The Quasimesenchymal Pancreatic Ductal Epithelial Cell Line PANC-1-A Useful Model to Study Clonal Heterogeneity and EMT Subtype Shifting.
Intratumoral heterogeneity (ITH) is an intrinsic feature of malignant tumors that eventually allows a subfraction of resistant cancer cells to clonally evolve and cause therapy failure or relapse. ITH, cellular plasticity and tumor progression are driven by epithelial-mesenchymal transition (EMT) and the reverse process, MET. During these developmental programs, epithelial (E) cells are successively converted to invasive mesenchymal (M) cells, or back to E cells, by passing through a series of intermediate E/M states, a phenomenon termed E-M plasticity (EMP). The induction of MET has clinical potential as it can block the initial EMT stages that favor tumor cell dissemination, while its inhibition can curb metastatic outgrowth at distant sites. In pancreatic ductal adenocarcinoma (PDAC), cellular models with which to study EMP or MET induction are scarce. Here, we have generated single cell-derived clonal cultures of the quasimesenchymal PDAC-derived cell line, PANC-1, and found that these differ strongly with respect to cell morphology and EMT marker expression, allowing for their tentative classification as E, E/M or M. Interestingly, the different EMT phenotypes were found to segregate with differences in tumorigenic potential in vitro, as measured by colony forming and invasive activities, and in circadian clock function. Moreover, the individual clones the phenotypes of which remained stable upon prolonged culture also responded differently to treatment with transforming growth factor (TGF)β1 in regard to regulation of growth and individual TGFβ target genes, and to culture conditions that favour ductal-to-endocrine transdifferentiation as a more direct measure for cellular plasticity. Of note, stimulation with TGFβ1 induced a shift in parental PANC-1 cultures towards a more extreme M and invasive phenotype, while exposing the cells to a combination of the proinflammatory cytokines IFNγ, IL1β and TNFα (IIT) elicited a shift towards a more E and less invasive phenotype resembling a MET-like process. Finally, we show that the actions of TGFβ1 and IIT both converge on regulating the ratio of the small GTPase RAC1 and its splice isoform, RAC1b. Our data provide strong evidence for dynamic EMT-MET transitions and qualify this cell line as a useful model with which to study EMP.


Genetic variants of interleukin-1RN and interleukin-1beta genes and risk of cervical cancer.
Inflammation plays a major role in pathogenesis of cervical cancer. We planned to study whether polymorphisms in inflammation-related genes, IL-1RN (VNTR) and IL-1beta (-511C/T), are associated with risk of cervical cancer. Case-control study. Uttar Pradesh state in India. One hundred and fifty, histopathologically confirmed cases with cervical cancer and 162 age-, ethnicity-matched, cervical cytology negative, healthy controls were recruited to this study. Genotyping of IL-1RN (VNTR) and IL-1beta (-511C/T) polymorphisms was performed using polymerase chain reaction (PCR)/PCR-restriction fragment length polymorphism. Power of study was 80% with type 1 error of 0.05. Haplotypes frequencies were obtained by computer package 'Arlequin'. Haplotype IL-1RN*2/IL-1beta*T is associated with higher risk and of cervical cancer. IL-1RN genotypes 1/2 and 2/2 were associated with significantly elevated risk of cervical cancer (OR = 3.3; P= 4.9 x 10(-6) and OR = 2.9, P= 0.02). Similarly, TT genotype of IL-1betapolymorphism was significantly higher in cases compared with controls (57.7 versus 38.3%; OR = 2.8; P = 0.012). 2/2 genotype of IL-1RN (OR = 4.8, P = 0.0006) and TT genotype of IL-1beta(OR = 5.2; P = 0.02) were associated with the higher stages (III) of cervical cancer. Haplotypes 1T (IL-1RN*1/IL-1beta*T) and 2T (IL-1RN*2/IL-1beta*T) were also significantly associated with higher susceptibility to cervical cancer and its progression. Logistic regression analysis suggests IL-1RN allele 2 and IL-1beta-511T were independently associated with increased risk for cervical cancer. IL-1RN*2 and IL-1beta -511*T in various combinations of genotypes and haplotypes are associated with higher susceptibility for cervical cancer.


Dynamic Coupling of Tyrosine 185 with the Bacteriorhodopsin Photocycle, as Revealed by Chemical Shifts, Assisted AF-QM/MM Calculations and Molecular Dynamic Simulations.
Aromatic residues are highly conserved in microbial photoreceptors and play crucial roles in the dynamic regulation of receptor functions. However, little is known about the dynamic mechanism of the functional role of those highly conserved aromatic residues during the receptor photocycle. Tyrosine 185 (Y185) is a highly conserved aromatic residue within the retinal binding pocket of bacteriorhodopsin (bR). In this study, we explored the molecular mechanism of the dynamic coupling of Y185 with the bR photocycle by automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) calculations and molecular dynamic (MD) simulations based on chemical shifts obtained by 2D solid-state NMR correlation experiments. We observed that Y185 plays a significant role in regulating the retinal cis-trans thermal equilibrium, stabilizing the pentagonal H-bond network, participating in the orientation switch of Schiff Base (SB) nitrogen, and opening the F42 gate by interacting with the retinal and several key residues along the proton translocation channel. Our findings provide a detailed molecular mechanism of the dynamic couplings of Y185 and the bR photocycle from a structural perspective. The method used in this paper may be applied to the study of other microbial photoreceptors.


Toll-like receptor 7 regulates cardiovascular diseases.
Cardiovascular disease (CVD) is the major leading cause of morbidity and mortality worldwide. According to the pro-inflammatory nature of CVD, recent studies highlighted the immune system's role in its pathogenesis and development. Toll-like receptors (TLRs) have been identified as dominant innate immune receptors. TLR-7 is an intracellular receptor expressed on endosomes or cytoplasmic reticulum and is responsible for detecting damage-associated molecular patterns, which are remarkable during inflammation and viral infection. In addition to immune cells, TLR-7 is expressed in endothelial cells, vascular smooth muscle cells, and platelets. TLR-7 ligands are single-stranded ribonucleic acid (ssRNA) and short interfering RNA, which can activate the signaling pathway and lead to both inflammatory (e.g., interleukin-1 (IL-1), IL-6, IL-12, tumor necrosis factor- α (TNF-α)) and anti-inflammatory (e.g., IL-10) cytokines release. By growing evidence, it has been proven that TLR-7 activated platelets can increase the risk of thrombus formation by neutrophil aggregation. At the same time, they have a protective role against thrombosis by releasing granulocyte-macrophage colony-stimulating factors. The same two-sided effect was observed between TLR-7 and atherosclerotic plaque formation. Moreover, recent studies explained an association between TLR-7 activation and increased risk of complete heart block, myocarditis, left ventricular remodeling, and rupture. Here we review the rapid progress that has been made in this field, which has improved our understanding of TLR-7 function in CVDs, and discuss the current treatments targeting this receptor.


Continued regulatory actions affecting the use of erythropoiesis-stimulating agents.
The FDA sent a "Complete Response and Safety Labeling Change Order" to the sponsors of ESAs on July 30, ordering changes to ESA labels in three important ways. For the first time, the FDA used its statutory authority to order a sponsor to make revisions to a product label.


Acetylcholine receptors in the ciliary ganglion and in the iris muscle of the chick: specific binding and effect on the synaptic transmission of the neurotoxin from Naja naja siamensis.
1 A specific binding of Naja naja siamensis neurotoxin was found both in the iris and in the ciliary ganglion of the chick. 2 Naja-toxin (125 nM) caused a complete block of the iris muscle contraction induced by carbamylcholine. 3 Naja-toxin had a different effect on the two neuronal populations present in the ganglion: it blocked the synaptically evoked response of the ciliary cells, while the response of the choroid ones was only slightly reduced. The effects were the same in a wide range of concentrations (125 to 2500 nM). 4 The results obtained in the iris show the existence of an acetylcholine receptor population similar to the nicotinic receptor of the skeletal muscle. 5 In the ciliary ganglion the results confirm the existence of different acetylcholine receptors on the two cell types.


Online extraction of 5-hydroxyindole acetic acid from urine for analysis by liquid chromatography-tandem mass spectrometry.
Urinary 5-hydroxyindole acetic acid (5-HIAA) is a useful marker for the turnover of tryptophan metabolites in the diagnosis and monitoring of carcinoid tumours and the carcinoid syndrome. We have developed a simple and cost-effective assay for urinary 5-HIAA using liquid chromatography-tandem mass spectrometry (LC-MS/MS) incorporating an online sample clean-up process to replace a liquid chromatography electrochemical (LC-EC) technique. Acidified urine was serially diluted in ammonium acetate buffer followed by ammonium acetate buffer enriched with 5-hydroxyindole-3-acetic-2,2-D2 acid internal standard. A 2.1 x 10 mm C18 column was used for primary online clean-up and eluted with 100% methanolic mobile phase onto a second dC18 Atlantis 2.1 x 20 mm column. Analytes were detected by mass spectrometry using transitions 192.1 > 146.3 and 194.1 > 148.0 for 5-HIAA and deuterated analyte, respectively. Run time was 3 min with 5-HIAA eluting at 1.37 min. The inter and intra-assay imprecision and accuracies of the three levels of inhouse quality control (QC) (30, 300 and 600 micromol/L) were acceptable with coefficient of variations (CVs) and deviation from target values <12% (n = 15). The average recovery of 5-HIAA spiked into urine was 93.7% with no ion suppression observed. The limit of detection was 2.8 and lower limit of quantification 4.0 micromol/L. Passing-Bablok regression of LC-EC with LC-MS/MS results showed good agreement between the methods, the relationship described as LC-MS/MS = 1.01(LC-EC)-1.22. No systematic or proportional biases were observed over the working range of the method. The assay was linear to at least 2000 micromol/L. We have developed a robust method offering a more than six-fold improvement in linearity compared to the existing LC-EC method.


