Treatment of chronic hepatitis C virus in allogeneic bone marrow transplant recipients.
We recently reported an increased incidence of cirrhosis in hepatitis C virus (HCV)-infected stem cell transplant (SCT) recipients. Here, we describe our experience in the treatment of these patients, which has been, to date, poorly reported in the literature. Among 99 HCV-infected HCT recipients, 36 had HCV-related liver lesions on biopsy requiring therapy. Owing to HCV treatment contraindications, only 61% of patients (22/36) could be treated. In all, 12 patients received more than one course of anti-HCV treatment if they had HCV RNA still detectable after the first course of treatment and no treatment contraindications. Combined therapy (pegylated interferon (IFN): n=9, or standard IFN: n=9, in combination with ribavirin) led to sustained virological response in 4/18 (20%) patients as compared to 2/20 (10%) in patients who received IFN alone. Hematological toxicity was more frequent with combined therapy. While anemia responded to erythropoietin and/or dose modification, thrombocytopenia usually led to treatment interruption (n=3). This study thus highlights the efficacy of combined therapy and emphasizes the fact that the undue safety concerns are not a problem when treating this particular population.


Polymer materials for the prevention of catheter-related infections.
Catheter-related infections are major problems in medicine because of severe consequences for the patient, prolongation of hospitalization, and increasing therapy costs. Beside progress in hygienic measures, development of catheters with antiinfective properties seems to be a promising approach to the prevention of such infections. Two approaches for infection-resistant catheter materials have been developed: materials with antiadhesive properties and materials with antimicrobial properties. Antiadhesive polymers shall prevent the adhesion of microorganisms to the medical device. However, up to now there has been no material which would lead to a complete inhibition of adherence ("zero adherence"). Materials with antimicrobial properties contain antimicrobial substances which are incorporated into the biomaterial or bound to the polymer surface. These devices seem to be effective in the prevention of "early onset infections". In this paper, an overview of the development and efficiency of antiadhesive or antimicrobial polymers is given.


[Quadrilateral analysis of lower face: an individualized and differential assessment for orthognathic surgery].
The authors describe the method of cephalometric diagnosis known as "quadrilateral analysis", proposed by Di Paolo R.J.: this method offers an accurate assessment of skeletal dysplasia, particularly for--orthodontic surgery.


Scorpions regulate their energy metabolism towards increased carbohydrate oxidation in response to dehydration.
Scorpions successfully inhabit some of the most arid habitats on earth. During exposure to desiccating stress water is mobilized from the scorpion hepatopancreas to replenish the hemolymph and retain hydration and osmotic stability. Carbohydrate catabolism is advantageous under these conditions as it results in high metabolic water production rate, as well as the release of glycogen-bound water. Hypothesizing that metabolic fuel utilization in scorpions is regulated in order to boost body water management under stressful conditions we used a comparative approach, studying energy metabolism during prolonged desiccation in four species varying in resistance performance. We used respirometry for calculating respiratory gas exchange ratios, indicative of metabolic fuel utilization, and measured metabolic fuel contents in the scorpion hepatopancreas. We found that hydrated scorpions used a mixture of metabolic fuels (respiratory exchange rates, RER~0.9), but a shift towards carbohydrate catabolism was common during prolonged desiccation stress. Furthermore, the timing of metabolic shift to exclusive carbohydrate oxidation (RER not different from 1.0) was correlated with desiccation resistance of the respective studied species, suggesting triggering by alterations to hemolymph homeostasis.


The "implicit" serial reaction time task induces rapid and temporary adaptation rather than implicit motor learning.
The serial reaction time task (SRTT) has been widely used to induce learning of a repeated motor sequence without the participants' awareness. The task has also been of major influence for defining current concepts of offline consolidation after motor learning. The present study intended to replicate previous findings in a larger population of 53 healthy individuals. We were unable to reproduce previous results of online and offline implicit motor learning with the SRTT. Trials with a repeated sequence rapidly induced shorter reaction times compared to random trials, but this improvement was lost in a post-test obtained a few minutes after the training block. Furthermore, no offline consolidation was observed as there was no change in sequence specific reaction time gain between the post-test immediately after training and a re-test obtained 8 h after training. Online or offline learning remained absent when we modulated the number of sequence repetitions, the error levels, and the structure of random sequences. We conclude that the SRTT induces a rapid and temporary adaptation to the sequence rather than learning, since the repeated motor sequence does not seem to be encoded in memory.


QuantiFERON-TB Gold and selected region of difference 1 peptide-based assays for the detection of Mycobacterium tuberculosis infection in a cohort of patients enrolled with suspected tuberculosis.
Recently, a simple whole blood test, QuantiFERON-TB Gold (QFT-Gold), has been adopted for immunologic diagnosis of Mycobacterium tuberculosis infection. A total of 369 individuals with suspected tuberculosis (TB) were tested with the QFT-Gold, whereas a subgroup of 62 patients was tested simultaneously with QFT-Gold test and an assay based on selected peptides from early secreted antigenic target 6 and culture filtrate protein 10 proteins. The sensitivity of the QFT-Gold assay for active TB was 72.9%, and the agreement between this test and tuberculin skin test was 75%. Using selected peptides, we found a positive response in the majority of active TB patients, with a sensitivity of 84% and a specificity of 89%. Our study suggests the usefulness of QFT-Gold in routine clinical practice on unselected patients with suspected TB. Moreover, the assay based on selected peptides is a useful tool to discriminate between active and latent TB and shows a high predictive value.


Identification of lncRNAs involved in maternal-to-zygotic transition of in vitro-produced porcine embryos by single-cell RNA-seq.
Long non-coding RNAs (lncRNAs) function through multiple tiers of molecular circuits and are vital to gamete maturation and early embryo development. However, in pig early embryos, identification and expression dynamics of lncRNAs remain less studied. Here, we systematically analysed the expression dynamics of lncRNAs based on our previously published single-cell RNA-seq data from pig mature oocytes (GSE160334), and single blastomeres biopsied from pig in vitro fertilized (IVF) and early parthenogenetically activated (PA) embryos (1- to 8-cell stages; GSE164812). With the progression of embryo development, the total number of expressed lncRNAs gradually decreased and showed great variation at each developmental stage for both IVF and PA groups. Consecutive stage pairwise comparison of MII oocytes, 1-cell zygotes, 2-cell, 4-cell and 8-cell IVF embryos identified 151, 245, 1119 and 188 differentially expressed (DE) lncRNAs, including 119, 80, 867, 77 up-regulated and 32, 165, 252, 111 down-regulated, while 289, 437, 895 and 495 DE lncRNAs (141, 89, 768, 97 up-regulated and 148, 348, 127, 398 down-regulated) were identified in PA embryos at the same stages. The DE lncRNAs identified within IVF embryos were much different from that identified within PA embryos, showing embryo type-specific manner. Further cross-comparison between PA and IVF embryos identified 184, 656, 2502 and 266 DE lncRNAs for the 1- to 8-cell embryo stages, respectively. Further GO and KEGG enrichment analysis of DE mRNAs targeted by DELs indicated that different signalling pathways were involved in maternal-only and bi-parental embryo development. Collectively, comparative profiling of lncRNA expression dynamics between pig IVF and PA embryos provides a valuable resource, to investigate further regulatory mechanisms of lncRNAs associated with ZGA and maternal RNA decay during early embryo development.


Predicting performance in a psychological statistics course.
In statistics courses for psychology students, only age and algebra skills predicted course performance of 71 students.


Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Vomiting in paracetamol overdose.
A short cut review was carried out to establish whether vomiting was a significant consequence of paracetamol (acetaminophen) overdose. Altogether 48 papers were found using the reported search, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.


Study of primary amines for nucleophilic cleavage of cyanylated cystinyl proteins in disulfide mass mapping methodology.
In a study of primary (methyl to butyl) amines as nucleophiles for cyano-induced cleavage of cysteinyl proteins, methylamine was found to be superior to ammonia for cyanylation (CN)-based disulfide mass mapping methodology. Reaction conditions such as nucleophile concentration, temperature, and reaction time were systematically studied using ribonuclease A as a model protein. The CN-induced cleavage products were monitored using reverse-phase chromatography and matrix-assisted laser desorption ionization mass spectrometry. Results showed that low temperature, short reaction time, and high nucleophile concentration optimize the cleavage reaction and minimize side reactions. These conditions shorten the analysis time and substantially improve the yield of cleavage products. Further, the concurrent use of homologous nucleophiles (e.g., ammonia and methylamine) facilitates recognition and identification of cleavage products.


Continuous psoas compartment blocks after major orthopedic surgery in children: a prospective computed tomographic scan and clinical studies.
Femoral shaft or hip surgeries are very painful for children. We conducted both computed tomographic (CT) and clinical prospective studies to define new landmarks in children and to evaluate the effectiveness of continuous psoas compartment blocks (CPCBs) using disposable elastomeric pumps. In a preliminary CT scan study of 20 patients, the plexus depth was correlated to patient age and the optimal point of puncture for CPCB was three-quarters of the distance from the spinous process of L4 to a line parallel to the spinal column passing through the posterior superior iliac spine. In a subsequent prospective series, a CPCB was administered before surgery to 15 children for pain relief after femoral and hip osteotomies. After general anesthesia, a 0.5 mL/kg bolus of a mixture of 1% lidocaine with epinephrine (1/200.000) and 0.5% ropivacaine was injected through the CPCB catheter. After contrast media assessment of the catheter location, a disposable pump (Infusor LV); Baxter, Paris, France) with 0.2% ropivacaine was connected and pump flow was adjusted to the patient's weight (0.2 mg x kg(-1) x h(-1)). Postoperative pain was evaluated using a visual analog scale or the Children and Infants Postoperative Pain Score at hour H1, H6, H12, H18, H24, H36, and H48, and in terms of rescue analgesia, adverse events, and motor blocks. All blocks were effective during surgery. Postoperative analgesia was excellent. The median pain scores were 1 for H1 and 0 beginning H6. The motor blockade was minimal before 24 h and absent thereafter. No major adverse event was noted. Parents of 93% of the children were satisfied. We conclude that postoperative analgesia with CPCB is a very effective technique in children after major proximal lower limb orthopedic surgery. The CT scan landmarks described in this study were more medial than the conventional landmarks used in the literature. Continuous psoas compartment blocks provide optimal pain relief in children after major orthopedic surgery without major adverse events. The landmarks used, defined in a preliminary computed tomographic scan study, were more medial than conventional landmarks.


