Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease.
To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD). We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis. This study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity. The data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.


[Therapeutic effect of miconazole on fungal infection in patients with hematological malignancies].
The effectiveness of miconazole was evaluated in 9 documented fungal infections, 4 of which were candidal sepsis. All patients were receiving therapy for hematological malignancies. Miconazole revealed the excellent effect in 3 patients with candidal esophagitis and 1 patient with candidal sepsis and esophagitis. Twelve patients who received miconazole for presumed or documented fungal infection were evaluated for toxicity. No particular side effects, except for only 1 case of mild hepatic dysfunction, were observed. Miconazole is apparently an effective antifungal agents for treatment of systemic fungal infection in patients with hematological malignancies.


[Importance of surgery of quick recovery program for surgical treatment of bladder tumors].
The article presents an analytical review of literature outlining the prospects for the use of the program "Surgery of quick recovery" in the surgical treatment of the bladder malignant tumors. The multi-modal program "Surgery of quick recovery" was found to reduce the number of postoperative complications and shorten recovery of patients with bladder cancer.


The use of psychiatric facilities by depressives: results of the Upper Bavarian Study.
Utilization of psychiatric facilities by noninstitutionalized persons aged 20 years and older, identified as "depressive cases", was examined. Data were based on the representative community sample of the Upper Bavarian follow-up field study with an original sample size of 1668 people. In the 5-year follow-up 1384 (83%) subjects were interviewed, while 80 subjects (4.8%) had died. The 5-year prevalence of depressive disorders, according to the definition used, was 10.3%. We analyzed which people with depressive disorders sought help from mental health professionals according to type of depressive disorder, sociodemographic data, psychosocial factors and course of disorder. The psychiatric treatment rate (in- or outpatient) was 23.9% of the depressive cases. The majority of treated persons were outpatients. Patients with the diagnosis of endogenous depression were most likely to have received psychiatric treatment. Limitation in the ability to work due to depression was the most important psychosocial factor influencing help-seeking behavior. The highest consultation rate in psychiatric facilities was obtained from the depressives who had grown up without their parents.


TNF-α Differentially Regulates Cell Cycle Genes in Promyelocytic and Granulocytic HL-60/S4 Cells.
Tumor necrosis factor alpha (TNF-α) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF-α are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF-α treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes. To investigate the interaction between cellular differentiation and TNF-α, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-α. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF-α treatment compared to the undifferentiated promyelocytes. The observed TNF-α responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF-α treated promyelocytes, and downregulated in TNF-α treated granulocytes. This is consistent with TNF-α induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, we found evidence that TNF-α treatment of granulocytes shifts the transcriptome toward that of a macrophage. We conclude that TNF-α treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF-α promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF-α stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.


Blue to true-blue phosphorescent Ir(III) complexes bearing a nonconjugated ancillary phosphine chelate: strategic synthesis, photophysics, and device integration.
We report the design and synthesis of Ir(III) complexes functionalized with substituted pyridyl cyclometalate or azolate chromophores, plus one newly designed nonconjugated phosphine chelate, which not only greatly restricts its participation in the lowest-lying electronic transition but also enhances the coordination strength. These two key factors lead to fine-tuning of the phosphorescence chromaticity toward authentic blue and simultaneously suppress, in part, the nonradiative deactivation. This conceptual design presents a novel strategy in achieving heretofore uncommon, high-efficiency blue and true-blue phosphorescence. The fabrication of the organic light-emitting devices (OLEDs) employing phosphorescent dopants [Ir(dfpbpy)(2)(P(wedge)N)] (1b) and [Ir(fppz)(2)(P(wedge)N)] (3) was successfully made, for which the abbreviations (dfpbpy)H, (fppz)H, and (P(wedge)N)H represent 2-(4,6-difluorophenyl)-4-tert-butylpyridine, 3-(trifluoromethyl)-5-(2-pyridyl)pyrazole, and 5-(diphenylphosphinomethyl)-3-(trifluoromethyl)pyrazole, respectively. Of particular interest is the 3-doped OLEDs, which exhibit remarkable maximum efficiencies of 6.9%, 8.1 cd A(-1), and 4.9 lm W(-1), together with a true-blue chromaticity CIE(x,y) = 0.163, with 0.145 recorded at 100 cd m(-2).


Profiling of the toxicity mechanisms of coated and uncoated silver nanoparticles to yeast Saccharomyces cerevisiae BY4741 using a set of its 9 single-gene deletion mutants defective in oxidative stress response, cell wall or membrane integrity and endocytosis.
The widespread use of nanosilver in various antibacterial, antifungal, and antiviral products warrants the studies of the toxicity pathways of nanosilver-enabled materials toward microbes and viruses. We profiled the toxicity mechanisms of uncoated, casein-coated, and polyvinylpyrrolidone-coated silver nanoparticles (AgNPs) using Saccharomyces cerevisiae wild-type (wt) and its 9 single-gene deletion mutants defective in oxidative stress (OS) defense, cell wall/membrane integrity, and endocytosis. The 48-h growth inhibition assay in organic-rich growth medium and 24-h cell viability assay in deionized (DI) water were applied whereas AgNO3, H2O2, and SDS served as positive controls. Both coated AgNPs (primary size 8-12nm) were significantly more toxic than the uncoated (~85nm) AgNPs. All studied AgNPs were ~30 times more toxic if exposed to yeast cells in DI water than in the rich growth medium: the IC50 based on nominal concentration of AgNPs in the growth inhibition test ranged from 77 to 576mg Ag/L and in the cell viability test from 2.7 to 18.7mg Ag/L, respectively. Confocal microscopy showed that wt but not endocytosis mutant (end3Δ) internalized AgNPs. Comparison of toxicity patterns of wt and mutant strains defective in OS defense and membrane integrity revealed that the toxicity of the studied AgNPs to S. cerevisiae was not caused by the OS or cell wall/membrane permeabilization.


Similar protective immunity induced by an inactivated enterovirus 71 (EV71) vaccine in neonatal rhesus macaques and children.
During the development of enterovirus 71 (EV71) inactivated vaccine for preventing human hand, foot and mouth diseases (HFMD) by EV71 infection, an effective animal model is presumed to be significant and necessary. Our previous study demonstrated that the vesicles in oral regions and limbs potentially associated with viremia, which are the typical manifestations of HFMD, and remarkable pathologic changes were identified in various tissues of neonatal rhesus macaque during EV71 infection. Although an immune response in terms of neutralizing antibody and T cell memory was observed in animals infected by the virus or stimulated by viral antigen, whether such a response could be considered as an indicator to justify the immune response in individuals vaccinated or infected in a pandemic needs to be investigated. Here, a comparative analysis of the neutralizing antibody response and IFN-γ-specific T cell response in vaccinated neonatal rhesus macaques and a human clinical trial with an EV71 inactivated vaccine was performed, and the results showed the identical tendency and increased level of neutralizing antibody and the IFN-γ-specific T cell response stimulated by the EV71 antigen peptide. Importantly, the clinical protective efficacy against virus infection by the elicited immune response in the immunized population compared with the placebo control and the up-modulated gene profile associated with immune activation were similar to those in infected macaques. Further safety verification of this vaccine in neonatal rhesus macaques and children confirmed the potential use of the macaque as a reliable model for the evaluation of an EV71 candidate vaccine.


Thioredoxin peroxidase from Onchocerca volvulus: a major hydrogen peroxide detoxifying enzyme in filarial parasites.
Random screening of an Onchocerca volvulus third-stage (L3) cDNA library identified a highly abundant cDNA encoding a newly discovered antioxidant enzyme, thioredoxin peroxidase (TPx), a member of the peroxidoxin superfamily. This TPx cDNA (Ov-tpx-2) encodes a polypeptide of 199 amino acid residues with a calculated molecular weight of 21,890 Da. The Ov-tpx-2 cDNA represents roughly 2.5% of the total cDNAs from the L3 cDNA library. The gene was expressed in Escherichia coli and the protein product was shown to have antioxidant activity. Antiserum raised against Ov-TPX-2 recognized a native protein from extracts of both the L3 and adult-stages with a molecular weight of 22 kD. The localization and stage-specificity of Ov-TPX-2 protein was analyzed by immunocytochemistry and immunoelectron microscopy using monospecific antibodies. Expression was detected in late first-stage larvae during development in the vector and increased in intensity during differentiation to the infective L3-stage. The antigen was also detected in post-infective larvae and adult worms. In larvae, Ov-TPX-2 protein was predominantly localized to the hypodermis and cuticle, with additional sites in the hypodermal chords and multivesicular bodies. In adult worms, the primary sites of expression were the uterine epithelium and intestine, with additional labeling of the body wall and cuticle. Developing embryos and microfilariae in utero were bathed in Ov-TPX-2 protein discharged from epithelial cells. These results suggest that Ov-TPX-2 may protect the parasites from being damaged by host-generated oxidative stress and that Ov-TPX-2 protein provides the H2O2-detoxifying activity predicted but not previously identified in filarial parasites. Its highly upregulated expression in infective larvae may aid in parasite establishment following transmission to the definitive host.


Human figure drawing size and body image in preschool children from a self-physique perspective.
To learn about the relationship between size of human figure drawings and the physiques of children, we investigated body image characteristics in childhood by using the Human Figure Drawing test. Height, weight, Kaup Index (a body mass index for children) and Human Figure Drawing traits (vertical height, horizontal width, waist size, surface area of head, surface area of the self-drawing) were measured for drawings of 122 4- to 6-yr.-old children (62 boys, 60 girls). Analysis showed that boys, who are physically larger than girls, produced self-drawings with somewhat larger surface areas. For vertical height of self-drawings of boys, 4-yr.-olds characteristically made taller self-drawings than 5-yr.-olds. While we hypothesized that taller children would make vertically taller self-drawings, we observed a negative relationship between children's physical height and the vertical height of the self-drawings. 4-yr.-old boys showed the most interest in their own physical height, making taller drawings and in doing so gave a clue to an early childhood feature of body image.