The prevalence and role of human papillomavirus genotypes in primary cervical screening in the northeast of China.
Studies have shown that type-specific persistence of high-risk human papillomavirus (HPV) infection contributed significantly to cervical carcinogenesis. In this population-based study (on 24041 women), we report on the prevalent genotypes of HPVs and the prevalent genotypes of HPV persistent infection in the northeast of China. Our results showed that in HPV infected women (45.6% in total), (95% CI, 44.97%-46.23%), 17.35% (95%CI, 16.87%-17.83%) suffered persistent infection. The most common high-risk HPV types in persistent positivity were HPV-16 (18.21%; 95%CI, 17.04%-19.38%), HPV-58 (13.2%; 95%CI, 12.17%-14.23%), HPV-18 (8.66%; 95%CI, 7.81%-9.51%), HPV-52 (7.06%; 95% CI, 6.28%-7.84%) and HPV-33 (6.78%; 95% CI, 6.02%-7.54%). The prevalence of persistent infections with HPV-16,-58, -18, -52 and 33 in cervicitis were lower compared to those in CIN (all P < 0.05). HPV-58, -33 and multiple HPV persistent positivity were significantly associated with older age (all P < 0.05). HPV-18 persistent positivity was significantly associated with adenocarcinoma and lymphatic metastasis (all P < 0.05). HPV-18 persistent positivity was associated with cervical cancer prognosis (P <0.0001). Multivariate analyses showed that HPV-18 persistent positivity, (RR = 1.704, 95%CI = 1.095-2.654, p = 0.028) and lymphatic metastasis (RR = 2.304, 95%CI = 1.354-3.254, P = 0.015) were independent predictors for 3-year survival in cervical cancer. we provided extensive results of HPV genotype prevalence and distribution in the northeast of China. HPV genotyping is worthwhile to perform because of its independent prognostic value in cervical cancer.


Changing trends in blood transfusion: an analysis of 244,013 hospitalizations.
Identifying recipients of blood transfusion and the trends in transfusion are needed to properly identify and target clinical services in need of patient blood management strategies. We determined the proportion of admissions to each clinical service that received blood, the mean number of units utilized, and the 5-year trends in utilization. We used a large administrative database, a repository for three campuses of one university-affiliated hospital, and included all adults that were hospitalized from November 1, 2006, to June 2012. The data were analyzed as the proportion of admissions transfused and the mean number units transfused per admission. Of 244,013 hospitalizations, 38,265 received at least one transfusion (29,165 for red blood cells [RBCs], 6760 for plasma, and 5795 for platelets [PLTs]). Although there has been a gradual decrease in the mean number of RBCs transfused (percent change, -9.8%; p = 0.002), an increase in the proportion of admissions receiving RBCs (17.2% increase, p < 0.0001) and PLTs (31.5% increase, p < 0.0001) was apparent while there has been a decrease in the proportion of admissions receiving plasma (23.9% decrease, p < 0.0001). Eight percent of cardiology admissions received RBCs, and the highest mean RBC utilization per admission, aside from the stem cell transplantation service, occurred in cardiology and critical care hospitalizations (mean, 4.7 units/hospitalization). Although there has been a reduction in the mean RBC units used, there has been an increase in the proportion of hospitalizations transfused. A better understanding of the indications for transfusion is required to facilitate the development of targeted blood conservation strategies.


Referred pain areas of active myofascial trigger points in head, neck, and shoulder muscles, in chronic tension type headache.
Our aim was to analyze the differences in the referred pain patterns and size of the areas of those myofascial trigger points (TrPs) involved in chronic tension type headache (CTTH) including a number of muscles not investigated in previous studies. Thirteen right handed women with CTTH (mean age: 38 ± 6 years) were included. TrPs were bilaterally searched in upper trapezius, sternocleidomastoid, splenius capitis, masseter, levator scapulae, superior oblique (extra-ocular), and suboccipital muscles. TrPs were considered active when both local and referred pain evoked by manual palpation reproduced total or partial pattern similar to a headache attack. The size of the referred pain area of TrPs of each muscle was calculated. The mean number of active TrPs within each CTTH patient was 7 (95% CI 6.2-8.0). A greater number (T = 2.79; p = 0.016) of active TrPs was found at the right side (4.2 ± 1.5) when compared to the left side (2.9 ± 1.0). TrPs in the suboccipital muscles were most prevalent (n = 12; 92%), followed by the superior oblique muscle (n =11/n = 9 right/left side), the upper trapezius muscle (n = 11/n = 6) and the masseter muscle (n = 9/n=7). The ANOVA showed significant differences in the size of the referred pain area between muscles (F = 4.7, p = 0.001), but not between sides (F = 1.1; p = 0.3): as determined by a Bonferroni post hoc analysis the referred pain area elicited by levator scapulae TrPs was significantly greater than the area from the sternocleidomastoid (p = 0.02), masseter (p = 0.003) and superior oblique (p = 0.001) muscles. Multiple active TrPs exist in head, neck and shoulder muscles in women with CTTH. The referred pain areas of TrPs located in neck muscles were larger than the referred pain areas of head muscles. Spatial summation of nociceptive inputs from multiple active TrPs may contribute to clinical manifestations of CTTH.


Deep amplicon sequencing reveals extensive allelic diversity in the erg11/CYP51 promoter and allows multi-population DMI fungicide resistance monitoring in the canola pathogen Leptosphaeria maculans.
Continued use of fungicides provides a strong selection pressure towards strains with mutations to render these chemicals less effective. Previous research has shown that resistance to the demethylation inhibitor (DMI) fungicides, which target ergosterol synthesis, in the canola pathogen Leptosphaeria maculans has emerged in Australia and Europe. The change in fungicide sensitivity of individual isolates was found to be due to DNA insertions into the promoter of the erg11/CYP51 DMI target gene. Whether or not these were the only types of mutations and how prevalent they were in Australian populations was explored in the current study. New isolates with reduced DMI sensitivity were obtained from screens on DMI-treated plants, revealing eight independent insertions in the erg11 promoter. A novel deep amplicon sequencing approach applied to populations of ascospores fired from stubble identified an additional undetected insertion allele and quantified the frequencies of all known insertions, suggesting that, at least in the samples processed, the combined frequency of resistant alleles is between 0.0376% and 32.6%. Combined insertion allele frequencies positively correlated with population-level measures of in planta resistance to four different DMI treatments. Additionally, there was no evidence for erg11 coding mutations playing a role in conferring resistance in Australian populations. This research provides a key method for assessing fungicide resistance frequency in stubble-borne populations of plant pathogens and a baseline from which additional surveillance can be conducted in L. maculans. Whether or not the observed resistance allele frequencies are associated with loss of effective disease control in the field remains to be established.


Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family.
Syndactyly is a clinical feature of split-hand foot malformation (SHFM), ectodermal-dysplasia-syndactyly (EDSS1) and Cenani-Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients. Whole exome sequencing (WES) analysis on one sample derived from a consanguineous family was performed. A causative variant in WES data was prioritized via standard bioinformatics tools. The selected variant was Sanger sequenced in all the available family members for autosomal recessive segregation. A novel missense variant (c.1151A>G; p.Tyr384Cys) was identified in the LRP4 gene. Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant. The variant is neither reported in 1000 human genomes, nor in 60 706 exomes databases, and is predicted as "pathogenic" by SIFT, Polyphen-2 and MutationTaster software. The present study broadens the pathogenic spectrum of the LRP4 gene in syndactyly syndromes. WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in syndactyly and related phenotypes.


Regulation of Toxoplasma gondii multiplication in BeWo trophoblast cells: cross-regulation of nitric oxide production and polyamine biosynthesis.
Materno-foetal transmission causes one of the most severe forms of infection with the protozoan parasite Toxoplasma gondii. Several studies have shown T. gondii in placental trophoblast cells, which form the barrier between maternal blood circulation and foetal tissue. Parasite multiplication in trophoblast cells is thus a critical step leading to infection of the foetus. Here, we show that multiplication of T. gondii tachyzoites was slow in BeWo trophoblast cells, compared with MRC-5 fibroblast cells. However, unlike MRC-5 cells, even combined stimulation with interferon-gamma and tumor necrosis factor-alpha did not reduce T. gondii replication in BeWo cells. This was associated with a lack of indoleamine-2,3-dioxygenase induction by these cytokines. Neither low availability of iron salts, nor an immunosuppressive action of cyclooxygenase-2 could be attributed to the low T. gondii multiplication rate in BeWo cells. However, treatment with the nitric oxide synthesis inhibitor N(G)-methyl-l-arginine and addition of ornithine enhanced the proliferation rate of the intracellular pathogen. Despite detection of inducible nitric oxide synthase-II mRNA in BeWo cells, nitric oxide production could not be detected during cell culture. Thus, inhibition of arginase activity by nitric oxide synthesis may be partially responsible for the lower multiplication rate in BeWo cells.


Synthesis and Characterization of New Ethylenediamine Platinum(IV) Complexes Containing Lipophilic Carboxylate Ligands.
A series of new ethylenediamine (en) platinum(IV) complexes of the type Pt((IV))enX(2)A(2), with X(2) = cyclobutane-1,1-dicarboxylato (CBDCA), dichloro or bis(decanoato) and A = acetato, dodecanoato, tetradecanoato, hexadecanoato, octadecanoato, adamantanecarboxylato (Ad) or 3alpha, 12alpha-diformoxy-5beta-cholato (DFCA) were synthesized and characterized by elemental analysis, infrared and NMR ((1)H and (13)C) spectroscopic techniques. Previous platinum(IV) compounds were usually restricted to trans-dihydroxo or trans-dichloro platinum(IV) complexes. Recently trans-dicarboxylato platinum(IV) complexes with mainly acetate, trifluoracetate or short-chain carboxylate groups (<11 carbons) in the axial position have been described in the literature([1,2,3]). In this paper we report on the synthesis and characterization of a new class of ethylenediamine platinum(IV) compounds that have high lipophilic long-chain carboxylate ligands either in the axial or equatorial position. The platinum(IV) compounds with the lipophilic trans-carboxylate ligands in the axial position were prepared by acylation of the trans-dihydroxo platinum(IV) species using an acyl halide in the presence of pyridine. In contrast to previous publications([1]) the yields were excellent (up to 94%!).


Short-latency vergence eye movements elicited by looming step in monkeys.
The looming associated with forward and backward motion of the observer has been shown to elicit vergence eye movements with short-latency (approximately 80 ms) in human subjects. We studied the vergence eye movements elicited by looming in three monkeys (Macaca fuscata). The animals faced a large tangent screen onto which a random dot pattern was back-projected. The movements of both eyes were recorded with an electromagnetic induction technique. Fifty milliseconds after a centering saccade, this first pattern was replaced with a new one that showed the same image viewed from a slightly different distance. This looming step (two-frame movie) included both radial optic flow and a size change. As expected from the optical geometry, centrifugal flow coupled with enlargement (signaling forward motion) increased the vergence angle, whereas the converse combination decreased the vergence angle. In both cases, the optimal step-change in apparent viewing distance was 2%. The latency of these vergence responses was very short and similar to those induced when disparity steps are applied to such large patterns (approximately 60 ms). We suggest that these two systems act in synergy to help maintain binocular alignment during forward and backward motion of the observer.


