Reduction of respiratory motion artifacts in PET imaging of lung cancer by respiratory correlated dynamic PET: methodology and comparison with respiratory gated PET.
This study proposes a new method to reduce respiratory motion artifacts in PET images of lung cancer. The method is referred to as respiratory-correlated dynamic PET (RCDPET). RCDPET enables the acquisition of 4-dimensional PET data without the need for a respiratory tracking device. In this article, we compare this method with respiratory-gated PET (RGPET). Both methods provide the ability to correct for motion artifacts and more accurately quantitate radiotracer uptake within lung lesions. Both methods were evaluated in phantom studies and 1 patient. With RCDPET, data are acquired in consecutive 1-s time frames. A point source attached to a rigid foam block is set on the patient's abdomen and is extended into the camera field of view at the level of the lesion by means of a low-density rod. The position of this source is used to track respiratory motion through the consecutive dynamic frames. Image frames corresponding to a user-selected lesion position within the breathing cycle, in correlation with the point source position, are then identified after scanning. The sinograms of the selected image frames are summed and then reconstructed using iterative reconstruction with segmented attenuation correction. The results from phantom studies with both RGPET and RCDPET were within 10% agreement, for both activity quantitation and image noise levels. In a clinical application, the quantitation of the SUV(max) and the lesion's size showed a 6% and 2% difference, respectively, between RCDPET and RGPET measurements. RCDPET can be considered as a comparable, or alternative, method to RGPET in reducing the smearing effects due to respiration and improving quantitation of PET in the thorax. One advantage of RCDPET over RGPET is the ability to retrospectively reconstruct the PET data at any phase or amplitude in the breathing cycle.


Bioinspired Structural Colors Fabricated with ZnO Quasi-Ordered Nanostructures.
Despite their advantages in different applications, structural colors are difficult to use because of the inability to change a structural color once it is implemented, as well as their high fabrication costs; implementing multiple structural colors simultaneously on one substrate is a challenge as well. In this study, structural colors were reproduced using quasi-ordered scattering to mitigate these issues. To this end, a ZnO flower-like structure having unimodal distributions of size and spacing was fabricated by ZnO hydrothermal growth. This fabricated nanostructure has a thickness on the order of 103 nm and a diameter on the order of 102 nm. The thickness and diameter increase in proportion with the synthesis time (thickness growth rate = 43 nm/min, diameter growth rate = 20 nm/min). The shape of the nanostructure can be easily tuned by simply adjusting the synthesis and etching times. This method combines the advantages of top-down and bottom-up synthetic approaches in that the structural color can be continuously modified once fabricated.


Electron optic aspects of sonically disintegrated influenza virus A(H1N1).
Purified influenza virus A(H1N1) was sonicated in a continuous flow Ultrasonics F600 device at 20 kHz, 600 W. Electron optic examination of samples collected at different time intervals revealed morphologic alterations of the virus particles, gradually increasing in intensity: detachment of surface components, disruption of the viral corpuscles and of their constitutive elements, appearance of ghosts and of clustered viral components different in size and orientation.


Unraveling the Roles of miR-204-5p and HMGA2 in Papillary Thyroid Cancer Tumorigenesis.
Thyroid cancer is the most common endocrine malignant tumor with an increasing incidence rate. Although differentiated types of thyroid cancer generally present good clinical outcomes, some dedifferentiate into aggressive and lethal forms. However, the molecular mechanisms governing aggressiveness and dedifferentiation are still poorly understood. Aberrant expression of miRNAs is often correlated to tumor development, and miR-204-5p has previously been identified in papillary thyroid carcinoma as downregulated and associated with aggressiveness. This study aimed to explore its role in thyroid tumorigenesis. To address this, gain-of-function experiments were performed by transiently transfecting miR-204-5p in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. We prove that this miRNA inhibits cell invasion by regulating several targets associated with an epithelial-mesenchymal transition, such as SNAI2, TGFBR2, SOX4 and HMGA2. HMGA2 expression is regulated by the MAPK pathway but not by the PI3K, IGF1R or TGFβ pathways, and the inhibition of cell invasion by miR-204-5p involves direct binding and repression of HMGA2. Finally, we confirmed in vivo the relationship between miR-204-5p and HMGA2 in human PTC and a corresponding mouse model. Our data suggest that HMGA2 inhibition offers promising perspectives for thyroid cancer treatment.


Formation of a monomeric DNA binding domain by Skn-1 bZIP and homeodomain elements.
Maternally expressed Skn-1 protein is required for the correct specification of certain blastomere fates in early Caenorhabditis elegans embryos. Skn-1 contains a basic region similar to those of basic leucine zipper (bZIP) proteins but, paradoxically, it lacks a leucine zipper dimerization segment. Random sequence selection methods were used to show that Skn-1 binds to specific DNA sequences as a monomer. The Skn-1 basic region lies at the carboxyl terminus of an 85-amino acid domain that binds preferentially to a bZIP half-site and also recognizes adjacent 5' AT-rich sequences in the minor groove, apparently with an amino (NH2)-terminal "arm" related to those of homeodomain proteins. The intervening residues appear to stabilize interactions of these two subdomains with DNA. The Skn-1 DNA binding domain thus represents an alternative strategy for promoting binding of a basic region segment recognition helix to its cognate half-site. The results point to an underlying modularity in subdomains within established DNA binding domains.


Sex specificity of asthma associated with objectively measured body mass index and waist circumference: the Humboldt study.
To investigate the possibility of sex specificity for the association of obesity and asthma using objective measures of body mass index (BMI) and waist circumference (WC). Cross-sectional study of adults (n = 2,057) living in Humboldt, SK, Canada in 2003. A rural community. Ever-asthma was defined as lifetime physician-diagnosed asthma, and recent asthma was defined as asthma diagnosed by a physician during the past 12 months. BMI and WC were objectively measured. Among the participants, 5.6% of men and 10.0% of women reported having ever-asthma, and 2.7% and 6.0% had recent asthma, respectively. Higher levels of both BMI and WC were significantly associated with asthma in women but not in men. The adjusted odds ratios for women with a BMI of at least 30.0 kg/m2 relative to women with a BMI of < 25.0 kg/m2 were 2.06 (95% confidence interval [CI], 1.42 to 4.05) for ever-asthma and 3.47 (95% CI, 1.64 to 7.32) for recent asthma. Our study demonstrated that the increased risk of asthma associated with obesity was only significant in women but not in men even when BMI was objectively measured, and this association was robust to the anthropometric measures.


Rapid identification of fungi in culture-negative clinical blood and respiratory samples by DNA sequence analyses.
Clinical diagnoses of fungal infections often rely upon culture techniques followed by microscopic examination of positive cultures and histopathological specimens. Culturing of microorganisms is prone to false negatives, while microscopy methods can be complicated by atypical phenotypes and organisms that are morphologically indistinguishable in tissues. Delays in diagnoses (or the lack thereof) and inaccurate identification of infectious organisms contribute to increased morbidity and mortality in patients. Two-hundred randomized, heterogeneous patient blood and respiratory samples that were culture-negative were tested using polymerase chain reaction (PCR) amplification of internal transcribed spacer regions of ribosomal RNA genes utilizing panfungal primers. Amplicons were sequenced, subjected to sequence similarity searches, and compared using phylogenetic analyses. Thirteen fungal sequences were detected in three whole-blood samples and nine respiratory samples. Bioinformatic analyses were performed which indicated the presence of multiple pathogens and potential pathogens. The results from this pilot study demonstrate the utility of PCR assays and sequence analyses in clinical tests for fungi to facilitate rapid diagnosis and appropriate treatments to deal with the false negatives from culture results.


Evaluation of the agricultural potential of the serpentinite rock as a soil remineralizer.
Magnesium is one of the essential elements for the plant growth. However, when the supply of magnesium is required exclusively, few economically feasible options are available. Serpentinite represents an alternative source of magnesium, although little is known about its potential and efficiency under tropical soil conditions. This work aimed to evaluate the use of serpentinite as a soil remineralizer, as well as magnesium fertilizer. The study was conducted in a greenhouse, using a completely randomized design, with seven treatments and four replications, as follows: three levels of serpentinite, mix of serpentinite and phonolite, and the controls with dolomitic limestone and without fertilization. Two plant species (Zea mays L. corn hybrid BRS - 1055 and Phaseolus vulgaris L. common bean variety BRS - Estilo) and two contrasting soils (clayey and sandy texture), were used in pots. Results showed that serpentinite's free silica and toxic element contents fitted the legal requirements. No statistically significant difference was observed for the plant dry matter weight production in the serpentinite and dolomitic limestone control, as well as in the pure serpentinite and the mix with phonolite treatments. The serpentinite was able to supply and to fullfil magnesium requirements for growth and development of corn and bean plants.


Radiologist observations of computed tomography (CT) images predict treatment outcome in TB Portals, a real-world database of tuberculosis (TB) cases.
The TB Portals program provides a publicly accessible repository of TB case data containing multi-modal information such as case clinical characteristics, pathogen genomics, and radiomics. The real-world resource contains over 3400 TB cases, primarily drug resistant cases, and CT images with radiologist annotations are available for many of these cases. The breadth of data collected offers a patient-centric view into the etiology of the disease including the temporal context of the available imaging information. Here, we analyze a cohort of new TB cases with available radiologist observations of CTs taken around the time of initial registration of the case into the database and with available follow up to treatment outcome of cured or died. Follow up ranged from 5 weeks to a little over 2 years consistent with the longest treatment regimens for drug resistant TB and cases were registered within the years 2008 to 2019. The radiologist observations were incorporated into machine learning pipelines to test various class balancing strategies on the performance of predictive models. The modeling results support that the radiologist observations are predictive of treatment outcome. Moreover, inferential statistical analysis identifies markers of TB disease spread as having an association with poor treatment outcome including presence of radiologist observations in both lungs, swollen lymph nodes, multiple cavities, and large cavities. While the initial results are promising, further data collection is needed to incorporate methods to mitigate potential confounding such as including additional model covariates or matching cohorts on covariates of interest (e.g. demographics, BMI, comorbidity, TB subtype, etc.). Nonetheless, the preliminary results highlight the utility of the resource for hypothesis generation and exploration of potential biomarkers of TB disease severity and support these additional data collection efforts.