Larval morphology of Hydryphantes clypeatus Thor, 1899, H. dispar Schaub, 1888 and H. planus Thon, 1899 (Acari, Hydrachnidia: Hydryphantidae).
Larvae of the water mite species Hydryphantes clypeatus Thor, 1899 are described for the first time, and redescriptions of the larvae H. dispar (Schaub, 1888) and H. planus Thon, 1899 are presented. The present data suggest that H. clypeatus and H. hellichi Thor, 1899, two species recently considered as a junior synonyms of H. planus resp. H. ruber (Geer, 1787) should be recognized as separate species. Separate keys to all named species based on larvae and adults are given.


Cigarette-smoking affects platelets and endothelium in chronic hemodialysis patients.
Previous work has shown that cigarette-smoking affects platelets and endothelium in men and women without renal failure. The present study compared 10 male habitual smokers receiving maintenance hemodialysis for chronic renal failure with 11 healthy male habitual smokers before and after controlled cigarette-smoking after a 12-hour period of abstinence. Collagen-induced platelet aggregation was not significantly different in the two groups of men before smoking. The platelet aggregate ratio was lower and the plasma concentration of platelet factor 4 was higher in the dialysis patients than in the healthy men (p < 0.05). Mean or median values before and after cigarette smoking by the dialysis patients were 42 and 62 chart units for collagen-induced platelet aggregation, 0.88 and 0.77 for the platelet aggregate ratio, 6.2 and 8.5 ng/ml for the plasma concentration of platelet factor 4, 0.8 and 1.7 per counting chamber for the endothelial cell count and 4 and 37 ng/ml for the plasma nicotine concentration (each p < 0.01). None of the changes which occurred in the dialysis patients was statistically significantly different from those in the healthy men. We conclude that cigarette-smoking has similar effects on platelets and endothelium in patients receiving maintenance hemodialysis and in healthy controls.


Improving the quality of transition and transfer of care in young adults with congenital heart disease.
The transition and transfer from pediatric to adult care is becoming increasingly important as improvements in the diagnosis and management of congenital heart disease allow patients to live longer. Transition is a complex and continuous process that requires careful planning. Inadequate transition has adverse effects on patients, their families and healthcare delivery systems. Currently, significant gaps exist in patient care as adolescents transfer to adult care and there are little data to drive the informed management of transition and transfer of care in adolescent congenital heart disease patients. Appropriate congenital heart disease care has been shown to decrease mortality in the adult population. This paper reviews the transition and transfer of care processes and outlines current congenital heart disease specific guidelines in the United States and compares these recommendations to Canadian and European guidelines. It then reviews perceived and real barriers to successful transition and identifies predictors of success during transfer to adult congenital heart disease care. Lastly, it explores how disease-specific markers of outcomes and quality indicators are being utilized to guide transition and transfer of care in other chronic childhood illnesses, and identifies existing knowledge gaps and structural impediments to improving the management of transition and transfer among congenital heart disease patients.


An overview of the genus Coprotus (Pezizales, Ascomycota) with notes on the type species and description of C. epithecioides sp. nov.
In a mycological research performed in the Sjeverni Velebit National Park, Croatia, a new species of Coprotus was discovered, described here as C. epithecioides. Along with the microscopic examination, phylogenetic analysis of the type material, based on ITS and LSU sequences, was performed in order to evaluate its relationship with the type species, C. sexdecimsporus. The type species was sequenced in this study for the first time, providing ITS and LSU sequences from two separate collections which displayed differences in macroscopic characters and content of paraphyses. An extended description of C. sexdecimsporus based on Croatian material is also provided. A worldwide identification key to the species assigned to the genus Coprotus is presented, along with a species overview, containing a data matrix. The phylogenetic position of Coprotus in the Boubovia-Coprotus clade within Pyronemataceae s.l. is discussed. Coprotus sexdecimsporus is also reported here as new to the Croatian mycobiota.


A transposon, Ping, is integrated into intron 4 of the DROOPING LEAF gene of rice, weakly reducing its expression and causing a mild drooping leaf phenotype.
The YABBY gene DROOPING LEAF (DL) regulates midrib formation in the leaves and carpel specification in the flowers of rice (Oryza sativa L). We found a new dl allele (dl-5) that caused a mild phenotype in the descendants of a mutable line, IM294. In plants homozygous for this allele, midrib structures were formed but their sizes were reduced. Molecular analysis revealed that a transposon, Ping, was inserted in the fourth intron of DL. Together with mPing and Pong, Ping is a member of a transposon family that was first identified as a group of active transposable elements in rice. Our finding of the Ping insertion in the DL gene is a first indication that Ping is active in planta, and that it can be transposed and integrated in a new locus. Ping seems to be still active because it was excised from intron 4 of DL at a relatively high frequency in rice calli. Real-time PCR analysis and in situ hybridization indicated that DL transcript levels were reduced in dl-5 without alterations in the spatial expression pattern of the DL gene. The reduction of DL expression may be due to inefficient splicing of the large intron caused by Ping insertion. By comparing the expression levels of DL and leaf phenotypes in the dl mutants with different severities, we confirmed our previous hypothesis that DL promotes cell proliferation in the central region of leaf primordia, and that this cell proliferation is critical for midrib formation in the mature leaves.


Surprisingly facile CO2 insertion into cobalt alkoxide bonds: A theoretical investigation.
Exploiting carbon dioxide as co-monomer with epoxides in the production of polycarbonates is economically highly attractive. More effective catalysts for this reaction are intensively being sought. To promote better understanding of the catalytic pathways, this study uses density functional theory calculations to elucidate the reaction step of CO2 insertion into cobalt(III)-alkoxide bonds, which is also the central step of metal catalysed carboxylation reactions. It was found that CO2 insertion into the cobalt(III)-alkoxide bond of [(2-hydroxyethoxy)Co(III)(salen)(L)] complexes (salen = N,N"-bis(salicyliden-1,6-diaminophenyl)) is exothermic, whereby the exothermicity depends on the trans-ligand L. The more electron-donating this ligand is, the more exothermic the insertion step is. Interestingly, we found that the activation barrier decreases with increasing exothermicity of the CO2 insertion. Hereby, a linear Brønsted-Evans-Polanyi relationship was found between the activation energy and the reaction energy.


[Analysis of genetic mutation and modifier genes in pulmonary arterial hypertension].
Mutations of the bone morphogenetic protein receptor II gene (BMPR2) have been reported in patients with pulmonary arterial hypertension (PAH). In hereditary hemorrhagic telangiectasia (HHT) patients with PAH, missense mutations of the activin receptor-like kinase 1 gene (ALK1) located in the serine-threonine kinase domain. Recently, the mutations of ALK1 in the serine-threonine kinase domain were observed in PAH patients. ALK1 mutations play a critical role in PAH without HHT as well as in PAH with HHT. Because only 10-20% carriers with BMPR2 mutations develop PAH, the existence of environmental factors or modifier genes as 5-HTT(serotonin transporter) and ACE (angiotensin converting enzyme) is highly probable.


Evaluation of the Foramen Magnum Area Calculated by Different Methods: A Radioanatomic Study.
The main objective of the study was to evaluate the probable diversity in the area of the foramen magnum (FM) calculated by different measuring methods. The study was conducted on 24 dry skulls, present in the collection of the Anatomy Department, Faculty of Medicine, Mersin University. The area of FM was calculated by different measurement methods including automatic field setting, Teixeria and Radinsky formulas obtained from anatomic (ASM), photographic (PSM) and radiologic (RSM) skull measurements. The areas of FMs calculated by Teixeria formula in RSM, PSM, and ASM were as follows: 857.96 ± 99.97 mm, 796.68 ± 105.08 mm, and 820.86 ± 96.40 mm, respectively. The areas calculated by Radinsky formula in RSM, PSM, and ASM were as follows: 851.37 ± 99.68 mm, 792.63 ± 104.18 mm, and 814.85 ± 94.99 mm, respectively. Lastly, the areas calculated by the automatic field setting of RSM and PSM software were as follows: 799.75 ± 103.38 mm and 752.83 ± 105.60 mm, respectively. Statistical significance was observed between the areas of FM obtained from RSM, ASM, and PSM when calculated by the automatic field setting, Teixeria formula, and Radinsky formula. The authors think that considering the amorphous shape of FM, the automatic field setting of the software should be used to obtain the most accurate numerical data related to the area of FM.