On-line high-performance liquid chromatography-mass spectrometric detection and quantification of N-acylhomoserine lactones, quorum sensing signal molecules, in the presence of biological matrices.
A protocol using reversed-phase liquid chromatography coupled with positive-ion electrospray ionization and ion trap mass spectrometry is described for the identification and quantification of N-acylhomoserine lactones (HSLs) in crude cell-free supernatants of bacterial cultures. The HSLs are produced by gram-negative bacteria and act as intercellular signals inducing density-dependent gene expression. Compared with the multi-step procedures previously reported, which included chemical extraction, purification and the use of Escherichia coli HSL biosensors, this on-line LC-MS-MS method is fast and detects 11 HSLs. Its speed and robustness allow the analysis of a large number of samples without loss of performance (no signal variation for a control sample after 90 chromatographic injections). The selectivity is based on the MS-MS fragment ions of the molecular [M+H]- ions and on their relative intensities. For quantification, the m/z 102 ion, specific for the lactone ring and detected with a good signal-to-noise ratio, allows low detection limits even in complex matrix samples (0.28 up to 9.3 pmol). Moreover, this method allows the quantification of 11 HSLs whatever their chemical structure, substituted or not. The protocol was applied to Vibrio vulnificus, a marine bacterium. Six HSLs were detected and quantified with relative standard deviations for repeatability of < 10%.


A motor-driven miniature multiple microelectrode manipulator for recording from the cortical neuropile of the awake monkey in operant behavior paradigms.
An improved version of the Blum and Feldman multiple microelectrode manipulator is described. The main innovation is a design based on miniaturization and light weight (75 g), which allows head mounting with minimal disturbance to the animal in awake monkey operant behavior studies. The major features of the previously described model are preserved: simultaneous independent manipulation of four microelectrodes, in order to record from at least four single units, that may be crosscorrelated. With the new design better adjustment of intermicroelectrode distances for studies of interneural distances of 300 microns to 7 mm, and an easier automatic, computer-controlled monitoring of distances transversed into the brain are possible.


δ-Opioid receptor activation ameliorates lipopolysaccharide-induced inflammation and apoptosis by inhibiting the MAPK/caspase-3 pathway in BV2 microglial cells.
Delta-opioid receptor (DOR) is widely distributed in the central nervous system, and its activation protects against ischaemic/hypoxic brain injury. However, the role of DOR in microglia in ischaemic stroke has not yet been fully investigated. We found that DOR was expressed in both human and mouse cerebral microglia, besides, it was upregulated in activated BV2 microglial cells by immunofluorescence staining and Western blot. DOR activation by the specific agonist TAN-67 significantly enhanced BV2 microglial cell viability and reduced apoptosis, as evidenced by decreased cleaved caspase-3 levels and TdT-mediated aUTP-X nick end labelling (TUNEL) staining after LPS stimulation. Furthermore, activation of DOR significantly inhibited inducible nitric oxide synthase (iNOS) production and dose-dependently inhibited the mRNA and protein expression levels of other pro-inflammatory cytokines, including IL-1β and IL-6, whereas it increased the expression of the anti-inflammatory cytokine IL-10 in LPS-stimulated BV2 microglial cells; these effects were correlated with diminished phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Moreover, these effects could be reversed by the DOR antagonist naltrindole. DOR activation can activate microglia to switch to the beneficial phenotype and inhibit LPS-induced inflammation and apoptosis via the mitogen-activated protein kinase (MAPK)/caspase-3 pathway in BV2 microglial cells. This study provides new insight into neuroprotection against and treatment of ischaemic stroke.


A long-term survival case of adult undifferentiated embryonal sarcoma of liver.
Undifferentiated embryonal sarcoma of the liver (USEL) is a rare malignant hepatic tumor with a poor prognosis that is usually observed in children (aged 6 to 10 years) and rarely seen in adults. We present a case of USEL in a 27-year-old woman with no previous history of the disease. Laboratory tests performed on admission showed that the patient had mildly elevated levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyl transpeptidase. The levels of viral hepatitis and tumor serum markers were all within normal limits. Computed tomography showed a large mass involving the right lobe and the medial segment of the liver. Right trisectionectomy was performed. Microscopically, the tumor was composed of pleomorphic and polynuclear dyskaryotic cells in a myxoid stroma with focal eosinophilic globules and no clear differentiation to muscle. Histological diagnosis showed undifferentiated embryonal sarcoma. Adjuvant therapy with cisplatin, vincristine, doxorubicin, cyclophosphamide, and actinomycin D was initiated. We administered a high dose of etoposide to extract the patient's peripheral blood stem cells and performed radiation therapy and peripheral blood stem cell transplantation. At 5-year follow-up, the patient was alive without any evidence of recurrence. Here, we describe the clinical and histopathological features of USEL as well as the therapeutic options for USEL in adults with this disease.


First in vivo application of microwave radiometry in human carotids: a new noninvasive method for detection of local inflammatory activation.
This study investigated whether temperature differences: 1) can be measured in vivo noninvasively by microwave radiometry (MR); and 2) are associated with ultrasound and histological findings. Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues. Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (ΔT) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed. ΔT was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p < 0.01). Fatty plaques had higher ΔT compared with mixed and calcified (p < 0.01) plaques. Plaques with ulcerated surface had higher ΔT compared with plaques with irregular and regular surface (p < 0.01). Heterogeneous plaques had higher ΔT compared with homogenous (p < 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher ΔT compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p < 0.01). MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation.


Supramolecular aggregation and organization in peripheral nerve myelin.
Under certain preparative conditions the lipid bilayers of glutaraldehyde-fixed, PNS myelin demonstrate a marked compartmentalization, which can be augmented by lipid extraction following sectioning. The results are interpreted as indicating a supramolecular domain pattern of arrangement centered upon the transmembrane protein (P0) molecules. The latter are thought to be surrounded by annuli of substantially immobilized phospholipids. In the lamellar planes particular lipids are considered to have a nonrandom distribution. The visualization of bilayer compartmentalization was seen only in negatively stained sections obtained from unembedded or glutaraldehyde-urea-embedded myelin. Lipids were unextracted in the basic preparations except in so far as some unfixed, amphipathic molecules escaped at the trough-fluid interface at the time of sectioning, an observed phenomenon which probably aided in the visualization of the compartmentalization. Visualization was also augmented by surface tension expanding section fragments as they floated on the trough fluid. All stages of transition between well-ordered myelin and dispersed globular units were commonly to be found. Deliberately delipidated myelin exposed more sharply defined and smaller globular units in bilayer regions, but even these are regarded as being supramolecular aggregates including residual lipid annuli around the transmembrane proteins. The addition of cadmium ions as a "fixative" for lecithin seemed to improve the preservation of glutaraldehyde-urea-embedded myelin but was not strictly necessary to reveal its domain structure. A secondary tannic acid fixation was required to process unembedded myelin so as to reveal the fundamental compartmentalization of its lipid bilayers.


[Legal pitfalls in urology].
The juridification of medicine affects all disciplines, including urology. Therefore, in this discipline it can well happen that patients not only feel wrongly treated or complain that a treatment was not performed lege artis but also demand compensation or even bring criminal charges. From the patient point of view, the doctor is often more likely to blame for a complication that has arisen or for a hoped for but failed treatment success, than that it is accepted that a complication is typical for the intervention, which, despite the greatest medical care, unfortunately can become reality and is a fateful course. Insurance against claims for damages can be taken out. Not to be underestimated, however, is the personal burden of the accusations with which doctors are confronted by patients, relatives, expert witnesses and courts and against which one must defend oneself. This can mean additional work in addition to the normal medical workload. Therefore, the legal pitfalls in urology should be known.


Sustainable upgrading of biological municipal wastewater treatment based on anammox: From microbial understanding to engineering application.
Anaerobic ammonium oxidation (anammox) has drawn increasing attention as a promising option to energy-neutral wastewater treatment. While anammox process still faces challenges in the low-strength and organics-contained municipal wastewater due to its susceptibility and the technical gaps in substrate supply. Effective strategies for extensive implementation of anammox in municipal wastewater treatment plants (WWTPs) remain poorly summarized. In view of the significance and necessity of introducing anammox into mainstream treatment, the growing understanding not only at level of microbial interactions but also on view of upgrading municipal WWTPs with anammox-based processes need to be considered urgently. In this review, the critical view and comprehensive analysis were offered from the perspective of microbial interactions within partial nitrification- and partial denitrification-based anammox processes. To minimize the microbial competition and enhance the cooperation among anammox bacteria and other functional bacteria, targeted control strategies were systematically evaluated. Based on the comprehensive overview of recent advances, the combination of flexible regulation of input organic carbon with anaerobic/oxic/anoxic process and the integration of sludge fermentation with anoxic biofilms in anaerobic/anoxic/oxic process were proposed as promising solutions to upgrade municipal WWTPs with anammox technology. Furthermore, a new perspective of coupling anammox with denitrifying dephosphatation was proposed as a promising method for in-depth nutrients removal from carbon-limit municipal wastewater in this study. This review provides the critical and comprehensive viewpoints on anammox engineering in municipal wastewater and paves the way for the anammox-based upgrading of municipal WWTPs.


The in-vitro digestion behaviors of micellar casein acting as wall materials in spray-dried microparticles: The relationships between colloidal calcium phosphate and the release of loaded blueberry anthocyanins.
Micellar casein (MC) is a natural carrier for delivering various bioactive substances, and its gastrointestinal digestion behavior has an important impact on the loaded materials. Studies have shown that the digestion behavior of MC is dominated by colloidal calcium phosphate (CCP) in micelle structure. In this paper, The MCs with different CCP levels were used as the carriers to prepare spray-dried microparticles loaded with blueberry anthocyanins (ACNs), then the release of ACNs during digestion was investigated. The results found that the microparticles with less CCP showed the faster dissolution and quicker protein hydrolysis, which caused weaker curd ability. The coagulation was believed as the critical issue to influence the digestion and release behaviors. Therefore, lowering CCP resulted in significantly more ACNs released. This study demonstrated the possibility of using CCP levels to control MC digestion behaviors, which can further determine the release of loaded bioactive substances in casein-based delivery systems.