Noninvasive intraoperative monitoring of carbon dioxide in children: endtidal versus transcutaneous techniques.
The current study prospectively compares the accuracy of the intraoperative use of transcutaneous (Tc) and endtidal (PE) CO2 monitoring during surgical procedures in 30 paediatric patients, ranging in age from 6 months to 15 years (6.15 +/- 4.35 years) and in weight from 4.7 to 73 kg (24.9 +/- 18.2 kg). Following calibration and an equilibration time for the TcCO2 monitor, arterial blood gas samples were obtained as clinically indicated. A total of 64 sample sets (PaCO2, PECO2 and TcCO2) were obtained from the 30 patients. The PECO2 to PaCO2 difference was 0.6-0.9 kPa (4.4 +/- 7.1 mmHg) while the TcCO2 to PaCO2 difference was 0.36-0.38 kPa (2.8 +/- 2.9 mmHg) (P=NS). The difference between the PaCO2 and PECO2 was 0.4 kPa (3 mmHg) or less in 37 of 64 sample sets while the difference between the PaCO2 and TcCO2 was 0.4 kPa (3 mmHg) or less in 49 of 64 sample sets (P=0.038). Linear regression analysis of PECO2 vs. PaCO2 revealed a slope of 0.434, r=0.8761, r2=0.7676. Linear regression analysis of TcCO2 vs. PaCO2 revealed a slope of 0.914, r=0.9472, r2=0.8972. Although in most circumstances, both noninvasive monitors of PCO2 provided a clinically acceptable estimate of PaCO2, TCCO2 provided a slightly more accurate estimate of PaCO2 during intraoperative anaesthetic care in children.


Animal development: an ancient β-catenin switch?
High and low nuclear levels of the conserved transcriptional regulator β-catenin distinguish multiple sister cell fates to specify endoderm and mesoderm during early embryogenesis in a chordate embryo.


Absence of recognition of low alkaline phosphatase level in a tertiary care hospital.
Low serum total alkaline phosphatase level (ALP), the hallmark for hypophosphatasia (HPP), must be recognized to provide appropriate care of the patients and to avoid antiresorptive treatment. The prevalence of persistent low ALP in a clinical setting is 0.13% and the recognition is very low (3%). A low serum total alkaline phosphatase level is the hallmark for the diagnosis of hypophosphatasia. Although very rare, HPP must be recognized to provide appropriate treatment of non-union fractures and to avoid potentially harmful drugs, such as antiresorptive treatments. The aim of this study was to assess the recognition of persistent low ALP in a tertiary care hospital. Between the 1st of January and the 31st of December 2013, 48,755 patients had ALP assessment in the Biochemistry Department of our hospital. Sixty-eight patients had all serum ALP values persistently below 40 IU/l. Among them, six had potential causes of secondary hypophosphatasia. We consulted the summary discharges of the 62 patients in order to check for the notation of low ALP. Patients from the departments of rheumatology and internal medicine were contacted to fulfill a questionnaire about clinical manifestations potentially related to HPP. 0.13% of hospitalized patients had persistently low value. They were 46.5 ± 17.7 years old, and 73% were females. The low ALP value was notified in the discharge summary for two patients (3%), without any comment. Twenty-four patients (46 + /-16 years old) were contacted. Eight patients had fractures; two had a diagnosis of rickets in the childhood; two had symptomatic chondrocalcinosis. Nine had dental abnormalities. Three were receiving a bisphosphonate; two of them had a fracture while being treated with bisphosphonate. Our study shows that low ALP is not recognized in a clinical setting in adults hospitalized in a tertiary care hospital.


Trixacarus caviae infection of guinea pigs with genetically determined differences in susceptibility to Trichostrongylus colubriformis infection.
Guinea pigs with genetically determined resistance or susceptibility to infection with the nematode parasite Trichostrongylus colubriformis were allowed to become infected with the sarcoptid mite Trixacarus caviae. Compared with nematode-susceptible guinea pigs, nematode-resistant animals had larger populations of mites and developed a more severe dermatitis, with greater mast cell hyperplasia and many more infiltrating eosinophils. The results suggest that animals bred for resistance to one parasite may have greater susceptibility to other parasites.


Ebola Virus Infection: Overview and Update on Prevention and Treatment.
In 2014 and 2015, the largest Ebola virus disease (EVD) outbreak in history affected large populations across West Africa. The goal of this report is to provide an update on the epidemic and review current progress in the development, evaluation and deployment of prevention and treatment strategies for EVD. Relevant information was identified through a comprehensive literature search using Medline, PubMed and CINAHL Complete and using the search terms Ebola, Ebola virus disease, Ebola hemorrhagic fever, West Africa outbreak, Ebola transmission, Ebola symptoms and signs, Ebola diagnosis, Ebola treatment, vaccines for Ebola and clinical trials on Ebola. Through 22 July 2015, a total of 27,741 EVD cases and 11,284 deaths were reported from all affected countries. Several therapeutic agents and novel vaccines for EVD have been developed and are now undergoing evaluation. Concurrent with active case investigation, contact tracing, surveillance and supportive care to patients and communities, there has been rapid progress in the development of new therapies and vaccines against EVD. Continued focus on strengthening clinical and public health infrastructure will have direct benefits in controlling the spread of EVD and will provide a strong foundation for deployment of new drugs and vaccines to affected countries when they become available. The unprecedented West Africa Ebola outbreak, response measures, and ensuing drug and vaccine development suggest that new tools for Ebola control may be available in the near future.


Swine as an in vivo model for electrophysiologic evaluation of cardiac pacing parameters.
Pre-clinical studies of cardiac pacemakers and new electrodes, materials, and designs are for the most part conducted in dogs. Dogs, however, have electrophysiological differences which may preclude accurate translation to clinical trials. The purpose of this study was to develop normal electrophysiological parameters for an animal whose cardiovascular system more closely resembles that of man than any nonprimate animal. The threshold (voltage and current) strength-duration curves of the pig showed the same inverse relationship between the pulse duration and threshold requirements as other species. At 0.5 ms the atrium had 3.5-5.5 times greater energy requirements, over twice the current (2.04 mA vs 0.72 mA) and twice the voltage (0.75 mV vs 0.32 mV) requirements when compared to the ventricles. The pig's S-A nodal P-wave was superior in amplitude (7.80 +/- 1.80 mV vs 4.28 +/- 2.27 mV) and the slew rate was faster (1.30 +/- 0.56 mV/ms vs 0.44 +/- 0.50 mV/ms) compared to that of the atrial appendage. The pig's left ventricular myocardial R-wave had significantly greater amplitude (19.00 +/- 6.44 mV vs 10.70 +/- 4.34 mV) and faster slew rate (1.60 +/- 0.62 mV/ms vs 0.90 +/- 0.30 mV/ms) compared to the right ventricular endocardial R-wave. The electrophysiological parameters of the pig were more similar to those of man than the dog; therefore, the pig is a useful animal model for electrophysiological studies and the testing of pacemaker equipment.


DISULFIND: a disulfide bonding state and cysteine connectivity prediction server.
DISULFIND is a server for predicting the disulfide bonding state of cysteines and their disulfide connectivity starting from sequence alone. Optionally, disulfide connectivity can be predicted from sequence and a bonding state assignment given as input. The output is a simple visualization of the assigned bonding state (with confidence degrees) and the most likely connectivity patterns. The server is available at http://disulfind.dsi.unifi.it/.


Curved corannulene dually targets mitochondria and endoplasmic reticulum, and initiates apoptosis via localized ROS induction upon light triggering.
Organelle-targeting agents are promising in both fundamental and applied biomedicine research, but such materials are very limited. As a curved 2D carbon material, corannulene (Cor) displays an uneven intramolecular electron distribution, producing a large dipole moment that can favor the electrostatic interaction. Based on the large negative mitochondrial membrane potential and the presence of a connection structure between mitochondria and endoplasmic reticulum (ER), we hypothesized that Cor could simultaneously target both mitochondria and ER. Such hypothesis was well validated by using the fluorescence tag-labelled Cor. The co-localization analysis in a model cell line (PC3) revealed a preferred accumulation of Cor in both organelles, as evidenced by a large Pearson correlation coefficient. The large dipole also empowered Cor the ability of controlled production of reactive oxygen species (ROS) upon light irradiation. This feature plus mitochondria targeting of Cor induced depletion of adenosine triphosphate (ATP) and caspase 9/3 activation. The triggered ROS generation in ER caused the calcium dumping in the cytosol, as revealed by a calcium-specific fluorescence probe. A significant degree of apoptosis was induced by Cor as a result of the interplay of dual mitochondria/ER targeting and triggered organelle-specific ROS delivery. This study demonstrated the subcellular targeting ability of Cor for potential ROS-based therapy, and implied that the dipole could be a valuable parameter for efficient design and tailored screening of organelle-targeting materials for various biomedical applications.


The instrumental resolution of a moire extensometer in light of its recent automatisation.
This paper assesses the instrumental resolution of a mechanical extensometer in light of its recent automatisation. The instrument takes advantage of the moire phenomenon of optical interference to measure angular rotation in two perpendicular planes and displacement in three dimensions. Our assessment systematically defines an analytical solution for the complete interpretation of a generic moire pattern and a set of mathematical approximations for the moire patterns used to measure rotation and displacement. The ultimate sensitivity of the automated instrument is determined on the basis of a generic least square differences fitting procedure while the instrumental resolution is defined on the basis of realistic, rather than optimal, scenarios: the resolution of the rotation measurements are in the order of 8.7*10-5 rad while the resolution of the displacement measurements are better than 5 μm. This assessment represents the first step towards a global numerical repository for processed data recorded by the automated extensometers.


Picky eating during childhood: a longitudinal study to age 11 years.
Picky eating is a common disorder during childhood often causing considerable parental anxiety. This study examined the incidence, point prevalence, persistence and characteristics of picky eating in a prospective study of 120 children and their parents followed from 2 to 11 years. At any given age between 13% and 22% of the children were reported to be picky eaters. Incidence declined over time whereas point prevalence increased indicating that picky eating is often a chronic problem with 40% having a duration of more than 2 years. Those with longer duration differed from those with short duration having more strong likes and dislikes of food and not accepting new foods. Parents of picky eaters were more likely to report that their children consumed a limited variety of foods, required food prepared in specific ways, expressed stronger likes and dislikes for food, and threw tantrums when denied foods. They were also more likely to report struggles over feeding, preparing special meals, and commenting on their child's eating. Hence, picky eating is a prevalent concern of parents and may remain so through childhood. It appears to be a relatively stable trait reflecting an individual eating style. However no significant effects on growth were observed.