Quantifying m6A and Ψ Modifications in the Transcriptome via Chemical-Assisted Approaches.
Since the discovery of the first chemically modified RNA nucleotide in 1951, more than 170 types of chemical modifications have been characterized in RNA so far. Since the discovery of the reversible and dynamic nature of N6-methyladenosine (m6A) in mRNA modification, researchers have identified about ten modifications in eukaryotic mRNA; together with modifications on the noncoding RNAs, the term "epitranscriptome" has been coined to describe the ensemble of various chemical RNA modifications. The past decade has witnessed the discovery of many novel molecular functions of mRNA modifications, demonstrating their crucial roles in gene expression regulation. As the most abundant modifications in mRNA, the study of m6A and Ψ has been facilitated by innovative high-throughput sequencing technologies, which can be based on antibodies, enzymes, or novel chemistry. Among them, chemical-assisted methods utilize selective chemistry that can discriminate modified versus unmodified nucleotides, enabling the transcriptome-wide mapping of m6A and Ψ modifications and functional studies.Our group has developed several sequencing technologies to investigate these epitranscriptomic marks including m6A, Ψ, m1A, and m6Am. Among them, we have recently developed two methods for absolute quantification of m6A and Ψ in the transcriptome based on chemical reactivity to distinguish and measure the two modifications. In GLORI, we used glyoxal and nitrite to mediate efficient deamination of regular adenosine, while m6A remained unaffected, thereby enabling efficient and unbiased detection of single-base resolution and absolute quantification of m6A modification. In CeU-seq and PRAISE, we used different chemistry to achieve selective labeling and detection of transcriptome-wide Ψ. CeU-seq is based on an azido-derivatized carbodiimide compound, while PRAISE utilizes the unique activity of bisulfite to Ψ. PRAISE results in the formation of ring-opening Ψ-bisulfite adduct and quantitatively detects Ψ as 1-2 nt deletion signatures during sequencing. The resulting base-resolution and stoichiometric information expanded our understanding to the profiles of RNA modifications in the transcriptome. In particular, the quantitative information on RNA methylome is critical for characterizing the dynamic and reversible nature of RNA modifications, for instance, under environmental stress or during development. Additionally, base-resolution and stoichiometric information can greatly facilitate the analysis and characterization of functional modification sites that are important for gene expression regulation, especially when one modification type may have multiple or even opposing functions within a specific transcript. Together, the quantitative profiling methods provide the modification stoichiometry information, which is critical to study the regulatory roles of RNA modifications.In this Account, we will focus on the quantitative sequencing technologies of m6A and Ψ developed in our group, review recent advances in chemical-assisted reactions for m6A and Ψ detection, and discuss the challenges and future opportunities of transcriptome-wide mapping technologies for RNA modifications.


Diagnostic accuracy of biomarkers to detect acute mesenteric ischaemia in adult patients: a systematic review and meta-analysis.
Acute mesenteric ischaemia (AMI) is a disease with different pathophysiological mechanisms, leading to a life-threatening condition that is difficult to diagnose based solely on clinical signs. Despite widely acknowledged need for biomarkers in diagnosis of AMI, a broad systematic review on all studied biomarkers in different types of AMI is currently lacking. The aim of this study was to estimate the diagnostic accuracy of all potential biomarkers of AMI studied in humans. A systematic literature search in PubMed, The Cochrane Library, Web of Science and Scopus was conducted in December 2022. Studies assessing potential biomarkers of AMI in (at least 10) adult patients and reporting their diagnostic accuracy were included. Meta-analyses of biomarkers' sensitivity, specificity, and positive and negative likelihood ratios were conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the study quality was assessed with the QUADAS-2 tool. Seventy-five studies including a total of 9914 patients assessed 18 different biomarkers in serum/plasma and one in urine (each reported in at least two studies), which were included in meta-analyses. None of the biomarkers reached a conclusive level for accurate prediction. The best predictive value overall (all studies with any type and stage of AMI pooled) was observed for Ischaemia-modified albumin (2 studies, sensitivity 94.7 and specificity 90.5), interleukin-6 (n = 4, 96.3 and 82.6), procalcitonin (n = 6, 80.1 and 86.7), and intestinal fatty acid-binding protein (I-FABP) measured in serum (n = 16, 73.9 and 90.5) or in urine (n = 4, 87.9 and 78.9). In assessment of transmural mesenteric ischaemia, urinary I-FABP (n = 2, 92.3 and 85.2) and D-dimer (n = 3, 87.6 and 83.6) showed moderate predictive value. Overall risk of bias was high, mainly because of selected study populations and unclear timings of the biomarker measurements after onset of symptoms. Combinations of biomarkers were rarely studied, not allowing meta-analyses. None of the studied biomarkers had sufficient sensitivity and specificity to diagnose AMI, although some biomarkers showed moderate predictive accuracy. Future studies should focus on timing of measurements of biomarkers, distinguishing between early stage and transmural necrosis, and between different types of AMI. Additionally, studies on combinations of biomarkers are warranted. PROSPERO registration: CRD42022379341.


Expectancy learning from probabilistic input by infants.
Across the first few years of life, infants readily extract many kinds of regularities from their environment, and this ability is thought to be central to development in a number of domains. Numerous studies have documented infants' ability to recognize deterministic sequential patterns. However, little is known about the processes infants use to build and update representations of structure in time, and how infants represent patterns that are not completely predictable. The present study investigated how infants' expectations fora simple structure develope over time, and how infants update their representations with new information. We measured 12-month-old infants' anticipatory eye movements to targets that appeared in one of two possible locations. During the initial phase of the experiment, infants either saw targets that appeared consistently in the same location (Deterministic condition) or probabilistically in either location, with one side more frequent than the other (Probabilistic condition). After this initial divergent experience, both groups saw the same sequence of trials for the rest of the experiment. The results show that infants readily learn from both deterministic and probabilistic input, with infants in both conditions reliably predicting the most likely target location by the end of the experiment. Local context had a large influence on behavior: infants adjusted their predictions to reflect changes in the target location on the previous trial. This flexibility was particularly evident in infants with more variable prior experience (the Probabilistic condition). The results provide some of the first data showing how infants learn in real time.


Clinical and functional outcomes of Paediatric femoral shaft fractures managed non-operatively at Nkhotakota District Hospital, Malawi.
Femoral shaft fracture is a common paediatric injury, managed non-operatively with skin traction in Malawian public hospitals. The clinical and functional outcomes of this treatment modality are unknown in Malawi. We retrospectively identified all children who were managed at Nkhotakota District Hospital with skin traction after sustaining closed femoral shaft fractures from January 1, 2013 to December 31, 2016. We collected demographic characteristics and treatment history from the patient's inpatient medical records, then invited each patient to undergo in-person follow-up clinical and functional assessment. We identified 149 patients. Gallows traction 26 (17%) and 123 Bucks skin traction (83%). The mean age for Gallows traction was 10 months (95% CI: 8-11), most were males (16, 62%). Fall was the most common cause of injury (19, 73%), and mean hospitalization of 15.8 days (95% CI: 13.8-17.9). Eighteen patients (69%) were followed up at a mean of 4.2 years after discharge, all were full weight bearing, had achieved radiographic fracture union, and had no functional limitations or pain during regular activity. Buck's skin traction mean age was 5.2 years (95% CI: 4.7-5.8), most were males (82, 67%), and fall (85, 69%). We followed up 83 patients (67%) at a mean of 4.1 years after hospital discharge, all of whom had achieved radiographic fracture union. All but one patient were full weight bearing and had normal gait. At follow-up, 14 patients (17%) reported some level of pain, 5 patients reported that their injury limited their return to household chores, and 2 reported that their injury also limited their return to school. Despite the limitations of this study, non-operative management of paediatric femoral shaft fractures at Nkhotakota District Hospital may have good clinical and functional outcomes and minimal complications. A future prospective study may be helpful to confirm these findings.


Brain-derived neurotrophic factor (BDNF) plasma concentration in patients diagnosed with premature ovarian insufficiency (POI).
Premature ovarian insufficiency (POI) is defined as a cessation of function of ovaries in women younger than 40 years old. Brain-derived neurotrophic factor (BDNF) is a protein critically involved in neuronal growth and metabolism. BDNF also has been shown to be important regulator of oocyte maturation. Recent data show that BDNF can be potentially involved in POI pathology. The aim of the study was to assess the BDNF plasma concentrations in patients diagnosed with idiopathic POI. 23 women diagnosed with POI (age 31 ± 7 years) and 18 (age 31 ± 3) controls were included to the study, matched according to age and body mass index. The BDNF concentrations were measured using competitive enzyme-linked immunosorbent assay (ELISA). Hormonal and metabolic parameters were measured in all individuals, in controls in late follicular phase. The POI group demonstrated lower mean plasma concentrations of BDNF (429.25 ± 65.52 pg/ml) in comparison to healthy controls (479.75 ± 34.75 pg/ml, p = 0.0345). The BDNF plasma concentration correlated negatively (R = -0.79, p < 0.001) with number of months since last menstrual period. There was a positive correlation between BDNF and progesterone in controls. In conclusion, POI patients show significantly lower BDNF plasma concentration and it correlates with the duration of amenorrhea. This observation brings important potential insights to the pathology of POI.


Iatrogenic limb ischemia caused by angiography closure devices.
Described are 2 cases of lower limb ischemia that resulted after deployment of 2 different arterial closure devices. One patient presented acutely with lower limb ischemia after an Angio-Seal (St Jude Medical, Minnetonka, Minn) device deployed at the conclusion of cerebral artery aneurysm embolization. The second patient, who underwent angioplasty for aortic recoarctation, presented with claudication 1 week after deployment of the Perclose (Perclose, Redwood City, Calif) device. The use of such devices can result in significant complications, and cardiologists, interventional radiologists, and vascular surgeons are advised to have a high index of suspicion for such complications and work in close conjunction to provide prompt and adequate treatment.


