Assessment of plasma biomarkers for their association with Multiple Sclerosis progression.
In a cross-sectional study involving 160 Multiple Sclerosis (MS) patients and 70 healthy controls we set out to determine the association of five blood biomarkers with MS risk and progression scores. High levels of Semaphorin3A (SEMA3A) in females, and low levels of prolactin and estradiol in males associated with MS risk. High MS disability correlated with higher SEMA3A levels in females. Our findings suggest the clinical applicability of SEMA3A, and prolactin as biomarkers for MS progression. However, these biomarkers had sex-specific associations with MS, and any therapeutic approaches utilizing them should take that into consideration.


First evaluation of wastewater discharge influence on marine water contamination in the vicinity of Arctowski Station (Maritime Antarctica).
In Antarctica, waste is generated mainly during scientific research programmes and related logistics. In this study, the impact of wastewater on the western shore of Admiralty Bay was investigated during austral summer in 2017 and 2019. A range of physicochemical parameters and the presence of selected trace metals, formaldehyde and different groups of surfactants were determined in wastewater coming from Arctowski Station and in nearby coastal waters. The presence of selected trace metals (e.g., Cr: 2.7-4.4 μg/L; Zn: 15.2-37.3 μg/L; and Ni: 0.9-23.3 μg/L) and the sums of cationic (0.3-1.5 mg/L), anionic (3.1-1.7 mg/L), and non-ionic (0.6-2.4 mg/L) surfactants in wastewater indicated the potential influence of anthropogenic factors on sea water. The determined surfactants are found in many hygiene products that end up in the waste water tank after human use and, if untreated, can be released into surface waters with discharge. In addition, the levels of some trace metals indicate that they cannot come only from natural sources, but are the result of human activity. The reported data show disturbances in the marine environment caused by non-treated wastewater discharge, e.g. by comparing the obtained results from the values of the no observed effect concentrations (NOECs) on selected Antarctic bioindicators, and provide information for the implementation of proper wastewater treatment at any Antarctic station in the future.


Communicator styles of hospital patients during nurse-patient counseling.
This article describes nurse-patient communication during counseling sessions. It focuses on the patient as a participant in a discussion and aims at a description of patients' communicator styles, which were observed on videotape based on 38 counseling sessions transcribed word by the word. Interviews of the participating nurses and patients were used for partial support of the interpretations. The analytic method chosen was typology, and it has been used for achieving a multifaceted qualitative description of patient communication. The research material yielded seven types of communicator styles: Quietly Assenting, Emotionally Expressive, Storyteller, Stoic Observer, Inquisitive of Detail, Dominant, and Critical Self-observer. The communicator styles were indicative of the multitude of ways in which patients participate in counseling discussions and they make it possible to describe the varying expressions of patient communication. This article presents new background information on patient communication and the outcome may prove to be useful for developing health counseling.


Hyperthermic intraperitoneal chemotherapy (HIPEC) for gynecological cancer.
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a method of administering anticancer agents directly while heating the abdominal cavity. The aim of this review is to know the current position of HIPEC in ovarian cancer and uterine sarcoma and its future prospects. This article reviews the current literature and evidence for the clinical trial of HIPEC in ovarian cancer and uterine sarcoma with consideration of the cases treated in our department. In January 2018, van Driel et al. reported the results of their phase 3, randomized, controlled trial and the usefulness of neoadjuvant chemotherapy followed by interval debulking surgery. With respect to greater than grade 3 complications, such as suture failure, intestinal perforation, postoperative bleeding, wound issues and death, there were no significant differences between the HIPEC group and the no-HIPEC group. In a meta-analysis including two randomized, controlled studies and 11 observational studies in 2019, the addition of HIPEC to cytoreductive surgery significantly improved overall survival of ovarian cancer patients. Moreover, growing evidence of the efficacy of cytoreductive surgery with HIPEC has also been reported in uterine sarcoma with peritoneal sarcomatosis in a multi-institutional study. HIPEC could be one of the new therapeutic strategies for such disseminated peritoneal lesions. Since the usage regimen and temperature setting of HIPEC are not standardized, and its effectiveness and adverse events are greatly affected by the time of administration, it is necessary to consider clinical trials for the optimization and establishment of HIPEC in Japan in the future.


Odontogenic Carcinosarcoma: An Updated Literature Review and Report of a Case.
Odontogenic carcinosarcoma (OCS) is an exceptionally rare malignant mixed odontogenic neoplasm, which mostly arises from recurrent benign odontogenic tumour that undergoes malignant transformation. A literature review was conducted using the keyword of "Odontogenic carcinosarcoma" and all relevant articles were screened. The data collected include demographic profile (age, gender), clinical information (symptoms, location, size), radiologic features, histopathological examination, management, recurrence, metastases, and survival status. A total of 17 OCS cases including a new case from our hospital. The incidence of OCS was highest in the third decades of life with predilection for male and posterior region of mandible. Clinically, patients may present with swelling and neurological symptoms. Radiographic examination often showed radiolucency with ill-defined border. This tumour demonstrates an aggressive behaviour with reported cases of distant metastases to the lung, lymph nodes, rib, and pelvis. Here, we report an interesting case of OCS in a 38-year-old man with a previous diagnosis of ameloblastoma. The patient was diagnosed with ameloblastoma but refused surgical intervention and returned after 10 years with rapidly enlarging mass on the right side of mandible. Microscopically, the lesion appears as biphasic odontogenic tumour with malignant cytological features seen in both epithelium and mesenchymal components. The spindle to round mesenchymal tumour cells were only positive for vimentin. Ki67 proliferation index was high in both epithelium and mesenchymal components. This case showed the tendency of untreated ameloblastoma to undergo malignant changes in the long term.


Increased resorption of embryos in O,O,S-trimethyl phosphorothioate-treated rats.
Pregnant rats (N = 7) were dosed p.o. with O,O,S-trimethyl phosphorothioate (OOS-TMP) (LD50 = 85) at 20 mg/kg on days G8 and G10. Seven animals were treated with corn oil and pair-fed. Five control animals were treated with corn oil. The abdomen was palpated on day G15 and in 4 animals out of 7 treated with OOS-TMP, complete resorption was observed. All pair-fed and control animals maintained pregnancy until day G21. Total number of resorption/number of implants was 60/95 (63.2%) in OOS-TMP animals, 21/82 (25.6%) in pair-fed animals and 4/65 (6.5%) in control animals. Incidence of complete resorption and % resorption were significantly higher (P less than 0.03 and P less than 0.01) in comparison with those in pair-fed animals. Fetuses from OOS-TMP mothers showed slight growth retardation. By skeletal examination, a missing vertebra and delayed ossifications were found in animals treated with OOS-TMP (20 mg/kg).


Intrahepatic metastatic nodules of hepatocellular carcinoma detected at lipiodol-CT: imaging-pathologic correlation.
The purpose of this study was to determine whether tiny (< 2 cm) areas of iodized-oil retention diagnosed as intrahepatic metastatic nodules of hepatocellular carcinoma (HCC) at computed tomography (CT) following intraarterial injection of Lipiodol (Lipiodol-CT) correlate with truly cancerous foci on the corresponding sectioned pathologic specimens. Thirty-two consecutive patients with biopsy-proven HCC (26 men and six women, aged 41-72 years) underwent prospective evaluation with Lipiodol-CT before undergoing surgery (hepatic resection, 30 patients; liver transplantation, two patients). Imaging findings were correlated with intraoperative and pathologic findings. Twenty-one areas of retained Lipiodol (0.5-1.6 cm in diameter, mean +/- SD: 0.9 +/- 0.3 cm) had features consistent with intrahepatic metastatic nodules of HCC on Lipiodol-CT scans. Nineteen of the 21 areas correlated with tumor deposits at pathologic examination of the surgical specimens, whereas two of 21 were due to abnormal retention of iodized oil within noncancerous liver parenchyma. The positive predictive value of findings at Lipiodol-CT for the diagnosis of intrahepatic metastatic nodule of HCC was 90.5%. Findings at Lipiodol-CT enable a reliable diagnosis of intrahepatic metastatic nodules of HCC.