Transcriptome-based identification and functional characterization of iridoid synthase involved in monotropein biosynthesis in blueberry.
Blueberries (Vaccinium spp.) are well known for their nutritional quality, and recent work has shown that Vaccinium spp. also produce iridoids, which are specialized metabolites with potent health-promoting benefits. The iridoid glycoside monotropein, which has anti-inflammatory and antinociceptive activities, has been detected in several wild blueberry species but in only a few cultivated highbush blueberry cultivars. How monotropein is produced in blueberry and the genes involved in its biosynthesis remain to be elucidated. Using a monotropein-positive (M+) and monotropein-negative (M-) cultivar of blueberry, we employed transcriptomics and comparative genomics to identify candidate genes in the blueberry iridoid biosynthetic pathway. Orthology analysis was completed using de novo transcript assemblies for both the M+ and M- blueberry cultivars along with the known iridoid-producing plant species Catharanthus roseus to identify putative genes involved in key steps in the early iridoid biosynthetic pathway. From the identified orthologs, we functionally characterized iridoid synthase (ISY), a key enzyme involved in formation of the iridoid scaffold, from both the M+ and M- cultivars. Detection of nepetalactol suggests that ISY from both the M+ and M- cultivars produce functional enzymes that catalyze the formation of iridoids. Transcript accumulation of the putative ISY gene did not correlate with monotropein production, suggesting other genes in the monotropein biosynthetic pathway may be more directly responsible for differential accumulation of the metabolite in blueberry. Mutual rank analysis revealed that ISY is co-expressed with UDP-glucuronosyltransferase, which encodes an enzyme downstream of the ISY step. Results from this study contribute new knowledge in our understanding of iridoid biosynthesis in blueberry and could lead to development of new cultivars with increased human health benefits.


Histopathologic changes in dental and oral soft tissues in 2-butoxyethanol-induced hemolysis and thrombosis in rats*.
2-Butoxyethanol (2-BE; ethylene glycol monobutyl ether) is extensively used as a solvent in surface coatings, such as lacquers, enamels, and varnishes in industrial and household cleaning products. Its major toxicity is manifested in the circulation, as it induces hemolytic anemia and thrombosis in various organs. While 2-BE has been implicated in the induction of anemia in different species, the rat has proven most sensitive, especially the female of this species. The purpose of this study was to document the effects of 2-BE on dentition, the periodontal ligament, the tongue, the salivary glands, and the oral mucosa in male and female Fischer 344 rats. The experiment included 40 rats divided into five groups. Four groups were exposed to 2, 3, or 4 daily doses of 2-BE, and a fifth group served as control. The rats were killed on days 2, 3, 4, and 29. The teeth and soft oral tissues were prepared for histopathologic observation. The histopathologic analysis showed that the major effect of 2-BE was exerted on the odontoblasts of the incisors and on molars, with greater effect on the incisors. Foci of damaged muscle cells in the tongue were also observed. The blood vessels were dilated and congested, and a primary thrombosis was seen in the dental pulp. The results of this study revealed a resemblance between the dental injuries in this rat model and those seen in sickle cell anemia in humans. This 2-BE animal model holds potential to assist in the discovery of preventive measures and/or treatment for dental injuries that occur in human diseases with hemolytic anemia.


Antennapedia-derived positively-charged peptide faces multiple problems upon their usage as targeting ligand for liposomal doxorubicin.
The positively-charged peptide antp derived from Antennapedia transcription protein is demonstrated to mediate the liposome translocation across the cell membrane. In the current investigation, we prepared a stable liposomal doxorubicin (Dox) formulation and targeted it with the antp peptide from 0 to 200 ligand/liposome. These antp-containing liposomes were investigated in terms of physical stability on storage in the refrigerator and upon incubation in blood. Also, other features like cell binding, uptake, biodistribution, and treatment efficiency were evaluated in C26 colon carcinoma BALB/c mice. The Antp in liposomes resulted in enhanced particle growth with the development of the enormously large liposomes from 2000 to 6000 nm. Upon incubation in blood, these large liposomes were removed. The antp also enhanced the cell binding affinity and cell uptake rate of the liposomes and resulted in the restriction of the cancer cell proliferation, but it failed to improve the chemotherapeutic property of the Dox-liposome. The i.v. injection of antp-liposomes (15 mg Dox/kg) caused severe body weight loss and early death incidence due to probably increased toxicity. The antp targeting offered no advantage to the Dox-liposome in the delivery of Dox to the tumor, and failed to enhance the treatment efficiency of the liposomes.


Anatomical structures, cell types, and biomarkers of the healthy human blood vasculature.
More than 150 scientists from 17 consortia are collaborating on an international project to build a Human Reference Atlas, which maps all 37 trillion cells in the healthy adult human body. The initial release of this atlas provided hierarchical lists of the anatomical structures, cell types, and biomarkers in 11 organs. Here, we describe the methods we used as part of this initiative to build the first open, computer-readable, and comprehensive database of the adult human blood vasculature, called the Human Reference Atlas-Vasculature Common Coordinate Framework (HRA-VCCF). It includes 993 vessels and their branching connections, 10 cell types, and 10 biomarkers. With this paper we are releasing additional details on vessel types and subtypes, branching sequence, anastomoses, portal systems, microvasculature, functional tissue units, mappings to regions vessels supply or drain, geometric properties of vessels, and links to 3D reference objects. Future versions will add variants and connections to the lymph vasculature; and, it will iteratively expand and improve the database as additional experimental data become available through the participating consortia.


Differential gene expression profile between progressive and de novo muscle invasive bladder cancer and its prognostic implication.
This study aimed to ascertain gene expression profile differences between progressive muscle-invasive bladder cancer (MIBC) and de novo MIBC, and to identify prognostic biomarkers to improve patients' treatment. Retrospective multicenter study in which 212 MIBC patients who underwent radical cystectomy between 2000 and 2019 were included. Gene expression profiles were determined in 26 samples using Illumina microarrays. The expression levels of 94 genes were studied by quantitative PCR in an independent set of 186 MIBC patients. In a median follow-up of 16 months, 46.7% patients developed tumor progression after cystectomy. In our series, progressive MIBC patients show a worse tumor progression (p = 0.024) and cancer-specific survival (CSS) (p = 0.049) than the de novo group. A total of 480 genes were found to be differently expressed between both groups. Differential expression of 24 out of the 94 selected genes was found in an independent cohort. RBPMC2 and DSC3 were found as independent prognostic biomarkers of tumor progression and CALD1 and LCOR were identified as prognostic biomarkers of CSS between both groups. In conclusion, progressive and de novo MIBC patients show different clinical outcome and gene expression profiles. Gene expression patterns may contribute to predict high-risk of progression to distant metastasis or CSS.


Rhodium-Catalyzed Asymmetric Synthesis of 1,2-Disubstituted Allylic Fluorides.
Although there are many methods for the asymmetric synthesis of monosubstituted allylic fluorides, construction of enantioenriched 1,2-disubstituted allylic fluorides has not been reported. To address this gap, we report an enantioselective synthesis of 1,2-disubstituted allylic fluorides using chiral diene-ligated rhodium catalyst, Et3 N ⋅ 3HF as a source of fluoride, and Morita Baylis Hillman (MBH) trichloroacetimidates. Kinetic studies show that one enantiomer of racemic MBH substrate reacts faster than the other. Computational studies reveal that both syn and anti π-allyl complexes are formed upon ionization of allylic substrate, and the syn complexes are slightly energetically favorable. This is in contrast to our previous observation for formation of monosubstituted π-allyl intermediates, in which the syn π-allyl conformation is strongly preferred. In addition, the presence of an electron-withdrawing group at C2 position of racemic MBH substrate renders 1,2-disubstituted π-allyl intermediate formation endergonic and reversible. To compare, formation of monosubstituted π-allyl intermediates was exergonic and irreversible. DFT calculations and kinetic studies support a dynamic kinetic asymmetric transformation process wherein the rate of isomerization of the 1,2-disubstituted π-allylrhodium complexes is faster than that of fluoride addition onto the more reactive intermediate. The 1,2-disubstituted allylic fluorides were obtained in good yields, enantioselectivity, and branched selectivity.


Computed tomographic colonography compared with colonoscopy in patients at increased risk for colorectal cancer.
To date, computed tomographic (CT) colonography has been compared with an imperfect test, colonoscopy, and has been mainly assessed in patients with positive screening test results or symptoms. Therefore, the available data may not apply to screening of patients with a personal or family history of colorectal polyps or cancer (increased risk). We prospectively investigated the ability of CT colonography to identify individuals with large (>or=10 mm) colorectal polyps in consecutive patients at increased risk for colorectal cancer. A total of 249 consecutive patients at increased risk for colorectal cancer underwent CT colonography before colonoscopy. Two reviewers interpreted CT colonography examinations independently. Sensitivity, specificity, and predictive values were determined after meticulous matching of CT colonography with colonoscopy. Unexplained large false-positive findings were verified with a second-look colonoscopy. In total, 31 patients (12%) had 48 large polyps at colonoscopy. This included 8 patients with 8 large polyps that were overlooked initially and detected at the second-look colonoscopy. In 6 of 8 patients, the missed polyp was the only large lesion. With CT colonography, 84% of patients (26/31) with large polyp(s) were identified, paired for a specificity of 92% (200-201/218). Positive and negative predictive values were 59%-60% (26/43-44) and 98% (200-201/205-206), respectively. CT colonography detected 75%-77% (36-37/48) of large polyps, with 9 of the missed lesions being flat. CT colonography and colonoscopy have a similar ability to identify individuals with large polyps in patients at increased risk for colorectal cancer. The large proportion of missed flat lesions warrants further study.


The SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptor.
Gene targeting experiments have shown that the cytokine erythropoietin (EPO), its cognate erythropoietin receptor (EPO-R), and associated Janus tyrosine kinase, JAK2, are all essential for erythropoiesis. Structural-functional and murine knock-in experiments have suggested that EPO-R Tyr-343 is important in EPO-mediated mitogenesis. Although Stat5 binds to EPO-R phosphotyrosine 343, the initial Stat5-deficient mice did not have profound erythroid abnormalities suggesting that additional Src homology 2 (SH2) domain-containing effectors may bind to EPO-R Tyr-343 and couple to downstream signaling pathways. We have utilized cloning of ligand target (COLT) screening to demonstrate that EPO-R Tyr(P)-343 and Tyr(P)-401 bind to the SH2 domain-containing adaptor protein SH2B1β. Immunoprecipitation and in vitro mixing experiments reveal that EPO-R binds to SH2B1 in an SH2 domain-dependent manner and that the sequence that confers SH2B1 binding to the EPO-R is pYXXL. Previous studies have shown that SH2B1 binds directly to JAK2, but we show that in hematopoietic cells, SH2B1β preferentially associates with the EPO-R. SH2B1 is capable of constitutive association with EPO-R, which is necessary for its optimal SH2-dependent recruitment to EPO-R-Tyr(P)-343/Tyr(P)-401. We also demonstrate that SH2B1 is responsive to EPO stimulation and becomes phosphorylated, most likely on serines/threonines, in an EPO dose- and time-dependent manner. In the absence of SH2B1, we observe enhanced activation of signaling pathways downstream of the EPO-R, indicating that SH2B1 is a negative regulator of EPO signaling.


New approach to great-vessel reconstruction in transposition complexes with interrupted aortic arch.
Interrupted aortic arch can be associated with transposition of the great arteries with ventricular septal defect and with the Taussig-Bing anomaly. This usually results in a marked disparity between the hypoplastic ascending aorta and the dilated main pulmonary artery. Currently, standard arterial switch and arch repair is a widely applied approach to the surgical management of these lesions. Though the morphology of the great vessels in these lesions does not preclude this approach, the great-vessel mismatch can result in difficulties at and beyond the proximal neo-aortic to ascending aortic suture line that cause excessive bleeding, obstruction, tension, distortion, and the need of patch augmentation of the ascending aorta or arch with nonviable material. We present an alternative surgical approach used in 2 patients, 1 with Taussig-Bing anomaly and interrupted aortic arch and the other with transposition of the great arteries, ventricular septal defect, and interrupted aortic arch, that greatly simplifies the reconstruction of the neo-aorta and repair of the interrupted arch and avoids these potential hazards.


Placental expression of D6 decoy receptor in preeclampsia.
The purpose of this study was to investigate the expression of the D6 decoy receptor that can bind chemokines and target them for degradation, resulting in inhibition of inflammation in placentas from preeclamptic and normal pregnancies. The current study was carried out in 35 pregnant women (23 patients with preeclampsia and 12 healthy, normotensive pregnant women) during the third trimester of pregnancy. The expressions of D6 decoy receptor in the placenta were determined with real time reverse transcriptase polymerase chain reaction and western blotting. The mRNA and protein of D6 decoy receptor were detected in all of placentas from preeclamptic and normal pregnancies. Placental D6 decoy receptor mRNA expression was significantly lower in patients with preeclampsia than in patients with normal pregnancies. Western blot analyses revealed decreased protein expression in cases of preeclampsia. The expression of the D6 decoy receptor in preeclamptic placentas was significantly lower than in normal placentas. Further studies are needed to clarify the underlying mechanisms that link decreased expression of placental D6 decoy receptor and preeclampsia.


High Pressure Phases of Some Compounds of Groups II-VI.
The high pressure phases of the mercury and cadmium sulfides. selenides, and tellutrides have been determined by means of x-raiy diffraction patterns obtained while the materials are under presssure.


Impaired myogenic development, differentiation and function in hESC-derived SMA myoblasts and myotubes.
Spinal muscular atrophy (SMA) is a severe genetic disorder that manifests in progressive neuromuscular degeneration. SMA originates from loss-of-function mutations of the SMN1 (Survival of Motor Neuron 1) gene. Recent evidence has implicated peripheral deficits, especially in skeletal muscle, as key contributors to disease progression in SMA. In this study we generated myogenic cells from two SMA-affected human embryonic stem cell (hESC) lines with deletion of SMN1 bearing two copies of the SMN2 gene and recapitulating the molecular phenotype of Type 1 SMA. We characterized myoblasts and myotubes by comparing them to two unaffected, control hESC lines and demonstrate that SMA myoblasts and myotubes showed altered expression of various myogenic markers, which translated into an impaired in vitro myogenic maturation and development process. Additionally, we provide evidence that these SMN1 deficient cells display functional deficits in cholinergic calcium signaling response, glycolysis and oxidative phosphorylation. Our data describe a novel human myogenic SMA model that might be used for interrogating the effect of SMN depletion during skeletal muscle development, and as model to investigate biological mechanisms targeting myogenic differentiation, mitochondrial respiration and calcium signaling processes in SMA muscle cells.


Barriers and Facilitators to the Implementation of Evidence-Based Lifestyle Management in Polycystic Ovary Syndrome: A Narrative Review.
Polycystic ovary syndrome (PCOS) is a complex condition that involves metabolic, psychological and reproductive complications. Insulin resistance underlies much of the pathophysiology and symptomatology of the condition and contributes to long term complications including cardiovascular disease and diabetes. Women with PCOS are at increased risk of obesity which further compounds metabolic, reproductive and psychological risks. Lifestyle interventions including diet, exercise and behavioural management have been shown to improve PCOS presentations across the reproductive, metabolic and psychological spectrum and are recommended as first line treatment for any presentation of PCOS in women with excess weight by the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2018. However, there is a paucity of research on the implementation lifestyle management in women with PCOS by healthcare providers. Limited existing evidence indicates lifestyle management is not consistently provided and not meeting the needs of the patients. In this review, barriers and facilitators to the implementation of evidence-based lifestyle management in reference to PCOS are discussed in the context of a federally-funded health system. This review highlights the need for targeted research on the knowledge and practice of PCOS healthcare providers to best inform implementation strategies for the translation of the PCOS guidelines on lifestyle management in PCOS.


[Involvement of hemoglobin in the therapeutic action of blood ultraviolet irradiation].
The objective of this work was to study the mechanism of therapeutic action of extracorporeal ultraviolet irradiation of circulating blood and to evaluate the possibility of its application to combined treatment of patients with acute coronary syndrome. It was shown that ultraviolet irradiation causes photodissociation ofoxyhemoglobin thereby altering the oxygen-carrying function of the blood and improving oxygen supply to cells and tissues. The UV-induced modification of blood properties not only prevents tissue hypoxia but also triggers a cascade of metabolic processes. Taken together, these effects have beneficial influence on the clinical course of cardiovascular and other diseases.


Reconstructive surgery in the rheumatoid hand.
Reconstructive hand surgery is an established, proved, and effective method to correct deformities and increase function in rheumatoid patients. As more experience has been gathered, the indications for both arthrodesis and arthroplasty have been better established, and a better approach to reconstructive hand surgery has developed. In this discussion we have evaluated in detail the surgical treatment indicated for wrist, metacarpophalangeal joint, and thumb deformities. The treatment of swan-neck deformities and boutonniere deformities is discussed in other sections in this volume.


[STRONGYLOIDES STERCORALIS: CLINICAL SEVERE FORMS ASSOCIATED TO HTLV-1 INFECTION]
A study was conducted in Lima to determine the HTLV-1 infection rate among patients with different clinical patterns of Strongyloidiasis. This study included 21 patients with Strongyloides Stercoralis (St St) hyperinfection (Group 1), and a group which consisted of sex and age matched asymptomatic healthy individuals whose stools were negative (Control Group Group 2). A third group included 33 patients with "probable hyperinfection", and another group of 63 patients with intestinal Strongyloidiasis, without evidence of systemic disease, was included. Serum from each studied individual was analized to find HTLV-1/II and ELISA; positive cases were confirmed by Western Blot. The hyperinfection rate was significantly higher [85.7% (18/21)] compared to the control group [4.7% (1/21)] p<0.001. Likewise, the "probable hyperinfection" group was considerably higher [69.7% (23/33)] in comparison to the control group p<0.01. The group with intestinal Strongyloidiasis was [10% (6/62)] lower than patients with Strongyloides hyperinfection, but did not differ significantly (p>0.05) from the control group. In this last group 3/6 were HTLV-1 positive, and their follow-up showed they developed hyperinfection forms. We conclude that severe forms of St St are considerably associated to HTLV-1 infection in adults and children over 5 years of age. No cases with HTLV-II were detected.


Double-Flanged polypropylene Suture for Scleral Fixation of Cionni Capsule Tension Ring.
To describe a new technique for transconjunctival intrascleral fixation of Cionni CTR using double-flanged polypropylens suture. This is a prospective interventional case series which included 7 cases with severe (more than 180 degrees) zonular dialysis. Three cases were hereditary lens subluxation (Marfan syndrome), 2 cases with traumatic subluxation and 2 cases with pseudo-exfoliation syndrome. All cases achieved a good postoperative stable and centered IOL with good visual results. No postoperative complications were recorded apart from PCO in 3 cases and mild bleeding during needle passage in one case. This described technique is a simple, time sparing and minimally invasive method for achieving good bag centration. It eliminates the need of conjunctival peritomy, subconjunctival vessels cautery and scleral fashioning of a flap, pocket or a groove. The use of 6/0 polypropylene theoretically can achieve better longevity.


The association of SARS-CoV-2 infection and tuberculosis disease with unfavorable treatment outcomes: A systematic review.
Whether SARS-CoV-2 infection and its management influence tuberculosis (TB) treatment outcomes is uncertain. We synthesized evidence on the association of SARS-CoV-2 coinfection (Coinfection Review) and its management (Clinical Management Review) on treatment outcomes among people with tuberculosis (TB) disease. We systematically searched the literature from 1 January 2020 to 6 February 2022. Primary outcomes included: unfavorable (death, treatment failure, loss-to-follow-up) TB treatment outcomes (Coinfection and Clinical Management Review) and/or severe or critical COVID-19 or death (Clinical Management Review). Study quality was assessed with an adapted Newcastle Ottawa Scale. Data were heterogeneous and a narrative review was performed. An updated search was performed on April 3, 2023. From 9,529 records, we included 11 studies and 7305 unique participants. No study reported data relevant to our review in their primary publication and data had to be contributed by study authors after contact. Evidence from all studies was low quality. Eight studies of 5749 persons treated for TB (286 [5%] with SARS-CoV-2) were included in the Coinfection Review. Across five studies reporting our primary outcome, there was no significant association between SARS-CoV-2 coinfection and unfavorable TB treatment outcomes. Four studies of 1572 TB patients-of whom 291 (19%) received corticosteroids or other immunomodulating treatment-were included in the Clinical Management Review, and two addressed a primary outcome. Studies were likely confounded by indication and discordant findings existed among studies. When updating our search, we still did not identify any study reporting data relevant to this review in their primary publication. No study was designed to answer our research questions of interest. It remains unclear whether TB/SARS-CoV-2 and its therapeutic management are associated with unfavorable outcomes. Research is needed to improve our understanding of risk and optimal management of persons with TB and SARS-CoV-2 infection. Registration: PROSPERO (CRD42022309818).