Outcomes Following Low-Profile Mesh Plate Osteosynthesis of Patella Fractures.
Treatment of patella fractures is fraught with complications and historically poor functional outcomes. A fixation method that allows for early mobilization and decreases symptomatic hardware rates will improve knee range of motion, postoperative functional status, and reoperation rates. The purpose of this study was to evaluate the functional outcomes after locked plate osteosynthesis of patella fractures at a Level 1 trauma center. A retrospective case series was conducted of patients who underwent open reduction internal fixation (ORIF) of a patella fracture using a locked mesh plating technique coupled with neutralization of forces on the distal pole of the patella. Twelve patients were evaluated at a mean follow-up of 19 months (range, 6-30) with physical exam, functional outcomes, and radiographs. There were 9 women and 3 men with an average age of 66.1 years (range, 53-75). Radiographic bony union was achieved in all patients by 3-month follow-up. Visual Analog Pain Score averaged 1.7 (median, 1.0; range, 0-8), the mean Knee Outcome Score - Activities of Daily Living Scale was 83.9 (median, 92.1; range, 45.7-100.0), the mean Short Form Musculoskeletal Function Assessment (SMFA) Function Index was 9.9 (median, 3.7; range, 0.7-41.2), and the mean SMFA Bother Index was 11.1 (median, 3.1; range, 0-62.5). The SF-36 Physical Component Score mean was 48.4 ± 8.5 and the SF-36 Mental Component Score mean was 54.1 ± 9.6. No complications developed and there were no reoperations for nonunion, infection, or symptomatic hardware. This study demonstrates that locked plate osteosynthesis for operative patella fractures can reliably achieve bony union with potentially superior functional outcomes as compared with traditional methods. Further studies are needed to evaluate plate fixation for patella fractures, but early results are promising.


Comparative effectiveness of metoprolol, ivabradine, and its combination in the management of inappropriate sinus tachycardia in coronary artery bypass graft patients.
Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG. An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment. IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups. Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.


The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis.
The increasing incidence of drug resistance in Mycobacterium tuberculosis has diminished the efficacy of almost all available antibiotics, complicating efforts to combat the spread of this global health burden. Alongside the development of new drugs, optimised drug combinations are needed to improve treatment success and prevent the further spread of antibiotic resistance. Typically, antibiotic resistance leads to reduced sensitivity, yet in some cases the evolution of drug resistance can lead to enhanced sensitivity to unrelated drugs. This phenomenon of collateral sensitivity is largely unexplored in M. tuberculosis but has the potential to identify alternative therapeutic strategies to combat drug-resistant strains that are unresponsive to current treatments. Here, by using drug susceptibility profiling, genomics and evolutionary studies we provide evidence for the existence of collateral drug sensitivities in an isogenic collection M. tuberculosis drug-resistant strains. Furthermore, in proof-of-concept studies, we demonstrate how collateral drug phenotypes can be exploited to select against and prevent the emergence of drug-resistant strains. This study highlights that the evolution of drug resistance in M. tuberculosis leads to collateral drug responses that can be exploited to design improved drug regimens.


[5-HT1A/5-HT7 receptor interplay: Chronic activation of 5-HT7 receptors decreases the functional activity of 5-HT1A receptor and its сontent in the mouse brain].
Serotonin receptors 5-HT1A and 5-HT7 are involved in the development of various psychopathologies. Some data indicate that there is an interplay between 5-HT1A 5-HT7 receptors that could be implicated in the regulation of their function. This work analyzed the effects of chronic 5-HT7 activation on the functional activity of 5-HT7 and 5-HT1A receptors, on the corresponding protein levels, and on the expression of genes encoding 5-HT7 and 5-HT1A receptors in the mouse brain. Chronic administration of the 5-HT7 selective agonist LP44 (20.5 nmol, i.c.v., 14 days) produced considerable desensitization of both 5-HT7 and 5-HT1A receptors. In LP44-treated mice, the hypothermic responses mediated by both 5-HT7 and 5-HT1A receptors were attenuated. Moreover, the levels of 5-HT1A receptor protein in the midbrain and the frontal cortex of LP44-treated mice were significantly decreased. However, the brain levels of 5-HT7 receptor protein did not differ between LP44-treated and control mice. Chronic LP44 treatment did not alter the expression of the 5-HT7 and 5-HT1A receptor genes in all investigated brain structure. These data suggest that 5-HT7 receptors participate in the posttranscriptional regulation of the 5-HT1A receptors functioning.


It is not all about salary: a discrete-choice experiment to determine community health workers' motivation for work in Nigeria.
Community health workers (CHWs) constitute the majority of primary healthcare (PHC) workers in Nigeria, yet little is understood about their motivations or the most effective interventions to meet their needs to ensure quality health coverage across the country. We aimed to identify factors that would motivate CHWs for quality service delivery. A discrete-choice experiment was conducted among 300 CHWs across 44 PHC facilities in the Federal Capital Territory, Abuja Nigeria. Based on the literature review and qualitative research, five attributes, namely: salary, educational opportunities, career progression and in-service training, housing and transportation, were included in the experiment. CHWs were presented with 12 unlabelled choice sets, using tablet devices, and asked to choose which of two hypothetical jobs they would accept if offered to them, or whether they would take neither job. Mixed multinomial logistic models were used to estimate stated preferences for the attributes and the likely uptake of jobs under different policy packages was simulated. About 70% of the respondents were women and 39% worked as volunteers. Jobs that offered career progression were the strongest motivators among the formally employed CHWs (β=0.33) while the 'opportunity to convert from CHW to another cadre of health workers, such as nursing' was the most important motivator among the volunteers' CHWs (β=0.53). CHWs also strongly preferred jobs that would offer educational opportunities, including scholarship (β=0.31) and provision of transport allowances (β=0.26). Policy scenario modelling predicted combined educational opportunities, career progression opportunities and an additional 10% of salary as incentives was the employment package that would be most appealing to CHWs. CHWs are motivated by a mix of non-financial and financial incentives. Policy interventions that would improve motivation should be adequate to address various contexts facing different CHWs and be flexible enough to meet their differing needs.


Wheat ROP proteins modulate defense response through lignin metabolism.
ROP is a subfamily of small GTP-binding proteins that uniquely exist in plants. It acts as versatile molecular switches that regulate various developmental processes. Some ROP proteins are also reported to affect defense responses, although their exact mechanism is not fully understood. Herein, ROP members in wheat were mined; the functions of three wheat ROP proteins were studied. RT-PCR results showed that the expression of TaRac1 was rapidly and strongly induced after leaf rust infection. TaRac1 interacted with TaCCR in yeast-hybridization assay. The overexpression of TaRac1 in tobacco promoted CCR and CAD gene expression, increased the total lignin content and sinapyl lignin proportion, and then enhanced resistance to tobacco black shank and bacterial wilt diseases. In contrast, TaRac3 and TaRac4 did not show to interact with TaCCR. Furthermore, the overexpression of TaRac3 and TaRac4 did not increase lignin gene expression and lignin accumulation either. Unlike TaRac1, the overexpression of TaRac3 increased susceptibility to both black shank and bacterial wilt pathogens, while overexpression of TaRac4 showed no effect on disease resistance but promoted the root growth in tobacco seedling. These data collectively suggest that TaRac1 in Group II is mainly involved in regulating lignin metabolism which, in turn, responsible for the observed roles in pathogen resistance. TaRac3 and TaRac4 have the minor roles in defense response but may act on regulation in plant developmental processes. These results shed light on the complexity and diverse function of ROP in plant defense pathway.


Nitrate Respiration Promotes Polymyxin B Resistance in Pseudomonas aeruginosa.
Aims: Polymyxin B (PMB) is known to require reactive oxygen species (ROS) for its bactericidal activity, but the mechanism of PMB resistance in various Pseudomonas aeruginosa strains has been poorly understood. This study examined the role of nitrate respiration (NR) of some P. aeruginosa strains in the PMB resistance. Results: We observed that the minimum inhibitory concentration (MIC) value of PMB against P. aeruginosa PA14 was eightfold reduced (from 2.0 to 0.25 μg/mL) by agitation, but not against P. aeruginosa PAO1 (from 2.0 to 1.0 μg/mL). Transcriptomic and phenotypic analyses using both strains and their NR mutants revealed that the higher NR in PAO1 than in PA14 accounted for the higher MIC value (i.e., PMB resistance) of PAO1, which was sufficient to compromise the antibacterial activity of PMB in Drosophila infections. We also confirmed the contribution of the NR to the PMB resistance is independent of the major catalase (KatA), suggesting that the NR might affect the ROS generation rather than the ROS disintegration. Furthermore, this PMB resistance was relatively common among clinical P. aeruginosa isolates and correlated with higher NR in those strains. Innovation and Conclusion: These results suggest P. aeruginosa strains could display intrinsic resistance to antibiotics in clinical settings and that NR is a crucial factor in the intrinsic antibiotic resistance, and also provide an insight into another key target for successful antibiotic treatment of P. aeruginosa infections. Antioxid. Redox Signal. 34, 442-451.


Quantitative computational models of molecular self-assembly in systems biology.
Molecular self-assembly is the dominant form of chemical reaction in living systems, yet efforts at systems biology modeling are only beginning to appreciate the need for and challenges to accurate quantitative modeling of self-assembly. Self-assembly reactions are essential to nearly every important process in cell and molecular biology and handling them is thus a necessary step in building comprehensive models of complex cellular systems. They present exceptional challenges, however, to standard methods for simulating complex systems. While the general systems biology world is just beginning to deal with these challenges, there is an extensive literature dealing with them for more specialized self-assembly modeling. This review will examine the challenges of self-assembly modeling, nascent efforts to deal with these challenges in the systems modeling community, and some of the solutions offered in prior work on self-assembly specifically. The review concludes with some consideration of the likely role of self-assembly in the future of complex biological system models more generally.


Fiber optical parametric amplified optical direct-detection OFDM signal with intensity modulation transfer blocking.
A fiber optical parametric amplified optical orthogonal frequency division multiplexing (OFDM) signal with intensity modulation transfer (IMT) blocking is proposed. A novel blank carrier blocking method is adopted to suppress pump to signal intensity interference. Compared with regular optical signal, the IMT induced interference can be well blocked in the experiment. The error vector magnitude (EVM) and signal gain are also investigated in the experiment.