Cleave a Septum, Leave a Cell: Bdellovibrio bacteriovorus Secretes a Specialized Lytic Transglycosylase to Clear Prey Cell Septum Obstruction.
Predatory microbes like Bdellovibrio feed on other bacteria by invading their periplasm, replicating within the bacterial shell that is now a feeding trough, and ultimately lysing the prey and disseminating. A new study by E. J. Banks, C. Lambert, S. Mason, J. Tyson, et al. (J Bacteriol 205:e00475-22, 2023, https://doi.org/10.1128/jb.00475-22) highlights the great lengths to which Bdellovibrio must go to affect host cell remodeling: A secreted cell wall lytic enzyme with specificity for the host septal cell wall maximizes the size of the attacker's meal and the size of the restaurant in which it can spread out. This study provides novel insights into bacterial predator-prey dynamics and showcases elegant co-option of an endogenous cell wall turnover enzyme refurbished as a warhead to enhance prey consumption.


Circulating interferon-gamma in women sensitized to sperm: new mechanisms of infertility.
The relationship between antisperm antibodies and IFN-gamma production was examined. Interferon-gamma was identified in 15 of 40 sera (37.5%) from women with antisperm antibodies, but in only 2 of 28 sera (7.4%) from women who lacked these antibodies. In four of six women with circulating antisperm antibodies, but in zero of six controls, in vitro incubation of their peripheral blood mononuclear cells led to the spontaneous release of both antisperm antibodies and IFN-gamma. In women sensitized to sperm, coitus-induced IFN-gamma production may impair fertility and early embryo development by mechanisms other than a direct effect of antisperm antibodies on the male gamete.


Orthobiologics: a review.
The use of biologic materials in orthopaedics (orthobiologics) has gained significant attention over the past years. To enhance the body of the related literature, this review article is aimed at summarizing these novel biologic therapies in orthopaedics and at discussing their multiple clinical implementations and outcomes. This review of the literature presents the methods, clinical applications, impact, cost-effectiveness, and outcomes, as well as the current indications and future perspectives of orthobiologics, namely, platelet-rich plasma, mesenchymal stem cells, bone marrow aspirate concentrate, growth factors, and tissue engineering. Currently available studies have used variable methods of research including biologic materials as well as patient populations and outcome measurements, therefore making comparison of studies difficult. Key features for the study and use of orthobiologics include minimal invasiveness, great healing potential, and reasonable cost as a nonoperative treatment option. Their clinical applications have been described for common orthopaedic pathologies such as osteoarthritis, articular cartilage defects, bone defects and fracture nonunions, ligament injuries, and tendinopathies. Orthobiologics-based therapies have shown noticeable clinical results at the short- and mid-term. It is crucial that these therapies remain effective and stable in the long term. The optimal design for a successful scaffold remains to be further determined.


MiR-182-5p enhances in vitro neutrophil infiltration in Kawasaki disease.
Kawasaki disease (KD) patients could develop coronary artery lesion (CAL) which threatens children's life. A previous study identified KD biomarker miRNAs that could discriminate KD patients from febrile non-KD patients. We wonder whether these KD prediction biomarkers could be further applied to predict CAL formation in KD patients. To examine this hypothesis, we conducted a meta-analysis, miRNA mimic transfection, in vitro cell model and microarray assays. We first showed that miR-182-5p and miR-183-5p kept higher levels in the KD patients with CAL than those without CAL (p < .05). Further machine learning alignment confirmed that CAL formation could be predicted, with an auROC value of 0.86. We further treated neutrophil cells with miR-182-5p mimic, followed by in vitro transendotherial migration assay. As a result, miR-182-5p overexpression significantly (p < .05) enhanced neutrophil cells to infiltrate the endothelial layer composed of human coronary artery endothelium cells. Further microarray assay and pathway enrichment analysis showed that the genes activated with miR-182-5p overexpression were significantly enriched in the leukocyte transendothelial migration pathway (kegg_pathway_194, p < .05). Therefore, our study suggested that miR-182-5p enhanced in vitro leukocyte infiltration by activating the leukocyte transendothelial migration pathway in CAL formation in KD.


Synthesis and antimicrobial evaluation of substituted 5,6-dihydro-5-nitrouracils.
Reaction of 5-nitrouracil derivatives with sodium borohydride in methanol-water, followed by neutralization of the product with acid, has produced 5,6-dihydro-5-nitrouracil (5) 5,6-dihydro-6-dihydro-6-methyl-5-nitrouracil (7), 5,6-dihydro-5-nitro-1-(4-nitrophenyl)uracil (10), and 5,6-dihydro-5-nitro-1(beta-D-ribofuranuronic acid ethyl ester)uracil (12). In assays for antimicrobial activity using strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Trichophyton mentagrophytes, significant inhibition of growth was not found.


Improved light output from thick β-Ga2O3 scintillation crystals via graded-refractive-index photonic crystals.
β-Ga2O3 is a promising candidate as a fast scintillation crystal for radiation detection in fast X-ray imaging and high-energy physics experiments. However, total internal reflection severely limits its light output. Conventional photonic crystals can improve the light output, but such improvement decreases dramatically with increased scintillator thickness due to the strong backward reflection by the photonic crystals. Here, graded-refractive-index photonic crystals composed of nanocone arrays are designed and fabricated on the surfaces of β-Ga2O3 crystals with various thicknesses. Compared to the conventional photonic crystals, there is still an obvious light output improvement by using the graded-refractive-index photonic crystals when the thickness of the crystals is increased by three times. The effect of thickness on the improved light output is investigated with numerical simulations and experiments. Overall, the graded-refractive-index photonic crystals are beneficial to the improvement of light output from thick scintillators.


Therapeutic effects of losartan on prostatic hyperplasia in spontaneously hypertensive rats.
We investigated the therapeutic effects of losartan, an angiotensin II type 1 receptor blocker, on prostatic hyperplasia in spontaneously hypertensive rats (SHRs). Male SHRs (age, 36 weeks) were perorally treated with losartan (3 or 10 mg·kg-1) or vehicle once daily for 18 weeks. Age-matched Wistar Kyoto rats (WKYs) were used as vehicle-treated controls (n = 8). The effects of losartan were evaluated by analyzing prostate weight, blood pressure, and prostatic blood flow. The tissue malondialdehyde (MDA), interleukin-6 (IL-6), and basic fibroblast growth factor (bFGF) levels were measured. Histological analysis for the ventral prostate involved hematoxylin and eosin staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Compared to the vehicle-treated WKYs, the vehicle-treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow. Treatment with losartan caused significant recovery of blood flow and decreased PBR and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs. Chronic losartan treatment could ameliorate prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might have therapeutic effects on not only hypertension but also prostatic hyperplasia in humans.


Vitamin E isomer δ-tocopherol enhances the efficiency of neural stem cell differentiation via L-type calcium channel.
The effects of the vitamin E isomer δ-tocopherol on neural stem cell (NSC) differentiation have not been investigated until now. Here we investigated the effects of δ-tocopherol on NSC neural differentiation, maturation and its possible mechanisms. Neonatal rat NSCs were grown in suspended neurosphere cultures, and were identified by their expression of nestin protein and their capacity for self-renewal. Treatment with a low concentration of δ-tocopherol induced a significant increase in the percentage of β-III-tubulin-positive cells. δ-Tocopherol also stimulated morphological maturation of neurons in culture. We further observed that δ-tocopherol stimulation increased the expression of voltage-dependent Ca(2+) channels. Moreover, a L-type specific Ca(2+) channel blocker verapamil reduced the percentage of differentiated neurons after δ-tocopherol treatment, and blocked the effects of δ-tocopherol on NSC differentiation into neurons. Together, our study demonstrates that δ-tocopherol may act through elevation of L-type calcium channel activity to increase neuronal differentiation.