The effects of uterine artery embolization with a new degradable microsphere in an experimental study.
Background Transarterial particle embolization is a common treatment of uterine fibroids, aiming to obtain ischemia resulting in shrinking of the fibroid with preservation of normal uterine tissue. Embolization with non-degradable microspheres is established, but causes permanent occlusion of the arteries, affecting both the uterus as well as the fibroids. Purpose To evaluate in vivo degradation, local tissue effects, and possible recanalization following intra-arterial deposition of the new, degradable starch microspheres (DSM), in a short-term experimental pilot study. Material and Methods Under general anesthesia, unilateral transarterial embolization of the uterine artery (UA) with DSM 500-700 µm was performed in five female sheep. The animals underwent renewed angiography at different intervals after embolization (19-65 h) and were subsequently sacrificed. Histological examination was performed. Results Embolization with absent flow in the UA could be completed in five of six animals. At final angiographic evaluation, recanalization of the embolized arteries was evident in three sheep. At the gross postmortem examination, edema and discoloration indicating ischemia of the uterus at the embolized side, was observed in all the sheep. At histopathological examination, different stages of DSM degradation in the arterial branches were observed in both endometrium and myometrium. Mild-to-moderate vasculitis and mild-to-extensive ischemic changes were present along with degeneration of the uterine glands. Conclusion This short-term pilot study proved efficacy of embolization with DSM causing ischemic changes in the embolized organ, but also degradation of the DSM with subsequent recanalization of the embolized arteries.


[Isolation of Legionella species from hot springs used for foot-soaking].
We aimed to investigate the presence of Legionella species in hot-spring baths for feet, which have been rapidly increasing in number in Japan in recent years. The investigations were conducted between March 2009 and November 2011, and hot springs throughout the country were sampled. Legionella isolates were confirmed on the basis of the method described in the "Manual for the countermeasure to legionellosis, 3rd Edition." In this method, the samples were concentrated and smeared on GVPCalpha agar medium after acid treatment and cultured for 7 days at 36 degrees C. Gram-negative rods that required L-cysteine were determined to be Legionella species. After the first identification using Duopath Legionella (Merck Ltd. Japan), isolates were identified on the basis of agglutination reaction of an immune serum or genetic examination. Legionella was isolated from 56 of the 196 samples (28.6%) and was confirmed to widely inhabit hot-spring baths from Hokkaido to Kyushu. The isolation rates were the highest (40.9%) in facilities installed around railway stations, including those on platforms. The average microbial density of Legionella species per 100 ml of hot spring water was 1.0 x 10(1) CFU, with a maximum value of 1.0 x 10(4) CFU, although the microbial density in most of the samples (34 samples; 60.7%) was less than 10(2) CFU. Legionella pneumophila was the dominant strain, and 16 strains (23.9%) of serogroup 1 were isolated. In addition, 7 strains (10.4%) of Legionella londiniensis and 4 strains (6.0%) of Legionella rubrilucens were isolated. Legionella species inhabit approximately 30% of all hot springs for foot-soaking in the country. Although the number of viable organisms is small, the dominant presence of Legionella pneumophila, a major pathogen responsible for legionnaire's disease, raises the possibility of legionnaire's disease in users of these hot springs. Therefore, each institute should understand the present distribution of Legionella species in these hot springs and undertake appropriate sanitary measures.


Colovesical Fistula Complicating Diverticular Disease: A 14-Year Experience.
Colovesical fistulas (CVF) constitute the most common type of spontaneously occurring fistulas associated with diverticular disease. One-stage laparoscopic resection has been shown to be feasible, but studies comparing this approach to open surgery are scarce. The aim of this study was to compare the clinical outcomes of open and laparoscopic surgery for CVF of diverticular origin. From January 2000 to July 2014, 37 colectomies were performed for diverticular disease-related CVF. Twenty-eight patients who underwent resection and primary anastomosis were divided in 2 groups: the laparoscopic surgery group (group A) and the open surgery group (group B). We have analyzed the following parameters: operative time, complication rate, hospital stay, recurrence, and early mortality rate. Groups A and B were comparable in terms of age, sex, diverticulitis episodes, previous abdominal surgery, and body mass index.The mean duration of surgery was significantly shorter in group B: 175 versus 237 minutes (P=0.011). There was a faster recovery of gastrointestinal transit in group A (2 vs. 13; P=0, 0002). However, there were no significant differences between the groups with respect to serious postoperative morbidity [(Clavien-Dindo scores of 3, 4, and 5) 4 vs. 0; P=0.098)] and with respect to hospital stay (10.5 vs. 9.5 d; P=0.537). There was no recurrence during a median follow-up of 12 months. Laparoscopic resection and primary anastomosis should be considered a safe and feasible option for the management of diverticular CVF. Despite progresses in minimally invasive colorectal surgery, the conversion rate and morbidity are still high.


Effects of untreated or insufficiently treated wastewater discharges on the spatial and temporal variability of nitrous oxide (N2O) emissions from different streams in southeastern Brazil.
Increasing atmospheric N2O concentrations is of great environmental concern due to the role of this gas in climate change and stratospheric ozone destruction. Nitrogen-enriched lotic water bodies are significant sources of N2O. However, N2O emissions from rivers and streams, particularly those that receive untreated or insufficiently treated wastewater discharge, are poorly understood, especially in Brazil. The present study investigated the effects of the discharge of untreated or insufficiently treated wastewater on the spatial-temporal variability of N2O emissions from different streams in Ilha Grande, located within the Abraão hydrographic system, in southeastern Brazil. Estimated N2O fluxes determined in Abraão streams and upstream of the urbanized stretch ranged from 18.4 and 96.5 μg N m-2 h-1. Inside the urbanized stretch, estimated N2O fluxes ranged from 110 to 561 μg N m-2 h-1 under non-limited dissolved oxygen (DO) conditions and 133 to 2,229 μg N m-2 h-1 under hypoxic conditions (DO < 2 mg O2 L-1). High spatial and temporal variability in N2O emissions were noted, with the highest emissions in Abraão urban areas. Therefore, the differences observed between N2O fluxes from the studied streams at Abraão seem to be associated with different lotic water body conditions, such as availability of reactive N and DO.


Impulsive approach tendencies towards physical activity and sedentary behaviors, but not reflective intentions, prospectively predict non-exercise activity thermogenesis.
Understanding the determinants of non-exercise activity thermogenesis (NEAT) is crucial, given its extensive health benefits. Some scholars have assumed that a proneness to react differently to environmental cues promoting sedentary versus active behaviors could be responsible for inter-individual differences in NEAT. In line with this reflection and grounded on the Reflective-Impulsive Model, we test the assumption that impulsive processes related to sedentary and physical activity behaviors can prospectively predict NEAT, operationalized as spontaneous effort exerted to maintain low intensity muscle contractions within the release phases of an intermittent maximal isometric contraction task. Participants (n = 91) completed a questionnaire assessing their intentions to adopt physical activity behaviors and a manikin task to assess impulsive approach tendencies towards physical activity behaviors (IAPA) and sedentary behaviors (IASB). Participants were then instructed to perform a maximal handgrip strength task and an intermittent maximal isometric contraction task. As hypothesized, multilevel regression analyses revealed that spontaneous effort was (a) positively predicted by IAPA, (b) negatively predicted by IASB, and (c) was not predicted by physical activity intentions, after controlling for some confounding variables such as age, sex, usual PA level and average force provided during the maximal-contraction phases of the task. These effects remained constant throughout all the phases of the task. This study demonstrated that impulsive processes may play a unique role in predicting spontaneous physical activity behaviors. Theoretically, this finding reinforces the utility of a motivational approach based on dual-process models to explain inter-individual differences in NEAT. Implications for health behavior theories and behavior change interventions are outlined.


An integrative view of Luria's perspective on arithmetic problem solving: the two sides of environmental dependency.
A. R. Luria was the first author to hypothesize that executive dysfunction can lead to specific deficits in arithmetic problem solving, showing that patients' performance depends on the structure of the tasks. Cummings (1995. Anatomic and behavioral aspects of frontal-subcortical circuits. Annals of the New York Academy of Sciences, 15, 1-13) proposed the term "environmental dependency" to define such behavioral disorders triggered by the characteristics of the test and pointed out also the role of executive impairments. Few studies compare executive functioning and problem solving in brain-damaged patients, and none have examined the question from this point of view. Thus, the main aim of the present paper was to study the relationship between environmental dependency and executive functions. Fifty neurological patients with frontal, subcortical, and posterior brain lesions were compared to 45 matched healthy controls and were divided into two groups (dysexecutive/nondysexecutive) according to their performances on executive tasks. Then, we confronted the results of the two groups on an experimental protocol designed in accordance with Luria's proposals. We made also comparisons between groups on the basis of lesion location. Our findings indicate a high association between executive functions and environmental dependency, showing that dysexecutive patients' performances were dependent on task demands. In addition, a specific frontal behavior not associated with executive functions and characterized by the solving of insoluble problems was highlighted. The discussion focused on the interest to take into account the methodological and clinical contributions of environmental dependency. Based on our findings and theoretical arguments, we highlight the need to fractionate this concept.