Acute toxicity of Zinc pyrithione to human skin cells in vitro.
Zinc pyrithione introduced into cultures of rapidly proliferating NCTC 2544 human skin epithelial cells and normal human skin fibroblasts had a rapid cytotoxic effect even at very low concentrations (0.1-0.5 microgram/ml); there was no dose-dependent suppression of cell proliferation and no apparent interference with mitosis. Sodium pyrithione had a similar effect. Zinc oxide and zinc sulphate were at least 100 times better tolerated than zinc pyrithione, but no stimulatory effect on cell growth was detected with low concentrations of either compound. These results suggest that zinc pyrithione's action against dandruff is more likely to arise from a non-specific toxicity for epidermal cells than by an anti-mitotic effect or by remedying a local zinc deficiency.


Negotiating intersubjectivity by interpersonal and appraisal shifts in Chinese-English government press conference interpreting.
This study investigates how interpreting shifts of interpersonal and appraisal resources facilitated the successful negotiation of intersubjectivity at China's premier press conferences (PPCs) from 2016 to 2021. This study conducts a corpus-based critical discourse analysis of interpersonal shifts at the PPCs as defined by systematic functional linguistics. Quantitative results show that the interpreter is strongly inclined to utilize appraisal shifts which enhance (or soften) the positive (or negative) evaluations of the Chinese government in interpreting the journalists' questions and uses shifts to first-person plurals and inclinational modal verbs in interpreting the Chinese Premier's answers. Qualitative results show these shifts facilitate the direct or indirect reproduction of the government's official ideology (especially the notions of solidarity, change, resolution, and people's wellbeing) and the existing power relations between the government, media, and Chinese people (both authority and solidarity). It is concluded that the interpreter displays a strong tendency to use interpersonal shifts to ensure successful negotiation of intersubjectivity at the PPCs by ultimately reproducing the social status quo.


[The status of chemotherapy in non-small-cell bronchial carcinoma].
In non-small-cell lung cancer the effect of chemotherapy has in the past been considered to be strictly palliative and of limited duration. Because of these limitations, cytostatic therapy has been applied more sparingly in non-small cell lung cancer than in small-cell lung cancer. It must be emphasized, however, that the relatively low remission rates of 30 to 40% cited in the medical journals over the past decades stem predominantly from patients who have reached the disseminated tumor stage IV. More recent results in clinical trials have indicated that the prognosis of stage III non-small cell lung cancer can be improved by multi-modality treatment regimens, whereby the early application of chemotherapy would appear to play a decisive role. By combining chemotherapy with subsequent radiotherapy the incidence of distant metastases can be reduced, despite the fact that the appearance of local relapses could not up until now be prevented by such treatment. New hope has arisen following the publication of results from studies in which polychemotherapy (with or without radiotherapy) was applied pre-operatively. It would appear possible to lengthen the survival time of patients with locally advanced cases of primarily inoperable tumors when, as study results indicate, chemotherapy induces a remission which allows for subsequent tumor surgery. These positive results which, up until now, have been derived solely from uncontrolled trials, must of course be substantiated by controlled phase III studies. In addition and parallel to the application of chemotherapy within a multi-modality treatment concept, improved results should also be sought by the usage of new drugs. We are hopeful that clinical trials with the topoisomerase I-inhibitors Topotecan and CPT 11 as well as the taxanes taxol, Taxotere and Gemcitabine, an analog of the cytosine-arabinoside, will prove successful.


Single-dose pharmacokinetics of leuprolide in humans following intravenous and subcutaneous administration.
A group of six normal adult male volunteers was divided into two groups (I and II) who received bolus intravenous and subcutaneous 1-mg doses of leuprolide. The study was of a randomized, complete-crossover design. Blood was collected from 0 to 48 h postdosing, and plasma was analyzed for leuprolide using a radioimmunoassay procedure. The data from the intravenous doses were fitted to a two-compartment open model with elimination from the central compartment, assuming a bolus (instantaneous) injection. The data from the subcutaneous doses were fitted to a two-compartment open model with elimination from the central compartment and first-order (monoexponential) absorption from the injection site. Statistical moments were also calculated for both sets of data. The mean beta half-life after the intravenous dosings was 2.9 h and after the subcutaneous dosings was 3.6 h. The difference between these two values, as well as those for plasma clearance, variance in residence time, and volume of distribution at steady state was not statistically significant; however, the differences between the mean values of k21, k12, kel, apparent volume of distribution of the central compartment, mean residence time, and area under the moment curve for the routes of administration were significant (p less than 0.05). The mean residence time following the intravenous dosings averaged 3.1 h and following the subcutaneous dosings averaged 4.3 h, indicating an average mean residence time at the subcutaneous injection site of 1.2 h. The mean volume of distribution at steady state from the intravenous and subcutaneous doses were 26.5 and 37.1 L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of acid-base balance and high or low intensity exercise on VEGF and bFGF.
The purpose of the present study was to compare the acute hormonal response to a short-term high-intensity training (HIT) versus a high-volume endurance training (HVT) and to investigate the effects of acid-base status on cytokines involved in angiogenesis (VEGF and bFGF). Eleven subjects participated in three experimental trials. Two times subjects performed four 30-s "all-out" exercise bouts on a cycle ergometer separated by 5-min rest each, at which subjects either received bicarbonate (HIT (B)) or a placebo (HIT (P)) before the exercise. The third exercise trail consisted of a constant load exercise for 1 h at 50% peak power output (PPO). Venous blood samples were taken under resting conditions, 10, 60, and 240 min after each exercise condition to determine VEGF and bFGF serum concentrations. Capillary blood samples were taken to determine lactate concentrations and blood gas parameters. Mean pH values were significantly higher during HIT (B) compared to HIT (P). Serum VEGF concentration was significantly increased 10-min post-exercise in both HIT interventions. HVT showed no significant effects on VEGF levels. The diminished acidosis during HIT (B) had no effects on the VEGF response. There were no significant changes in bFGF in response to HIT or HVT. The present study suggests that HIT is a stimulus for exercise-induced VEGF secretion. These findings might be relevant for the arrangement of training, due to the fact that most of the training is often performed at low intensities possibly leading to an insufficient stimulus for VEGF secretion and angiogenesis.


States of emotional control during psychotherapy.
The authors' objective was to develop a simple and reliable descriptive method for categorizing patient states during psychotherapy. The categories would be based on the degree of apparent control over emotional expressions. Methods involved scoring videotapes of psychotherapy for 5 patients with neurotic-level Axis I disorders. Three judges rated each 30-second segment as predominantly one of these four states: well modulated, overmodulated, undermodulated, or shimmering. Shimmering states combine emotional display with efforts to stifle that expression. The results showed that judges could reliably rate states by the definitions used in this study. This technique can provide a simplified and general approach to observation of degrees of defensive control of emotion of patients in psychotherapy.


Evaluation of Nutrient Consumption for the Prevention of Chronic Diseases in Health Promotion Services: A Controlled and Randomized Community Trial to Promote Fruits and Vegetables.
To evaluate the effectiveness of a collective intervention to encourage the consumption of fruits and vegetables on the nutrients intake for the prevention of chronic non-communicable diseases (NCDs), a randomized controlled community trial was conducted with a representative sample from the Health Academy Program. While the individuals in the control group (CG) participated in regular physical exercise, those in the intervention group (IG) also participated in a collective intervention. After 12 months, IG and CG showed a reduction in energy, omega 3 and sodium intake and an increase in the consumption of carbohydrates, fiber, vitamins, and minerals. Individuals from the CG showed an increase in phosphorus consumption and, in the IG, a reduction in the consumption of total, saturated, and polyunsaturated fats as well as an increase in the consumption of monounsaturated fats was seen. In both groups, there was an increase in the prevalence of adequate nutrients. Participation in the nutritional intervention was associated with lower consumption of energy and protein in the diet. The results pointed to the importance of individuals' participation in the program, which, associated with nutritional intervention, promoted an improvement in the nutrient profile of the diet and the prevention and control of NCDs.


A case of polymorphic dermal angiitis in a B-cell chronic lymphocytic leukemia patient during rituximab therapy.
The aim of the study is to describe a case is of clinical interest as the first known occurrence of skin vasculitis during rituximab treatment. The article describes a case of polymorphic dermal angiitis, a combination of hemorrhagic and ulcerative-necrotic forms against the background of rituximab treatment in a 53-year-old woman suffering from chronic lymphocytic leukemia (b-CLL). During four hours after the 5th intravenous administration of rituximab, the appearance of painful rashes on the skin of both shins of a patient was observed. In the following few days, a progression of the pathological skin process was noted. The treatment with prednisolone in the amount of 50 mg/day, amoxicillin and clavulanic acid in the amount of 1000 mg twice per day and Diflucan in a dosage of 50 mg/day for 15 days was prescribed. In a local therapy, wet-drying bandages with antiseptic solutions, combined topic glucocorticosteroid preparations, drugs that improve trophic and tissue regeneration were recommended. After discharge, the patient continued to receive prednisolone in the amount of 50 mg/day for 14 days with a slow decrease in the dosage of the drug until the withdrawal under the supervision of a dermatologist. The described experience of how combined forms of polymorphic dermal angiitis are developing can be considered a result of toxic drug response to rituximab.