Evaluation of monkey skin as a model for in vitro percutaneous penetration and metabolism of [3H]T-2 toxin in human skin.
Discs of abdominal skin (obtained from humans and hybrid monkeys at autopsy) were mounted on diffusion cells. The epidermal surfaces were dosed with [3H]T-2 dissolved in dimethyl sulfoxide (DMSO). The rate of [3H]T-2 penetration (expressed as ng/cm2/hr) through human skin was 0.38 +/- 0.10 and 3.85 +/- 0.96 (means +/- 95% confidence limit) when dosed with 74 and 582 ng/cm2, respectively. [3H]T-2 penetrated through monkey skin at the rate of 0.37 +/- 0.14, 0.80 +/- 0.43, 4.13 +/- 1.71, and 6.55 +/- 3.45 when dosed with 70, 155, 555 and 1063 ng/cm2, respectively. Analysis of the receptor fluid bathing human skin revealed 15% of the radioactivity was associated with T-2, 71% with HT-2 toxin (HT-2), and 6.3% with an unknown metabolite more polar than HT-2. The radioactivity in the receptor fluid bathing monkey skin was associated with T-2 (87%) and HT-2 (1.0%). The results are consistent with the hypothesis that metabolism of T-2 occurred during penetration through the excised skin and did not occur in the receptor fluid due to enzymes leaching out of the skin. These findings indicate that excised monkey skin is a good model for T-2 penetration through human skin when DMSO is the vehicle, but that dermal metabolism of T-2 is different in these two species.


Contribution of light chain rearrangement in peripheral B cells to the generation of high-affinity antibodies.
Recently, peripheral B cells have been shown to undergo secondary V(D)J rearrangement of immunoglobulin genes, but the physiological role of this event has not been fully elucidated. To investigate whether rearrangement of L chain genes in the periphery is involved in the generation of high-affinity antibodies (Ab), we used the 17.2.25 rearranged VHDJH gene (VHT)-knockin mouse whose B cell diversity is limited due to the expression of the site-directed transgene. Immunization of the mouse with p-nitrophenylacetyl (pNP)-conjugated chicken gamma-globulin preferentially led to the production of anti-pNP IgG Ab comprised of non-VHT-encoded H chains and lambda chains. lambda(+) IgG constituted a majority of high-affinity Ab to this hapten. RAG-2 mRNA and the recombination signal sequence break of the lambda1 gene increased in the draining lymph node of immunized mice, but not of nonimmunized animals. There was a close correlation between the levels of these parameters implicating lambda gene rearrangement and the production of lambda(+ )high-affinity anti-pNP IgG. These observations were reproduced in RAG-1-deficient mice that were reconstituted with the spleen cells ofthe knockin mouse. Thus, our findings suggest that L chain rearrangement that occurs in the periphery can contribute to affinity maturation of Ab.


Efficient Aerobic Oxidation of Organic Molecules by Multistep Electron Transfer.
This Minireview presents recent important homogenous aerobic oxidative reactions which are assisted by electron transfer mediators (ETMs). Compared with direct oxidation by molecular oxygen (O2 ), the use of a coupled catalyst system with ETMs leads to a lower overall energy barrier via stepwise electron transfer. This cooperative catalytic process significantly facilitates the transport of electrons from the reduced form of the substrate-selective redox catalyst (SSRCred ) to O2 , thereby increasing the efficiency of the aerobic oxidation. In this Minireview, we have summarized the advances accomplished in recent years in transition-metal-catalyzed as well as metal-free aerobic oxidations of organic molecules in the presence of ETMs. In addition, the recent progress of photochemical and electrochemical oxidative functionalization using ETMs and O2 as the terminal oxidant is also highlighted. Furthermore, the mechanisms of these transformations are showcased.


Replication of pBR322 DNA in stringent and relaxed strains of Escherichia coli.
Synthesis of both chromosomal and plasmid (pBR322) DNA was measured in E. coli strains differing in their relA allele (relA+:CP78; relA:CP79). It was found that upon limitation of a required amino acid or after valine treatment to trigger a stringent response synthesis of pBR322 DNA was stimulated only in the relaxed strain and was inhibited in its stringent counterpart. The results suggest that replication of plasmid DNA is negatively controlled by the relA+ allele.


Frailty and hearing loss: From association to causation.
Observational studies suggest that frailty is associated with hearing loss (HL) but with inconsistent results. This study aims to examine such association and to assess its causality. The cross-sectional data from the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression models were used to assess the association between HL and frailty index (FI). Genetic variants associated with the FI and HL were obtained from a large genome-wide association study (GWAS) meta-analysis and UK Biobank GWAS. The inverse variance weighting (IVW) method was used to estimate causal effects. Sensitivity analyses were performed to further validate the robustness of results. In this cross-sectional analysis, results support the possibility that frailty may be associated with a higher risk of developing HL, with self-reported [odds ratio (OR) = 2.813; 95% CI, 2.386, 3.317; p < 0.001], speech frequency HL (OR = 1.975; 95% CI, 1.679-2.323; p < 0.001), and high frequency HL (OR = 1.748; 95% CI, 1.459-2.094; p < 0.001). In the adjusted model, frail participants remained at high risk of HL. Mendelian randomization (MR) studies showed a bidirectional causal association between genetically predicted FI and risk of HL (FI for exposure: OR = 1.051; 95% CI, 1.020-1.083; p = 0.001; HL for exposure: OR = 1.527; 95% CI, 1.227-1.901; p < 0.001). Our observational study found that inter-individual differences in frailty were associated with the risk of developing HL. Genetic evidence suggests a potential bidirectional causal association between FI and HL. Furthermore, the potential mechanisms of this association require investigation.


Psychological Stress and Chronic Urticaria: A Neuro-immuno-cutaneous Crosstalk. A Systematic Review of the Existing Evidence.
It has been observed that certain patients with chronic spontaneous or idiopathic urticaria (CSU/CIU) have a personal history of a significant stressor before urticaria onset, while the prevalence of any psychopathology among these patients is significantly higher than in healthy individuals. Research has confirmed that skin is both an immediate stress perceiver and a target of stress responses. These complex interactions between stress, skin, and the nervous system may contribute to the onset of chronic urticaria. This systematic review investigated the association between CSU/CIU and neuroimmune inflammation with or without evidence of co-existing psychological stress from in vivo and ex vivo studies in human beings. PubMed and Scopus were searched to September 2019 for reports in human beings describing neuroimmune inflammation, stress, and CSU/CIU. A comprehensive search strategy was used that included all the relevant synonyms for the central concept. A total of 674 potentially relevant articles were identified. Only 13 satisfied the predefined inclusion criteria and were included in the systematic review. Five of these 13 studies evaluated the correlation between CSU/CIU, stress, and neuro-immune-cutaneous factors, while the remaining 8 focused on the association between CSU/CIU and these factors without examining any evidence of stress. The complex neuro-immune-cutaneous model that involves numerous neuropeptides and neurokinins, inflammatory mediators and cells, hypothalamic-pituitary-adrenal axis hormones, and the skin may better explain the underlying pathophysiological mechanisms involved in the onset of urticaria. In addition, the elevated psychological stress level that has been closely related to CSU/CIU could be attributed to the imbalance or irregularity of this neuro-immune-cutaneous circuit. It is still unclear and must be further investigated whether any psychological stress results in or triggers CSU/CIU onset on top of a preexisting neuroimmune dysregulation. Nevertheless, new psycho-phenotypic or neuro-endotypic CSU/CIU subsets should be considered as the era of personalized treatment strategies emerges. A better understanding of CSU/CIU pathophysiology and consideration of the patient as a whole is vital for identifying targets for new potential treatment options.


Coriolopsis trogii hydrophobin genes favor a clustering distribution and are widely involved in mycelial growth and primordia formation.
Hydrophobins are small, secreted proteins with important physiological functions in mycelial growth and fungal development. Here, 1 nucleus-specific and 35 allelic hydrophobin genes were identified in the genome of a white rot fungus, Coriolopsis trogii. Among these, 22 were eight-cysteine class I hydrophobin genes and the other 14 were uncommon six-cysteine hydrophobin genes. The six-cysteine hydrophobins were speculated to have originated from a common ancestor. The hydrophobin genes favored a clustering distribution and two recent duplication pairs were identified. The genes had conserved gene structures with three exons and two introns. Cthyd18, Cthyd19, and Cthyd32 were constitutively highly expressed in all developmental stages. Cthyd20, Cthyd21, Cthyd22, Cthyd28, Cthyd30, Cthyd31, and Cthyd33 were highly expressed in mycelia, and Cthyd12 and Cthyd35 in the reproductive stages. Sixteen hydrophobin genes were regulated differently in the transition from mycelia to primordia; Cthyd35 showed maximal upregulation of 1922-fold, and Cthyd23 showed maximal downregulation of 552-fold. Most (32) hydrophobin genes showed significant differential expression between mycelia cultured in different media (potato dextrose agar or broth). Weighted gene co-expression network analysis and promoter analysis revealed that C2H2 zinc finger proteins may regulate hydrophobin genes. These results may support further research into the function and evolution of hydrophobins.