Short Video-Based Mental Health Intervention for Depressive Symptoms in Junior High School Students: A Cluster Randomized Controlled Trial.
Digital interventions for adolescent mental health are emerging in high-income countries, but have faced challenges and are scarce in China. This study investigated the effect of a short video-based mental health intervention on depressive symptoms in Chinese adolescents. A three-arm cluster randomized controlled trial was conducted in four junior high schools in Shanghai from December 2020 to December 2021 with the measurement at baseline, 6 months after study entry, and 12 months. Outcomes were collected by self-completed questionnaires administered by teachers masked to allocation. The primary outcome was depressive symptoms assessed by the Depression Self-Rating Scale for Children (DSRSC). Mixed effects models were used to compare psychologist-led intervention (n=428 students) and teacher-led intervention (n=385) including six short video-based sessions to usual school provision (n=751). Using intention-to-treat analyses, psychologist-led intervention showed more reduction in depressive symptoms compared to usual school provision at 6 months (coefficient -1.00, 95% CI -1.94 to -0.05), but not at 12 months. Using per-protocol analyses among participants who watched at least three video episodes, both psychologist-led (-1.14, -2.20 to -0.09) and teacher-led intervention (-1.23, -2.45 to -0.02) reduced depressive symptoms compared to usual school provision at 6 months, and the effect of teacher-led intervention persisted at 12 months (-1.58, -3.13 to -0.03). Further exploration found that compared with urban students, the between-group differences for depressive symptoms in rural students were more significant (p<0.05 for interaction) and the effects were maintained at 12 months. The short video-based mental health intervention showed potential to reduce depressive symptoms among Chinese adolescents, and the effects were more significant if the minimum video viewing frequency was reached.


A new intraurethral sphincter prosthesis with a self contained urinary pump.
An intraurethral sphincter prosthesis with a self contained urinary pump for the management of atonic bladder in women was developed and tested. The prosthesis is comprised of a short, self retaining silicone catheter in which there is a valve and pump. Available in a range of lengths and diameters according to urethral size, its insertion is similar to that of a urethral catheter. The prosthesis is secured by a novel fixation method that has soft expandable silicone fins at the bladder neck and a flexible flange at the external meatus. It is activated by a small hand-held control device. To urinate, the activator is placed on the lower abdomen area and the "on" button is pressed, providing energy to the pump by a magnetic coupling method. Once activated, the valve opens and the pump rotates at a high speed, drawing urine from the bladder and pushing it forward, allowing the patient to "void" with a urine flow of 10 to 12 cc/sec. When the bladder is completely evacuated, the pumping ceases and the valve closes, restoring continence. The device was evaluated clinically in 17 women. Fifteen of the patients had a range of use of 2 weeks to 16 months during which they were dry and had complete bladder emptying. Two patients did not tolerate the device because of uninhibited detrusor contractions and, in both cases, it was removed without complication after 5 days.


Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
Dihydropyrimidinase (DHP) is the second enzyme in the catabolism of 5-fluorouracil (5FU), and it has been suggested that patients with a deficiency of this enzyme are at risk from developing severe 5FU-associated toxicity. In this study, we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP. Analysis of the DHP gene showed that the patient was heterozygous for the missense mutation 833G>A (G278D) in exon 5. Heterologous expression of the mutant enzyme in Escherichia coli showed that the G278D mutation leads to a mutant DHP enzyme without residual activity. An analysis for the presence of this mutation in 96 unrelated Dutch Caucasians indicates that the allele frequency in the normal population is <0.5%. Our results show that a partial DHP deficiency is a novel pharmacogenetic disorder associated with severe 5FU toxicity.


Nucleotide sequence of the ARG3 gene of the yeast Saccharomyces cerevisiae encoding ornithine carbamoyltransferase. Comparison with other carbamoyltransferases.
The complete nucleotide sequence of the ARG3 structural gene encoding the monomer of the trimeric ornithine carbamoyltransferase (OTCase) (EC 188.8.131.52) has been determined. It consists of 338 codons with a corresponding molecular mass of 37842 Da. Comparing OTCases from Escherichia coli, yeast, Aspergillus, rat and man emphasizes peculiarities of the yeast enzyme but also brings to light an important degree of conservation between these proteins. Comparing the various OTCases with E. coli aspartate carbamoyltransferase (ATCase) (EC 18.104.22.168) confirms the evolutionary relationship previously noted between the two types of carbamoyltransferases and points to residues probably involved in catalysis and structural folding in OTCases.


Depth-Dependent Glycosaminoglycan Concentration in Articular Cartilage by Quantitative Contrast-Enhanced Micro-Computed Tomography.
A quantitative contrast-enhanced micro-computed tomography (qCECT) method was developed to investigate the depth dependency and heterogeneity of the glycosaminoglycan (GAG) concentration of ex vivo cartilage equilibrated with an anionic radiographic contrast agent, Hexabrix. Full-thickness fresh native (n = 19 in 3 subgroups) and trypsin-degraded (n = 6) articular cartilage blocks were imaged using micro-computed tomography (μCT) at high resolution (13.4 μm(3)) before and after equilibration with various Hexabrix bathing concentrations. The GAG concentration was calculated depth-dependently based on Gibbs-Donnan equilibrium theory. Analysis of variance with Tukey's post hoc was used to test for statistical significance (P < 0.05) for effect of Hexabrix bathing concentration, and for differences in bulk and zonal GAG concentrations individually and compared between native and trypsin-degraded cartilage. The bulk GAG concentration was calculated to be 74.44 ± 6.09 and 11.99 ± 4.24 mg/mL for native and degraded cartilage, respectively. A statistical difference was demonstrated for bulk and zonal GAG between native and degraded cartilage (P < 0.032). A statistical difference was not demonstrated for bulk GAG when comparing Hexabrix bathing concentrations (P > 0.3214) for neither native nor degraded cartilage. Depth-dependent GAG analysis of native cartilage revealed a statistical difference only in the radial zone between 30% and 50% Hexabrix bathing concentrations. This nondestructive qCECT methodology calculated the depth-dependent GAG concentration for both native and trypsin-degraded cartilage at high spatial resolution. qCECT allows for more detailed understanding of the topography and depth dependency, which could help diagnose health, degradation, and repair of native and contrived cartilage.


Evolution of wave-packet spread under sequential scattering of particles of unequal mass.
Under assumptions on initial wave-packet spreads and particle interactions, different mass particles scattering off one another will have the product sigma(2)(i)m(i) converge to a common value, where sigma(i) is the spread and m(i) is the mass of the ith particle. When this relation is satisfied, kinematic entanglement vanishes.


Decreased globin messenger RNA in thalassemia detected by molecular hybridization.
In previous studies of patients with beta thalassemia, mRNA extracted from reticulocytes in peripheral blood when added to cell-free systems reproduces the deficient beta-chain synthesis characteristic of intact cells. The present studies with specific probes for alpha and beta mRNA were designed to decide whether the decreased beta mRNA activity is due to the presence of abnormal or reduced beta globin mRNA in these cells. Purified alpha and beta complementary DNAs (cDNAs) have been synthesized with RNA-instructed DNA polymerase; alpha and beta mRNAs isolated from heavy (beta-producing) and light (alpha-producing) polyribosomes of rabbit reticulocytes were used as templates. Each of the cDNAs is more than 80% pure by the criterion of biological activity. The alpha cDNA labeled with [(32)P]dCTP and the beta cDNA labeled with [(3)H]dCTP have been added simultaneously to reaction mixtures containing various concentrations of mRNA from thalassemic and nonthalassemic subjects. The extent and rate of hybridization were determined, permitting a comparison of relative alpha and beta mRNA content in the same annealing mixture. In six nonthalassemic patients, relatively equal amounts of hybridizable alpha and beta mRNA appear to be present. In five of seven patients with beta-thalassemia, significantly decreased amounts of beta mRNA compared to alpha mRNA can be demonstrated. In two patients with Hemoglobin H disease, there is a decreased amount of alpha mRNA compared to beta mRNA.


Physicians' reasons not to discontinue long-term used off-label antipsychotic drugs in people with intellectual disability.
People with intellectual disability (ID) frequently use antipsychotic drugs on an off-label base, often for many years. Physicians' decisions to discontinue these drugs not only depend on patient characteristics, like the presence of mental or behavioural disorders, but also on environmental factors, such as inappropriate living circumstances, and on attitudes, knowledge and beliefs of staff, clients and their representatives towards the effects of antipsychotic drug use. In this study, we therefore investigated the influence of participant and setting-related factors on decisions of physicians not to discontinue off-label prescribed antipsychotics. The study took place in living facilities of six service providers for people with ID spread over the Netherlands and staffed with support professionals, nurses, behavioural scientist and physicians and was part of an antipsychotics discontinuation trial. ID physicians had to decide whether the off-label use of antipsychotics could be discontinued. Medical and pharmaceutical records were used to establish the prevalence of antipsychotic drug use in the study population, along with duration of use and whether the use was off-label. Reasons of physicians not to discontinue the prescription of antipsychotics in those participants who used off-label antipsychotics for more than a year were collected and categorised as related to participant or setting characteristics, including lack of consent to discontinue, and staff members, participants or their legal representatives. Of the 3299 clients of the service providers, 977 used one or more antipsychotic drugs. The prevalence of antipsychotic drug use was 30%. Reasons for use were in 5% of cases, a chronic psychotic disorder classified according to Diagnostic System Mental Disorders, Fourth Edition, criteria, in 25%, present or past (suspected) non-schizophrenia-related psychotic symptoms and in 69%, challenging behaviours. Overall, physicians were willing to discontinue their prescriptions in 51% of cases, varying from 22% to 87% per service provider. The odds for decisions of physicians to discontinue off-label prescriptions varied from 0.19 to 13.95 per service provider. The variables 'a living situation with care and support' and 'challenging behaviour' were associated with a higher chance of discontinuation. The main reasons for decisions not to discontinue were concerns for symptoms of restlessness, the presence of an autism spectrum disorder, previously unsuccessful attempts to discontinue and objections against discontinuation of legal representatives. Reasons for physicians' decisions not to discontinue the off-label use of antipsychotics varied largely between the service providers. The prevalence of antipsychotic drug use for off-label indications in people with ID remains high. The results of this study indicate that there is a large variation in clinical practice of physicians regarding discontinuation of long-term antipsychotic drug prescriptions, which may be partially related to environmental factors as setting culture and attitudes of staff towards off-label antipsychotic drug use in persons with ID.