A three-dimensional finite element model of round window membrane vibration before and after stapedotomy surgery.
Piston stapes prostheses are implanted in patients with refractory conductive or mixed hearing loss due to stapes otosclerosis to stimulate the perilymph with varying degrees of success. The overclosure effect described by the majority of researchers affects mainly low and medium frequencies, and a large number of patients report a lack of satisfactory results for frequencies above 2 kHz. The mechanics of perilymph stimulation with the piston have not been studied in a systematic manner. The objective of this study was to assess the influence of stapedotomy surgery on round window membrane vibration and to estimate the postoperative outcomes using the finite element (FE) method. The study hypothesis is that the three-dimensional FE model developed of the human inner ear, which simulates the round window (RW) membrane vibration, can be used to assess the influence of stapedotomy on auditory outcomes achieved after the surgical procedure. An additional objective of the study was to enable the simulation of RW membrane vibration after stapedotomy using a new type of stapes prosthesis currently under investigation at Warsaw University of Technology. A three-dimensional finite element (FE) model of the human inner ear was developed and validated using experimental data. The model was then used to simulate the round window membrane vibration before and after stapedotomy surgery. Functional alterations of the RW membrane vibration were derived from the model and compared with the results of experimental measurements from temporal bones of a human cadaver. Piston stapes prosthesis implantation causes an approximately fivefold (14 dB) lower amplitude of the RW membrane vibrations compared with normal anatomical conditions. A satisfactory agreement between the FE model and the experimental data was found. The new prosthesis caused an increase of 20-30 dB in the RW displacement amplitude compared with the 0.4-mm piston prosthesis. In all frequencies, the FE model predicted a RW displacement curve that was above the experimental curves for the normal ear. The stapedotomy can be well simulated by the FE model to predict the auditory outcomes achieved following this otosurgery procedure. The 3D FE model developed in this study may be used to optimize the geometry of a new type of stapes prosthesis in order to achieve a similar sound transmission through the inner ear as for a normal middle ear. This should provide better auditory outcomes for patients with stapedial otosclerosis.


Inhibition of Crandell-Rees Feline Kidney cell proliferation by X-ray-induced senescence.
Radioresistance and radiotoxicity have been reported following cancer treatments in felines. Optimizing radiation doses to induce cytotoxic effects to only cancer cells and not normal cells is critical in achieving effective radiation therapy; however, the mechanisms of radiation resistance, radiotoxicity, and DNA damage response (DDR) in feline cells have not yet been elucidated. A DNA double-strand break (DSB) is the most toxic type of DNA damage induced by X-rays and heavy ion beams used in treating cancers. Crandell-Rees Feline Kidney (CRFK) cells is one of the most widely used cat cells in life science research. Here, we report that DSB-triggered senescence induced by X-rays is important in inhibiting the proliferation of CRFK cells. We demonstrated through cell proliferation assay that X-rays at doses 2 Gy and 10 Gy are toxic to CRFK cells that irradiating CRFK cells inhibits their proliferation. In X-irradiated CRFK cells, a dose-dependent increase in DSB-triggered senescence was detected according to morphological changes and using senescence-associated β galactosidase staining assay. Moreover, our data indicated that in CRFK cells, the major DDR pathway, which involves the phosphorylation of H2AX at Ser139, was normally activated by ATM kinases. Our findings are useful in the understanding of X-rays-induced cellular senescence and in elucidating biological effects of radiation, e.g., toxicity, in feline cells. Furthermore, our findings suggest that the CRFK cell line is an excellent matrix for elucidating radioresistance and radiotoxicity in cat cells.


The burden of vestibular disorders among military health system (MHS) beneficiaries, fiscal years 2018-2019.
Vestibular disorders affect an estimated 33 million adults and 3.5 million children and adolescents in the United States. Previous research relying on self-reported symptoms versus actual diagnosis has limited the ability to provide prevalence estimates for specific vestibular disorders at the population level. This study seeks to describe the burden of vestibular disorders among children and working-age adult beneficiaries in the Military Health System (MHS). Using the MHS Data Repository (MDR), we conducted a cross-sectional study of all TRICARE Prime and Plus MHS beneficiaries aged 0 to 64 years from fiscal years (FY) 2018 to 2019. Study analyses included descriptive statistics of patient demographics and assessing the prevalence of vestibular disorders in pediatric and working-age adult beneficiaries. Of the 5,541,932 TRICARE Prime/Prime Plus MHS beneficiaries, 52,878 (0.95%) had a diagnosis of vestibular disorder during fiscal years 2018 to 2019, of which 1,359 were pediatric and adolescents (aged 0 to 17 years) and 51,519 were working-age adults (18 to 64 years). Vertigo was the most common diagnosis in both age-group populations (11.46 per 1,000 working-age adults; 0.52 per 1,000 children and adolescents), with benign vertigo being the most prevalent of the three diagnoses and occurring at a seven times higher rate in adults versus pediatric and adolescents. This study demonstrates the effectiveness of using medical claims data to estimate prevalence compared to self-reported survey data and supports prevalence estimates of vestibular disease in <1% of children overall, but indicate much higher prevalence for adolescents.


Canadian national survey of point-of-care ultrasound training in family medicine residency programs.
To assess the current state of point-of-care ultrasound (POCUS) training in Canadian family medicine residency programs. Cross-sectional survey to evaluate POCUS education in accredited Canadian family medicine residency programs; only 1 completed survey was accepted per residency program. Seventeen accredited Canadian family medicine residency programs. Fourteen directors of family medicine programs across Canada. Opinions of program directors in family medicine education on the relevance of POCUS in family medicine, and the role of POCUS training in family medicine residency programs. The Web-based, anonymous survey, which was completed during the months of March and April 2016, achieved a response rate of 82% (14 out of 17 program directors). About one-fifth (21%) of program directors reported having an established ultrasound curriculum. Almost all directors (93%) believed that POCUS teaching should be integrated into family medicine residency curricula. Barriers to establishing training included the following: lack of adequate equipment (57%), lack of instructors (57%), lack of available time in the curriculum (57%), and lack of funding available to support training (71%). Seventy-one percent of respondents believed that POCUS could be used in outpatient family medicine clinics to alter clinical decision making. Some potential benefits associated with POCUS in primary care include more rapid diagnosis, improved patient outcomes, and potential to reduce health care costs. Although only a few Canadian family medicine residency program directors reported actually having an established ultrasound curriculum, most of them believed that POCUS training should be offered to family medicine residents and that its use could positively affect primary care. A growing number of family medicine residency programs are considering incorporating ultrasound training into their curricula, but resource availability remains a considerable barrier to implementation.


Assays of protein palmitoylation.
Protein palmitoylation plays an important role in the structure and function of a wide array of proteins. Unlike other lipid modifications, protein palmitoylation is highly dynamic and cycles of palmitoylation and depalmitoylation can regulate protein function and localization. The dynamic nature of palmitoylation is poorly resolved because of limitations in assay methods. Here, we discuss various methods that can be used to measure protein palmitoylation and identify sites of palmitoylation. We describe new methodology based on "fatty acyl exchange labeling" in which palmitate is removed via hydroxylamine-mediated cleavage of the palmitoyl-thioester bond and then exchanged with a sulfhydryl-specific labeling compound. The techniques are highly sensitive and allow for quantitative estimates of palmitoylation. Unlike other techniques used to assay posttranslational modifications, the techniques we have developed can label all sites of modification with a variety of probes, radiolabeled or non-radioactive, and can be used to assay the palmitoylation of proteins from tissue samples.


Mitochondria, sex, and mortality.
It has been proposed that prior to the evolution of sex, the endosymbiotic relationship between mitochondria and nuclear genomes would have selected mechanisms that maintained the optimum interaction between the two genomes. Once sex evolved, mating would introduce different, competitive, mtDNA and/or nDNA gene products that could well upset the balance. Mechanisms, such as the specific degradation of one mitochondrial genome that is known to occur, could have been selected to prevent part of such competition. Unlike most protein complexes in the cell, the proteins of the multienzyme complexes of the ox-phos system are derived from both nuclear-genome-coded genes and mitochondrial-genome-coded genes. Minor mutations in either mtDNA or nDNA coding for these proteins are known to lead to major and catastrophic diseases of humans, suggesting that very tight and precise interactions are required. To maintain the evolutionarily established balance after mating, monoallelic expression of the nuclear-coded genes would be advantageous and prevent subtly different competitive proteins from interacting with the resident mitochondria. This would require regulation of the expression of those specific nuclear genes, possibly under the control of the resident mitochondria. It is possible that aging cells could lose the requisite tight regulation and allow expression of proteins derived from the formerly repressed nuclear alleles that would compete for mitochondrial complex sites. With age, random failure of this control could lead to increasingly inefficient mitochondria in different tissues and organs and eventually to senescence and death.


The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections.
It is now generally accepted that excitotoxic cell death involves bioenergetic failure resulting from the cycling of Ca2+ and the generation of reactive oxygen species (ROS) by mitochondria. Both Ca2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Deltapsi(m)) that results from the proton gradient that is generated across the inner membrane. Mitochondrial uncoupling refers to a condition in which protons cross the inner membrane back into the matrix while bypassing the ATP synthase. As a consequence of this "short-circuit," there is a reduction in Deltapsi(m). We have previously demonstrated that animals treated with the classic uncoupling agent 2,4-dinitrophenol (DNP) show significant protection against brain damage following striatal injections of the NMDA agonist quinolinic acid (QA). In an effort to elucidate the mechanism of neuroprotection, we have assessed the effects of DNP on several parameters of mitochondrial function caused by QA. The results presented herein demonstrate that treatment with DNP attenuates QA-induced increases in mitochondrial Ca2+ levels and ROS formation and also improves mitochondrial respiration. Our findings indicate that DNP may confer protection against acute brain injury involving excitotoxic pathways by mechanisms that maintain mitochondrial function.