Phenotypic plasticity of gut structure and function during periods of inactivity in Apostichopus japonicus.
Apostichopus japonicus is a common sea cucumber that undergoes seasonal inactivity phases and ceases feeding during the summer months. We used this sea cucumber species as a model in which to examine phenotypic plasticity of the digestive tract in response to food deprivation. We measured the body mass, gross gut morphology and digestive enzyme activities of A. japonicus before, during, and after the period of inactivity to examine the effects of food deprivation on the gut structure and function of this animal. Individuals were sampled semi-monthly from June to November (10 sampling intervals over 178 days) across temperature changes of more than 18 degrees C. On 5 September, which represented the peak of inactivity and lack of feeding, A. japonicus decreased its body mass, gut mass and gut length by 50%, 85%, and 70%, respectively, in comparison to values for these parameters preceding the inactive period. The activities of amylase, cellulase and lipase decreased by 77%, 98%, and 35% respectively, in comparison to mean values for these enzymes in June, whereas pepsin activity increased two-fold during the inactive phase. Alginase and trypsin activities were variable and did not change significantly across the 178-day experiment. With the exception of amylase and cellulase, all body size indices and digestive enzyme activities recovered and even surpassed the mean values preceding the inactive phase during the latter part of the experiment (October-November). Principal Component Analysis (PCA) utilizing the digestive enzyme activity and body size index data divided the physiological state of this cucumber into four phases: an active stage, prophase of inactivity, peak inactivity, and a reversion phase. These phases are all consistent with previously suggested life stages for this species, but our data provide more defined characteristics of each phase. A. japonicus clearly exhibits phenotypic plasticity (or life-cycle staging) of the digestive tract during its annual inactive period.


CCK- and VIP-induced glycoprotein secretion from mouse gallbladder epithelium following vagotomy: a quantitative electron microscopic study.
The glycoprotein secretion from the mouse gallbladder epithelium induced by vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) was investigated by electron microscopic morphometry. Both VIP and CCK caused a decrease in the volume density of the glycoprotein-containing granules of the principal cells. The effect on the gallbladder epithelium of a left-sided vagotomy was examined. Three and six weeks postvagotomy, slight decreases in cell and nuclear profile area and secretory granule volume density were noted. CCK induced a secretion of glycoprotein granules, whereas no such secretory effect due to VIP could be detected in animals 3 and 6 weeks after vagotomy. The results demonstrate that VIP, like CCK, is involved in glycoprotein secretion from the mouse gallbladder epithelium, but the secretory effect of VIP would appear to be dependent on an intact vagal innervation. The results are of interest in relation to the hypothesis that glycoprotein release may be a precipitating factor in the production of gallstones.


Sex-specific constitutive expression of the pre-neoplastic marker glutathione S-transferase, YfYf, in mouse liver.
Hepatic glutathione S-transferase isoenzyme content has been investigated in both sexes of three inbred strains of mice (DBA/2, C3H/He, C57BL6). A polypeptide (Mr 24,800), which is immunologically related to Yf purified from rat lung, was found to be expressed as a major form in all male mouse livers but represented only a minor enzyme form in female mouse liver. Glutathione S-transferases comprising subunits with molecular masses of 25,800 (Ya) or 26,400 (Yb) were present in males and females of the three strains under investigation. Cytosolic isoenzymes from all strains and sexes were purified to apparent homogeneity and no significant inter-strain differences in the properties of the individual forms were observed. In addition, no differences were detected in the microsomal glutathione S-transferase content of the different strains or sexes.


Terminology of Peters' anomaly variants: Summary of histopathological findings in 6 corneas and detailed clinicopathological correlation in 2 cases.
Peters' anomaly accounts for the highest type of Anterior Segment Dysgenesis (ASD). The main features of Peters' anomaly are: congenital corneal opacity centrally, defect in the posterior stroma and absence of Descemet's membrane and the endothelium. However, this condition has wide clinical and histopathological variations in appearance, associations and severity. In this case series, we summarize 6 corneas in 5 Saudi cases of Peters' anomaly (and describe 2 in detail) with unique histopathological findings that are additional to the typical known ones, shedding some light on the nomenclature of these variants according to the reported cases in the English-written literature. This will widen the spectrum of findings known to ophthalmic pathologists and ophthalmologists about this anomaly. This is also of importance in the assessment of the congenital glaucoma cases commonly seen in Saudi Arabia that often happens in association with ASD.


An improved algorithm for design of broadband excitation, inversion, and mixing pulse sequences by iterative optimization of phases: TOPS-2.
This paper presents an improved iterative algorithm (TOPS-2) for the design of broadband inversion, excitation and coherent transfer mixing sequence (TOCSY) pulses. The evolution of the Bloch vector is presented as a sequence of small constant flip angle pulses with varying phases and constant amplitude. This paper describes an improved algorithm for iterative optimization of piece-wise constant phases as we incorporate the quadratic terms in the propagators. In our iterative optimization we obtain a closed-form expression for each phase, and these phases are optimized sequentially using the new improved algorithm. This paper compares the simulation results of the TOPS vs TOPS-2 and shows that TOPS-2 perform better. Experimental validation of excitation and inversion TOPS-2 pulse sequence is performed with .5% H2O in 99.5% D2O, and experimental validation of TOPS-2 mixing (TOCSY) pulse sequence is done with 0.1% of Ethylbenzene (EB) in CDCl3 solvent.


The crystal structure of Atg18 reveals a new binding site for Atg2 in Saccharomyces cerevisiae.
Macroautophagy (hereafter referred to as autophagy) is a highly conserved catabolic eukaryotic pathway that is critical for stress responses and homeostasis. Atg18, one of the core proteins involved in autophagy, belongs to the PROPPIN family and is composed of seven WD40 repeats. Together with Atg2, Atg18 participates in the elongation of phagophores and the recycling of Atg9 in yeast. Despite extensive studies on the PROPPIN family, the structure of Atg18 from Saccharomyces cerevisiae has not been determined. Here, we report the structure of ScAtg18 at a resolution of 2.8 Å. Based on bioinformatics and structural analysis, we found that the 7AB loop of ScAtg18 is extended in Atg18, in comparison to other members of the PROPPIN family. Genetic analysis revealed that the 7AB loop of ScAtg18 is required for autophagy. Biochemical and biophysical experiments indicated that the 7AB loop of ScAtg18 is critical for interaction with ScAtg2 and the recruitment of ScAtg2 to the autophagy-initiating site. Collectively, our results show that the 7AB loop of ScAtg18 is a new binding site for Atg2 and is of functional importance to autophagy.


After DES implantation, DAPT for 1 y vs. ≤6 mo increased major bleeding in patients with high baseline bleeding risk.
Palmerini T, Bruno AG, Redfors B, et al. Risk-benefit of 1-year DAPT after DES implantation in patients stratified by bleeding and ischemic risk. J Am Coll Cardiol. 2021;78:1968-86. 34763774.


Back to Basics: Is There a Good Reason to Not Systematically Measure Urine Creatinine in Acute Kidney Injury Monitoring?
Regardless of the recent advancements in the understanding of the pathophysiology of acute kidney injury (AKI), its diagnosis remains fundamentally dependent on the serum creatinine (sCr) level and urine output (UO), both of which are considered late markers of AKI, offering only a vague idea of the actual creatinine clearance (CrCl). Although not ideal, CrCl is still the most common alternative of the glomerular filtration rate (GFR) in clinical practice. It is generally accepted that early diagnosis of AKI must reveal kidney impairment before sCr increases. Much effort has been made to find tubular and glomerular markers of injury which increase (in blood and/or in urine) before the 'official' diagnosis of AKI. Most of these markers are expensive and not widely available, especially in developing countries. Urine creatinine (CrU), the major link between sCr and UO, has been systematically ignored and clinicians are usually unaware of its value. The reasons for this are unclear, but it may be related to the lack of a reference range, dependence of its concentration value on the urine flow (which in turn is only adequately assessed with an indwelling urinary catheter) and the clinical unavailability of its counterbalance part - creatinine production. Changes in urine tend to precede changes in blood in the course of AKI development and recovery. Hence, it is important to bear in mind that changes in sCr signal renal dysfunction with a significant delay. The search for a more dynamic, 'real-time' but pragmatic assessment of renal function, especially in patients at risk of abrupt decrease in GFR is certainly one of the most relevant focus of research in the field of AKI monitoring. Systematic CrU assessment may be highly relevant in this case.


Antisense Oligonucleotides for the Study and Treatment of ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.


Familial inclusion body myositis: evidence for autosomal dominant inheritance.
We report a kindred manifesting clinical features and muscle biopsy findings of inclusion body myositis (IBM). In this family, multiple members were affected in two generations with direct male-to-male and female-to-male transmission. This is the first reported instance of autosomal dominant inheritance in IBM, which usually occurs sporadically or, rarely, may be transmitted as an autosomal recessive disorder.


Vitamin A deficiency potentiates carbon tetrachloride-induced liver fibrosis in rats.
Earlier studies have shown that retinoid administration suppresses the generation of hepatic fibrosis and stimulates its regression in normal (i.e., vitamin A-sufficient) carbon tetrachloride-treated rats. This study focuses on the possible role of a marginal or deficient vitamin A status on carbon tetrachloride-induced fibrosis. This experimental study in rats shows that vitamin A status, reflected by hepatic retinoid content (retinol and retinyl esters), modulates the development of hepatic fibrosis induced by carbon tetrachloride. In rats with low hepatic retinoid levels (12 +/- 0.9 micrograms/gm liver), carbon tetrachloride-induced liver fibrosis was more pronounced than in rats with sufficient hepatic retinoid levels (1,065 +/- 327 micrograms/gm liver). Enhanced liver fibrogenesis was confirmed both morphologically and by a higher hydroxyproline content of the liver. It was associated with a reduced liver weight and the development of parenchymal regeneration nodules. Furthermore, carbon tetrachloride treatment itself reduced the hepatic retinoid content in rats independently of the liver vitamin A status before treatment and increased serum retinol levels in vitamin A-sufficient rats. The results show that the vitamin A status of the liver plays an important role in hepatic fibrogenesis. Low hepatic vitamin A levels, which can be the result not only of low dietary intake but also of interference with vitamin A metabolism by agents such as ethanol and carbon tetrachloride, may be a risk factor for the development of liver fibrosis. We suggest that retinoids modulate collagen synthesis and deposition irrespective of the degree of hepatocellular necrosis induced by carbon tetrachloride.(ABSTRACT TRUNCATED AT 250 WORDS)


Biological activity in the repopulating rat spermatocyte after the withdrawal of gossypol treatment: I. The activity for DNA synthesis.
Mature male rats were treated with gossypol for various lengths of time after which the treatment was stopped to allow the arrested spermatogonia to revive. Fifteen days after withdrawal of the drug treatment, the arrested spermatogonia entered into the meiotic division and then reached the pachytene stage. The meiotic cells derived from the arrested spermatogonia were the first generation of the differentiated germ cells after long-term gossypol treatment. Centrifugal elutriation technique was used to isolate the repopulating pachytene spermatocytes (RPS) or the control pachytene spermatocytes (CPS) from the rat testis with or without receiving gossypol pretreatment. In vitro culture condition for RPS and CPS was established for the synthesis of DNA by the measurement of 3H-thymidine incorporation. The activity for DNA synthesis in RPS was studied and compared to that of the CPS. It was concluded that after gossypol treatment for various times, the incorporation of 3H-thymidine into the cellular thymidine pool of RPS was not affected. However, the activity for DNA synthesis in RPS was significantly lower than that in the CPS. The synthetic activity for DNA was reduced by 14%, 26%, 42%, 40%, and 40% in the RPS for the gossypol pretreatment of 3, 4, 6, 7, and 8 weeks, respectively.