Microarray-based characterization of the Listeria monocytogenes cold regulon in log- and stationary-phase cells.
Whole-genome microarray experiments were performed to define the Listeria monocytogenes cold growth regulon and to identify genes differentially expressed during growth at 4 and 37 degrees C. Microarray analysis using a stringent cutoff (adjusted P < 0.001; >/=2.0-fold change) revealed 105 and 170 genes that showed higher transcript levels in logarithmic- and stationary-phase cells, respectively, at 4 degrees C than in cells grown at 37 degrees C. A total of 74 and 102 genes showed lower transcript levels in logarithmic- and stationary-phase cells, respectively, grown at 4 degrees C. Genes with higher transcript levels at 4 degrees C in both stationary- and log-phase cells included genes encoding a two-component response regulator (lmo0287), a cold shock protein (cspL), and two RNA helicases (lmo0866 and lmo1722), whereas a number of genes encoding virulence factors and heat shock proteins showed lower transcript levels at 4 degrees C. Selected genes that showed higher transcript levels at 4 degrees C during both stationary and log phases were confirmed by quantitative reverse transcriptase PCR. Our data show that (i) a large number of L. monocytogenes genes are differentially expressed at 4 and 37 degrees C, with more genes showing higher transcript levels than lower transcript levels at 4 degrees C, (ii) L. monocytogenes genes with higher transcript levels at 4 degrees C include a number of genes and operons with previously reported or plausible roles in cold adaptation, and (iii) L. monocytogenes genes with lower transcript levels at 4 degrees C include a number of virulence and virulence-associated genes as well as some heat shock genes.


Identification of specific genes involved in schizophrenia aetiology - what difference does it make?
Genes in which rare, damaging variants substantially increase risk of developing schizophrenia have now been identified. These findings can influence how we think about mental illness in general as well as yielding specific insights into schizophrenia aetiology. Better understanding of underlying biology might eventually lead to improved treatments.


Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors.
Synthesis of new potential COX-1 and/or COX-2 inhibitors, derivatives of 1,1-di-(3-carboxyphenyl)ethane, their biological activity, docking results on COX-1 enzyme and absorption, distribution, metabolism, excretion (ADME) properties are presented. In addition to known interactions between ketoprofen and ibuprofen, leading NSAID agents and COX-1 active site, the possibility of formation of additional interactions is explored. Interactions with Ala527, and with one of the water molecules situated within the active site are identified. Molecular mechanics and DFT calculations for studied compounds have revealed free rotation around two central bonds (C1-C3' and C1-C3"), making them flexible, thus easier to enter and adjust to the active site. Further modifications of core structure have been undertaken to optimize biological activity and ADME properties. As a result, two of the compounds are indicated as novel COX-1 inhibitors.


Using multivariate techniques to assess the effects of urbanization on surface water quality: a case study in the Liangjiang New Area, China.
Rapid urbanization in China has been causing dramatic deterioration in the water quality of rivers and threatening aquatic ecosystem health. In this paper, multivariate techniques, such as factor analysis (FA) and cluster analysis (CA), were applied to analyze the water quality datasets for 19 rivers in Liangjiang New Area (LJNA), China, collected in April (dry season) and September (wet season) of 2014 and 2015. In most sampling rivers, total phosphorus, total nitrogen, and fecal coliform exceeded the Class V guideline (GB3838-2002), which could thereby threaten the water quality in Yangtze and Jialing Rivers. FA clearly identified the five groups of water quality variables, which explain majority of the experimental data. Nutritious pollution, seasonal changes, and construction activities were three key factors influencing rivers' water quality in LJNA. CA grouped 19 sampling sites into two clusters, which located at sub-catchments with high- and low-level urbanization, respectively. One-way ANOVA showed the nutrients (total phosphorus, soluble reactive phosphorus, total nitrogen, ammonium nitrogen, and nitrite), fecal coliform, and conductivity in cluster 1 were significantly greater than in cluster 2. Thus, catchment urbanization degraded rivers' water quality in Liangjiang New Area. Identifying effective buffer zones at riparian scale to weaken the negative impacts of catchment urbanization was recommended.


Encapsulated microRNA by gemcitabine prodrug for cancer treatment.
Although microRNAs (miRNAs) function as the important tumor gene regulators, they still confront with many challenges in systemic delivery. Here, the amphiphilic gemcitabine-oleic acid prodrugs (GOA) binding miRNAs with hydrogen bond are assembled into nanoparticles (GOA/miR NPs) through hydrophobic interaction via denaturation-annealing processes and nano-precipitation technique. The non-cationic GOA/miR NPs with an average size of ~150 nm and a zeta potential of ~ - 15 mV exhibit a stable encapsulation of miRNAs with non-sequence selectivity. Either miR-122 or miR-34a encapsulated in the GOA/miR NPs is efficiently delivered into HepG2 cells and significantly downregulate the expression levels of target gene after lysosome escape and pH-responsive disassembly. Moreover, in vivo experiments demonstrate that the GOA/miR-122 NPs exhibit higher tumor accumulation. Compared to GOA micelles, GOA/miR-122 NPs displayed stronger tumor inhibition (73% regression) after intravenous injection in nude mice xenografted with HCC, along with rapid clearance in normal liver tissues. Furthermore, there is no significant influence on biochemical indicators and immune factors during the systematic administration of GOA/miR-122 NPs. The non-cationic GOA/miR NPs engineered by hydrogen bond interaction and hydrophobic forces show the enhanced synergistic antitumor efficacy and good biosafety, which will provide a potential nanomedcine for HCC treatment.


Is intergenerational social mobility related to the type and amount of physical activity in mid-adulthood? Results from the 1946 British birth cohort study.
Greater levels of leisure-time or moderate-vigorous physical activity have consistently been found in those with greater socioeconomic position (SEP). Less is known about the effects of intergenerational social mobility. We examined the influence of SEP and social mobility on mid-adulthood physical activity in the Medical Research Council National Survey of Health and Development. Two sub-domains of SEP were used: occupational class and educational attainment. Latent classes for walking, cycling, and leisure-time physical activity (LTPA) were used, plus sedentary behavior at age 36. Associations between types of physical activity and SEP were examined with the use of logistic or multinomial logistic regression. Being a manual worker oneself or having a father who was a manual worker was, relative to nonmanual work, associated with lower levels of sedentary behavior and greater walking activity, but also with lower LTPA. Compared with those who remained in a manual occupational class, upward occupational mobility was associated with more sedentary behavior, less walking, and increased LTPA. Associations with downward mobility were in the opposite directions. Similar results were obtained for educational attainment. This study found clear evidence of social differences in physical activity. Persistently high SEP and upward social mobility were associated with greater levels of LTPA but also increased sedentary behavior and less walking.


Effects of methylene chloride, trichloroethane, trichloroethylene, tetrachloroethylene and toluene on the development of chick embryos.
Toluene and 5 aliphatic chlorinated hydrocarbons of wide industrial use were injected into the air space of fertilized chicken eggs at 2, 3 and 6 days of incubation. The embryotoxicity was evaluated as survival and death incidences after 14 days of incubation, and also the weights and lengths of the embryos were recorded. The approximate LD50 value for trichloroethylene and trichloroethanes varied between 50 and 100 mumol/egg while for toluene, tetrachloroethylene and methylene chloride it was over 100 mumol/egg. Macroscopic malformations of various kinds were produced with doses of 5-100 mumol/egg. The teratogenic potential of the tested compounds decreased in the following order: 1,1,1-trichloroethane greater than trichloroethylene greater than methylene chloride, tetrachloroethylene, 1,1,2-trichloroethane greater than toluene greater than olive oil control.


Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.
(1) Sixty-eight convergent dorsal horn neurones have been recorded at the lumbar level in anaesthetized intact rats. All cells received prominent A alpha and C fibre afferents and correspondingly could be activated by high and low threshold stimuli applied to the peripheral excitatory receptive field. (2) The activity of 67/68 of these neurones was powerfully inhibited by noxious stimuli applied to various parts of the body. Since non-noxious stimuli were ineffective in this respect, the term "diffuse noxious inhibitory controls" (DNIC) is proposed. (3) DNIC could be evoked by noxious pinch applied to the tail, the contralateral hind paw, the forepaws, the ears and the muzzle; the most effective areas were the tail and muzzle. Noxious heat applied to and transcutaneous electrical stimulation of the tail were extemely effective in eliciting DNIC as was the intraperitoneal injection of bradykinin. (4) DNIC strongly depressed by 60-100% both the C fibre response following suprathreshold transcutaneous electrical stimulation and the responses to noxious radiant heat. (5) The spontaneous activity and the responses to low threshold afferents induced either by A alpha threshold electrical or natural stimulation were also powerfully inhibited. (6) In the majority of cases, long lasting post-effects directly related to the duration of conditioning painful stimulus were observed.


Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion.
Peripheral neuropathy is a common adverse effect of paclitaxel treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of paclitaxel-induced thermal hyperalgesia, TRPV1 expression in the rat dorsal root ganglion (DRG) was analyzed after paclitaxel treatment. Behavioral assessment using the tail-flick test showed that intraperitoneal administration of 2 and 4 mg/kg paclitaxel induced thermal hyperalgesia after days 7, 14, and 21. Paclitaxel-induced thermal hyperalgesia after day 14 was significantly inhibited by the TRP antagonist ruthenium red (3 mg/kg, s.c.) and the TRPV1 antagonist capsazepine (30 mg/kg, s.c.). Paclitaxel (2 and 4 mg/kg) treatment increased the expression of TRPV1 mRNA and protein in DRG neurons. Immunohistochemistry showed that paclitaxel (4 mg/kg) treatment increased TRPV1 protein expression in small and medium DRG neurons 14 days after treatment. Antibody double labeling revealed that isolectin B4-positive small DRG neurons co-expressed TRPV1. TRPV1 immunostaining was up-regulated in paw skin day 14 after paclitaxel treatment. Moreover, in situ hybridization histochemistry revealed that most of the TRPV1 mRNA-labeled neurons in the DRG were small or medium in size. These results suggest that paclitaxel treatment increases TRPV1 expression in DRG neurons and may contribute to functional peripheral neuropathic pain.


