respond to conventional agents, exhibiting pharmacoresistance (PR)--a high percentage that has not changed significantly in decades. This is not surprising given that all current pharmaceutical agents merely reduce the incidence of seizures ("antiictogenic"); they do not interfere with the natural history of epilepsy and are therefore not antiepileptogenic. The two prevailing hypotheses of pharmacoresistance, the target hypothesis and the transporter hypothesis, can only partially explain the complexity and the diversity of PR. It is a neuropharmacologic priority that we change our approach to understanding PR. Herein we suggest the need to regard PR as a complex puzzle in which the target and transporter hypotheses represent a very small piece of the whole. Indeed, we do not even know if this piece of the whole is epiphenomenal or neurobiologically causal. To grasp the whole, we need to constantly gather information (look around for other pieces) from other perspectives and insights coming from clinical, epidemiologic, neuroradiologic, genetic, and other data. A recent research workshop on PR, the 2nd Halifax International Epilepsy Conference & Retreat, chose this eclectic and all-encompassing approach. The participants were fully aware that their diverse contributions represent only still-fragmented pieces of this frustrating but clinically important puzzle.


Near-infrared hyperspectral unmixing based on a minimum volume criterion for fast and accurate chemometric characterization of counterfeit tablets.
A rapid detection of the nonauthenticity of suspect tablets is a key first step in the fight against pharmaceutical counterfeiting. The chemical characterization of these tablets is the logical next step to evaluate their impact on patient health and help authorities in tracking their source. Hyperspectral unmixing of near-infrared (NIR) image data is an emerging effective technology to infer the number of compounds, their spectral signatures, and the mixing fractions in a given tablet, with a resolution of a few tens of micrometers. In a linear mixing scenario, hyperspectral vectors belong to a simplex whose vertices correspond to the spectra of the compounds present in the sample. SISAL (simplex identification via split augmented Lagrangian), MVSA (minimum volume simplex analysis), and MVES (minimum-volume enclosing simplex) are recent algorithms designed to identify the vertices of the minimum volume simplex containing the spectral vectors and the mixing fractions at each pixel (vector). This work demonstrates the usefulness of these techniques, based on minimum volume criteria, for unmixing NIR hyperspectral data of tablets. The experiments herein reported show that SISAL/MVSA and MVES largely outperform MCR-ALS (multivariate curve resolution-alternating least-squares), which is considered the state-of-the-art in spectral unmixing for analytical chemistry. These experiments are based on synthetic data (studying the effect of noise and the presence/absence of pure pixels) and on a real data set composed of NIR images of counterfeit tablets.


Treatment of symptoms in multiple sclerosis.
The current focus regarding treatment of multiple sclerosis (MS) to be on therapies that may alter the course of the disease. Some of the evidence regarding the efficacy of these treatments is based on changes in the appearance of neuroimaging studies of the brain and spinal cord and not on the effect of these treatments on clinical symptomatology. Since most of our patients with MS continue to be symptomatic despite the use of immunomodulating agents, it is important for the treating neurologist to be familiar with treatments for these symptoms, many of which are extremely disabling to the patient. Knowing how to deal with common complaints/symptoms of MS enables us to better practice the art of neurological care.


Safety of Staphylococcus aureus four-antigen and three-antigen vaccines in healthy adults: A meta-analysis of randomized controlled trials.
Two new Staphylococcus aureus vaccines, S. aureus four-antigen (SA4Ag) and three-antigen (SA3Ag) vaccines, have good immunogenicity and tolerance. However, the safety of these vaccines is worth exploring. Here, we performed a meta-analysis to investigate the safety of SA3Ag and SA4Ag by evaluating systemic and local adverse events. The Medline, EMBASE, and Cochrane databases were searched for randomized clinical trials confirming the safety of SA4Ag and SA3Ag. Two investigators independently selected suitable trials, assessed trial quality, and extracted data. Three studies comprising a total of 1,148 participants were included in this review. The two S. aureus vaccines did not increase systemic adverse events (relative ratio 1.1 [95% confidence interval 0.98, 1.24]), but increased the incidence of local adverse events (2.89 [2.15, 3.90]). However, the incidence of severe local adverse events (4.06 [0.78, 21.24]) did not rise significantly. SA4Ag and SA3Ag have acceptable safety in adults.


Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo.
Previous studies using immunohistochemistry suggest that loss of the expression of the prostate-derived Ets transcription factor (PDEF) is a strong indicator for cancer cell malignancy. However, the underlying mechanism for this has not been well elucidated. We determined the role of PDEF in breast cancer cell growth and tumor formation using a series of experiments including Western blotting, promoter-luciferase reporter assay, RNA interference technology and a mouse xenograft model. We also determined the relationship between PDEF expression in human breast tumor specimen and cancer patient survivability. These studies revealed that PDEF expression is inversely associated with survivin expression and breast cancer cell xenograft tumor formation. PDEF-specific shRNA-mediated silencing of PDEF expression resulted in the upregulation of survivin expression in MCF-7 cells, which was associated with increased cell growth and resistance to drug-induced DNA fragmentation (apoptosis). In contrast, survivin-specific siRNA-mediated silencing of survivin expression decreased MCF-7 cell growth. Ectopic expression of PDEF inhibited both survivin promoter activity and endogenous survivin expression. Importantly, shRNA-mediated silencing of PDEF expression in MCF-7 breast cancer cells enhanced survivin expression and xenograft tumor formation in vivo. Furthermore, loss of PDEF expression in breast cancer tissues tends to be associated with unfavorable prognosis. These studies provide new information for the role of PDEF and survivin in breast cancer cell growth and tumor formation.


Impact of Histone H1 on the Progression of Allergic Rhinitis and Its Suppression by Neutralizing Antibody in Mice.
Nuclear antigens are known to trigger off innate and adaptive immune responses. Recent studies have found that the complex of nucleic acids and core histones that are derived from damaged cells may regulate allergic responses. However, no fundamental study has been performed concerning the role of linker histone H1 in mast cell-mediated type I hyperreactivity. In this study, we explored the impact of histone H1 on mast cell-mediated allergic responses both in vitro and in vivo. In the course of a bona-fide experimental allergen sensitization model upon co-injection with alum adjuvant, ovalbumin (OVA), but not PBS, induced elevated levels of circulating histone H1. Intranasal challenge with histone H1 to OVA/alum- (but not PBS/alum)-sensitized mice induced significantly severer symptoms of allergic rhinitis than those in mice sensitized and challenged with OVA. A monoclonal antibody against histone H1 not only suppressed mast cell degranulation, but also ameliorated OVA-induced nasal hyperreactivity and IgE-mediated passive cutaneous anaphylaxis. Our present data suggest that nuclear histone H1 represents an alarmin-like endogenous mediator acting on mast cells, and that its blockage has a therapeutic potential for mast cell-mediated type I hyperreactivity.


Plasticity in the rat prefrontal cortex: linking gene expression and an operant learning with a computational theory.
The plasticity in the medial Prefrontal Cortex (mPFC) of rodents or lateral prefrontal cortex in non human primates (lPFC), plays a key role neural circuits involved in learning and memory. Several genes, like brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Synapsin I, Calcium/calmodulin-dependent protein kinase II (CamKII), activity-regulated cytoskeleton-associated protein (Arc), c-jun and c-fos have been related to plasticity processes. We analysed differential expression of related plasticity genes and immediate early genes in the mPFC of rats during learning an operant conditioning task. Incompletely and completely trained animals were studied because of the distinct events predicted by our computational model at different learning stages. During learning an operant conditioning task, we measured changes in the mRNA levels by Real-Time RT-PCR during learning; expression of these markers associated to plasticity was incremented while learning and such increments began to decline when the task was learned. The plasticity changes in the lPFC during learning predicted by the model matched up with those of the representative gene BDNF. Herein, we showed for the first time that plasticity in the mPFC in rats during learning of an operant conditioning is higher while learning than when the task is learned, using an integrative approach of a computational model and gene expression.