Mycobacteria directly induce cytoskeletal rearrangements for macrophage spreading and polarization through TLR2-dependent PI3K signaling.
Macrophage migration and adhesion are important for the control of mycobacterial infection and are critically dependent on the reorganization of the cytoskeleton. Mycobacteria elicit rapid morphological changes, such as cell spreading, a process relevant to in vivo changes of macrophage shape during extravasation and migration. In this study, we investigated the BCG mycobacteria-induced signaling events leading to macrophage cytoskeletal rearrangements employing specific pharmacological inhibitors to suppress distinct kinase pathways known to be elicited by infection. Viable or lysed mycobacteria, as well as purified cell wall lipoprotein p19, TLR2 agonist, induced RAW264.7 cells to extend actin-rich pseudopods, which impart radial spreading within 3 h, leading later to persistent cell polarization. BCG induced rapid activation of phosphatidylinositol 3-kinase, PI3K, activation that was recruited to the activated TLR2 receptor. TLR2- neutralizing antibody inhibited macrophage spreading and PI3K activation induced by p19. Additionally, BCG induced spreading and polarization of bone marrow-derived macrophages from TLR2- expressing mice in contrast to their TLR2-knockout counterparts. Neither MEK1/ERK, p38 MAPK, nor NF-kappaB activation were important for the early cytoskeletal rearrangements observed, although suppression of these pathways is known to inhibit chemokine secretion by activated macrophages. Beta2-integrins blockade with a corresponding antibody inhibited macrophage spreading and polarization but had no effect on pseudopodia protrusions demonstrating the downstream position of integrin-mediated adhesion in PI3K- dependent signaling pathway leading to the motility phenotype. The obtained data demonstrate that the direct effect of mycobacteria on macrophage shape might be mediated through TLR2-dependent PI3K activation.


[Bilateral ovarian carcinoma during pregnancy (author's transl)].
A case of bilateral ovarian carcinoma during pregnancy is reported. The diagnosis was obtained at 18 weeks gestation by laparoscopy and bilateral salpingo-oophorectomy with excision of macroscopically evident tumour was carried out. The gravid uterus was retained because of the high desire for childbearing of the 27 year old primirgravida. At 39 weeks gestation the pregnancy was terminated by Cesarean section and a small retrouterine metastasis were excised. Post-partum a single agent chemotherapy with Cyclophosphami was started. Eight years later mother and child are in good condition. The treatment of this case is compared to reports from the literature.


Do All Children Who Present With a Complex Febrile Seizure Need a Lumbar Puncture?
We assess the prevalences of bacterial meningitis and herpes simplex virus meningoencephalitis (HSV-ME) in children with a complex febrile seizure and determine these prevalences in the subgroup of children with a clinical examination result not suggestive of meningitis or encephalitis. This multicenter retrospective study was conducted in 7 pediatric emergency departments (EDs) in the region of Paris, France. Visits of patients aged 6 months to 5 years for a complex febrile seizure from January 2007 to December 2011 were analyzed. We defined a subgroup of patients whose clinical examination result was not suggestive of meningitis or encephalitis. Bacterial meningitis and HSV-ME were sequentially sought for by analyzing bacteriologic and viral data at the visit, looking for data from a second visit to the hospital after the index visit, and telephoning the child's parents. From a total of 1,183,487 visits in the 7 pediatric EDs, 839 patients presented for a complex febrile seizure, of whom 260 (31.0%) had a lumbar puncture. The outcomes bacterial meningitis and HSV-ME were ascertainable for 715 (85%) and 657 (78.3%) visits, respectively, and we found 5 cases of bacterial meningitis (0.7% [95% confidence interval [CI] 0.2% to 1.6%]) and no HSV-ME (0% [95% CI 0% to 0.6%]). Among the 630 visits of children with a clinical examination result not suggesting meningitis or encephalitis, we found no bacterial meningitis (0% [95% CI 0% to 0.7%]) and no HSV-ME (0% [95% CI 0% to 0.8%]). In children with a complex febrile seizure, bacterial meningitis and HSV-ME are unexpected events when the clinical examination after complex febrile seizure is not suggestive of meningitis or encephalitis.


Non-canonical Interactions between Heat Shock Cognate Protein 70 (Hsc70) and Bcl2-associated Anthanogene (BAG) Co-Chaperones Are Important for Client Release.
Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. The release of nucleotide is known to be mediated by interactions between the conserved BAG domain and the Hsc70 NBD. However, less is known about the regions required for client release, and it is often assumed that this activity also requires the BAG domain. It is important to better understand this step because it determines how long clients remain in the inactive, bound state. Here, we report the surprising observation that truncated versions of either human Bag1 or Bag3, comprised only the BAG domain, promoted rapid release of nucleotide, but not client, in vitro Rather, we found that a non-canonical interaction between Bag1/3 and the Hsc70 SBD is sufficient for accelerating this step. Moreover, client release did not seem to require the BAG domain or Hsc70 NBD. These results suggest that Bag1 and Bag3 control the stability of the Hsc70-client complex using at least two distinct protein-protein contacts, providing a previously under-appreciated layer of molecular regulation in the human Hsc70 system.


TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis.
Transforming growth factor β-activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense-mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients' fibroblasts. Immunofluorescence analyses and ECM-related polymerase chain reaction-array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen-related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss-of-function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2.


Induction of serotonin-S2 receptor blockade during early or late stage of acute respiratory distress syndrome in double-muscled calves: a comparative study.
Ninety-four Belgian White and Blue double-muscled calves were involved in this study which aimed to compare the efficacy of a serotonin-S2 receptor blockade at two different stages of an acute respiratory distress syndrome (ARDS), i.e. at the occurrence of first clinical signs or when another anti-inflammatory compound was clinically shown to be ineffective. Metrenperone, a 5-hydroxytryptamine (5-HT2) blocker, was injected (intramuscularly, 5 times, at 12 hourly intervals, dose rate: 0.1 mg/kg) to (1) 58 calves referred to our laboratory after a treatment (group I) which lasted from 3 to 5 days and which did not improve the clinical status of the animals and (2) 36 calves investigated as soon as first clinical signs occurred (group II). Following the severity of the ARDS, the animals from group I needed to be classified into 2 groups: group IA (moderate ARDS - n = 45) and group IB (severe ARDS - n = 13). For animals in group I, the antibacterial compound previously used was maintained and administered during 4 more days whilst the previous anti-inflammatory drug was suppressed and replaced by metrenperone administered as mentioned above. In group II, each animal was treated with ceftiofur sodium as an antibacterial agent. A clinical score and a breathing score were calculated at each step of the investigation period, i.e. before (T0) and 1 hour (T1) after the first treatment, during the interval 12H-48H (T2) which followed this treatment and 168 H (T3) after this treatment. Four clinical parameters were also taken into account separately: rectal and cutaneous temperatures, respiratory and heart rates.(ABSTRACT TRUNCATED AT 250 WORDS)


Development of water-dispersible Dy(III)-based organic framework as a fluorescent and electrochemical probe for quantitative detection of tannic acid in real alcoholic and fruit beverages.
Tannic acid (TA) is a water-soluble polyphenol and used in beverages, medical fields as clarifying and additive agents. In daily life, TA is unavoidable, and excessive consumption of tannin containing foods can harm health. Thus, rapid and sensitive quantification is highly necessary. Herein, an eco-friendly fluorometric and electrochemical sensing of TA was developed based on a dysprosium(III)-metal-organic framework (Dy(III)-MOF). An aqueous dispersion of Dy(III)-MOF exhibits strong dual emissions at 479 and 572 nm with an excitation at 272 nm, due to the 4f-4f electronic transition and "antenna effect". Chromophore site of the functional ligand, and Dy(III) ion could potentially serve as a sensing probe for TA via quenching (fluorescence). The fluorometric sensor worked well in a wide linear range concentrations from 0.02 to 25 μM with a limit of detection (LOD) of 0.0053 μM. Secondly, the cyclic voltammetric of TA at Dy(III)-MOF modified screen-printed carbon electrode (SPCE) has been investigated. The Dy(III)-MOF/SPCE showed an anodic peak signal at +0.22 V with a five-fold stronger current than the control electrode surface. Under optimized sensing parameters, the Dy(III)-MOF/SPCE delivered wide linear concentrations from 0.01 to 200 μM with a LOD of 0.0023 μM (S/N = 3). Accessibility of real practical samples in alcoholic and juice-based beverages were quantified, resulting in superior recovery rates (98.13-99.53%), F-test, and t-test confirmed high reliability (<95% confidence level (n = 3)). Finally, practicability result of the electrochemical method was validated by fluorometric with a relative standard deviation (RSD) of 0.18-0.46 ± 0.17% (n = 3). The designed probe has proven to be a key candidate for the accurate analysis of TA in beverage samples to ensure food quality.


Anastomotic leaks in gastrointestinal surgery and their prevention.
Anastomotic leak in the gastrointestinal tract is one of the most important complications of resection. They are the main cause of reoperation, their occurrence worsens the prognosis of the patient, increasing the proportion of direct mortality, as well as being a significant risk factor for recurrence of cancer. The risk of leaks within the gastrointestinal tract is greatly varied, depending on the location and extent of the resection, but also on patient, disease or a surgical procedure, including surgeon. To determine the potential risk of leakage can be significant for introduction some prophylactic actions. Some of them have the character of general recommendations, as proper nutrition of the patient in the perioperative period, while another part is directly connected to the surgical procedure. The second group includes protective stoma, the use of tissue glues, insertion transrectal drain for rectal anastomosis decompression, the use of stents or the use of collagen matrix coated with fibrinogen and thrombin. Important to reduce the proportion of leaks can be more precise and targeted prophylactic recommendations, based on the individualized determination of risk factors leaks. Further research for this purpose are necessary for this purpose, the big hope can be associated with data obtained through mobile applications.