Relationship between amount of cigarette smoking and coronary atherosclerosis on coronary CTA in asymptomatic individuals.
Current smoking is a powerful independent predictor of coronary atherosclerosis in asymptomatic individuals. Many researchers have suggested a cigarette dose-response relationship between smoking and subclinical coronary atherosclerosis. Our study purposes were (a) to investigate the prevalence and plaque characteristics of coronary atherosclerosis in asymptomatic smokers and (b) to assess the cigarette dose-response relationship between smoking and subclinical coronary atherosclerosis using coronary CT angiography (CTA). We consecutively enrolled 7,104 self-referred asymptomatic subjects who underwent coronary CTA as part of a general health evaluation. Current smokers (n = 1,784) were categorized according to total pack years (TPY) with four grades (A, 0.1-10; B, 10-20; C, 20-30; D, >30), smoking duration (SD, years) with four grades (A, 0.1-10; B, 10-20; C, 20-30; D, >30), and number of cigarettes per day (CPD) with four grades (A, 1-20; B, 10-20; C, 20-40; D, >40). After adjusting for other cardiovascular risk factors, adjusted odds ratios for current smokers versus never-smokers as a control group were estimated for the presence of plaques, significant stenosis, and non-calcified plaques (NCP). Current smokers had a statistically significant higher prevalence of any plaque, significant stenosis, NCP, and coronary artery calcium score >100 than never-smokers. According to each categorization of TPY, SD, and CPD, the subclinical coronary atherosclerosis risk increased as grades increased in asymptomatic current smokers relative to never-smokers after adjusting for variable clinical and chemical risk factors. Our study suggests a cigarette dose-response relationship between current smoking and coronary atherosclerosis in asymptomatic individuals.


Derivations of relative biological effectiveness for the high-let radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo.
Relative biological effectiveness (RBE) values for the high linear-energy-transfer particles produced during boron neutron capture therapy have generally been based on theoretical considerations or in vitro experiments. The purpose of this study was to independently determine RBE values for all of the boron neutron capture therapy dose components. Clonogenic cell survival data were obtained for 9L rat gliosarcoma cells irradiated in the Brookhaven Medical Research Reactor thermal neutron beam both in vitro and as an intracerebral tumor. These data were analyzed using the linear quadratic model for cell survival to derive measured RBE values for all beam components and for a number of different boron compounds. In the absence of boron, the combined effects of the protons from the nitrogen capture, 14N(n,p)14C, and the fast neutron scatter, 1H(n,n')p, reactions generated RBEs of 3.7 in vitro and 3.2 in an in vivo/in vitro excision assay, compared to 250 kVp X rays using an end point of 1% cell survival. Apparent RBEs for the 10B(n,alpha)7Li reaction products were calculated from cell survival data following reactor irradiations in the presence of the amino acid p-boronophenylalanine, the sulfhydryl dodecaborate monomer or dimer, or boric acid. Apparent RBEs for the 10B(n,alpha)7Li reaction ranged from 1.2 to 9.8 depending on which boron compound was used. RBEs from the in vitro studies were consistently higher than from the in vivo/in vitro studies. Under any conditions, the apparent RBE for the 10B(n,alpha)7Li reaction with p-boronophenylalanine was higher than that with any other boron compound tested. Generally accepted RBE values for the fast neutron and 14N(n,p)14C reaction components of the total dose are too low. The apparent RBEs calculated for the 10B(n,alpha)7Li reaction were compound-dependent and consistent with differences in the distribution of 10B relative to glioma cell nuclei.


Effect of musical expertise on visuospatial abilities: evidence from reaction times and mental imagery.
Recently, the relationship between music and nonmusical cognitive abilities has been highly debated. It has been documented that formal music training would improve verbal, mathematical or visuospatial performance in children. In the experiments described here, we tested if visual perception and imagery abilities were enhanced in adult musicians compared with nonmusicians. In our main experiment, we measured reaction times of subjects who had to detect on which side of a horizontal or a vertical line a target dot was flashed. In the "imagery" condition the reference line disappeared before the target dot was presented. In order to accomplish the task, subjects had to keep a mental image of the position of the line until the dot appeared. In the "perception" condition, the procedure and stimuli were the same except that the line remained on the screen until the dot was displayed. In both groups, reaction times were shorter for horizontal compared to vertical discrimination, but reaction times were significantly shorter in musicians in all conditions. Moreover, discrimination on the vertical dimension, especially in imaging condition, seemed to be greatly improved on the long term by musical expertise. Simple and choice visual reaction times indicate that this advantage could only be partly explained by better sensorimotor integration in adult musicians.


Cardiovascular responses to exercise in children and adolescents with myocardial dysfunction.
The objective of this study was to understand the expected hemodynamic responses to exercise in children and adolescents with myocardial dysfunction. With the use of Doppler and M-mode echocardiography, cardiovascular changes during maximal semisupine exercise in 11 patients (7 to 17 years old) with myocardial dysfunction were compared with those of a healthy control group (n = 11). Endurance fitness and mean values for maximal cardiac index, stroke index, heart rate, peak aortic velocity, and left ventricular shortening fraction were all significantly lower in the patients (P <.05). Stroke volume rose at the onset of exercise in both groups; whereas values were subsequently stable in the control subjects, stroke volume declined at high-intensity exercise in the patients. These findings imply that augmented myocardial contractility is necessary to sustain stroke volume during exercise. Moreover, the results suggest that pattern of stroke volume response to exercise may serve as a useful marker of myocardial function in children with heart disease.


Evaluation of the Training Session in Elite Paralympic Powerlifting Athletes Based on Biomechanical and Thermal Indicators.
Paralympic powerlifting (PP) is performed on a bench press, aiming to lift as much weight as possible in a single repetition. To evaluate thermal asymmetry and dynamic force parameters with 45 and 80% 1 Repetition Maximum (1 RM) in PP athletes. Twelve elite PP male athletes were evaluated before and after a training session regarding skin temperature (thermography) and dynamic force indicators (Average Propulsive Velocity-MPV, Maximum Velocity-VMax, and Power). The training consisted of five series of five repetitions (5 × 5) with 80% 1 RM. The force indicators and dynamics before and after (45% 1 RM) were evaluated in series "1" and "5" with 80% 1 RM. The temperature did not present asymmetry, and there were differences between the moment before and after. In MPV, Vmax, and Power, with 45% 1 RM, there were differences both in asymmetry and in moments (p < 0.005). With 80% 1 RM, asymmetry was observed, but no differences between moments (p < 0.005). No thermal asymmetry was observed. There were reductions in MVP and VMax at 45 and 80% 1 RM but without significant differences between time points (before and after). However, there was asymmetry in the moments before and after within a safety standard, where Paralympic powerlifting was safe in terms of asymmetries.


Single-strand-conformation polymorphism of ribosomal DNA for rapid species differentiation in genus Phytophthora.
Single-strand-conformation polymorphism (SSCP) of ribosomal DNA of 29 species (282 isolates) of Phytophthora was characterized in this study. Phytophthora boehmeriae, Phytophthora botryosa, Phytophthora cactorum, Phytophthora cambivora, Phytophthora capsici, Phytophthora cinnamomi, Phytophthora colocasiae, Phytophthora fragariae, Phytophthora heveae, Phytophthora hibernalis, Phytophthora ilicis, Phytophthora infestans, Phytophthora katsurae, Phytophthora lateralis, Phytophthora meadii, Phytophthora medicaginis, Phytophthora megakarya, Phytophthora nicotianae, Phytophthora palmivora, Phytophthora phaseoli, Phytophthora pseudotsugae, Phytophthora sojae, Phytophthora syringae, and Phytophthora tropicalis each showed a unique SSCP pattern. Phytophthora citricola, Phytophthora citrophthora, Phytophthora cryptogea, Phytophthora drechsleri, and Phytophthora megasperma each had more than one distinct pattern. A single-stranded DNA ladder also was developed, which facilitates comparison of SSCP patterns within and between gels. With a single DNA fingerprint, 277 isolates of Phytophthora recovered from irrigation water and plant tissues in Virginia were all correctly identified into eight species at substantially reduced time, labor, and cost. The SSCP analysis presented in this work will aid in studies on taxonomy, genetics, and ecology of the genus Phytophthora.


Early follicular phase follicle-stimulating hormone treatment of endometrial luteal phase deficiency.
Fifteen infertile women with inadequate luteal phase, histologically documented in at least two separate cycles, and normal midluteal plasma levels of progesterone (greater than or equal to 10 ng/mL), estradiol (70 to 300 pg/mL), and prolactin (less than 20 ng/mL) received "pure" follicle-stimulating hormone (pFSH), 150 IU intramuscularly, for 4 days (days 1 to 4 of the cycle). The endometrial defect was corrected in 7 of the 15 (46.7%) patients during the first treated cycle. Hormonal levels were similar in control and treatment cycles. Two of 5 patients with no additional infertility factors except luteal phase deficiency (LPD) became pregnant and carried to term singleton pregnancies. In 5 additional infertile patients with normal luteal function as assessed by endometrial histological study (2 cycles) and hormone measurements (first study cycle), a third biopsy was performed in a consecutive cycle under pFSH administration. In no case was the normal secretory pattern impaired. It is concluded that (1) some forms of LPD may be successfully treated by early follicular pFSH therapy and (2) pFSH does not alter the normal endometrial secretory pattern.