Closed genome sequences of Staphylococcus lloydii sp. nov. and Staphylococcus durrellii sp. nov. isolated from captive fruit bats (Pteropus livingstonii).
The increasing availability of whole genome sequencing of bacteria has accelerated the discovery of novel species which may not have been easy to discriminate using standard phenotypic or single gene methods. Phylogenomic analysis of genome sequences from a collection of coagulase-negative staphylococcal species isolated from captive fruit bats revealed two clusters which were close to Staphylococcus kloosii. To assess the relatedness of the strains we used digital DNA-DNA hybridization (dDDH) and two methods for average nucleotide identity (ANI) computation which predicted two novel species having dDDH less than 70 % and ANI less than 95%. We propose these species as Staphylococcus lloydii sp. nov. (type strain 23_2_7_LYT=NCTC 14453T=DSM 111639T) and Staphylococcus durrellii sp. nov (type strain 27_4_6_LYT=NCTC 14454T=DSM 111640T).


tRNAIni CAT inhibits proliferation and promotes apoptosis of laryngeal squamous cell carcinoma cells.
Laryngeal squamous cell carcinoma (LSCC) brings a heavy blow to the patient's voice. Transfer RNA (tRNA) is a common RNA, the roles of tRNAs in LSCC are largely unknown. The tRNA expression profile in LSCC tissues and adjacent normal tissues was measured by a tRNA qRT-PCR array. The expression level of tRNAIni CAT in LSCC tissues and plasmas was detected by qRT-PCR. The receiver operating characteristic (ROC) curve was established. tRNAIni CAT was upregulated by a lentivirus vector in the LSCC cell line. Moreover, tRNAIni CAT was upregulated in LSCC xenograft nude mouse model and the xenografts were used for pathological analysis and transmission electron microscope (TEM) observation. The top 10 upregulated tRNAs were tRNALys CTT -1, tRNALeu TAA , tRNAPhe GAA , tRNALeu CAG , tRNATyr ATA , tRNAMet CAT , tRNATyr GTA -1, tRNAThr CGT , tRNATyr GTA -2, tRNAAla AGC ; and the top 10 downregulated tRNAs were tRNAIni CAT , mt-tRNAGlu TTC , tRNAVal CAC -3, mt-tRNATrp TCA , mt-tRNATyr GTA , mt-tRNALys TTT , mt-tRNAThr TGT , mt-tRNAAsp GTC , mt-tRNAAsn GTT , mt-tRNAPro TGG . tRNAIni CAT was downregulated in LSCC tissues and plasma. The area under the ROC curve (AUC) in LSCC tissues and the plasma of patients with LSCC was 0.717 and 0.808, respectively. tRNAIni CAT inhibited LSCC cell proliferation and promoted apoptosis. The in vivo results showed that tRNAIni CAT inhibited the growth of the xenografts and promoted apoptosis. This is the first study to provide tRNA expression profiles for LSCC tissues. tRNAIni CAT may be used as a new biomarker for the early diagnosis of LSCC. tRNAIni CAT inhibits cell proliferation and promotes apoptosis in vitro and in vivo.


Postpartum spontaneous coronary artery dissection (SCAD) managed conservatively.
Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome and has been described in young women during the peripartum period. Management of these patients has been controversial. A 35 year old Caucasian female, 11 days postcesarean section delivery presented with acute myocardial infarction. She underwent angiography within a few hours of presentation, which showed dissection of LAD. Repeat angiography six days later showed improvement of dissection. Patient showed clinical improvement on conservative treatment and no recurrence of symptoms over the past two years follow-up. There is no consensus on the treatment and our case is one of the cases managed successfully with conservative treatment.


Biological Aspects and Movements of Neotropical Fruit-Feeding Butterflies.
The patterns of insect movement are the cumulate product of many individual decisions and can be shaped by the way morphology and behaviour interacts with landscape structure and composition. Hence, the ongoing process of habitat fragmentation increases the distance among suitable habitats and changes those in such a way that it may favour some movement behaviour. Our study described some biological traits (sex ratio, age structure and individual permanence in a population), as well as the movements of fruit-feeding butterflies along the horizontal dimension (among habitats: forest interior, natural forest transition - ecotone and anthropogenic forest transition - edge) and the vertical dimension (between canopy and understory). We sampled butterflies monthly over 1 year in the Atlantic rainforest, South-eastern Brazil, following a standardized design using bait traps. We found that sex ratio was male biased for five out of the six more abundant species and the age structure showed an increase in recruitment of new individuals in the dry season followed by a noticeable aging of the populations in the wet season. In general, our results revealed an aggregated spatial distribution, in which few individuals travelled long distances while most individuals were recaptured in the same trap, suggesting that all studied habitats currently provide the necessary conditions for the maintenance of butterfly populations, favouring fewer movements and narrow home ranges for both sexes and species. Conservation of a set of heterogeneous habitats it is especially important for the maintenance of sedentary butterflies and of those that move large distances.


Catalytic performance of carbon nanotubes in H2O2 decomposition: experimental and quantum chemical study.
The catalytic performance of multi-walled carbon nanotubes (MWCNTs) with different surface chemistry was studied in the decomposition reaction of H2O2 at various values of pH and temperature. A comparative analysis of experimental and quantum chemical calculation results is given. It has been shown that both the lowest calculated activation energy (∼18.9 kJ/mol) and the highest rate constant correspond to the N-containing CNT. The calculated chemisorption energy values correlate with the operation stability of MWCNTs. Based on the proposed quantum chemical model it was found that the catalytic activity of carbon materials in electron transfer reactions is controlled by their electron donor capability.


Screening of the MERTK gene for mutations in Japanese patients with autosomal recessive retinitis pigmentosa.
To determine whether mutations in the MERTK gene are present in Japanese patients with autosomal recessive retinitis pigmentosa (arRP). The coding sequence of all 19 exons and the adjacent flanking intron sequences of the MERTK gene were directly sequenced in 96 unrelated Japanese patients with arRP. Seventeen sequence variants were found; six missense changes, three isocoding changes, and eight intron changes were also observed. One arRP patient had a novel homozygous Leu12Pro missense mutation in the MERTK gene. Mutations in the MERTK gene are relatively rare in Japanese patients with arRP.


A population study of screening history and diagnostic outcomes of women with invasive cervical cancer.
Despite advances to prevent and detect cervical cancer, national targets for screening have not been met in the United States. Previous studies suggested that approximately half of women who developed cervical cancer were not adequately screened. This study aimed to provide an updated examination of women's screening and diagnostic practices five years prior to an invasive cervical cancer diagnosis. The study included women age 21 years and older diagnosed with invasive cervical cancer in 2013-2016 from three population-based state cancer registries in the United States. Medical records abstraction identified screening history and diagnostic follow-up. A mailed survey provided sociodemographic data. Screening was a Pap or human papillomavirus (HPV) test between 6 months and 5 years before diagnosis. Adequate follow-up was defined per management guidelines. Of the 376 women, 60% (n = 228) had not been screened. Among women who received an abnormal screening result (n = 122), 67% (n = 82) had adequate follow-up. Predictors of: (a) being screened were younger age, having a higher income, and having insurance; (b) adequate follow-up were having a higher income, and (c) stage 1 cervical cancer were being screened and younger age. Unlike other cancer patterns of care studies, this study uses data obtained from medical records supplemented with self-report information to understand a woman's path to diagnosis, her follow-up care, and the stage of her cervical cancer diagnosis. This study provides findings that could be used to reach more unscreened or under screened women and to continue lowering cervical cancer incidence in the United States.