Femtosecond X-ray emission study of the spin cross-over dynamics in haem proteins.
In haemoglobin the change from the low-spin (LS) hexacoordinated haem to the high spin (HS, S = 2) pentacoordinated domed deoxy-myoglobin (deoxyMb) form upon ligand detachment from the haem and the reverse process upon ligand binding are what ultimately drives the respiratory function. Here we probe them in the case of Myoglobin-NO (MbNO) using element- and spin-sensitive femtosecond Fe Kα and Kβ X-ray emission spectroscopy at an X-ray free-electron laser (FEL). We find that the change from the LS (S = 1/2) MbNO to the HS haem occurs in ~800 fs, and that it proceeds via an intermediate (S = 1) spin state. We also show that upon NO recombination, the return to the planar MbNO ground state is an electronic relaxation from HS to LS taking place in ~30 ps. Thus, the entire ligand dissociation-recombination cycle in MbNO is a spin cross-over followed by a reverse spin cross-over process.


Advances of exosomal miRNAs in the diagnosis and treatment of ovarian cancer.
Ovarian cancer is a tumor with the highest fatalities among female malignant tumors. This disease has no typical symptoms in its early stage, and most of the patients are in an advanced stage when being treated. The treatment effect is poor and it is easy to develop chemotherapy resistance. Therefore, it is particularly urgent to clarify the pathogenesis of ovarian cancer, explore its early diagnosis of biomarkers, and discover new treatment methods. As a carrier of intercellular information and genetic material transfer, exosomes are widely distributed in body fluids (e.g. blood and urine), which are regarded as latent tumor markers and take effects on tumor occurrence and invasion. Several articles have recently signified that exosomal miRNAs are widely implicated in the formation of the ovarian cancer tumor microenvironment, disease initiation and progression, and the generation of chemotherapy resistance. This article reviews the research on exosomal miRNAs in ovarian cancer.


Automated annotation and quantification of glycans using liquid chromatography-mass spectrometry.
As a common post-translational modification, protein glycosylation plays an important role in many biological processes, and it is known to be associated with human diseases. Mass spectrometry (MS)-based glycomic profiling techniques have been developed to measure the abundances of glycans in complex biological samples and applied to the discovery of putative glycan biomarkers. To automate the annotation of glycomic profiles in the liquid chromatography-MS (LC-MS) data, we present here a user-friendly software tool, MultiGlycan, implemented in C# on Windows systems. We tested MultiGlycan by using several glycomic profiling datasets acquired using LC-MS under different preparations and show that MultiGlycan executes fast and generates robust and reliable results. MultiGlycan can be freely downloaded at http://darwin.informatics.indiana.edu/MultiGlycan/. Supplementary data are available at Bioinformatics online.


NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics, tissue blood flow and arteriovenous shunting in the pig.
The effects of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the endothelial nitric oxide (NO) biosynthesis, on systemic and pulmonary haemodynamics, and tissue as well as arteriovenous anastomotic blood flows were investigated in the anaesthetized pig, using simultaneous injections of radioactive microspheres of two different sizes (diameter: 15 and 50 microns). L-NAME (1, 3 and 10 mg.kg-1) reduced systemic and pulmonary artery conductance and cardiac output, but heart rate and mean arterial blood pressure remained unchanged. L-arginine reversed the systemic and pulmonary haemodynamic changes induced by L-NAME. As detected with 15 microns microspheres, L-NAME (1 and 3 mg.kg-1) decreased tissue blood flow to and vascular conductance in the eyes, lungs, atria, kidneys, adrenals and liver. Furthermore, the difference between blood flows simultaneously measured with 15 and 50 microns microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 microns, was reduced by L-NAME (3 mg.kg-1) in the skin of head and gluteal regions and, as indicated by the microsphere content of the lungs, in the total systemic circulation. These results suggest that in the anaesthetized pig (i) NO is involved in the regulation of both systemic and pulmonary vascular conductance, (ii) the decrease in systemic vascular conductance is in part due to constriction of systemic arteriovenous anastomoses, and (iii) the decrease in pulmonary vascular conductance, leading to reduction of cardiac output, seems to negate the expected rise in arterial blood pressure observed, for example, in rats and rabbits following inhibition of NO-synthesis.


Reproductive ecology of red-chinned lizards (Sceloporus undulatus erythrocheilus) in Southcentral Colorado: comparisons with other populations of a wide-ranging species.
We studied the reproductive ecology of a population of Sceloporus undulatus erythrocheilus near Walsenburg, CO during the summers of 1987-1990. Reproductive activity commences soon after emergence in early May and continues until the middle of July. Females mature in their second year following hatching at an age of 20-21 months and a size of 60-63 mm snout-vent length (SVL). Two clutches, averaging10.9 eggs, are produced per year. Larger females produce larger clutches with an increase of one egg per 3 mm SVL. Average SVL of females was 71 mm. Eggs are reasonably large (0.32 g) and relative clutch mass was the largest reported for the species (34% of body mass). A principal component analysis was used to examine relationships among reproductive characters in 12 populations of Sceloporus undulatus. The analysis suggested that patterns of reproduction in this wide-ranging species result from several factors reflecting both adaptive and phylogenetic sources of variation.


PCR-based analysis of PD-L1 RNA expression in lung cancer: comparison with commonly used immunohistochemical assays.
PD-L1 testing is currently performed by immunohistochemistry (IHC). We questioned whether the results of PCR-based measurement of PD-L1 RNA expression correlate with IHC scores obtained by different commercial assays. 167 consecutive non-squamous non-small cell lung carcinomas (NSCLCs) were analyzed for PD-L1 RNA expression and 22C3, SP263, and SP142 IHC scoring using recommended cut-offs. RNA expression was divided into low, moderate, and high categories. RNA and protein expression demonstrated moderate correlation as continuous variables. Using prespecified RNA cut-offs, PCR testing showed a high negative predictive value towards the IHC analysis: the share of PD-L1 protein-negative tumors among cases classified as PD-L1-low by the PCR test reached 92-99% for all three antibodies. Meanwhile, about half of cases with moderate to high PD-L1 RNA expression had IHC staining in less than 1% tumor cells as determined by 22C3 or SP263 antibodies. Among the 51 discordant cases, which had <1% tumor staining by both 22C3 and SP263 clones but high RNA level, 29 (57%) showed ≥1% positive immune cells by SP263 and/or 22C3, 14 cases (27%) had detectable IHC expression in 0.1-0.9% tumor or immune cells by SP263 and/or 22C3, and 8 (16%) were entirely negative by IHC. Some NSCLCs demonstrate readily detectable PD-L1 expression on the level of RNA, but fall below commonly accepted cut-offs by IHC. It remains to be studied whether these discrepancies are attributed to technical or biological reasons. Clinical sensitivity of these tumors to immune therapy deserves additional investigations.


Video see-through augmented reality for oral and maxillofacial surgery.
Oral and maxillofacial surgery has not been benefitting from image guidance techniques owing to the limitations in image registration. A real-time markerless image registration method is proposed by integrating a shape matching method into a 2D tracking framework. The image registration is performed by matching the patient's teeth model with intraoperative video to obtain its pose. The resulting pose is used to overlay relevant models from the same CT space on the camera video for augmented reality. The proposed system was evaluated on mandible/maxilla phantoms, a volunteer and clinical data. Experimental results show that the target overlay error is about 1 mm, and the frame rate of registration update yields 3-5 frames per second with a 4 K camera. The significance of this work lies in its simplicity in clinical setting and the seamless integration into the current medical procedure with satisfactory response time and overlay accuracy. Copyright © 2016 John Wiley & Sons, Ltd.


Effects of modification of trauma bleeding management: A before and after study.
We hypothesised that the association of tranexamic acid (TXA) administration and thromboelastometry-guided haemostatic therapy (TGHT) with implementation of Damage Control Resuscitation (DCR) reduced blood products (BP) use and massive transfusion (MT). Retrospective comparison of 2 cohorts of trauma patients admitted in a university hospital, before (Period 1) and after implementation of DCR, TXA (first 3-hours) and TGHT (Period 2). Patients were included if they received at least 1 BP (RBC, FFP or platelet) or coagulation factor concentrates (fibrinogen or prothrombin complex) during the first 24-hours following the admission. 380 patients were included. Patients in Period 2 (n = 182) received less frequently a MT (8% vs. 33%, P < 0.01), significantly less BP (RBC: 2 units [1-5] vs. 6 [3-11]; FFP: 0 units [0-2] vs. 4 [2-8]) but more fibrinogen concentrates (3.0 g [1.5-4.5] vs. 0.0 g [0.0-3.0], P < 0.01). Multivariate logistic regression analysis identified Period 1 as being associated with an increased risk of receiving MT (OR: 26.1, 95% CI: 9.7-70.2) and decreased survival at 28 days (OR: 2.0, 95% CI: 1.0-3.9). After propensity matching, the same results were observed but there was no difference for survival and a significant decrease for the cost of BP (2370 ± 2126 vs. 3284 ± 3812 €, P: 0.036). Following the implementation of a bundle of care including DCR, TGHT and administration of TXA, we observed a decrease to the use of blood products, need for MT and an improvement of survival.


Memorizing and recalling spatial-temporal patterns in an oscillator model of the hippocampus.
We describe the model of the hippocampus consisting of interactive oscillators with input from the entorhinal cortex (modulating the main information flow by a theta rhythm) and the septum (a theta rhythm generator). When interconnections between oscillators are allowed to strengthen in an adaptive way, the network can be trained using a series of lessons. This results in a connection matrix that memorizes the temporal sequence of inputs. Presenting one of the lessons to the trained network results in reproduction of the remainder of the sequence. In this paper, we create such a connection matrix, derive from it an appropriate Markov chain and simulate the chain to illustrate its dynamics.


Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome.
This study investigated the characteristics of congenital rubella syndrome (CRS)-associated cardiac complications, particularly patent ductus arteriosus (PDA). We reviewed the medical records of patients with CRS who were admitted to the Children's Hospital 1 in Vietnam between December 2010 and December 2012, and patients with CRS who underwent PDA transcatheter occlusion therapy at the cardiology department between December 2009 and December 2015. We compared the characteristics of PDA treated with transcatheter closure between children with CRS (CRS-PDA) and those without CRS (non-CRS-PDA) who underwent PDA transcatheter closure between July 2014 and December 2015. One-hundred-and-eight children with CRS were enrolled. Cardiac defects (99%), cataracts (72%), and hearing impairment (7%) were detected. Fifty CRS-PDA and 290 non-CRS-PDA patients were examined. CRS-PDA patients had smaller median birthweight (p < 0.001), more frequent pulmonary (p < 0.001) and aortic stenosis (p < 0.001), higher main pulmonary artery pressure, and higher aortic pressure in systole/diastole (p < 0.001 for each) than did non-CRS-PDA patients. The proportion of tubular-type PDA was higher in CRS-PDA patients (16%) than in non-CRS-PDA patients (3%) (p = 0.020). Tubular-type PDA was frequently seen in patients with CRS and accompanied by pulmonary/systemic hypertension and pulmonary/aortic stenosis; in these patients, more cautious device selection is needed for transcatheter PDA closure.


Simple Mobile Application for Calculating "Ergotrauma" Made Using an Excel Sheet.
How to cite this article: Anand A, Saigal S, Panda R, Kodamanchili S, Shrivastava P, Das A, et al. Simple Mobile Application for Calculating "Ergotrauma" Made Using an Excel Sheet. Indian J Crit Care Med 2021;25(9):1081.


Heterozygous protein C deficiency type I.
Protein C is a vitamin K-dependent plasma protein which has anticoagulatory and profibrinolytic properties as a result of inactivating coagulation factors Va and VIIIa and enhancing fibrinolysis. Heterozygous protein C deficiency is well known to be a risk factor for thromboembolic diseases. We here present a family with 16 members deficient in protein C, out of which only two persons were suffering from thromboembolic disorders. In patients suffering from heterozygous protein C deficiency thromboembolic complications in childhood are rare and are not obligatory in adults. These patients should therefore not be treated with oral anticoagulants unless thromboembolic complications have already occurred or are imminent. Coumarin anticoagulation implicates a serious risk of coumarin skin necrosis in protein C deficient patients during the initial therapeutic phase. This risk may be avoided by initiating coumarin therapy with low doses of the drug and in cases of thromboembolic complications by overlapping with heparin anticoagulation.


The significance of prostacyclin produced by pregnant rat myometrium: the relationship between myometrial prostacyclin producing activity and passive stretch of myometrium by growing conceptus.
The present experiment was performed to elucidate the significance of prostacyclin (PGI2) produced by pregnant rat myometrium. PGI2-like substance producing activity of various portions of the uterus was measured at selected gestational stages by platelet bioassay; surface area per 1 gm of uterine wall enveloping one conceptus was calculated; and spontaneous contractility of myometrium of both conceptus and non-conceptus regions and the effects of authentic PGI2 on it were examined. PGI2-like substance producing activity increased with advancing pregnancy, but the activity varied according to area of the myometrium, being highest in the area where it was most greatly stretched by the growing conceptus and lowest where no conceptus was contained. Spontaneous contractility was reduced in regions with high PGI2 producing activity. Though authentic PGI2 generally exhibited a stimulatory effect, it had an inhibitory effect on Day 10 pregnant myometrium. From these results, it may be concluded that the producing activity of PGI2, which remarkably increases in the conceptus region with the advance of pregnancy, keeps the uterine wall relaxed, making the uterus adapt to the growth of the fetus. Passive myometrial stretch by the growing conceptus is thought to be one of factors which enhance myometrial PGI2 producing activity.


Technique for converting an existing complete denture to a tissue-integrated prosthesis.
A technique for modification of an existing complete denture into a tissue-integrated prosthesis is described. An acceptable conventional denture is clinically attached to titanium abutments in the maxillomandibular position that has proved to function well during a trial period. The framework is fabricated to fit the reduced denture base (Fig. 16). The advantages of this technique include (1) the appearance of the tissue-integrated prosthesis is known in advance; (2) the technique is simple and requires only four visits to complete; (3) the framework fit is predictable; (4) there is minimum insertion and removal; (5) the base has a natural look and the lips have support; and (6) minimum phonetic problems are encountered.


Persisting pain after endovascular treatment of a symptomatic aortic aneurysm.
Usually patients are admitted to hospital with a single diagnosis, but if complaints persist it is important to consider a synchronous secondary diagnosis. A 74-year-old woman presented with severe abdominal and back pain. On physical examination, a tender abdominal aortic aneurysm (AAA) was noted. Following endovascular treatment of the AAA, pain in the right lower abdomen persisted. Review of the pre-EVAR CT images revealed a foreign body in the terminal ileum, which was surgically removed. Patients with foreign-body-related intestinal pain present with complaints of abdominal pain at initial presentation. The accompanied back pain and abdominal tenderness of the abdominal aorta in our case could indicate another diagnosis. Persisting complaints post-intervention should not only arouse suspicion of an intervention-related complication, but also of a synchronous second diagnosis.


Emerging role of E2F8 in human cancer.
E2F8 is a multifaceted transcription factor that plays a crucial role in mediating the hallmarks of cancer, including sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Aberrant E2F8 expression is associated with poor clinical outcomes in most human cancers. However, E2F8 also exhibits tumor-suppressing activity; thus, the role of E2F8 in cell-fate determination is unclear. In this review, we highlight the recent progress in understanding the role of E2F8 in human cancers, which will contribute to building a conceptual framework and broadening our knowledge pertaining to E2F8. This review provides insight into future challenges and perspectives regarding the translation of biological knowledge into therapeutic strategies for the treatment of cancer.


Impact of systemic treatment of psoriasis on inflammatory parameters and markers of comorbidities and cardiovascular risk: results of a prospective longitudinal observational study.
Several markers of comorbidities and cardiovascular (CV) risk are disturbed in moderate to severe psoriasis (PsO). The effect of systemic treatments of psoriasis on these markers remains poorly understood. To study the frequency of disturbance of inflammatory parameters and markers of comorbidities and CV risk associated with moderate to severe PsO and psoriatic arthritis (PsA), and to assess their evolution under systemic treatments. Monocentric prospective study on patients with PsO and PsA starting a systemic treatment for their psoriasis. The following markers were evaluated at baseline (M0), 3 months (M3) and 6 months (M6); weight, fasting blood glucose, blood pressure, uric acid, hepatic steatosis, smoking, lipid, metabolic and inflammatory parameters. Forty-three patients, 31 PsO and 12 PsA, were included. Forty completed the study. Response to treatment was good, with 71% of the population obtaining a Psoriasis Area and Severity Index (PASI) of 75. All patients had at least one comorbidity, and 45% had two or more. A statistically significant decrease was observed only for inflammatory parameters (C-reactive protein [CRP], P = 0.004) and erythrocyte sedimentation rate (ESR, P = 0.002). We did not observe any correlation between the PASI and CRP (correlation coefficient 0.128, P = 0.438) or ESR (correlation coefficient 0.294, P = 0.069) for responding patients. We observed a high frequency of disturbance of inflammatory parameters and markers of comorbidities and CV risk in a population with moderate to severe PsO and PsA, most of which were not detected before. A significant decrease in inflammatory parameters was noted after the introduction of systemic therapy, while other parameters remained unaffected by the treatment, except the weight that increased under biologics therapies.


Cytostasis of tumor cell lines by promyelocytic leukemia cell line HL60 differentiated to granulocyte lineage.
The human promyelocytic leukemia cell line HL60, when cultured in medium containing dimethyl sulfoxide (DMSO) or granulocyte colony-stimulating factor (G-CSF), stopped dividing and differentiated into cells with granulocyte characteristics. We found that differentiated HL60 cells have no detectable cytolytic activity against cultured human bladder cell line (T24 cell), as measured by release of (3H) thymidine, or against K562 cells, as measured by release of chromium-51. Differentiated HL60 cells inhibited incorporation of (3H) thymidine into the DNA of adherent T24 cells. Decreased incorporation was not caused by detachment of the target T24 cells from the culture wells. The degree of cytostasis was dependent on the E/T ratio, with a 70%-80% inhibition usually reached at the E/T ratio of 200:1. A wide variety of target cells was also shown to be sensitive to differentiated HL60 cell-mediated cytostasis.


Combined imaging-histological study of cortical laminar specificity of fMRI signals.
Since the commencement of functional magnetic resonance imaging (fMRI), great effort has been put into increasing its spatial resolution and signal specificity from vessel-weighted to more tissue-specific signals. The working assumption is that the "tissue" signals closely mirror changes at the neuronal level. While great progress has been made, the basic and most fundamental questions remain unanswered: where in the gray matter do these "tissue fMRI" changes occur? Recently, the temporal correspondence of hemodynamic-based fMRI signals and neurophysiological activity was explored. The data suggest, although not conclusively, that the local field potential (LFP) response gives a better estimate of changes that accompany increased neuronal activity. LFP are thought to be generated by synaptic activity reflecting input signals into layer IV within a cortical region. If so, the spatial distribution of the fMRI signal should be specific to the corresponding cortical lamina. Here, in a combined imaging and histological study, the spatial characteristics of fMRI signals across the lamina were explored. In a high-resolution fMRI study (0.15 x 0.15 x 2 mm3), the spatial specificity of fMRI signals was correlated with the underlying cortical laminar cytoarchitectonic obtained within the same animal and tissue region. We demonstrate that when surface vessels are excluded high-resolution fMRI signals peak at cortical layer IV.


Comparing glutamatergic neuron population in the mediodorsal thalamic nucleus of genetic absence epilepsy rats from strasbourg (GAERS) and normal control Wistar rats.
An imbalance between GABAergic inhibition and glutamatergic excitation is suspected to play a role in the genesis of epileptic processes. In the present study we quantified the number of glutamate+ve neurons in the mediodorsal thalamic nucleus (MD) of genetic absence epilepsy rats from Strasbourg (GAERS) and compared these with values for normal Wistar rats. The MD thalamic nucleus was removed from each animal and the glutamatergic neurons were labelled using light-microscopy glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in the MD thalamic nucleus of GAERS and Wistar rats. The data were statistically analyzed. In the Wistar animals glutamate+ve neurons formed 89% and in GAERS 92.3% of the total neurons in 1000μm3 of MD thalamic nucleus. In GAERS glutamate+ve neurons showed statistically significant increase in the MD thalamic nucleus compared to Wistar animals. In Wistar animals the glutamate-ve neurons formed 11% and in GAERS 7.7% of the total neurons in 1000μm3 of MD thalamic. No significant difference was observed in glutamate-ve neurons between the two strains. The average diameter of glutamate+ve neurons showed no significance, while glutamate-ve neurons were significant between the two strains. The results of the present study, on genetic absence epilepsy model, GAERS, confirms the role of MD thalamic nucleus in chemically induced absence epilepsy.