Development of soleus muscles in SHR: relationship of muscle deficits to rise in blood pressure.
Skeletal muscles from 24- to 28-wk-old spontaneously hypertensive rats (SHR) exhibit decreased contractile capacity and resistance to fatigue. The present study was designed to determine the age at which these deficits first appear and their relationship to the development and progression of the rise in blood pressure. SHR soleus was significantly weaker than age-matched Wistar-Kyoto (WKY) soleus at all ages studied, but resistance to fatigue varied with age. Soleus muscles in 6- to 8-wk-old SHR were, on average, more fatigue resistant than age-matched WKY muscles. Fatigue resistance in 16- to 18-wk-old animals, however, was similar in the two strains. There were no significant differences in soleus growth or fiber type distributions in the strains between 6 and 18 wk of age. WKY soleus in 24- to 28-wk-old animals were hyperpolarized after the fatigue test. SHR fibers, in contrast, did not hyperpolarize after exercise, possibly reflecting an age-related reduction in sarcolemmal Na+ pump number or function. Soleus in younger SHR also provided an indication of a developing membrane dysfunction, since extracellularly recorded M waves showed greater changes in SHR than in age-matched WKY muscles during exercise. The rise of blood pressure in SHR is genetically based, but it is not clear that the genetic defects responsible for hypertension also produce the observed deficits in skeletal muscle function.


Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma.
Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN. All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0-3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR-gamma immunostaining was assessed on a 0-3 scale in glomeruli, vessels and tubules. Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9+/-1.7 years. Average time after transplant at time of biopsy was 60.5+/-4.9 months (range 7-229). Glomerulosclerosis extent in CAN was on average 26.5+/-2.4% compared with 3.6+/-1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0+/-1.2%), whereas transplant controls showed very minimal fibrosis (2.0+/-2.0%). Interstitial fibrosis in CAN kidneys was on average 47.9+/-2.4%. Glomerular PAI-1 and PPAR-gamma staining scores were markedly increased in CAN (1.8+/-0.1, 2.3+/-0.1, respectively) compared with normal control kidneys from native kidney cancer nephrectomies (PAI-1 0.2+/-0.2 and PPAR-gamma 0.4+/-0.2, P<0.001) and transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN (PAI-1 0 and PPAR-gamma 0, P<0.001). Tubular PAI-1 and PPAR-gamma staining scores were 1.9+/-0.1 and 1.9+/-0.1, respectively, and also increased over both native and transplant kidney controls (0.8+/-0.2 for both categories for PAI-1, 1.2+/-0.2 for both categories for PPAR-gamma, respectively). Vascular sclerosis in CAN was 1.0+/-0.1 with increased PAI-1 and PPAR-gamma scores (1.7+/-0.1, 1.2+/-0.1, respectively) compared with controls. Infiltrating macrophages were increased in CAN, and were positive for both PAI-1 and PPAR-gamma. Biopsies with less sclerosis overall showed a trend for less PAI-1 and PPAR-gamma staining. PAI-1 and PPAR-gamma are both increased in CAN compared with non-scarred native or transplant control kidneys. We speculate that altered matrix metabolism and macrophage function might be involved in the development of CAN.


Laparoscopic ablation of hepatocellular carcinoma in cirrhotic patients unsuitable for liver resection or percutaneous treatment: a cohort study.
The aim of this study was to demonstrate the safety and efficacy of laparoscopic ablation for cirrhotic HCC patients. Between January 2004 and December 2009, laparoscopic ablation was applied prospectively in 169 consecutive HCC patients (median age 62 years, 43% hepatitis C positive) considered ineligible for liver resection and/or percutaneous ablation. There was clinically relevant portal hypertension in 72% of cases. A significant proportion of subjects (50%) had multinodular tumors or nodules larger than 25 mm. The main ablation techniques used were radiofrequency in 103 patients (61%), microwave ablation in 8 (5%), and ethanol injection in 58 (34%). The primary endpoint was 3-year survival. There was no perioperative mortality. The overall morbidity rate was 25%. The median postoperative hospital stay was 3 days (range 1-19 days). Patients survived a median 33 months with a 3-year survival rate of 47%. Cox's multivariate analysis identified patient age, presence of diabetes, albumin ≤37 g/l, and alpha-fetoprotein >400 µg/l as significant preoperative predictors of survival, while the chance to undergo liver transplantation and postoperative ascites were the only independent postoperative predictor of survival. Laparoscopic ablation is a safe and effective therapeutic option for selected HCC patients ineligible for liver resection and/or percutaneous ablation.


Nanodisplacement measurement using spectral shifts in a white-light interferometer.
We report a novel experimental method to measure nanometer displacements using wavelength shifts of spectral peaks around spectral switch or singular phase points in the interference spectra due to temporal correlation in a Michelson interferometer illuminated by a broadband white-light source. Dramatic changes in the spectral characteristics are recorded as a function of path difference between the interfering beams around the spectral switch position. These are then compared with measurements far from it in order to demonstrate the higher sensitivities involved in the proposed method.


Inhibition of protein kinase C induces differentiation in Neuro-2a cells.
1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a potent inhibitor of protein kinase C, induced neuritogenesis in Neuro-2a cells, whereas N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), which inhibits more efficiently cAMP- and cGMP-dependent protein kinases, did not. The effect, noticeable after 3 hr, was maximum (13-fold increase at 500 microM H7) between 1 and 3 days and was maintained over 2 months. In controls, 90% of the cells were undifferentiated, whereas after 3 hr with 500 microM H7 only 25% of the cells remained undifferentiated. DNA synthesis decreased as the number of differentiated cells increased. Differentiation is also functional since acetylcholinesterase activity increased approximately 7-fold after 48 hr with 500 microM H7. Phorbol 12-myristate 13-acetate, a specific activator of protein kinase C, prevented or reversed the induction of neuritogenesis and the inhibition of DNA synthesis by H7. There is a good correlation between the level of protein kinase C and the percentage of differentiated cells. The results indicate that protein kinase C may play a key role in the control of differentiation of neural cells. Some possible clinical implications are briefly discussed.


Lipoprotein(a) concentration is associated with plasma arachidonic acid in subjects with familial hypercholesterolaemia.
Elevated lipoprotein(a) (Lp(a)) is associated with CVD and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FA) in the regulation of Lp(a); however, no studies have investigated the association between plasma Lp(a) concentration and n-6 FA. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary n-6 FA intake and plasma levels of arachidonic acid (AA) in subjects with familial hypercholesterolaemia (FH). We included FH subjects with (n 68) and without (n 77) elevated Lp(a) defined as ≥75 nmol/l and healthy subjects (n 14). Total FA profile was analysed by GC-flame ionisation detector analysis, and the daily intake of macronutrients (including the sum of n-6 FA: 18 : 2n-6, 20 : 2n-6, 20 : 3n-6 and 20 : 4n-6) were computed from completed FFQ. FH subjects with elevated Lp(a) had higher plasma levels of AA compared with FH subjects without elevated Lp(a) (P = 0·03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared with controls (P < 0·001). The multivariable analyses showed associations between dietary n-6 FA intake and plasma levels of AA (P = 0·02) and between plasma levels of Lp(a) and AA (P = 0·006). Our data suggest a novel link between plasma Lp(a) concentration, dietary n-6 FA and plasma AA concentration, which may explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a).


A bi-directional communication paradigm between parallel NEURON and an external non-neuron process.
In order to accurately model the pattern of activation due to electrical stimulation of the hippocampus, a multi-scale computational approach is necessary. At the system level, the Admittance Method (ADM) is used to calculate the extracellular voltages created by a stimulating electrode. At the network and cellular levels, a large-scale multi-compartmental neuron network is used to calculate cellular activation. This paper presents a bi-directional communication paradigm between the NEURON model and an external surrogate for the ADM solver, where at each time step, neurons share their membrane currents with the external process, and the external process shares calculated extracellular voltages with the neuronal network. This work constitutes an important first step towards a full multi-scale NEURON-ADM model with bi-directional communication.


Effectiveness of orthodontic miniscrew implants in anchorage reinforcement during en-masse retraction: A systematic review and meta-analysis.
The aim of this systematic review was to compare the effectiveness of orthodontic miniscrew implants-temporary intraoral skeletal anchorage devices (TISADs)-in anchorage reinforcement during en-masse retraction in relation to conventional methods of anchorage. A search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was performed. The keywords were orthodontic, mini-implants, miniscrews, miniplates, and temporary anchorage device. Relevant articles were assessed for quality according to Cochrane guidelines and the data extracted for statistical analysis. A meta-analysis of raw mean differences concerning anchorage loss, tipping of molars, retraction of incisors, tipping of incisors, and treatment duration was carried out. Initially, we retrieved 10,038 articles. The selection process finally resulted in 14 articles including 616 patients (451 female, 165 male) for detailed analysis. Quality of the included studies was assessed as moderate. Meta-analysis showed that use of TISADs facilitates better anchorage reinforcement compared with conventional methods. On average, TISADs enabled 1.86 mm more anchorage preservation than did conventional methods (P <0.001). The results of the meta-analysis showed that TISADs are more effective than conventional methods of anchorage reinforcement. The average difference of 2 mm seems not only statistically but also clinically significant. However, the results should be interpreted with caution because of the moderate quality of the included studies. More high-quality studies on this issue are necessary to enable drawing more reliable conclusions.