Lycopene ameliorates atrazine-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus of mice.
Atrazine (ATR) is a commercially available herbicide that is used worldwide. The intensive use of ATR poses potential risks to animals' and humans' health. Lycopene (LYC) is an anti-oxidative phytochemical that normalizes health hazards triggered by environmental factors. In this study, we aimed to investigate the toxic effects of ATR on the hippocampus and its amelioration by LYC. Male mice were exposed to ATR (50 mg/kg/day or 200 mg/kg/d) and/or LYC (5 mg/kg/d) for 21 days. The results showed that ATR exposure induced hippocampus-dependent learning and memory impairments. ATR-induced ferroptosis in hippocampal cells affects the homeostasis of lipid metabolism, whereas LYC ameliorates the neurotoxic effects of ATR in the hippocampus. LYC inhibited ATR-induced ferroptosis by increasing the expression of HO-1, Nrf2 and SLC7A11. Therefore, this study established that LYC ameliorates ATR-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus and also provides a novel approach for the treatment in contradiction of environmental pollutants.


An investigation into the effect of number of trials during proprioceptive testing in patients with patellofemoral pain syndrome.
The purpose of this study was to investigate the effect of increasing the number of test trials in the assessment of knee joint position sense, in a group of patellofemoral patients, and second, to investigate the effects of joint angle and type of test. Thirty-two patients with a diagnosis of patellofemoral pain syndrome were admitted to this study. Knee joint position sense was measured by performing an ipsilateral matching activity at target angles of 20 degrees and 60 degrees using two techniques; Passive Angle Reproduction (PAR), and Active Angle Reproduction (AAR). The results show that five repetitions are required for AAR and six for PAR. A two-way repeated-measures ANOVA showed that there was no significant difference (p = 0.559) in the accuracy of angle reproduction for the two angles (60 degrees and 20 degrees ); however, there was a significant difference (p = 0.001) between the two types of test (AAR and PAR). The results of this study have implications for clinicians and researchers who examine knee joint proprioception as part of functional assessment in a variety of knee joint pathologies including PFPS. A "quick" one-off assessment of knee joint position sense may give erroneous data; subjects need to have several trials before a true picture of their proprioceptive status emerges. Type of testing performed, active or passive, is also important, although the angle of testing may not be relevant.


The personal utility and uptake of genomic sequencing in pediatric and adult conditions: eliciting societal preferences with three discrete choice experiments.
To estimate the personal utility and uptake of genomic sequencing (GS) across pediatric and adult-onset genetic conditions. Three discrete choice experiment (DCE) surveys were designed and administered to separate representative samples of the Australian public. Bayesian D-efficient explicit partial profile designs were used. Choice data were analyzed using a panel error component random parameter logit model. Overall, 1913 participants completed the pediatric (n = 533), symptomatic adult (n = 700) and at-risk adult (n = 680) surveys. The willingness-to-pay for GS information in pediatric conditions was estimated at $5470-$15,250 (US$3830-$10,675) depending on the benefits of genomic information. Uptake ranged between 60% and 81%. For symptomatic adults, the value of GS was estimated at $1573-$8102 (US$1100-$5671) and uptake at 34-82%. For at-risk adults, GS was valued at $2036-$5004 (US$1425-$3503) and uptake was predicted at 35-61%. There is substantial personal utility in GS, particularly for pediatric conditions. Personal utility increased as the perceived benefits of genomic information increased. The clinical and regulatory context, and individuals' sociodemographic and attitudinal characteristics influenced the value and uptake of GS. Society values highly the diagnostic, clinical, and nonclinical benefits of GS. The personal utility of GS should be considered in health-care decision-making.


Dissolution of calcium bilirubinate and calcium carbonate debris remaining after methyl tert-butyl ether dissolution of cholesterol gallstones.
Methyl tert-butyl ether rapidly dissolves cholesterol gallstones, although insoluble debris may remain. Total gallstone dissolution could be achieved if safe solvents for these noncholesterol components can be developed. We evaluated the in vitro ability of ethylenediaminetetraacetic acid, citrate, dimethyl sulfoxide, and ionic or nonionic detergents to dissolve the predominantly calcium bilirubinate and calcium carbonate debris remaining after methyl tert-butyl ether gallstone dissolution. Ethylenediaminetetraacetic acid 1% or 2% at pH 9.5 was the most effective of the solvents studied for dissolving calcium and bile pigment. The addition of cholate (25-200 mM) or polysorbate (1%-10%) to ethylenediaminetetraacetic acid 1% at pH 9.5 enhanced pigment dissolution compared to ethylenediaminetetraacetic acid alone. Dissolution of pellets prepared from human gallstones and composed predominantly of either calcium bilirubinate or calcium carbonate was 80% and 85% at 4 h using ethylenediaminetetraacetic acid 1% plus polysorbate-20 1% at pH 9.5. We conclude that ethylenediaminetetraacetic acid, either alone or with a detergent, is an effective solvent for methyl tert-butyl ether-insoluble gallstone debris and deserves assessment in vivo.


Legal and Policy Implications in Mexico of Changes in ICD-11 Paraphilic Disorders.
The World Health Organization (WHO) has made substantial changes to the classification of paraphilic disorders for the Eleventh Revision of the International Classification of Diseases and Related Health Problems (ICD-11), recently approved by the World Health Assembly. The most important is to limit paraphilic disorders primarily to persistent and intense patterns of atypical sexual arousal involving non-consenting individuals, manifested through persistent sexual thoughts, fantasies, urges, or behaviors, that have resulted in action or significant distress. To analyze the legal, regulatory, and policy implications of the changes in the ICD-11 classification of paraphilic disorders for forensic practice, health systems, adjudication of sex offenders, and the provision of treatment in Mexico. An expert Mexican advisory group was appointed to conduct this evaluation following an assessment guide provided by the WHO. The WHO assessment guide covered (i) laws related to sexual behaviors; (ii) the relationship between legal and clinical issues for non-forensic health professionals; (iii) implications of mental disorder classification for forensic practice; (iv) other implications of ICD-11 paraphilic disorders proposals; and (v) contextual issues. A variety of factors in Mexico make it highly unlikely that appropriate, evidence-based treatments for paraphilic disorders will be provided to those who need them, even if they seek treatment voluntarily and have not committed a crime. Mexican law focuses on the punishment of specific sexual behaviors rather than on underlying disorders. A paraphilic disorder would not be considered sufficient grounds for exemption from criminal responsibility. The application and scope of mental health evaluations in Mexican legal proceedings are quite limited, and individuals who commit sexual crimes almost never undergo forensic evaluations to establish the presence of paraphilic disorders. Psychiatric services may be mandated for sex offenders in highly specific circumstances but cannot exceed the duration of the criminal sentence. Evaluation and treatment guidelines should be developed based on international evidence and standards and promulgated for use with individuals with paraphilic disorders in forensic and non-forensic poopulations. The much greater specificity and operationalization of the ICD-11 guidelines as compared with the ICD-10 guidelines provide a better basis for identification and case formulation. Major strengths of this analyses were that it was conducted to facilitate international comparability across several participating countries and the fact that it was conducted by a diverse multidisciplinary group representing various relevant legal, forensic and and clinical sectors. A limitation was that it was only possible to examine relevant federal laws and those of Mexico City rather than those of all 32 Mexican states. The descriptions of paraphilic disorders in the ICD-11 could support substantial improvements in the treatment of individuals with paraphilic disorders and the adjudication of sex offenders in Mexico, but specific changes in Mexican law would be required. Martínez-López JNI, Robles R, Fresán A, et al. Legal and Policy Implications in Mexico of Changes in ICD-11 Paraphilic Disorders. J Sex Med 2019;16:1623-1637.


The role of radiotherapy in tumor immunity and the potential of PET/CT in detecting the expression of PD-1/PD-L1.
Upregulation of PD-1/PD-L1 allows cancer cells to escape from host immune systems by functionally inactivating T-cell immune surveillance. Clinical blockade strategies have resulted in an increased prevalence of patients with late-stage cancers. However, many cancer patients had limited or no response to current immunotherapeutic strategies. Therefore, how to improve the sensitivity of immunotherapy has become the focus of attention of many scholars. Radiotherapy plays a role in the recruitment of T cells in the tumor microenvironment, increases CD4 + and CD8 + T cells, and increases PD-L1 expression, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. Radiotherapy can cause changes in tumor metabolism, especially glucose metabolism. Tumor glycolysis and tumor immune evasion are interdependent, glycolytic activity enhances PD-L1 expression on tumor cells and thus promotes anti-PD-L1 immunotherapy response. Therefore, the mechanism of radiotherapy affecting tumor immunity may be partly through intervention of tumor glucose metabolism. Furthermore, some authors had found that the uptake of 2'-deoxy-2'-[18F]fluoro-D-glucose(18F-FDG) was correlated with PD-1/PD-L1 expression. Positron emission tomography/computed tomography (PET/CT) is a non-invasive detection method for PD-1/PD-L1 expression and has several potential advantages over immunohistochemical (IHC), PET/CT can dynamically reflect the expression of PD-1/PD-L1 inside the tumor and further guide clinical treatment.