Analysis of Malignant Thyroid Neoplasms with a Striking Rise of Papillary Microcarcinoma in an Endemic Goiter Region.
According to National Cancer Registry Program, Thiruvananthapuram district of Kerala, has the highest relative frequency of thyroid carcinomas; nevertheless, limited data exist regarding its socio-demographic and clinico-pathological characteristics. The aims of the study were to assess the: (1) demographic characteristics, (2) histopathological features and the relative frequency of various thyroid carcinoma cases and papillary thyroid carcinoma (PTC) subtypes, (3) rising trend of papillary microcarcinomas, and (4) associated lesions. A retrospective study wherein 170 cases of thyroid malignancies reported in our single institution over a period of 8 years period was reviewed. PTC accounted for 97% cases, followed by medullary (n = 4; 2.4%) and follicular carcinoma (n = 1; 0.6%). There was female preponderance (p = 0.0379) with a lower median age in females (p = 0.0275). Among the PTCs, conventional type constituted 53.4% cases (n = 87), followed by microcarcinomas (n = 34; 20.9%), follicular variant (n = 28; 17.2%), and others 14 cases (8.5%). Thirty-three cases (19.4%) showed multifocality, 5 cases (2.9%) extra-thyroid extension, and 19 cases (11.2%) lymph node metastasis. Two cases developed recurrences and three cases, metastasis. The associated lesions were significantly higher in females (p = 0.0059); most common being multinodular goiter (MNG; n = 67; 41.1%), followed by Hashimoto thyroiditis (n = 44; 27%) and lymphocytic thyroiditis (n = 28; 17.2%); MNG being associated with follicular (p = 0.0129), and Hashimoto thyroiditis with conventional variant (p = 0.0475). The frequency of microcarcinomas significantly increased in the past 4 years (p = 0.0291) and was associated with MNG (p = 0.0055), Hurthle cell nodule (p = 0.0315) and absent lymph node metastasis (p = 0.0147). The primary treatment modality was total thyroidectomy. Papillary microcarcinoma cases increased significantly in the past 4 years and were significantly associated with MNG and Hurthle cell nodule. It is challenging to distinguish the various PTC subtypes as recognition of these histological variants warrants better patient management.


Large language models for oncological applications.
Large language models such as ChatGPT have gained public and scientific attention. These models may support oncologists in their work. Oncologists should be familiar with large language models to harness their potential while being aware of potential dangers and limitations.


Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses.
We report that mitochondrial DNA (mtDNA) is inflammatogenic in vitro and in vivo as a result of the presence of unmethylated CpG sequences and its oxidative status. Purified human and murine mtDNAs induced arthritis when injected intra-articularly (i.a.) in mice. Importantly, oligodeoxynucleotide that contained a single oxidatively damaged base also induced arthritis when injected i.a. in mice. In contrast, neither human nor murine nuclear DNA induced inflammation. mtDNA-induced arthritis was neither B cell- nor T cell-dependent but was mediated by monocytes/macrophages. mtDNA-induced nuclear factor-kappaB stimulation resulted in the production of tumor necrosis factor alpha, a potent, arthritogenic factor. Finally, extracellular mtDNA was detected in the synovial fluids of rheumatoid arthritis patients but not of control subjects. We conclude that endogenous mtDNA displays inflammatogenic properties as a result of its content of unmethylated CpG motifs and oxidatively damaged adducts.


Localization of DNase I-hypersensitive regions during rat spermatogenesis: stage-dependent patterns and unique sensitivity of elongating spermatids.
DNase I-hypersensitivity of rat spermatogenic cells was analyzed 1) to establish overall patterns of hypersensitivity in individual cell types, 2) to correlate these patterns with known changes in chromatin organization and function, and 3) to provide a foundation for further analyses examining DNase I-hypersensitivity and the localization of specific genes during spermatogenesis. Parameters for in situ nick translation, using radioactive and fluorescent probes to visualize DNase I-hypersensitive regions (DHR), were established for fixed and sectioned testicular preparations, permeabilized cells, and isolated germ cell nuclei. As anticipated, the pattern of DHR changed in a cell-type specific manner during the course of spermatogenesis, reflective of known stage-dependent alterations in the composition and structure of both the chromatin and the nuclear lamina/matrix as well as changes in gene expression. DHR in preleptotene spermatocytes were primarily peripheral, while in pachytene spermatocytes they were localized along the condensed chromosomes. The pattern of DHR changed from "checkerboard" in steps 7-8 round spermatid nuclei to "lamellar" in steps 10-11 elongating spermatids. In steps 12-13 elongating spermatids. DHR were localized throughout the nuclei or in a graded manner--increasing from anterior to posterior and mirroring the pattern of chromatin condensation. However, unlike the case in other stages, DNA of steps 12-13 elongating spermatids was exquisitely sensitive to nick translation even in the absence of exogenous DNase I. In contrast to the labeling of earlier stages, steps 16-19 spermatids and mature spermatozoa did not demonstrate DNase I-hypersensitivity under any conditions employed. A variety of agents that interact with topoisomerase II and DNA (teniposide, novobiocin, ethidium bromide, and adenosine triphosphate) were tested to determine the basis for the unique sensitivity to nick translation of steps 12-13 elongating spermatids. None of the agents tested, however, affected this unique labeling. The sensitivity of steps 12-13 elongating spermatids to nick translation in the absence of exogenous nuclease indicators the presence of endogenous nicks, which may relieve torsional stress and aid rearrangement as the chromatin is packaged into a form characteristic of the mature spermatozoon.


[Living wills under close scrutiny: Medical consultation is indispensable].
Since September 2009 the handling of living wills has been regulated by law. Even though a medical consultation is not imperative for the drawing up of a living will, first surveys have shown that medical information about clinical pictures and treatment options lead to an important specification of living wills. For the first time in Germany, a questionnaire has been developed to investigate the impact of medical consultations on the content of living wills. It revealed that nearly all the people surveyed who had already drawn up a living will wished to change the content of their completed will after attending the seminar because the previous version was no longer in accordance with their wishes. In the light of the frequent difficulties in hospitals concerning how to apply a living will to an actual clinical situation, we believe structured medical consultations to be indispensable.


Examining the attitudes and preferences of health care decision-makers in relation to access, equity and cost-effectiveness: a discrete choice experiment.
To describe the views of health care decision-makers and providers operating in the UK National Health Service (NHS) concerning the concepts of cost-effectiveness, equity and access through a series of attitudinal questions; to evaluate the preferences of health care providers in relation to each of these concepts using a discrete choice experiment (DCE); to assess the impact of prior completion of an attitude questionnaire on preferences elicited through a DCE. Three versions of a DCE questionnaire were developed with and without a series of attitudinal questions and randomly distributed to 1456 health care decision-makers and providers. The questionnaire sought to elicit their preferences between the competing objectives of cost-effectiveness, equity and access within the context of different hypothetical, specialist treatment programmes for cardiovascular disease. The response rate was 26%. Female respondents exhibited a stronger preference than males for reducing health inequalities by targeting the worst off (Wald test, P<0.001). Primary Care Trusts (PCTs), Strategic Health Authorities (SHA) or Department of Health (DoH) staff were also more likely than hospital managers to favour programmes that targeted the worst off (Wald test, P<0.001 in each case). Those who were clinically trained and currently in a clinical post had a stronger preference for programmes with shorter waiting times compared to those in a managerial or non-clinical posts, who exhibited stronger preferences for equity. Completion of a series of attitudinal questions prior to completing the DCE task resulted in a lower proportion of dominant responses and an increased willingness to make trade-offs between attributes.


The diagnostic accuracy of hand-held ultrasonography in evaluation of costal cartilage calcification for grafting in rhinoplasty: A cadaveric study.
Autologous costal cartilage graft (ACC) is considered a gold standard in complex rhinoplasty. Costal cartilage calcification remains a problematic issue, causing not only difficulties during the harvesting, carving, and fixation procedures but also worsening the long-term outcome with resorption. This study aims to establish diagnostic accuracy of hand-held ultrasonography in not only detecting the degree and pattern of costal cartilage calcification but also assessing its ability to predict the volume of the harvestable cartilage graft. The study was performed on 50 fresh cadavers with an age range between 17 and 80 years (mean 53.4 ± 16.2 years). An ultrasonographic examination of the costal cartilage of 5th, 6th, and 7th ribs of both hemithoraces was performed. The presence of calcification of the cartilages and the pattern, length, width, cross-sectional area, and depth of calcification were observed and recorded. These results were compared against direct visualization and measurement via surgical dissection. Hand-held ultrasonography has a sensitivity of 94% and a specificity of 96% in detecting calcification with 96% positive predictive value and 93% negative predictive value. The positive likelihood ratio was 20.81 and the negative likelihood ratio was 0.06. Overall, the modality has demonstrated the ability to determine dimensions of the costal cartilage to within millimeters. The pattern of calcification was also correctly predicted in all 300 specimens. Hand-held ultrasonography is an affordable and accessible choice of demonstrating the presence and pattern of calcification as well as the general dimensions of the harvestable rib cartilage.