End-to-end deep learning model for segmentation and severity staging of anterior cruciate ligament injuries from MRI.
The purpose of this study was to develop a semi-supervised segmentation and classification deep learning model for the diagnosis of anterior cruciate ligament (ACL) tears on MRI based on a semi-supervised framework, double-linear layers U-Net (DCLU-Net). A total of 297 participants who underwent of total of 303 MRI examination of the knee with fat-saturated proton density (PD) fast spin-echo (FSE) sequence in the sagittal plane were included. There were 214 men and 83 women, with a mean age of 37.46 ± 1.40 (standard deviation) years (range: 29-44 years). Of these, 107 participants had intact ACL (36%), 98 had partially torn ACL (33%), and 92 had fully ruptured ACL (31%). The DCLU-Net was combined with radiomic features for enhancing performances in the diagnosis of ACL tear. The different evaluation metrics for both classification (accuracy, sensitivity, accuracy) and segmentation (mean Dice similarity coefficient and root mean square error) were compared individually for each image class across the three phases of the model, with each value being compared to its respective value from the previous phase. Findings at arthroscopic knee surgery were used as the standard of reference. With the addition of radiomic features, the final model yielded accuracies of 90% (95% CI: 83-92), 82% (95% CI: 73-86), and 92% (95% CI: 87-94) for classifying ACL as intact, partially torn and fully ruptured, respectively. The DCLU-Net achieved mean Dice similarity coefficient and root mean square error of 0.78 (95% CI: 0.71-0.80) and 0.05 (95% CI: 0.06-0.07), respectively, when segmenting the three ACL conditions with pseudo data (P < 0.001). A dual-modules deep learning model with segmentation and classification capabilities was successfully developed. In addition, the use of semi-supervised techniques significantly reduced the amount of manual segmentation data without compromising performance.


Solid-phase stereoselective synthesis of 2'-O-methyl-oligoribonucleoside phosphorothioates using nucleoside bicyclic oxazaphospholidines.
The use of 2'-OMe-ribonucleoside bicyclic oxazaphospholidines derived from (R)- or (S)-2-pyrrolidinemethanol has enabled the stereoselective synthesis of (Rp)-, and (Sp)-2'-O-methyloligoribonucleoside phosphorothioates. Interestingly, higher stereoselectivity (96-98%) was observed in the synthesis of (Sp)-2'-O-methyl-oligoribonucleoside phosphorothioates compared to that in the case of (Sp)-oligodeoxyribonucleoside phosphorothioates (90%).


Unusual genetic codes and a novel gene structure for tRNA(AGYSer) in starfish mitochondrial DNA.
The nucleotide sequence of a 3849-bp fragment of starfish mitochondrial genome was determined. The genes for NADH dehydrogenase subunits 3, 4, 5, and COIII, and three kinds of (tRNA(UCNSer), tRNA(His), and tRNA(AGYSer) were identified by comparing with the genes of other animal mitochondria so far elucidated. The gene arrangement of starfish mitochondrial genome was different from those of vertebrate and insect mitochondrial genomes. Comparison of the protein-encoding nucleotide sequences of starfish mitochondria with those of other animal mitochondria suggested a unique genetic code in starfish mitochondrial genome; both AGA and AGG (arginine in the universal code) code for serine, AUA (isoleucine in the universal code but methionine in most mitochondrial systems) for isoleucine, and AAA (lysine) for asparagine. It was also inferred that these AGA and AGG codons are decoded by serine tRNA(AGYSer) originally corresponding to AGC and AGU codons. This situation is similar to the case of Drosophila mitochondrial genome. Variations in the use of AGA and AGG codons were discussed on the basis of the evolution of animals and decoding capacity of various tRNA(AGYSer) species possessing different sizes of the dihydrouridine (D) arm.


Detection of basophil-activating IgG autoantibodies in chronic idiopathic urticaria by induction of CD 63.
Approximately 40% to 50% of patients with chronic idiopathic urticaria (CIU) have functional IgG autoantibodies against FcepsilonRIalpha or IgE, which induce histamine release from basophils and cutaneous mast cells. A positive autologous serum skin test response is believed to reflect the presence of these autoantibodies. We sought to further define the functional properties of and develop a sensitive functional assay for detection of autoantibodies in patients with CIU. Sera from patients with CIU (n=61) and sera from healthy control subjects (n=23) were incubated with donor basophils. Activation of basophils was determined on the basis of CD 63 surface expression, as analyzed on a FACScan flow cytometer. A positive basophil activation test result was found in 51% of patients with CIU, and basophil-activating properties were present in the IgG fractions of sera. When both the in vitro test and the autologous serum skin test were considered, basophil/mast cell-activating autoantibodies were present in 62% of the patients. Patients with a positive basophil activation test result had a significantly higher prevalence of other autoantibodies, had more severe urticaria, and were more likely to have angioedema. The results demonstrate the presence of basophil-activating autoantibodies in about 50% of patients with CIU. The data support the autoimmune cause of the disease and provide a simple test for detection of these autoantibodies.


Virtual lesion clinic - Evaluation of a teledermatology triage system for referrals for suspected melanoma.
The Virtual Lesion Clinic (VLC) of Waitematā District Health Board (WDHB) improves melanoma assessment and treatment using teledermatology. The VLC is reserved for pigmented lesions referred as suspected melanoma from primary care but indeterminate at the initial triage. To assess the efficacy of the VLC diagnosis of melanoma. A retrospective audit of suspected melanoma referrals (1 January 2012 to 31 December 2016) was conducted. Lesions were referred to the VLC if diagnostic uncertainty remained at the initial triage. VLC patients attended MoleMap imaging centres, a dermatologist reviewed history and images remotely and suggested a diagnosis and management plan. Post VLC provisional diagnosis of melanoma, all lesions subsequently excised were reviewed. A positive predictive value (PPV) was calculated using concordance between VLC diagnosis of melanoma and histopathological diagnosis of melanoma. Number needed to excise (NNE) for melanoma was derived, as well as an invasive to in-situ melanoma ratio (IM:MIS) and false negative rate (FNR). The VLC received 1874 referrals for 3546 lesions during the 5-year study period. Six hundred and seventy-nine lesions were recommended excision/biopsy or specialist face-to-face assessment, and 504 lesions were subsequently excised. The PPV was 62%, NNE 1.62 and IM:MIS 0.76 for lesions suspected to be melanoma at VLC assessment. The VLC had a melanoma-specific FNR of 7%. The VLC is effective in early diagnosis of melanoma with a high positive predictive value, low number needed to excise and low false negative rate amongst lesions referred as suspected melanoma.


Ribonucleotide levels in six nematodes, a cestode and a trematode.
The levels of ribonucleotides in the nematodes Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus colubriformis, Nippostrongylus brasiliensis, Ascaris suum and Stephanurus dentatus, the cestode Moniezia expansa and the trematode Fasciola hepatica were measured by high pressure liquid chromatography. The adenylate charge, ATP and total adenine nucleotide levels were in general agreement with those determined enzymatically and with published data. UDP and guanine nucleotide levels were found to be higher than those present in mammals and previously reported for helminth parasites. Cytidine nucleotide levels varied considerably between parasite species. On the other hand inosine nucleotides were present at low concentrations in all species. Adenylate and guanylate charges were similar.


Dorsal displacement of the facial nerve in acoustic neuroma surgery: clinical features and surgical outcomes of 21 consecutive dorsal pattern cases.
In acoustic neuroma surgery, the facial nerve (FN) course varies among patients, but a dorsal pattern is rarely observed. We retrospectively reviewed and classified 556 acoustic neuromas operated on via a lateral suboccipital retrosigmoid (LSO) approach into two groups: dorsal (group D) and non-dorsal (group ND). The clinical features and outcomes including functional preservation of the FN, the extent of tumor resection, and the retreatment rate were compared. Among 556 cases, 21 (3.8%) patients with dorsal patterns were identified. No significant differences in clinical features or preoperative status were noted between groups D and ND. No significant differences in functional FN preservation were found between groups D and ND in the immediate postoperative period (90.5 and 83.0%, respectively) or 1-year postoperatively (95.2 and 97.0%, respectively). Compared with group ND, the extent of tumor resection was significantly less (p < 0.0001) and the retreatment rate was significantly higher in group D (hazard ratio, 33.6; 95% confidence interval [CI], 11.7-96.1; p < 0.0001). In one dorsal pattern case, surgical resection was abandoned based on the intraoperative findings. Dorsal displacement of the FN was accurately predicted with preoperative imaging evaluations in just two cases. Functional preservation of the FN during acoustic neuroma surgery is achievable if the FN runs along the dorsal side of the tumor. However, a dorsal pattern, especially when the FN is broadened, is clearly associated with less complete tumor removal and a higher rate of retreatment than typical pattern cases.


A fully water coupled oblique light-sheet microscope.
Recently developed descanned versions of the oblique light-sheet microscope promise to enable high-frame rate volumetric imaging in a variety of convenient preparations. The efficiency of these microscopes depends on the implementation of the objective coupling that turns the intermediate imaging plane. In this work, we developed a fully immersed coupling strategy between the middle and end objectives of the oblique light-sheet microscope to enable facile alignment and high efficiency coupling. Our design outperformed conventional designs that used only air objectives in resolution and light-collection power. We further demonstrated our design's ability to capture large fields-of-view when paired with a camera with built-in electronic binning. We simultaneously imaged the forebrain and hindbrain of larval zebrafish and found clusters of activity localized to each region of the brain.


Hormone interactions in the Sertoli cells.
The effects of follicle-stimulating hormone (FSH) and testosterone in rat Sertoli cells were investigated in vitro by means of isolated cell populations. The Sertoli cells selectively bind FSH, and respond to FSH stimulation with increased accumulation of endogenous cyclic AMP and secretion of androgen-binding protein (ABP). FSH binding and cyclic AMP response in the Sertoli cells change dramatically during sexual maturation. Cyclic AMP response decreases despite an increase in FSH-binding receptors per cell. Evidence has been provided for the existence of cytoplasmic and nuclear androgen receptors and chromatin acceptor-sites that specifically bind the androgen-receptor complex in the Sertoli cells. A model has been proposed for the hormonal interactions in the seminiferous tubule and the possible role of Sertoli cells in mediating the hormonal effects on spermatogenesis.


[Personalisation in mental health: a promising way].
To demonstrate the pertinence of putting personalisation at the heart of mental health services. Review of littérature of personalisation research and intervention in the United Kingdom, the country where the personalisation is one of the key themes of the health and social services reform agenda. Presentation of the key challenges in the personalisation agenda and also of web tool directly inspired by research and practices in the UK. We think that individuals want to be treated as citizens that want control and choice over their destiny.