Genomic and genetic variation in E2F transcription factor-1 in men with nonobstructive azoospermia.
To identify gene dosage changes associated with nonobstructive azoospermia (NOA) using array comparative genomic hybridization (aCGH). Prospective study. Medical school. One hundred ten men with NOA and 78 fertile controls. None. The study has four distinct analytic components: aCGH, a molecular karyotype that detects copy number variations (CNVs); Taqman CNV assays to validate CNVs; mutation identification by Sanger sequencing; and histological analyses of testicular tissues. A microduplication at 20q11.22 encompassing E2F transcription factor-1 (E2F1) was identified in one of eight men with NOA analyzed using aCGH. CNVs were confirmed and in an additional 102 men with NOA screened using Taqman CNV assays, for a total of 110 NOA men analyzed for CNVs in E2F1. Eight of 110 (7.3%) NOA men had microduplications or microdeletions of E2F1 that were absent in fertile controls. E2F1 microduplications or microdeletions are present in men with NOA (7.3%). Duplications or deletions of E2F1 occur very rarely in the general population (0.011%), but E2F1 gene dosage changes, previously reported only in cancers, are present in a subset of NOA men. These results recapitulate the infertility phenotype seen in mice lacking or overexpressing E2f1.


Controlled release of tetracycline--III: A physiological pharmacokinetic model of the pregnant rat.
A controlled tetracycline delivery device, consisting of a membrane enclosed trilaminate disc fabricated from a series of 2-hydroxyethylmethacrylate/methylmethacrylate copolymers, demonstrated the ability to deliver tetracycline at zero-order rates in vitro and in vivo in rats and was applied to study the pharmacokinetics of tetracycline in the pregnant rat. The trilaminate discs containing tetracycline were implanted in pregnant Sprague-Dawley rats on the eighth day of gestation. The animals were sacrificed on days 19, 20, and 21 of gestation in order to measure the distribution of the controlled release tetracycline in the maternal, fetal, and placental tissues. Constant plasma tetracycline levels were attained in both the maternal and fetal circulations after 4 to 5 days postimplantation of the trilaminate discs. Placental transfer of tetracycline appeared rapid and no partitioning of the drug was observed between the maternal and fetal soft tissue (liver, kidney, G.I. tract, muscle, placenta) as measured over the last 3 to 4 days of the animal's gestational period. Highest tetracycline concentrations were determined in the fetal bone samples. In addition, some accumulation of the drug occurred in the amniotic fluid. A flow-limited pharmacokinetic model was constructed to simulate the distribution of tetracycline, delivered at a constant rate from the trilaminate device, in the pregnant rats. Predictions of fetal growth and maternal and fetal tissue tetracycline concentrations were in good agreement with the experimental measurements. The ability of these copolymer systems to deliver tetracycline at zero-order rates over extended periods offers numerous potential therapeutic and investigational applications, especially where such drug delivery characteristics are beneficial to the elucidation of physiological rate mechanisms, as in the pregnant animal.


Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity.
This Letter describes the synthesis and structure-activity-relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of alternative halogenated piperidinyl benzimidazolone privileged structures, in combination with a key (S)-methyl group, novel PLD inhibitors with low nM potency and unprecedented levels of PLD1 isoform selectivity (approximately 1700-fold) over PLD2 were developed.


Oral selenium improved the disease activity in patients with mild Graves' orbitopathy.
Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD), an autoimmune disorder arising from the activity of T lymphocytes against antigens that infiltrate thyroid tissue, orbital tissue and extraocular muscles. An increase in oxidative stress has been discovered in autoimmune thyroid disease, encouraging investigation into new forms of treatment. Selenium has been described as a treatment option given its antioxidant properties. The present study evaluates the decrease of progression and inflammatory signs in patients with mild GO with oral selenium supplementation. Controlled, randomized, single center trial at an ophthalmology referral center in Mexico City. Patients at least 18years of age with mild GO according to the CAS classification were included; exclusion criteria in addition to corticosteroid treatment included smokers or selenium allergy. Each patient was randomized into one of two groups. Group A took placebo tablets which consisted of 100μg of starch twice a day for 6months, and group B took a 100μg selenium tablet twice a day for 6months. The patients from both groups were examined and evaluated using a CAS score before and after the first, third and sixth month of treatment. Thirty eyes of 30 patients were studied. The pretreatment values showed no statistically significant differences between groups (P>0.05). Intergroup analysis showed statistically significant differences in palpebral fissure and CAS score between the pretreatment values and six months after treatment in the selenium group (P<0.05). No differences were found in any variables in the placebo group during the study period (P>0.05). No adverse events were reported. This is the first study in a Mexican population demonstrating that oral selenium decreases clinical activity and stops progression in patients with mild GO.


Multiphase flow in microfluidics: From droplets and bubbles to the encapsulated structures.
Microfluidic technologies have a unique ability to control more precisely and effectively on two-phase flow systems in comparison with macro systems. Controlling the size of the droplets and bubbles has led to an ever-increasing expansion of this technology in two-phase systems. Liquid-liquid and gas-liquid two-phase flows because of their numerous applications in different branches such as reactions, synthesis, emulsions, cosmetic, food, drug delivery, etc. have been the most critical two-phase flows in microfluidic systems. This review highlights recent progress in two-phase flows in microfluidic devices. The fundamentals of two-phase flows, including some essential dimensionless numbers, governing equations, and some most well-known numerical methods are firstly introduced, followed by a review of standard methods for producing segmented flows such as emulsions in microfluidic systems. Then various encapsulated structures, a common two-phase flow structure in microfluidic devices, and different methods of their production are reviewed. Finally, applications of two-phase microfluidic flows in drug-delivery, biotechnology, mixing, and microreactors are briefly discussed.


Optimal planning of safety improvements on road sites belonging to different categories within large networks: An integrated multi-layer framework.
Planning road safety interventions on large road networks implies several layers of complexity in the decision-making process. In fact, the following simultaneous problems should be addressed: estimating safety performances on the different road elements of the network, identifying sites showing high potential for improvement with respect to reference values, defining the possible types of safety measures to be implemented and their anticipated effect on traffic safety, limiting the number of interventions given fixed budget constraints. This study proposes an integrated multi-layer framework which takes into account the above-defined problems into a single optimization procedure which provides the number and type of safety interventions to be implemented over a wide road network composed of different categories of road elements. The proposed framework is based on the following peculiar aspects: the potential for safety improvement is quantitatively assessed based on the estimation of safety performances for each road category, a bi-level thresholding process integrated in the optimization process is used to highlight sites for interventions, the anticipated outcome of safety measures is quantitatively assessed as well through available crash reduction factors. The proposed methodology is applied to a case study which analyzes a sample of real roads belonging to a province-wide road network composed of various road elements (i.e., different categories of segments and intersections), under different budget constraints. Results demonstrate the applicability and flexibility of the proposed approach, which could be used for planning purposes, independently of the particular geographic location. Clearly, the approach is valid at the planning stage, given that several details of the different layers of analysis are necessarily simplified, while they should be studied in detail at the single intervention project stage.


LncRNA-encoded peptides: More than translational noise?
Long non-coding RNAs (lncRNAs) belong to the ever-increasing number of transcripts that are thought not to encode proteins. A recent study has now identified a small polypeptide encoded by the lncRNA LINC00961 that inhibits amino acid-induced mTORC1 activation in skeletal muscle.