Altered Brain Functional Hubs and Connectivity in Type 2 Diabetes Mellitus Patients: A Resting-State fMRI Study.
Type 2 diabetes mellitus (T2DM) affects a vast population and is closely associated with cognitive impairment. However, the mechanisms of cognitive impairment in T2DM patients have not been unraveled. Research on the basic units (nodes or hubs and edges) of the brain functional network on the basis of neuroimaging may advance our understanding of the network change pattern in T2DM patients. This study investigated the change patterns of brain functional hubs using degree centrality (DC) analysis and the connectivity among these hubs using functional connectivity and Granger causality analysis. Compared to healthy controls, the DC values were higher in the left anterior cingulate gyrus (ACG) and lower in the bilateral lateral occipital cortices (LOC) and right precentral gyrus (PreCG) in T2DM patients. The functional connectivity between the left ACG and the right PreCG was stronger in T2DM patients, whereas the functional connectivity among the right PreCG and bilateral LOC was weaker. A negative causal effect from the left ACG to left LOC and a positive effect from the left ACG to right LOC were observed in T2DM patients, while in healthy controls, the opposite occurred. Additionally, the reserve of normal brain function in T2DM patients was negatively associated with the elevated glycemic parameters. This study demonstrates that there are brain functional hubs and connectivity alterations that may reflect the aberrant information communication in the brain of T2DM patients. The findings may advance our understanding of the mechanisms of T2DM-related cognitive impairment.


Pregnancy-induced changes in substance P and neurokinin 1 receptor (NK1-R) expression in the rat uterus.
Adrenergic nerve fibres of the mammalian uterus degenerate during pregnancy. The behaviour of peptidergic fibres, such as substance P-positive fibres and of its preferred neurokinin 1 receptor (NK1-R), is poorly studied in the pregnant rat uterus. The present study analysed the changes in substance P immunoreactivity and in the expression of NK1-R protein in the uterus of non-pregnant, pregnant (days 7, 14 and 21) and postpartum rats (days 1, 8 and 22) by immunohistology, dot blot analysis and western blot analysis. In non-pregnant rats, substance P-positive fibres were localized to the myometrium; these fibres progressively disappeared during gestation and were almost absent at term (day 21). At day 22 post partum, substance P-positive fibres had recovered to numbers comparable with those in the non-pregnant uterus. Dot blot analysis revealed a significant decrease in the immunoreactivity of substance P in the uterus at mid-pregnancy (day 14) and especially at term. Expression of the NK1-R protein showed a progressive increase throughout pregnancy reaching a peak on day 1 post partum; downregulation of NK1-R protein occurred on day 8 post partum. The low and high expressions of NK1-R protein were coincident with a large number of eosinophils and almost no eosinophils in the uterus at oestrus and at term, respectively. It was concluded that substance P immunoreactivity is inversely correlated with NK1-R protein expression in the pregnant and postpartum uterus. The marked upregulation of NK1-R protein at term and after birth indicates that the NK1-R may be involved in the complex regulation of labour and postpartum physiology. However, it is likely that the NK1-protein is not involved in the recruitment of eosinophils into the uterus at oestrus.


Neonatal necrotizing enterocolitis: an update.
Necrotizing enterocolitis (NEC) is a leading cause of mortality and morbidity in neonatal intensive care units. Here we review selected manifestations of NEC, risk factors involved in its pathophysiology as well as putative mechanisms associated with how an immature gut might be more susceptible to NEC. Treatment and potential preventive strategies are discussed.


Missing the early signs of thiamine deficiency. A case associated with a liquid-only diet.
Wernicke encephalopathy (WE) predominantly occurs in alcoholic patients. Few case reports have described this diagnosis as a result of dieting. The diagnosis is often missed or delayed resulting in permanent and severe neurologic sequelae and even death. The typical neurological signs may be absent or missed during the early stages of thiamine deficiency. A 23-year-old female presented to the hospital with confusion, bilateral lateral rectus palsy, and ataxia. Based on the typical neurological triad, WE was suspected. The brain MRI was also typical for WE. Prompt clinical improvement was seen within days after intravenous thiamine supplementation. A detailed medical history revealed that during the past 3 months she had been following a liquid-only diet and had lost about 30 kg. During that time, she had visited the emergency department on multiple occasions due to fatigue, nausea, and vomiting. A high level of suspicion is required by physicians to recognize that fatigue, nausea, and vomiting may represent early signs of thiamine deficiency in patients at risk for nutritional deficiencies. Empirical thiamine supplementation may be reasonable in such cases.


Effector Memory-Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor-Dependent Proinflammatory and Migratory Responses.
The mechanisms regulating CD8+ T cell migration to nonlymphoid tissue during inflammation have not been fully elucidated, and the migratory properties of effector memory CD8+ T cells that re-express CD45RA (TEMRA CD8+ T cells) remain unclear, despite their roles in autoimmune diseases and allotransplant rejection. We used single-cell proteomic profiling and functional testing of CD8+ T cell subsets to characterize their effector functions and migratory properties in healthy volunteers and kidney transplant recipients with stable or humoral rejection. We showed that humoral rejection of a kidney allograft is associated with an accumulation of cytolytic TEMRA CD8+ T cells in blood and kidney graft biopsies. TEMRA CD8+ T cells from kidney transplant recipients exhibited enhanced migratory properties compared with effector memory (EM) CD8+ T cells, with enhanced adhesion to activated endothelium and transmigration in response to the chemokine CXCL12. CXCL12 directly triggers a purinergic P2×4 receptor-dependent proinflammatory response of TEMRA CD8+ T cells from transplant recipients. The stimulation with IL-15 promotes the CXCL12-induced migration of TEMRA and EM CD8+ T cells and promotes the generation of functional PSGL1, which interacts with the cell adhesion molecule P-selectin and adhesion of these cells to activated endothelium. Although disruption of the interaction between functional PSGL1 and P-selectin prevents the adhesion and transmigration of both TEMRA and EM CD8+ T cells, targeting VLA-4 or LFA-1 (integrins involved in T cell migration) specifically inhibited the migration of TEMRA CD8+ T cells from kidney transplant recipients. Our findings highlight the active role of TEMRA CD8+ T cells in humoral transplant rejection and suggest that kidney transplant recipients may benefit from therapeutics targeting these cells.


Umbilical artery Doppler waveform in pregnancies with uncomplicated intra-uterine growth retardation.
Seventy-four pregnancies with uncomplicated intra-uterine growth retardation were assessed at the time of diagnosis by Doppler ultrasound umbilical artery flow velocity waveform. The results were not disclosed to the clinicians. Only those pregnancies with a complete absence of pre-existing disease or pregnancy complications were included. Ten patients showed evidence of fetal compromise due to asphyxia either before or during labour. In all cases the umbilical artery flow velocity waveform had been abnormal, and this abnormality always preceded cardiotocogram abnormality by up to 5 weeks. Though the resistance index was significantly associated with birth weight (p less than 0.001), this relationship was clearly dependent on the compromised fetuses who tended to be very small, and the true association is probably between resistance index and compromise, with birth weight being an intervening variable.


Socioecological Factors Associated With Physical Activity and Sedentary Behavior Among Workers: Using the PRECEDE-PROCEED Model.
Physical inactivity is a major global health problem. Industrial automation has led to an increased number of workers who are sedentary at work. We examined whether three socioecological factors (i.e., predisposing, reinforcing, and enabling factors) derived from the PRECEDE-PROCEED model would be significantly associated with the physical activity and sedentary behavior among workers. A cross-sectional study was conducted among 539 employees at an electronic manufacturing plant in Gumi, South Korea. Physical activity variables of energy expenditure (MET-min/week) and sitting time at work (minutes/day) were measured by the International Physical Activity Questionnaire and the Workforce Sitting Questionnaire, respectively. Of the socioecological factors, a predisposing factor defined as self-determined motivation was measured by the Exercise Self-Regulation Questionnaire; a reinforcing factor defined as autonomy support was measured by the Work Climate Questionnaire; and an enabling factor defined as supportive workplace environment was measured by the Perceived Workplace Environment Scale. Self-determined motivation (i.e., autonomous and controlled forms of motivation), autonomy support, and a supportive workplace environment were all significantly associated with increased physical activity energy expenditure during leisure-time. However, they were not significantly associated with sitting time on working and non-working days. Three socioecological factors of the PRECEDE-PROCEED model were significantly associated with leisure-time physical activity among workers. Our findings may help occupational health nurses use a socioecological approach for designing effective workplace strategies to increase leisure-time physical activity among workers.


Heat illness in the emergency department: keeping your cool.
Heat illness spans a broad spectrum of disease, with outcomes ranging from benign rash to fatal heat stroke. Heat illness is broadly divided into 2 types: classic and exertional. Both types occur as a result of exposure to elevated temperature with inadequate thermoregulation; however, classic illness occurs without preceding physical activity. Treatment consists of rapid cooling, fluid replacement, and physiologic support. Other milder forms of heat illness include heat fatigue, heat syncope, heat edema, and heat rash. Drugs, drug combinations, drug side effects, and infections can also cause or complicate heat illness and these manifestations may not respond to standard cooling maneuvers and treatments alone; each requires specific additional therapy or antidotes to reverse the cycle of heat and organ damage. This review examines the physiology, diagnosis, and treatment of exertional, classic, and drug-induced hypothermia. Field and prehospital diagnosis and treatment are also reviewed, with recommendations for rehydration and monitoring in rhabdomyolysis.


Effects of isoflurane on oxygen-glucose deprivation-induced changes of gene expression profiling in glial-neuronal cocultures.
Isoflurane decreases ischemia-induced neuronal injury. The mechanisms of this effect are largely unknown. We hypothesize that isoflurane induces expression of protective stress genes and decreases expression of apoptosis-related genes. The mRNA expression of about 1300 genes related to neurobiology in rat glial-neuronal cocultures was evaluated by microarray technology. Four experimental conditions were examined: control; 2% isoflurane; oxygen-glucose deprivation (OGD, to simulate ischemia in vitro); or isoflurane (2%) plus OGD. There were four immediate early genes/transcription factors (early growth response 1, c-fos, nerve growth factor-induced factor A and Knox-24) whose mRNA expression was increased to more than 1.4-fold of control levels under the conditions of isoflurane, OGD or isoflurane plus OGD. Isoflurane increased the mRNA expression of heme oxygenase, a 32-kDa heat-shock protein, and decreased the mRNA expression of caspase-2, calpain 1 and the Bcl-2-associated death agonist. These isoflurane effects were still apparent under the condition of isoflurane plus OGD. The mRNA expression of Gbeta1, early growth response 1 and the death effector domain-containing protein DEFT in the samples used for microarray assay was determined by reverse transcriptase-polymerase chain reaction, and the results were consistent with the patterns of changes across the experimental conditions as revealed by microarray technology. Our data suggest that the effects of isoflurane on the mRNA expression of multiple genes in glial-neuronal cocultures are consistent with its neuroprotection against ischemia. A coordinated change in expression of many genes (increased expression of potentially protective gene and decreased expression of potentially damaging genes) after the exposure of isoflurane was revealed by this study.