Simple descriptors and simple rules of the International Ovarian Tumor Analysis (IOTA) Group: a prospective study of combined use for the description of adnexal masses.
External validation of the IOTA group's three-step diagnostic model (Strategy 1) and comparison with assessment by an expert sonographer (Strategy 2). Prospective study in patients with persistent adnexal masses, in which an inexperienced sonographer performed transvaginal ultrasound applying simple descriptors (SD) and rules (SR) for classifying as benign or malignant. Any non-classifiable mass was then submitted to an expert examiner for subjective assessment (SA). Eighty-one patients (mean age, 43; 27.2% postmenopausal) were included in this prospective study. Surgery was performed for 30 (8 malignant and 22 benign) masses; 51 masses were considered as benign and managed expectantly (they were assumed to be benign for statistical purposes). Diagnostic performance for Strategy 1 (SD+SR+SA) was sensitivity (SN): 87.5% (7/8, 95% CI, 47.3-99.7%) and specificity (SP): 100% (73/73, 95% CI, 95.1-100%). For Strategy 2 (SA only) it was SN 87.5% (7/8, 95% CI, 47.3-99.7%), SP 98.6% (72/73, 95% CI, 92.6-100%). The three-step diagnostic strategy designed by the IOTA group for adnexal masses has a diagnostic performance comparable to that of subjective expert assessment and could be used as a triage method by nonexpert sonographers.


Neonatal stress augments the hypoxic chemoreflex of adult male rats by increasing AMPA receptor-mediated modulation.
Neonatal stress disrupts the developmental trajectory of homeostatic systems. Adult (8- to 10-week-old) male rats exposed to maternal separation (a form of neonatal stress) display several traits reported in patients suffering from sleep-disordered breathing, including an augmented hypoxic chemoreflex. To understand the mechanisms behind this effect, we tested the hypothesis that neonatal stress augments glutamatergic neurotransmission in three regions involved in respiratory regulation, namely the nucleus of the solitary tract, the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus. Maternal separation was performed for 3 h day(-1) from postnatal day 3 to 12. Control pups were undisturbed. Adult rats were instrumented for intracerebroventricular injection of the AMPA/kainate receptor antagonist CNQX (0-4.3 μm). Using plethysmography, ventilatory activity was measured at rest in awake animals during normoxia (fractional inspired O2 = 0.21) and during acute hypoxia (fractional inspired O2 = 0.12; 20 min). Following vehicle injection, the hypoxic ventilatory response of stressed rats was 35% greater than that of controls. Microinjection of CNQX attenuated the hypoxic ventilatory response, but the effect observed in stressed rats was greater than that in control animals. Autoradiography experiments showed that neonatal stress augments expression of AMPA receptors within the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus. Quantification of brain-derived neurotrophic factor showed that neonatal stress augments brain-derived neurotrophic factor expression only within the paraventricular nucleus. We conclude that neonatal stress augments the hypoxic chemoreflex by increasing the efficacy of glutamatergic synaptic inputs projecting onto key respiratory structures, especially the paraventricular nucleus of the hypothalamus. These data provide new insight into the aetiology of sleep-disordered breathing.


Retrospective analysis of clinical outcomes in bilateral cleft lip and palate patients after secondary alveolar bone grafting and premaxilla osteotomy, using a new dento-maxillary scoring system.
Evaluation of relevant clinical outcomes in patients with bilateral cleft lip and palate (BCLP) after secondary aveolar bone grafting (SABG) and premaxilla osteotomy (PMO), through the use of a new scoring system. Data were collected retrospectively from all patients with BCLP who were operated on between 2004 and 2014, at the end of follow-up. The treatment protocol consisted of SABG + PMO in patients aged between 9 and 13 years. At the end of follow-up, the following parameters were scored: (un)interrupted dental arch, skeletal sagittal relationship, bone height using the Bergland/Abyholm criteria, and the presence of postoperative fistula. These parameters were combined to produce a dento-maxillary scoring system, giving a final score between 1 and 10. For statistical analysis, the independent t-test was used. Of 55 children, 45 were suitable for analysis. The mean age at time of surgery was 12.0 years (8.9-16.4 yrs), and the mean follow-up time was 11.7 years (5.8-15.8 yrs). The average number of surgeries executed under general anesthesia was 6 (range: 3-11). The average dento-maxillary score in this patient cohort was 7.6 (1-10; median: 8). Among these patients, 31 had an uninterrupted dental arch; the average Bergland/Abyholm score was 2.07; 30 patients exhibited an Angle class I incisor relationship; and, in 38 cases, the oronasal communication was closed after SABG + PMO treatment. A significant effect of fistulas was seen on dento-maxillary score (p = 0.001). Specifically, a significant effect of fistulas was seen on interrupted dental arch (p = 0.002) and on Bergland/Abyholm score (p = 0.037). The proposed dento-maxillary scoring system is a straightforward tool that can be used to describe and analyze the amount of dento-maxillary rehabilitation at the end of the treatment. Persistence of oronasal fistulas in patients with BCLP has a significant impact on interruption of the dental arch, and can influence dental results at the end of the second decade.


Recovery of adenine-nucleotide pools in terrestrial blue-green algae after prolonged drought periods.
The response of Nostoc commune and Nostoc flagelliforme (terrestrial blue-green algae), grown in their natural habitat, towards rewetting after prolonged drought periods (2 weeds up to five years) has been investigated. In Nostoc flagelliforme, the energy charge (EC) about 0.18 in dry condition increases rapidly (EC=0.7 after 1 h) and more slowly in a second phase (EC=0.8 after 6 h). The total content of AXP (=ATP+ADP+AMP) apparently increases due to de novo synthesis of adenine nucleotides. ATP-build-up after a drought period is probably provided by oxidative phosphorylation. It has been found to be about the same, regardless of whether the foregoing drought period had been extended over 6 months or 5 years.Dry samples of colony mats of N. commune exhibit very low ATP-, but high ADP-contents. Within 6 h after rewetting, the final level of extractable ATP (60-100 nmol/mg chlorophyll) is recovered.


T-2 toxin induced changes in liver and serum enzymes of rats.
The effects on liver and serum enzymes of feeding a single dose (2 mg/kg) and daily doses (0.75 mg/kg) of T-2 toxin were studied in young male rats. Sample times were 8, 16 and 24 hr for single dose administration and 7, 14 and 21 days for daily dose administration. T-2 toxin in single and daily doses significantly reduced activities of hepatic glutamate pyruvate transaminase (GPT) and alkaline and acid phosphatases at all the sampling periods. In both feeding trials, levels of serum GPT increased, while that of acid and alkaline phosphatases significantly decreased at all the sampling times. This study indicates that the liver is affected by feeding T-2 toxin to rats.


Effect of 5-azacytidine on deoxyribonucleic acid methylation in Escherichia coli K12.
5-Azacytidine inhibits Escherichia coli DNA(cytosine-5)methylase when added to growing cells. The time-course of recovery of methylase activity and the appearance of 5-methylcytosine in DNA following removal of the drug was studied. When E. coli K12 was treated with 5-azacytidine for 30 min, DNA (cytosine-5)methylase levels decreased to less than 10% of control levels and slowly recovered to control levels after seven generations of growth. 5-Methylcytosine synthesis in DNA remained at less than 10% of control levels for three generations after treatment and returned to control levels after six generations of growth. In contrast, beta-galactosidase levels in induced cells, which declined to 66% of control one generation after treatment, returned to control by the third generation of growth. The rate of induction of beta-galactosidase had returned to the control rate two generations after growth resumed. Since azacytidine-containing DNA inhibits DNA-cytosine methylases in vitro, the prolonged inhibition of cytosine methylation in E. coli K12 following treatment with the drug could be due to the persistence of the drug in DNA and thus inhibition of newly synthesized enzymes.


Assembly of lipopolysaccharide in Escherichia coli requires the essential LapB heat shock protein.
Here, we describe two new heat shock proteins involved in the assembly of LPS in Escherichia coli, LapA and LapB (lipopolysaccharide assembly protein A and B). lapB mutants were identified based on an increased envelope stress response. Envelope stress-responsive pathways control key steps in LPS biogenesis and respond to defects in the LPS assembly. Accordingly, the LPS content in ΔlapB or Δ(lapA lapB) mutants was elevated, with an enrichment of LPS derivatives with truncations in the core region, some of which were pentaacylated and exhibited carbon chain polymorphism. Further, the levels of LpxC, the enzyme that catalyzes the first committed step of lipid A synthesis, were highly elevated in the Δ(lapA lapB) mutant. Δ(lapA lapB) mutant accumulated extragenic suppressors that mapped either to lpxC, waaC, and gmhA, or to the waaQ operon (LPS biosynthesis) and lpp (Braun's lipoprotein). Increased synthesis of either FabZ (3-R-hydroxymyristoyl acyl carrier protein dehydratase), slrA (novel RpoE-regulated non-coding sRNA), lipoprotein YceK, toxin HicA, or MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase) suppressed some of the Δ(lapA lapB) defects. LapB contains six tetratricopeptide repeats and, at the C-terminal end, a rubredoxin-like domain that was found to be essential for its activity. In pull-down experiments, LapA and LapB co-purified with LPS, Lpt proteins, FtsH (protease), DnaK, and DnaJ (chaperones). A specific interaction was also observed between WaaC and LapB. Our data suggest that LapB coordinates assembly of proteins involved in LPS synthesis at the plasma membrane and regulates turnover of LpxC, thereby ensuring balanced biosynthesis of LPS and phospholipids consistent with its essentiality.


Cognitive impairments in breast cancer survivors treated with chemotherapy: a study based on event-related potentials.
Chemotherapy-related cognitive impairments in breast cancer patients were usually reported through cognitive questionnaires or scales which may be subjective and insensitive. This study is to assess the effect of chemotherapy on cognitive function in breast cancer patients stratified by age using objective electrophysiological measure, the P300 component of event-related potentials (ERPs) with a large sample size. Totally, 529 primary breast cancer patients, including 178 cases at initial diagnosis stage and before chemotherapy (Group1), 167 cases during chemotherapy (Group2), and 184 cases post chemotherapy and during follow-up period (Group3), were examined with ERPs (P300 component) to assess the effect of chemotherapy on their cognitive function. There were significant differences of P300 latency in Group2 (364.74 ± 15.73 ms) and Group3 (364.02 ± 17.12 ms, mean follow-up period of 2.42 years) compared with Group1 (355.13 ± 19.47 ms, P < 0.001), respectively. With further age stratification: in patients of < 50 years, P300 latency was significantly prolonged in Group2 and Group3 compared with Group1 (P < 0.001), respectively; in patients of 50-59 years, P300 latency was significantly prolonged in Group2 compared with Group1 (P < 0.05), but without difference in Group1 and Group3 (P>0.05); In patients of ≥ 60 years, there were no differences of P300 latency among three the groups (P>0.05). It is first suggested by our objective detection data that the side effect of chemotherapy on cognitive functions in breast cancer patients may decrease with age. Electrophysiological cognitive impairments mainly occur in younger breast cancer patients undergoing chemotherapy and would last for years after chemotherapy, which highlights the importance of early intervention for those patients, especially in younger patients.