Chronic and acute tolerance to the heart rate effects of nicotine.
Tolerance to the effects of nicotine reflects physiological adaptation and may be related to the development and persistence of smoking behavior. However, little is known about tolerance to nicotine in humans, in part due to methodological difficulties. This study examined chronic and acute tolerance to nicotine's effect on heart rate (HR) using a measured-dose nasal spray nicotine procedure. Eight "Light" smokers (less than 20 cigarettes per day) and ten "Heavy" smokers (greater than or equal to 20 per day) participated in two sessions on separate days in which they received four administrations (1 every 20 min) of a high nicotine dose (15 micrograms per kg body weight, equivalent to a typical cigarette) or a low nicotine dose (7.5 micrograms/kg) while HR was monitored during the 5 min following each administration. Compared with Light smokers, Heavy smokers had significantly smaller HR responses to the high dose, indicating greater chronic tolerance, but there was no difference between groups in response to the low dose. Acute tolerance to HR response across the four 5-min periods was not observed with either dose. However, subsequent examination of HR response in the first 2 min following each dose administration did suggest acute tolerance, particularly for the low dose, as this more acute HR response declined from the first to the last administration. These results demonstrate chronic and, to a lesser extent, acute tolerance to HR effects of nicotine and suggest that both may be dose dependent.


True or apparent reversal of elution order during chiral high-performance liquid chromatography monitored by a polarimetric detector under different mobile phase conditions.
The use of all chromatographic modes (i.e. reversed-phase, normal-phase and polar organic modes) is becoming more and more systematic in chiral HPLC method development. When this method development is monitored by polarimetric detection, which is a widespread technique, one should not forget that the observed positive or negative rotation angle for a given absolute configuration depends on the solvent. As a cautionary illustration, a new example is reported for a racemate which is separated with the same elution order in ethanol or acetonitrile mobile phase on a CHIRALCEL OD-R column whereas the signs of polarimetric detection are reversed.


Editorial Commentary: Arthroscopic-Assisted Coracoclavicular Ligament Reconstruction Leads to Improved Patient-Reported Outcomes, But Patient Satisfaction Is a Harder Threshold to PASS.
There are numerous described techniques for surgical management of high-grade acromioclavicular (AC) joint injuries, and the associated clinical outcomes can be quite variable. Contemporary techniques are typically directed at anatomic reconstruction of the coracoclavicular (CC) ligaments through either an arthroscopy-assisted or an open approach. Most patients treated with acute surgery improve, whereas in chronic cases, the majority improve, but a significant number have persistent recurrent deformity due to loss of anatomic reduction. In addition, whether acute or chronic, over one quarter of patients do not have a PASS (patient acceptable symptomatic state). Of interest, PASS may not primarily be related to the final deformity in terms of coracoclavicular distance, and investigation is still required in terms of the effect of anteroposterior or rotational instability of the AC joint after injury and surgery. Finally, PASS values for AC separation are not well established, resulting in a current limitation of the strength of applying threshold values to this pathology.


Lethal pedestrian--passenger car collisions in Berlin. Changed injury patterns in two different time intervals.
To expand the passive safety of automobiles protecting traffic participants technological innovations were done in the last decades. Objective of our retrospective analysis was to examine if these technical modifications led to a clearly changed pattern of injuries of pedestrians whose death was caused by the accidents. Another reduction concerns the exclusion of injured car passengers--only pedestrians walking or standing at the moment of collision were included. We selected time intervals 1975-1985 and 1991-2004 (=years of construction of the involved passenger cars). The cars were classified depending on their frontal construction in types as presented by Schindler et al. [Schindler V, Kühn M, Weber S, Siegler H, Heinrich T. Verletzungsmechanismen und Wirkabschätzungen der Fahrzegfrontgestaltung bei Pkw-Fussgänger-Kollisionen. Abschlussbericht im Auftrag der Deutschen Versicherungswirtschaft e.V. TU-Berlin Fachgebiet Kraftfahrzeuge (GDV) 2004:36-40]. In both periods more than 90% of all cars were from the usual types small/medium/large class. Hundred and thirty-four autopsy records of such cases from Department of Forensic Medicine (Charité Berlin) data were analysed. The data included technical information of the accidents and vehicles and the external and internal injuries of the victims. The comparison of the two periods showed a decrease of serious head injuries and femoral fractures but an increase of chest-, abdominal and pelvic injuries. This situation could be explained by an increased occurrence of soft-face-constructions and changed front design of modern passenger cars, resulting in a favourable effects concerning head impact to the car during accident. Otherwise the same kinetic energy was transferred to the (complete) victim - but because of a displacement of main focus of impact the pattern of injuries modified (went distally).


Attenuation of reactive hyperemia caused by aspirin in canine coronary artery.
Effects of intracoronary aspirin on coronary blood flow and reactive hyperemia were evaluated in closed-chest, anesthetized dogs. In 18 dogs the left circumflex coronary artery was cannulated and perfused by arterial blood at a constant pressure. Coronary blood flow was measured by an electromagnetic flowmeter. Intracoronary aspirin at doses of 5, 10, and 20 mg reduced coronary blood flow in a dose-dependent manner. Injection of aspirin at doses of 10 to 25 mg also inhibited reactive hyperemia following the coronary occlusion for fifteen seconds. The mean peak flow ratio was reduced from 2.13 +/- 0.42 to 1.75 +/- 0.35 (p less than 0.005). The increment of coronary blood flow provoked by intracoronary arachidonic acid at doses of 150 to 300 micrograms was almost entirely inhibited by the pretreatment of the coronary artery with aspirin. The authors conclude that aspirin increases coronary arterial resistance in a dose-dependent manner and also restricts the maximal dilating capacity, possibly by inhibition of prostacyclin synthesis.


Antibody-drug conjugates, immune-checkpoint inhibitors, and their combination in breast cancer therapeutics.
Advanced breast cancer (aBC) remains incurable and the quest for more effective systemic anticancer agents continues. Promising results have led to the FDA approval of three antibody-drug conjugates (ADCs) and two immune checkpoint inhibitors (ICIs) to date for patients with aBC. With the anticipated emergence of newer ADCs and ICIs for patients with several subtypes of breast cancer, and given their potential synergy, their use in combination is of clinical interest. In this article, we review the use of ADCs and ICIs in patients with breast cancer, assess the scientific rationale for their combination, and provide an overview of ongoing trials and some early efficacy and safety results of such dual therapy. Improvement in the medicinal chemistry of next-generation ADCs, their rational combination with ICIs and other agents, and the development of multiparametric immune biomarkers could help to significantly improve the outlook for patients with refractory aBC.


Hepatoprotective effects of Tagetes lucida root extract in carbon tetrachloride-induced hepatotoxicity in Wistar albino rats through amelioration of oxidative stress.
The roots of Tagetes lucida Cav. (Asteraceae) have antioxidant and antimicrobial properties. This study aimed to examine the hepatoprotective effects of T. lucida roots ethanol extract (TLRE) using carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. The active ingredients of TLRE were identified by high-performance liquid chromatography, infra-red spectrum, and mass spectrometric procedures. Ninety rats were distributed into four main groups: positive, therapeutic, protective, and negative group. The therapeutic group was implemented using CCl4 (a single dose of 2 mL/kg) before TLRE or silymarin administration. Meanwhile, the protective group was implemented by administering CCl4 (a single dose of 2 mL/kg) after force-feeding TLRE or silymarin. Each therapeutic and protective group was divided into three subgroups: force-fed with saline, TLRE (500 mg/kg), and silymarin (25 mg/kg). The positive group was split into two subgroups that were force-fed TLRE and silymarin. Positive, therapeutic, and protective groups were compared to the negative group (untreated rats). CCl4, TLRE, and silymarin were orally administrated using a gastric tube. In the therapeutic and protective groups, TLRE significantly reduced liver enzymes, i.e., aspartate aminotransferase (12.47 and 6.29%), alanine aminotransferase (30.48 and 11.39%), alkaline phosphatase (17.28 and 15.90%), and cytochrome P450-2E1 (39.04 and 48.24%), and tumour necrosis factor-α (53.72 and 53.72%) in comparison with CCl4-induced hepatotoxicity controls. TLRE has a potent hepatoprotective effect with a good safety margin. After a repeated study on another type of small experimental animal, their offspring, and an experiment with a large animal, this study may lead to clinical trials.