A holistic miRNA-mRNA module discovery.
The regulatory role of the Micro-RNAs (miRNAs) in the messenger RNAs (mRNAs) gene expression is well understood by the biologists since some decades, even though the delving into specific aspects is in progress. In this paper we will focus on miRNA-mRNA modules, where regulation jointly occurs in miRNA-mRNA pairs. Namely, we propose a holistic procedure to identify miRNA-mRNA modules within a population of candidate pairs. Since current methods still leave open issues, we adopt the strategy of postponing any decision on the value of the module ingredients exactly at the end, i.e. at the moment of biologically exploiting the results. This diverts chains of statistical tests into sequences of specially-devised-evolving metrics on the possible solutions. This strategy is rather expensive under a computational perspective, so needing implementations on HPC. The reward stands in the discovery of new modules, possibly hosting non differentially expressed miRNAs and mRNAs and pairs containing genes that currently are considered not targeted. In the paper we implement the procedure on a Multiple Myeloma dataset publicly available on GEO platform, as a template of a cancer instance analysis, and hazard some biological issues. These results, jointly with the normal manageability of the computations, suggest that the discovery procedure may be profitably extended to a wide spectrum of diseases where miRNA-mRNA interactions play a relevant role.


Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics.
Melanoma is a malignant proliferative disease originated in melanocytes, characterized by high metastatic activity and by the activation of oncogenes, such as B-RAF (40-60% of cases). Recent studies have shown that vemurafenib (a MAPK inhibitor) promoted disturbance of mitochondrial bioenergetics, although underlying mechanisms are not fully comprehended. Here we showed that MAPK inhibition by vemurafenib in B-RAFV600E-mutated human melanoma culminated in the inhibition of DRP1 phosphorylation, associated to a large mitochondrial network remodeling to the hyperfused phenotype, and increased oxidative phosphorylation capacity. Such alterations may be associated to melanoma resistance to vemurafenib, since the impairment of oxidative phosphorylation increased the vemurafenib cytotoxicity. These results point to the potential of mitochondrial dynamics as a targetable pathway in melanoma.


YAP and the Hippo pathway in cholangiocarcinoma.
Cholangiocarcinoma (CCA) has an increasing incidence and remains a difficult to treat malignancy. In a search for more effective treatment options, progress has been made in identifying molecular drivers of oncogenic signaling including IDH mutations and FGFR2 fusions. In addition, multiple investigators have identified increased activity of YAP, the effector protein of the Hippo pathway, in CCA. The Hippo pathway regulates organ size, cellular proliferation, and apoptosis via YAP, a transcriptional co-activator. Targeting of the pathway has been difficult due the lack of a dedicated cell-surface receptor. However, more recently, additional cross-regulatory pathways have been identified that are potentially targetable. In this review, we address the current treatment landscape for CCA, the Hippo pathway broadly, animal models of CCA with attention to Hippo-related models, and the current strategies for targeting YAP.


Draft Genome Sequence of Exiguobacterium sp. Strain BMC-KP, an Environmental Isolate from Bryn Mawr, Pennsylvania.
Exiguobacterium sp. strain BMC-KP was isolated as part of a student environmental sampling project at Bryn Mawr College, PA. Sequencing of bacterial DNA assembled a 3.32-Mb draft genome. Analysis suggests the presence of genes for tolerance to cold and toxic metals, broad carbohydrate metabolism, and genes derived from phage.


Mobile Health Technologies in Cardiopulmonary Disease.
Mobile health (mHealth) technologies are modernizing medicine by affording greater patient engagement, monitoring, outreach, and health-care delivery. The cardiopulmonary fields have led the integration of mHealth into clinical practice and research. mHealth technologies in these areas include smartphone applications, wearable devices, and handheld devices, among others, and provide real-time monitoring of numerous important physiological measurements and other key parameters. Use of mHealth-compatible devices has increased in recent years, and age and socioeconomic gaps of ownership are narrowing. These tools provide physicians and researchers with a better understanding of an individual's health and well-being. mHealth interventions have shown utility in the prevention, monitoring, and management of atrial fibrillation, heart failure, and myocardial infarction. With the growing prevalence of cardiopulmonary disease, mHealth technologies may become a more essential element of care within and outside of traditional health-care settings. mHealth is continuously developing as a result of technologic advancements and better understandings of mHealth utility. However, there is little regulation on the mHealth platforms available for commercial use and even fewer guidelines on implementing evidence-based practices into mHealth technologies. Online security is another challenge and necessitates development in data collection infrastructure to manage the extraordinary volume of patient data. Continued research on long-term implications of mHealth technology and the integration of effective interventions into clinical practice is required.


The Belgian experience with the cyranose heat moisture exchange filter. A multicentric pilot study of 12 total laryngectomees.
It is known that heat and moisture exchangers have a positive effect on the respiratory system in patients after total laryngectomy. The ATOS and INHEALTH devices are most frequently used in Belgium. However, recently a new device, the HME filter Cyranose, has become available. As a pilot study, this device has been applied to a total of 12 patients in three different centres. The temperature of the inspired air was considered as good or excellent in 90% of our patients at the 1st week and up to 100% at the 3rd month. The air humidification was considered as good or excellent in 100% of the patient population, and the HME filter positively influenced the phlegm production in 78% of our laryngectomy population. Our study stresses the benefits of a HME filter in general and seems promising for the Cyranose HME filter.


Differential repair responses in the coronal and radicular areas of the exposed rat molar pulp induced by recombinant human bone morphogenetic protein 7 (osteogenic protein 1).
Bone morphogenetic protein 7 (BMP 7), also termed osteogenic protein 1, a member of the transforming growth-factor superfamily, was examined for its efficacy in inducing reparative dentinogenesis in the exposed pulps of rat molars. To determine if the reaction was dose-dependent, collagen pellets containing 1, 3 or 10 microgram of recombinant BMP 7 were inserted in intentionally perforated pulps (10-12 pulps per group) in the deepest part of half-moon class V-like cavities cut in the mesial aspect of upper first molars. As controls, the collagen carrier (CC group) alone and calcium hydroxide (Ca group) were used as capping agents. All cavities were then restored with a glass-ionomer cement. Half of the animals were killed after 8 days and the other half after 28 days, by intracardiac perfusion of fixative. The molars were processed for histological evaluation by light microscopy. No difference in effect could be detected between the three concentrations of BMP 7 groups at either time interval. After 8 days, all groups showed varying inflammation, from mild of severe, and the Ca group demonstrated early formation of a reparative dentine bridge. At 28 days the CC group displayed irregular osteodentine formation, leaving some unmineralized areas at the exposure site and interglobular unmineralized areas containing pulp remnants. In the Ca-treated pulps, the initial formation of thick reparative osteodentine bridges that sealed more or less completely the pulp perforation was followed, in the deeper part, by irregular tubular dentine. In most BMP 7-treated specimens, the initial inflammation has resolved at 8 days and at 28 days heterogeneous mineralization or osteodentine filled the mesial coronal pulp. They also had complete filling of the radicular pulp by homogenous mineralization in the mesial root; this reaction was found in 11 teeth in the BMP 7 group, one tooth in the CC group an none of the Ca group. These results emphasize the biological differences the coronal and radicular parts of the pulp, and the potential of bioactive molecules such as BMP 7 to provide an a alternative conventional endodontic treatments.


Influence of hydrogen bonding in the activation of nucleophiles: PhSH-(catalytic) KF in N-methyl-2-pyrrolidone as an efficient protocol for selective cleavage of alkyl/aryl esters and aryl alkyl ethers under nonhydrolytic and neutral conditions.
The nucleophilicity of arenethiols can be augmented via hydrogen bonding with "naked" halide anion. The activity of the halide anions follow the order F(-) >> Cl(-) approximately Br(-) approximately I(-) and is dependent on the countercation (Bu(4)N approximately Cs approximately K > Na >> Li). The solvent plays an important role in nucleophilic activation as well as regeneration of the effective nucleophile (e.g. ArS(-)) and those with high dielectric constant, high molecular polarizability, high donor number (DN), and low acceptor number (AN) are the most effective. Selective deprotection of alkyl/aryl esters and aryl alkyl ethers can be achieved under nonhydrolytic and neutral conditions by the treatment with thiophenol in 1-methyl-2-pyrrolidone (NMP) in the presence of a catalytic amount of KF. Aryl esters are selectively deprotected in the presence of alkyl esters and alkyl methyl ethers during intramolecular competitions.


Does cerebrospinal fluid pulsation affect diffusion-weighted imaging thermometry? A study in healthy volunteers.
Diffusion-weighted imaging (DWI)-based thermometry offers potential as a noninvasive method for measuring temperatures deep inside the human brain. However, DWI might be influenced by the pulsatile flow of cerebrospinal fluid (CSF). This study aimed to investigate the influence of such pulsations on DWI thermometry in healthy individuals. A total of 104 participants (50 men, 54 women; mean [± standard deviation] age, 44.2 ± 14.3 years; range 21-69 years) were investigated. DWI-based brain temperature (TDWI ) was acquired at three speeds (maximum and minimum speeds of ascending flow and random timing at the cerebral aqueduct) of CSF pulsation using a 3-T magnetic resonance imaging scanner. Magnetic resonance spectroscopy (MRS)-based temperature (TMRS ) at the thalamus was also obtained as a reference standard for brain temperature. The three different CSF pulsatile flows were monitored by heart rate during the scan. The difference between reference temperature and brain temperature (ΔT = TDWI - TMRS ) along with the three CSF speeds were statistically compared using Student's matched pair t-test. No significant difference in ΔT was evident among CSF speeds (p > 0.05). No significant linear correlation between ΔT and CSF flow speed at the cerebral aqueduct was observed. Using DWI thermometry with clinical acquisition settings, which utilizes mean values within thresholds, no effect of CSF pulsation speed was observed in the estimation of ΔT.


Wax ester synthesis in the mouse preputial gland tumour.
The microsomal fraction from the mouse preputial gland tumour contains an acyltransferase which catalyzes the synthesis of wax esters. The enzyme is inhibited by moderate concentrations of free fatty acids (40 muM or more) but the inhibition is relieved by the addition of bovine serum albumin. The specific activity of the enzyme increases markedly between the 20th and 30th days of tumor growth. A number of other lipid synthesizing enzymes show similar trends for specific activity as related to tumour age.