The significance of dense fine speckled pattern in antinuclear antibody-associated rheumatic disease and coexisting autoantibodies: A propensity score-matched cohort study.
To investigate the relationship between the prevalence of antinuclear antibody (ANA) -associated rheumatic diseases (AARD) and the presence of dense fine speckled (DFS) and homogeneous patterns in ANA tests. This retrospective study enrolled adult patients with either a DFS or homogeneous pattern in their ANA test. A mixed pattern was defined as the presence of more than one pattern reported in the test. The presence of anti-DFS70 antibodies and other common autoantibodies were detected using EUROLINE ANA Profile 23. A 1:2 propensity score matching was applied to control for demographic and other interfering factors. A total of 59 patients with a DFS pattern were enrolled and compared with a matched homogeneous group. The DFS group had a significantly lower prevalence of AARD (3.4% vs. 16.9%, p = .008) and the subgroup with anti-DFS70 antibodies showed an even lower prevalence (2% vs. 20%, p = .002). Among the 33 patients with monospecific anti-DFS70 antibodies, five had a mixed pattern, and all patients with common autoantibodies had an isolated DFS pattern. The findings of this study suggest that patients with a DFS pattern in their ANA test may have a lower prevalence of AARD compared with those with a homogeneous pattern. However, an isolated DFS pattern in ANA testing does not necessarily indicate the presence of monospecific anti-DFS70 antibodies or AARD. Confirmatory testing for the monospecific anti-DFS70 antibody is mandatory to exclude AARD.


Synthesis of 3-aminoalkyl derivatives of 5-5-diphenylhydantoin.
The nucleophilic substitution of 3-bromoalkyl-5,5-diphenylhydantoins will appropriate amines gave new 3-aminoalkyl derivatives of 5,5-diphenylhydantoin.


Predicting Environmental and Ecological Drivers of Human Population Structure.
Landscape, climate, and culture can all structure human populations, but few existing methods are designed to simultaneously disentangle among a large number of variables in explaining genetic patterns. We developed a machine learning method for identifying the variables which best explain migration rates, as measured by the coalescent-based program MAPS that uses shared identical by descent tracts to infer spatial migration across a region of interest. We applied our method to 30 human populations in eastern Africa with high-density single nucleotide polymorphism array data. The remarkable diversity of ethnicities, languages, and environments in this region offers a unique opportunity to explore the variables that shape migration and genetic structure. We explored more than 20 spatial variables relating to landscape, climate, and presence of tsetse flies. The full model explained ∼40% of the variance in migration rate over the past 56 generations. Precipitation, minimum temperature of the coldest month, and elevation were the variables with the highest impact. Among the three groups of tsetse flies, the most impactful was fusca which transmits livestock trypanosomiasis. We also tested for adaptation to high elevation among Ethiopian populations. We did not identify well-known genes related to high elevation, but we did find signatures of positive selection related to metabolism and disease. We conclude that the environment has influenced the migration and adaptation of human populations in eastern Africa; the remaining variance in structure is likely due in part to cultural or other factors not captured in our model.


[Application of the third generation cementing technique in total hip anthroplasty].
To investigate the effect of the third generation cementing technique in total hip anthroplasty (THA). The clinical data of THA performed on 107 hips in 90 patients suffering from different kinds of orthopedic diseases, 54 males and 36 females, with an average age of 55 years and the average follow-up period of 36 months, were analyzed. According to the Harris scoring system, the 90 patients achieved a score of 34 (range 4 - 78) before the operation and achieved a score of 91 (range 64 - 100) after the operation. 97.1% of the patients showed good or excellent results during the short-term follow-up. The third generation cementing technique is rather effective in total hip anthroplasty.


Exposure to a standard culture medium alters the response of cartilage explants to injurious unconfined compression.
Previous studies on chondral explants have not clearly described to what extent the degree and the distribution of cell death are dependent on the amount of free swelling seen during tissue equilibration in a standard culture medium. The current study hypothesized that increased fluid content inside equilibrated chondral explants, when subjected to injurious compression, would lead to greater matrix damage during unconfined compression. Equilibrated and non-equilibrated chondral explants were loaded to 30 MPa at a fast rate of loading ( approximately 600 MPa/s). Stress-strain curves were documented for each explant. Matrix damage was assessed by the length of surface fissures. Chondrocyte viability was also measured in the various layers of the explants. The stiffness of the equilibrated specimens was less than non-equilibrated specimens, and it correlated with the amount of fluid absorbed during equilibration. More matrix damage and associated cell death in the superficial zone were documented in equilibrated than non-equilibrated explants, and these correlated positively with fluid absorbed during equilibration. This study indicated that equilibration of chondral explants in a standard culture medium alters their response to mechanical loading in terms of stiffness, matrix damage and cell viability.


Pain-related evoked potentials after intraepidermal electrical stimulation to Aδ and C fibers in patients with neuropathic pain.
Neuropathic pain can result from neuronal hyperexcitability and complex interactions of the nociceptive pathways. Intraepidermal electrical stimulation (IES) is a novel technique that can selectively activate Aδ and C fibers. To investigate patterns of changes in Aδ- and C-mediated brain responses in patients with neuropathic pain using IES, we recorded pain-related evoked potential (PREP) after IES of Aδ and C fibers in 20 patients with neuropathic pain and 15 age-matched healthy volunteers. We evaluated PREP latencies, amplitudes, and amplitude ratios of PREPs after C/Aδ-fiber stimulation. PREP amplitudes after Aδ-fiber stimulation tended to be smaller in the patient group, whereas there were no significant differences in amplitudes after C-fiber stimulation between the patient and normal control groups. PREP amplitude ratios after C/Aδ-fiber stimulation were significantly greater in the patient group than in the control group, and the higher ratio tended to be associated with a greater visual analog scale score. Patients with neuropathic pain had a tendency towards decreased Aδ amplitudes and significantly increased C/Aδ PREP amplitude ratios and this ratio appeared to be associated with the intensity of pain. Our findings suggest that decreased inhibition of the Aδ to C nociceptive systems is associated with generation of neuropathic pain.


Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): impact of vehicle for topical induction.
The development of this Brown Norway (BN) rat asthma model was focused on the duplication of at least some hallmarks of human diisocyanate asthma using the skin as the initial priming route of exposure. Equal total doses of polymeric diphenylmethane-diisocyanate (MDI) were applied to similar surface areas either dissolved in di-n-octyl sebacic acid ester (20%) (SEBA), in acetone:olive oil (20%) (AOO) or undiluted. The elicitation of respiratory allergy utilized four repeated nose-only inhalation challenges of 30 min with 39 mg/m(3) MDI-aerosol approximately every 2 weeks. Emphasis was directed towards the analysis of respiratory responses delayed in onset. Endpoints suggestive of an allergic inflammatory response were examined by bronchoalveolar lavage (BAL) 1 day after the last inhalation challenge and comprised protein, LDH, cytodifferentiation of BAL cells, MCP-1, and some Th1 and Th2 cytokines. MCP-1 and cytokines were comparatively determined in three compartments: BAL fluid, BAL cells, and lung-associated lymph nodes (LALN). In all groups sensitized topically to MDI typical delayed-onset respiratory responses occurred. The lung and LALN weights, BAL-protein and -LDH were significantly increased as compared to the naïve control group challenged identically. There was compelling evidence of a neutrophilic rather than an eosinophilic inflammatory response. The patterns of interleukin (IL) IL-1alpha, TNF-alpha, IFN-gamma, GM-CSF, and IL-4 differed appreciably from one compartment to another and were essentially maximal in BAL cells. In contrast, MCP-1 was increased to the same extent in all compartments measured. Collectively, changes were slightly, although consistently more pronounced when using SEBA as vehicle when compared with the vehicle AOO or undiluted MDI. Notable was a discordance of cytokine profiles and respiratory responses. In conclusion, the priming potency of topically administered MDI and subsequent asthma-like responses following repeated inhalation exposures appear to be dependent on multiple factors, one of them appears to be associated with the type of matrix used to dissolve MDI. This animal model provides a versatile and robust experimental tool to evaluate and assess at least some features of MDI-related asthma.


Birth weight of Hausa infants in Northern Nigeria.
The birth weight of 1460 Hausa singleton infants was recorded and analysed. The birth weight of Hausa infants (Mean +/- SD) was 3.03 +/- 0.45 kg, being higher in males (3.08 +/- 0.47 kg) than females (2.97 +/- 0.48 kg). The difference was significant (P less than 0.001). The mean birth weight of first born children was significantly lower than the subsequent born, and increasing birth order was associated with higher birth weight irrespective of maternal age. The birth weight was influenced more by the parity as compared to maternal age. The incidence of low birth weight was 15.8 per cent, being lower in males (13.6 per cent) as compared to females (18.1 per cent). Comparison were made with studies from other parts of the country as well as from other countries.


[Experience with the postgraduate training of pathologo-anatomists at the Novokuznets Institute for the Advanced Training of Physicians].
The authors report the experience in training clinical anatomists gained at the Chair of General Clinical Pathology (Pathoanatomy) in the Novokuznetsk Institute for Advanced Medical Training. Altogether 366 specialists in clinical pathology have been trained for the 10-year period (1976-1985). Problems of composing the curricula for the training cycles and their contents are discussed. The significance of such institutes for advanced training of those who specialize in pathoanatomy is emphasized.


Comparison of gastrointestinal ultrasound with capsule endoscopy in patients with small bowel Crohn's disease.
We aimed to investigate the association between gastrointestinal ultrasound (GIUS) and capsule endoscopy (CE) in assessing disease activity in patients with small bowel Crohn's disease (CD). Medical records of 74 patients with small bowel CD who were treated at our hospital between January 2020 and March 2022 were retrospectively reviewed, including 50 men and 24 women. All patients underwent both GIUS and CE within one week after their admissions. The Simple Ultrasound Scoring of Crohn's Disease (SUS-CD) and Lewis score were used to assess disease activity during GIUS and CE, respectively. P < 0.05 was considered as statistically significant. The area under the receiver operating characteristic curve (AUROC) of SUS-CD was 0.90 (95% confidence interval [CI] 0.81-0.99; P < 0.001). And the diagnostic accuracy of GIUS was 79.7%, with a sensitivity of 93.6%, a specificity of 81.8%, a positive predictive value of 96.7%, a negative predictive value of 69.2% in predicting active small bowel CD. Furthermore, the agreement between GIUS and CE was assessed using Spearman's correlation analysis and SUS-CD was correlated with Lewis score (r = 0.82, P < 0.001) CONCLUSION: Our findings demonstrate a strong correlation between GIUS and CE in assessing the disease activity in patients with CD affecting the small intestine.