Structural and spectroscopic study of reactions between chelating zinc-binding groups and mimics of the matrix metalloproteinase and disintegrin metalloprotease catalytic sites: the coordination chemistry of metalloprotease inhibition.
To understand the coordination chemistry of zinc-binding groups (ZBGs) with catalytic zinc centers in matrix metalloproteinases (MMPs) and disintegrin metalloproteases (ADAMs), we have undertaken a model compound study centered around tris(3,5-methylphenypyrazolyl)hydroboratozinc(II) hydroxide and aqua complexes ([Tp(Ph,Me)ZnOH] and [Tp(Ph,Me)Zn(OH2)]+, respectively, wherein (Tp(Ph,Me))- = hydrotris(3,5-methylphenylpyrazolyl)borate) and the products of their reactions with a class of chelating Schiff's base ligands. The results show that the protic ligands, HL (HL = N-propyl-1-(5-methyl-2-imidazolyl)methanimine (5-Me-4-ImHPr), N-propyl-1-(4-imidazolyl)methanimine (4-ImHPr), and N-propyl-1-(2-imidazolyl)methanimine (2-ImHPr)), react with [Tp(Ph,Me)ZnOH] and give products with the general formula [Tp(Ph,Me)ZnL], whereas reactions with neutral aprotic ligands, L' (L' = N-propyl-1-(1-methyl-2-imidazolyl)methanimine (1-Me-2-ImPr) and N-propyl-1-(2-thiazolyl)methanimine (2-TaPr)), yield the corresponding [Tp(Ph,Me)ZnL]+ complexes. Although the phenol group of N-propyl-1-(2-hydroxyphenyl)methanimine (2-HOPhPr) is protic, this ligand forms a cationic four-coordinate complex containing an intraligand hydrogen bond. The solid-state structures of these complexes were determined by single-crystal X-ray diffraction, and the results showed that the protic ligands form five-membered chelates of the Zn2+ ion. All ligands displace the aqua ligand in [Tp(Ph,Me)Zn(OH2)]+ to yield complexes having 1H NMR spectra consistent with the formation of five membered chelates. The 1H resonance frequencies of the chelating ligands typically shift upfield upon coordination to the zinc center, due to ring current effects from the pendant phenyl groups of the (Tp(Ph,Me))- ligand. Thus, the 1H NMR spectra provide a convenient and sensitive means of tracking the solution reactions by titration. The resulting series of spectra showed that the stabilities of the chelates in solution depend on the propensity of the ligands to deprotonate upon chelation of the zinc center. The behaviors of these bidentate ZBGs provide insight into the structural and electronic factors that contribute to the stabilities of inhibited MMPs and ADAMs and suggest that the proton acidity of the coordinated ZBG may be a crucial criterion for inhibitor design.


Effects of dietary intervention combined with insulin aspart on serum nesfatin-1 and CTRP12 levels and pregnancy outcomes in pregnant women with gestational diabetes mellitus.
To analyze the effects of dietary intervention combined with insulin aspart on the serum levels of nesfatin-1, C1q/TNF related protein-12 (CTRP12), and pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM). In this retrospective cohort study, 513 women with GDM admitted to Tangshan Central Hospital (Tangshan, China) between January 2019 and December 2022 were selected and divided into an observation group (dietary intervention combined with insulin aspart therapy; n = 284) and a control group (insulin aspart therapy, n = 229). The general characteristics, clinical outcomes, serum nesfatin-1 and CTRP12 levels, 2-hour postprandial blood glucose levels, pregnancy outcomes, and perinatal outcomes of the 2 groups were compared. After treatment, the total effective rate in the observation group was significantly higher than that of the control group (97.54% vs 86.03%, respectively; P < .001). Compared with the pretreatment levels, nesfatin-1 and CTRP12 levels were decreased in both groups; nesfatin-1 and CTRP12 levels in the observation group were significantly higher than those in the control group. After treatment, the preprandial and 2-hour postprandial blood glucose levels in the observation group were significantly lower than those in the control group. Compared with the control group, the observation group had significantly fewer cesarean sections, and a significantly lower incidence of postpartum hemorrhage, premature rupture of membranes, and other adverse pregnancy outcomes. After treatment, the risks of preterm birth, macrosomia, fetal distress, neonatal asphyxia, neonatal hypoglycemia, and other adverse perinatal outcomes were significantly lower in the observation group than in the control group. In pregnant women with GDM, dietary intervention combined with insulin aspart can improve clinical outcomes; reduce nesfatin-1, CTRP12, and blood glucose levels; and reduce the incidence of adverse pregnancy outcomes.


Rate optimization for relaying VLC system with simultaneous lightwave information and power transfer.
In this paper, the rate optimization problem in a relaying visible light communication system with simultaneous lightwave information and power transfer (SLIPT) is investigated, where the power splitting (PS) transmission strategy is adopted. The expressions of the transmission rate and energy harvesting at the target node are derived, based on which, the rate maximization problem is formulated. Then, this problem is solved by optimizing the PS factor, and a closed-form solution is given. Numerical results reveal that the existence of the relay node improves the system performance.


Thrombin activation of human platelets dissociates a complex containing gelsolin and actin from phosphatidylinositide-specific phospholipase Cgamma1.
We have examined the association of two cytoskeleton proteins, gelsolin and actin, with phosphatidylinositide-specific phospholipase Cgamma1 (PLCgamma1) in resting and thrombin-stimulated human platelets. In unstimulated platelets, gelsolin, actin and PLCgamma1 were immunoprecipitated as a complex by a polyclonal antibody to PLCgamma1. The association of gelsolin and actin was specific for PLCgamma1 because immunoprecipitates of PLCs beta2, beta3, gamma2 and delta1, which are also expressed in human platelets, did not contain detectable gelsolin or actin. Activation with thrombin resulted in platelet aggregation and the dissociation of gelsolin and actin from PLCgamma1. Inhibition of thrombin-induced platelet aggregation blocked the dissociation of gelsolin and actin from PLCgamma1. After stimulation with thrombin, PLCgamma1 activity in immunoprecipitates was increased 2-3-fold. This elevation in PLCgamma1 activity in response to thrombin activation was not observed when platelet aggregation was blocked. Although PLCgamma1 is tyrosine phosphorylated in response to many agonists, we could not detect, by Western analysis with anti-phosphotyrosine antibodies, tyrosine phosphorylation of PLCgamma1 immunoprecipitated from thrombin-stimulated platelets. These results demonstrate that PLCgamma1 is associated with gelsolin and actin in resting platelets, and that thrombin-induced platelet aggregation results in the dissociation of PLCgamma1 from gelsolin and actin, and the stimulation of PLCgamma1 activity.


Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial.
Aortic stiffness is increased in Marfan syndrome contributing to aortic dilatation and rupture, the major cause of premature death in this population. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness. To determine whether perindopril therapy reduces aortic stiffness and attenuates aortic dilatation in patients with Marfan syndrome. A randomized, double-blind, placebo-controlled trial of 17 patients with Marfan syndrome (mean [SD], 33 [6] years) taking standard beta-blocker therapy, initiated in January 2004 and completed in September 2006, at Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia. Patients were administered 8 mg/d of perindopril (n = 10) or placebo (n = 7) for 24 weeks. Indices of arterial stiffness were assessed via systemic arterial compliance, and central and peripheral pulse wave velocities. Aortic root diameters were assessed at 4 sites via transthoracic echocardiography. Perindopril reduced arterial stiffness as indicated by increased systemic arterial compliance (mean [SEM], 0.33 [0.01] mL/mm Hg at baseline to 0.54 [0.04] mL/mm Hg at 24 weeks in perindopril group vs 0.30 [0.01] mL/mm Hg to 0.29 [0.01] mL/mm Hg in placebo group, P = .004), and reduced central (7.6 [0.4] m/s to 5.9 [0.3] m/s in perindopril group, P < .001 vs placebo) and peripheral (10.9 [0.4] m/s to 8.7 [0.4] m/s in perindopril group, P < .001 vs placebo) pulse wave velocities. In addition, perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (P<.01 to P < .001 for all comparisons between groups). Although perindopril marginally reduced mean arterial pressure (from 81 [2] mm Hg to 80 [1] mm Hg in perindopril group vs 83 [2] mm Hg to 84 [3] mm Hg in placebo group, P = .004), the observed changes in both stiffness and left ventricular outflow tract diameter remained significant when mean arterial pressure was included as a covariate. Transforming growth factor beta (TGF-beta), which contributes to aortic degeneration in Marfan syndrome, was reduced by perindopril compared with placebo in both latent (59 [6] ng/mL to 45 [3] ng/mL in perindopril group, P = .01 vs placebo) and active (46 [2] ng/mL to 42 [1] ng/mL in perindopril group, P = .02 vs placebo) forms. Perindopril reduced both aortic stiffness and aortic root diameter in patients with Marfan syndrome taking standard beta-blocker therapy, possibly through attenuation of TGF-beta signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome. clinicaltrials.gov Identifier: NCT00485368.


Exposure to and Speaking Up Against Online Ethnic Hate Speech: The Role of Xenophobia in a Three-Wave Longitudinal Study.
Nowadays, adolescents have extensive access to Information and Communication Technologies, which allow them to engage in social networking activities that may expose them to Online Hate Speech (OHS). While there are few cross-sectional studies about the effects of OHS Exposure on attitudes and aggressive behavior, no study aims to analyze the tendency to Speak Up when exposed to certain content (e.g., reporting, etc.). In addition, no instruments have yet been validated to assess these constructs. The aim of the present study, focused on Online ethnic Hate Speech (OeHS), is double: (a) develop a scale to measure OeHS Exposure and the tendency to Speak Up and analyze its psychometric properties; (b) analyze the longitudinal association between Xenophobia (XEN), OeHS Exposure, and Speaking Up against OeHS, while taking into account gender differences and the nested nature of the data. Six hundred sixty-six Italian high school students (52.7 percent male; MAge = 15[0.64]), nested in 36 ninth grade classes (10 schools), took part in the longitudinal study. The first wave of data collection occurred in early 2020, before the COVID-19 pandemic. The second and third waves took place 12 and 15 months later, respectively. Findings suggest that the OeHS Scale has good psychometric properties. Moreover, according to the findings, while the three variables of interest are always cross-sectionally correlated, a longitudinal negative association have been found between XEN and both Exposure and Speaking Up. Regarding the impact of OeHS Exposure, the good news is related to the absence of a longitudinal association with both XEN and Speaking Up.