Monoclonal autoantibodies to histones from autoimmune NZB/NZW F1 mice.
Fusion of spleen cells from autoimmune NZB/NZW female mice with drug-resistant myeloma cells (clones NSI/1, X63-Ag8.653 and NSO/1) produced hybrid clones which secreted antibodies to various nuclear components. Roughly 50% of the anti-nuclear hybridomas produced antibodies reacting with DNA, 20% with RNA and 30% reacted with other nuclear antigens. Two hybridomas of the latter group were cloned and studied in detail. They secreted antibodies which produced bright fluorescence staining of nuclei and metaphase chromosomes. The specificity of the antibodies was determined by testing them in an enzyme-linked immunosorbent assay and a radioimmunoassay against individual acid- and salt-extracted histones, against histones mixed two and three at a time and against histone complexes isolated as such from chromatin. One of the monoclonal antibodies was specific for histone H2B and reacted with the histone free in solution or when present as a H2A-H2B complex. The second monoclonal antibody recognized a specific conformation in the H3-H4 complex that was present only when the complex was obtained from chromatin by salt extraction. The same conformation, however, could be induced by adding histone H2B to a mixture of acid-extracted H3 and H4. Our findings show that the autoimmune syndrome in NZB/NZW mice resembles human systemic lupus erythematosus not only in the incidence of antibodies to DNA and RNA, but also in the production of autoantibodies to histones.


Electrochemical aptasensor based on gold nanoparticle decorated Ti3C2Tx nanocomposites for chloramphenicol detection.
Using gold (Au) nanoparticle decorated Ti3C2Tx (Ti3C2Tx-Au) nanocomposites, a highly sensitive electrochemical aptasensor for the effective detection of chloramphenicol has been developed. As a two-dimensional layered material, the prepared composite not only provides high surface area, good conductivity, and thermal stability but also substantial binding sites for aptamers with high sensitivity and selectivity for the accurate determination of chloramphenicol. Interestingly, the conductivity and active sites were enhanced by freeze-drying Ti3C2Tx and in situ formation of Ti3C2Tx-Au nanocomposite. The fabricated aptasensor exhibited a very low detection limit (S/N ≥ 3) of 13.18 fg mL-1 with a linear range of 1 ~ 700 pg mL-1 and correlation coefficient of 0.9992. The fabricated aptasensor demonstrated an excellent reproducibility, repeatability, long-term stability, and high selectivity toward chloramphenicol. Further, the aptasensor was applied to real milk samples, and the recoveries were ranged from 98.93 to 101.93%.


Ultrastructural observations on stumpy (stm), a new chondrodystrophic mutant in the mouse.
Stumpy (stm) is a new chondrodystrophic mutant in the mouse. Light microscopy of cartilage reveals a slightly increased mitotic rate, more chondrocytes than is usual per lacuna and a wide zone of hypertrophy. Electron microscopy shows that many chondrocytes are in close approximation with some tight junctions: in cartilage from 14-day-old mice there is much interdigitation and folding of the cell membranes of adjacent chondrocytes.


Outcomes of primary Latarjet vs. revision Latarjet after prior surgery for anterior shoulder instability: a systematic review and meta-analysis.
Latarjet has become an increasingly popular treatment option for recurrent anterior shoulder instability. With the reported complication rates for primary Latarjet surgery, there are concerns about the complications of Latarjet as a revision surgery. It remains unclear if poor results after previous surgical management can be improved with revision Latarjet as well as with primary Latarjet. The aim of this systematic review and meta-analysis is to compare the outcomes of primary Latarjet and revision Latarjet for the treatment of anterior shoulder instability. A systematic search was performed on 3 databases for studies that compared primary Latarjet with revision Latarjet used after failed arthroscopic stabilization or failed free bone block procedures. From the included studies, demographic data, clinical outcome scores, range of motion measurements, and postoperative complications were obtained. A total of 11 studies were included for data analysis. Compared with the primary Latarjet cohort, revision Latarjet cohorts had a higher infection rate (1.2% vs. 2.6%; RR 0.46, P = .039). The primary Latarjet group showed a greater rate of return to sport (89.7% vs. 80.5%; RR 1.12, P = .41) and less subjective feeling of instability (12.6% vs. 20.9%; RR 0.60, P = .085) compared with the revision Latarjet group; however, this was not statistically significant. There were no significant differences in complication rates, reoperation, recurrence, and range of motion between primary Latarjet and revision Latarjet groups. Clinical outcome scores such as visual analog scale and Rowe scores were not significantly different between the cohorts. Based on the current evidence, primary Latarjet presents reduced infection rates but similar clinical outcome measures, overall complication, and range of motion measurements than revision Latarjet performed after failed prior operative treatment.


Mixed-longitudinal growth of breastfeeding children in Moroto District, Uganda (Karamoja subregion). A loss of biological resiliency?
This study examines the pattern of growth, underlying growth velocity and nutritional status in a sample of thirty breastfeeding Karimojong children, aged from birth to three years. A mixed-longitudinal structure was adopted for the study, which was carried out between August and December, 2004, in two communities in Moroto District, Uganda. Monthly anthropometric and health examinations were administered to mothers and children during this interval. Children in the study were small at birth but grew relatively rapidly for their first six months. Thereafter they experienced falling off of growth in weight, length, and head circumference. Loss of growth velocity and deterioration in nutritional status after six months was a result of physiologic stress arising from high parasite loads, introduction of inappropriate weaning foods, and psychosocial stress associated with patterns of maternal behavior. Environmental and maternal effects on child growth were exacerbated by widespread armed violence and related subsistence change in these communities. Growth of these children reflects loss of growth plasticity resulting from worsening environmental and social conditions in Moroto in 2004.


The importance of outlier detection and training set selection for reliable environmental QSAR predictions.
Empirical QSAR models are only valid in the domain they were trained and validated. Application of the model to substances outside the domain of the model can lead to grossly erroneous predictions. Partial least squares (PLS) regression provides tools for prediction diagnostics that can be used to decide whether or not a substance is within the model domain, i.e. if the model prediction can be trusted. QSAR models for four different environmental end-points are used to demonstrate the importance of appropriate training set selection and how the reliability of QSAR predictions can be increased by outlier diagnostics. All models showed consistent results; test set prediction errors were very similar in magnitude to training set estimation errors when prediction outlier diagnostics were used to detect and remove outliers in the prediction data. Test set prediction errors for substances classified as outliers were much larger. The difference in the number of outliers between models with a randomly and systematically selected training illustrates well the need of representative training data.


Circulating lipoprotein(a) levels and health outcomes: Phenome-wide Mendelian randomization and disease-trajectory analyses.
Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic and valvular diseases, but its possible role in other diseases has not yet been established. We conducted phenome-wide Mendelian randomization and disease-trajectory analyses to assess any associations of circulating Lp(a) levels with a broad range of diseases. A weighted polygenic risk score was constructed using independent genetic variants in the LPA gene and with an established effect on Lp(a) levels. The PheWAS analysis included 1081 phenotype outcomes ascertained among 385,917 White participants of the UK Biobank. Novel findings were investigated in MR analysis using data from the FinnGen consortium. Disease-trajectory and comorbidity analyses were further conducted to explore the sequential patterns of multiple morbidities related to high circulating Lp(a) levels. PheWAS revealed statistically significant associations of higher circulating Lp(a) levels with increased risk of a large number of circulatory system diseases (including various cardiac diseases, peripheral vascular disease, hypertension, and valvular and cerebrovascular diseases) as well as some endocrine/metabolic diseases (including hyperlipidemia, hypercholesterolemia, disorders of lipoid metabolism, and type 2 diabetes), genitourinary system diseases (renal failure), and hematologic diseases (including different types of anemia). Two-sample MR analysis supported the association between Lp(a) and risk of anemia, showed a suggestive association with type 2 diabetes, but found no association with renal failure. Disease-trajectory and comorbidity analyses identified 3 major sequential patterns of multiple morbidities, mainly in the cardiovascular, metabolic, and mental disorders, related to high circulating Lp(a) levels. Genetically predicted higher circulating Lp(a) levels were associated with increased risk of many circulatory system diseases and anemia. Additionally, this study identified three major sequential patterns of multiple morbidities related to high Lp(a).


Pemetrexed improves tumor selectivity of 111In-DTPA-folate in mice with folate receptor-positive ovarian cancer.
Folate-based radiopharmaceuticals can be used as imaging agents and for potential radiotherapy of folate receptor (FR)-positive malignant tissue (e.g., ovarian carcinomas). However, substantial FR expression in the kidneys results in undesired renal retention of radioactivity. Recently, we found that the preinjection of an antifolate significantly improved tumor selectivity of organometallic 99mTc-radiofolates in mice. The aim of this study was to corroborate the effect of pemetrexed with the clinically tested 111In-DTPA-folate (DTPA is diethylenetriaminepentaacetic acid) in a human ovarian cancer xenografted mouse model. In vivo studies were performed in female athymic nude mice bearing subcutaneous FR-positive ovarian tumors (IGROV-1 and SKOV-3) or metastases (after intraperitoneal SKOV-3 cell inoculation). Biodistribution studies were performed 1, 4, and 24 h after administration of 111In-DTPA-folate (0.7 MBq/mouse, 0.35 mug) with or without preinjection of pemetrexed (PMX, 400 microg) 1 h before the radiofolate. Images were acquired with a high-resolution, high-sensitivity SPECT/CT camera, 4 and 24 h after injection of the radiotracer (30-50 MBq/mouse, 4.5-10 microg). In biodistribution studies the tumor uptake of 111In-DTPA-folate (IGROV-1: 9.79 +/- 3.21 %ID/g [percentage injected dose per gram]; SKOV-3: 7.57 +/- 0.61 %ID/g, 4 h after injection) was high and retained over the time of investigation. However, considerable retention of radioactivity was found in kidneys (85-105 %ID/g, 4 h after injection), resulting in unfavorably low tumor-to-kidney ratios ( approximately 0.10). Preinjection of PMX resulted in a significant reduction of renal uptake (20%-30% of control values, P < 0.03) at all time points after injection of 111In-DTPA-folate, whereas the tumor uptake was retained. Thus, the tumor-to-kidney ratio was significantly increased to approximately 0.50. SPECT/CT images confirmed the superior tumor-to-background ratio in mice injected with PMX. These findings were particularly evident in mice with SKOV-3 metastases that could be visualized only when 111In-DTPA-folate was administered in combination with PMX. The application of PMX resulted in a significant reduction of undesired radioactivity accumulation in kidneys, whereas the tumor uptake remained unaffected. These observations suggest a general validity of the reducing effect of PMX on the uptake of radiofolates in kidneys. Our findings will lead the way toward the development of folate-based radiotherapy.