Inferior vena cava injury repair, a successful outcome.
Inferior ver a cava (IVC) injuries are very very infrequent; yet it still happens to be the most frequently injured retroperitoneal vascular structure. Fifty percent of the patients can't even make it to the hospital. Even when half of them manage to attend the hospital the mortality rates for the great vessel injury are still very high perhaps due to the low index of suspicion, delayed or inadequate volume resuscitation, difficulty in diagnosis and also due to some technical problems associated in its repair. We present a young male with an abdominal stab injury who had a near transected inferior vena cava at operation. Aggressive perioperative management and the correct judgement by our team at the right time possibly made the patient survive. The rarity of this condition and a review of the literature with some discussion are presented.


Nobel laureates at the Stazione Zoologica Anton Dohrn: phenomenology and paths to discovery in neuroscience.
The practice of science usually involves more than a solitary genius in a solitary room, coping with the problem of her/his life. From the second half of the 19th century onwards, scientific research, especially in the field of the Natural Sciences, has grown into a more and more complex practice, which often entangles very special needs, in terms of research objects, techniques, sources, and perspectives. A few special places, such as the Stazione Zoologica di Napoli, have represented in this period the focal points of an ever growing international scientific network, promoting independent research, exchange and diffusion of novel practices and techniques and unrestricted confrontation. The so-called "Naples experience" has been cited by a large number of renowned scientists of the last two centuries as a key moment in their scientific life. Here we have tried to test it against the experience of three great scientists par excellence, i.e. three Nobel laureates (T. H. Morgan, Otto Warburg, J. D. Watson). The different experiences they have had at Naples represent, in our view, three different moments of the professional life of almost every scientist. Therefore, we have chosen to present them as a phenomenology. The final section is dedicated to a survey of the Zoological Station's contribution to neurosciences, especially to the Naples experience of the Nobel Prize winner Sir Bernard Katz and his assistant Ricardo Miledi, between 1965 and 1970. Their work on the squid at Naples allowed probing and quantitative refinement of results already obtained on different animals and contributed to reinforce the long lasting neurophysiological tradition of the institute.


MaizeGDB update: new tools, data and interface for the maize model organism database.
MaizeGDB is a highly curated, community-oriented database and informatics service to researchers focused on the crop plant and model organism Zea mays ssp. mays. Although some form of the maize community database has existed over the last 25 years, there have only been two major releases. In 1991, the original maize genetics database MaizeDB was created. In 2003, the combined contents of MaizeDB and the sequence data from ZmDB were made accessible as a single resource named MaizeGDB. Over the next decade, MaizeGDB became more sequence driven while still maintaining traditional maize genetics datasets. This enabled the project to meet the continued growing and evolving needs of the maize research community, yet the interface and underlying infrastructure remained unchanged. In 2015, the MaizeGDB team completed a multi-year effort to update the MaizeGDB resource by reorganizing existing data, upgrading hardware and infrastructure, creating new tools, incorporating new data types (including diversity data, expression data, gene models, and metabolic pathways), and developing and deploying a modern interface. In addition to coordinating a data resource, the MaizeGDB team coordinates activities and provides technical support to the maize research community. MaizeGDB is accessible online at http://www.maizegdb.org.


Vulvar carcinoma: dilemma, debates, and decisions.
Vulvar carcinoma is a rare and aggressive gynecological malignancy. It affects elderly females, with the mean age at diagnosis being 55-60 years. Regional metastasis to inguinal lymph nodes is common. There is a high incidence of pelvic node involvement, especially in those with pathologically positive inguinal nodes. Surgery appears to be the only curative treatment option in the early stages of the disease. But in most patients, surgery is associated with considerable morbidities and psychosexual issues. Hence, in the quest for a less morbid form of treatment, multimodality approaches with various combinations of surgery, chemotherapy, and radiation therapy have been suggested for advanced vulvar cancers. Due to the low incidence of the disease, the level of evidence for the success of these treatment modalities is poor. In countries like India, a heterogeneous incidence of vulvar carcinoma exists across the country, with patients presenting at advanced stages when the option of surgery is often supplemented or replaced by chemotherapy and radiotherapy. In this review, we attempt to study the available published literature and trials and discuss the treatment options in various stages of vulvar carcinoma.


Liquid chromatography tandem mass spectrometry with triple stage fragmentation for highly selective analysis and pharmacokinetics of alarelin in rat plasma.
Alarelin, a gonadotropin-releasing hormone analogue, is widely used in China for the treatment of endometriosis and uterine leiomyoma. In order to investigate its pharmacokinetic behavior and support the preclinical application of new formulations, we have developed a novel and highly selective bioanalytical method to determine alarelin in rat plasma based on liquid chromatography tandem mass spectrometry with triple stage fragmentation. After sample preparation by protein precipitation followed by reversed phase solid phase extraction, alarelin and triptorelin (internal standard) were chromatographed on an Ascentis® Express C18 column (50 mm × 4.6 mm, 2.7 µm) using gradient elution with 0.1% formic acid in water and acetonitrile at a flow rate of 1 mL/min. Detection was by positive mode electrospray ionization followed by triple stage fragmentation using the transitions at m/z 584.6→249.1→221.0 for alarelin and 656.5→249.1→176.0 for triptorelin, The assay was linear in the concentration range 0.3-10 ng/mL with excellent precision and accuracy. It was successfully applied to a pharmacokinetic study in rats administered a dose of 13.5 µg/kg alarelin by intramuscular injection. The results show that the triple stage fragmentation strategy allows highly selective analysis of alarelin and has the potential to be widely applied to the bioassay of other peptidic drugs.


Biased signaling of G protein-coupled receptors - From a chemokine receptor CCR7 perspective.
Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space. Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how the cell-based immune system is controlled. Bias comes in three forms; ligand-, receptor- and tissue-bias. Biased signaling is increasingly being recognized as playing an important role in contributing to the fine-tuned coordination of immune cell chemotaxis. In the current review we discuss the recent findings related to ligand- and tissue-biased signaling of CCR7 and summarize what is known about bias at other chemokine receptors. CCR7 is expressed by a subset of T-cells and by mature dendritic cells (DCs). Together with its two endogenous ligands CCL19 and CCL21, of which the carboxy terminal tail of CCL21 displays an extraordinarily strong glycosaminoglycan (GAG) binding, CCR7 plays a central role in coordinating the meeting between mature antigen presenting DCs and naïve T-cells which normally takes place in the lymph nodes (LNs). This process is a prerequisite for the initiation of an antigen-specific T-cell mediated immune response. Thus CCR7 and its ligands are key players in initiating cell-based immune responses. CCL19 and CCL21 display differential interaction- and docking-modes for CCR7 leading to stabilization of different CCR7 conformations and hereby preferential activation of distinct intracellular signaling pathways (i.e. ligand bias). In general CCL19 seems to generate a strong temporal signal, whereas CCL21 generates a weaker, but more persistent signal. Tissue differential expression of these two ligands, and the generation of a third ligand "tailless-CCL21", through DC specific protease activity (tissue bias), orchestrates DC and T-cell LN homing and priming, with each ligand serving overlapping, but also distinct roles.


The effect of oestrogen pretreatment on subsequent response to luteinizing hormone releasing hormone in normal women.
Twenty-two normal, regularly menstruating female subjects had an LHRH test performed before and after pretreatment with 0.5 mg, 1 mg. or 2.5 mg of oestradiol benzoate during the follicular phase of their menstrual cyclees (days 4-8). Two further women acted as controls and received no oestrogen; they showed identical responses for both LH and FSH release when LHRH tests were performed at intervals of 48 h. Oestrogen pretreatment induced a biphasic effect upon subsequent LHRH response. Four subjects retested 20 h after 0.5 mg oestradiol benzoate showed either no change or a slight suppression of LH and FSH release. Fifteen of the eighteen women pretreated with oestradiol benzoate and retested 44 h later showed significantly increased LH release and fourteen significantly increased FSH release when compared to their control responses. The responses appeared to be dose related with a positive correlation between sum of LH increments and basal oestradiol levels (R = 0.61; P less than 0.001) and a similar correlation (r = 0.67; P less than 0.001) between sum of FSH increments and basal oestradiol levels. The physiological significance of this biphasic action of oestrogen upon pituitary sensitivity is discussed in relation to the control of the menstrual cycle.


[Intra-atrial cardioversion in supraventricular tachycardial arrhythmia].
Cardioversion by rapid atrial stimulation has been carried out in 29 patients with supraventricular tachycarida and 12 patients with "coarse" atrial fibrillation. Atrial stimulation rates of 60-1200/min and electrical impulses of 6-25 mA were used. Intracardial conversion was successful in 86% of the cases presenting supraventricular tachycardia. Cardioversion was not achieved with atrial fibrillation but atrial flutter and atrial tachycardia were both found to be easily converted. Transformation of an arrhythmia into sinus rhythm or into stable atrial fibrillation with a slowed ventricular rate was the criterion for a successful conversion. Transient arrhythmias prior to an eventual stable rhythm was observed in 28% of the cases. Two mechanisms to explain the induced change in supraventricular tachycardias are discussed: (1) interruption of atrial or junctional foci (overdrive suppression) and (2) interruption of a re-entry circle by single premature beats. Cardioversion using atrial stimulation is indicated in atrial flutter, atrial tachycardias and junctional tachycardias. The method is of advantage in that it does not require anesthesia or interruption of digitalis therapy and its use involves no complications. Cardioversion using DC-shock is to be preferred in all cases of atrial fibrillation.


Possible role of endothelium in the vasodilator response of rat thoracic aorta to platelet activating factor (PAF).
As the endothelium has an important role in the vasodilating effect of acetylcholine, we investigated the possible role of the endothelium in the vasodilating effect of platelet activating factor (PAF). Experiments were done on spirally cut rat thoracic aorta either containing or denuded of endothelial cells. It was demonstrated that relaxation by PAF and acetylcholine of pre-contracted strips required the presence of endothelial cells. The results strongly suggested the possible involvement of endothelium in the vasodilation produced by PAF as well as by ACh.