Lower urinary cotinine level is associated with a trend toward more myopic refractive errors in Korean adolescents.
PurposeTo investigate the association between urinary cotinine levels as an objective biological marker for exposure to nicotine and refractive status.Patients and methodsThis cross-sectional study analyzed data from the Korea National Health and Nutrition Examination Survey between 2008 and 2011. A total of 1139 Korean adolescents aged 12-18 years were enrolled. Urinary cotinine concentrations and other potential risk factors for myopia were examined. Correlation analyses and multivariate regression analysis were performed to investigate the association between urinary cotinine level and refractive error.ResultsSpherical equivalent correlated significantly with urinary cotinine concentration (r=0.104, P=0.011). Lower urinary cotinine level was associated with a trend toward more myopic refractive errors (P for trend=0.003). After adjusting for age, sex, area of residence, physical activity, serum 25-hydroxyvitamin D level, parental income level, and receipt of basic livelihood security, subjects with a low urinary cotinine level had a significantly increased risk of myopia <-0.5 D (odds ratio (OR) 1.95, 95% confidence interval (CI) 1.18-3.21), <-3.0 D (OR 2.03, 95% CI 1.29-3.2), and <-6.0 D (OR 2.2, 95% CI, 1.15-4.23) when compared with subjects with a high urinary cotinine level. As urinary cotinine level decreased, the risks of myopia <-0.5 D, <-3.0 D, and <-6.0 D increased significantly (P for trend <0.05).ConclusionA trend toward less myopic refractive error was observed among Korean adolescents with higher urinary cotinine levels. This result provides the epidemiologic evidence implying nicotine as a potential modulator related with refractive development. Further studies with full consideration for myopia-associated risk factors are required to yield clear answers on the direct effect of smoking to the refractive status.


Evaluation of Long-Term Outcomes and Toxicity After Stereotactic Phosphorus-32-Based Intracavitary Brachytherapy in Patients With Cystic Craniopharyngioma.
Interstitial brachytherapy based on phosphorus-32 (P-32) has an established role as a minimally invasive treatment modality for patients with cystic craniopharyngioma. However, reporting on long-term outcomes with toxicity profiles for large cohorts is lacking in the literature. The purpose of this study is therefore to evaluate the long-term visual, endocrinal, and neurocognitive functions in what is the largest patient series having received this treatment to date. We retrospectively evaluated 90 patients with cystic craniopharyngiomas who were treated with stereotactic intracavitary brachytherapy between 1998 and 2010. Colloidal activity of injected radioisotope P-32 was based on an even distribution within the tumor. After treatment, patients were followed-up for a minimum of 5 years and over a mean of 121 months (60-192 months) to assess radiographic and clinical responses. The 90 patients included in our study cohort underwent a total of 108 stereotactic surgical procedures for 129 craniopharyngioma-related cysts. Of the included tumors, 65 (72.2%) were associated with a single cyst, 15 (16.7%) were associated with 2 cysts, and 10 (11.1%) tumors had developed septations with 3 to 4 cysts. Stereotactic cyst puncture and content aspiration were used to drain a mean cyst fluid volume of 21.4 mL (1.0-55.0 mL). Each cyst was then instilled for interstitial brachytherapy with colloidal P-32 solution. Based on radiographic follow-up assessments, 56 cysts (43.4%) showed resolution and/or nonrecurrence, which was classified as a complete response to treatment; 47 cysts (36.4%) showed a partial response; and 5 cysts (3.9%) displayed a stable appearance. Treatment resulted in immediate and clinically significant vision improvement in 54 of 63 (86%) symptomatic patients, and this improvement was maintained. Progression-free survival rates at 5 and 10 years were 95.5% and 84.4%, respectively. P-32-based interstitial brachytherapy can play an effective role in managing patients with cystic craniopharyngiomas. It can be considered a valid alternative to surgery in select patients with a favorable toxicity profile and long-term clinical outcomes.


Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress.
Both Myc and Ras oncogenes impact cellular metabolism, deregulate redox homeostasis and trigger DNA replication stress (RS) that compromises genomic integrity. However, how are such oncogene-induced effects evoked and temporally related, to what extent are these kinetic parameters shared by Myc and Ras, and how are these cellular changes linked with oncogene-induced cellular senescence in different cell context(s) remain poorly understood. Here, we addressed the above-mentioned open questions by multifaceted comparative analyses of human cellular models with inducible expression of c-Myc and H-RasV12 (Ras), two commonly deregulated oncoproteins operating in a functionally connected signaling network. Our study of DNA replication parameters using the DNA fiber approach and time-course assessment of perturbations in glycolytic flux, oxygen consumption and production of reactive oxygen species (ROS) revealed the following results. First, overabundance of nuclear Myc triggered RS promptly, already after one day of Myc induction, causing slow replication fork progression and fork asymmetry, even before any metabolic changes occurred. In contrast, Ras overexpression initially induced a burst of cell proliferation and increased the speed of replication fork progression. However, after several days of induction Ras caused bioenergetic metabolic changes that correlated with slower DNA replication fork progression and the ensuing cell cycle arrest, gradually leading to senescence. Second, the observed oncogene-induced RS and metabolic alterations were cell-type/context dependent, as shown by comparative analyses of normal human BJ fibroblasts versus U2-OS sarcoma cells. Third, the energy metabolic reprogramming triggered by Ras was more robust compared to impact of Myc. Fourth, the detected oncogene-induced oxidative stress was due to ROS (superoxide) of non-mitochondrial origin and mitochondrial OXPHOS was reduced (Crabtree effect). Overall, our study provides novel insights into oncogene-evoked metabolic reprogramming, replication and oxidative stress, with implications for mechanisms of tumorigenesis and potential targeting of oncogene addiction.


Relative extraction ratio (RER) for arsenic and heavy metals in soils and tailings from various metal mines, Korea.
This study focused on the evaluation of leaching behaviours for arsenic and heavy metals (Cd, Cu, Ni, Pb and Zn) in soils and tailings contaminated by mining activities. Ten representative mine soils were taken at four representative metal mines in Korea. To evaluate the leaching characteristics of the samples, eight extraction methods were adapted namely 0.1 M HCl, 0.5 M HCl, 1.0 M HCl, 3.0 M HCl, Korean Standard Leaching Procedure for waste materials (KSLP), Synthetic Precipitation Leaching Procedure (SPLP), Toxicity Characteristic Leaching Procedure (TCLP) and aqua regia extraction (AR) methods. In order to compare element concentrations as extraction methods, relative extraction ratios (RERs, %), defined as element concentration extracted by the individual leaching method divided by that extracted by aqua regia based on USEPA method 3050B, were calculated. Although the RER values can vary upon sample types and elements, they increase with increasing ionic strength of each extracting solution. Thus, the RER for arsenic and heavy metals in the samples increased in the order of KSLP < SPLP < TCLP < 0.1 M HCl < 0.5 M HCl < 1.0 M HCl < 3.0 M HCl. In the same extraction method, the RER values for Cd and Zn were relatively higher than those for As, Cu, Ni and Pb. This may be due to differences in geochemical behaviour of each element, namely high solubility of Cd and Zn and low solubility of As, Cu, Ni and Pb in surface environment. Thus, the extraction results can give important information on the degree and extent of arsenic and heavy metal dispersion in the surface environment.


Anatomy of the Dorsal Meningeal Artery Including Its Variations: Application to Skull Base Surgery and Diagnostic and Interventional Imaging.
The blood supply to the skull base is important to surgeons and those performing interventional and diagnostic procedures in this region. However, 1 vessel with a vast distribution in this area, the dorsal meningeal artery (DMA), has had few anatomic studies performed to investigate not only its normal anatomy but also its variations. Therefore the current study aimed to analyze the DMA via cadaveric dissection. In 10 adults, latex-injected, cadaveric heads (20 sides), the DMA was dissected using a surgical microscope. This artery and its branches were documented and measured. A DMA was identified on all sides. In the majority (85%), it was a branch of the meningohypophysial trunk or common stem with either the inferior hypophysial or tentorial arteries and always had branches that traversed the basilar venous plexus. Multiple branches of the DMA were identified and categorized as bony, dural, neural, and vascular. Surgeons operating at the skull base or clinicians interpreting imaging of this area should have a good working knowledge of the DMA and its typical and variant anatomy.


Cortical spreading depression decreases Fos expression in rat periaqueductal gray matter.
The migraine headache involves activation and central sensitization of the trigeminovascular pain pathway. The migraine aura is likely due to cortical spreading depression (CSD), a propagating wave of brief neuronal depolarization followed by prolonged inhibition. The precise link between CSD and headache remains controversial. Our objectives were to study the effect of CSD on neuronal activation in the periaqueductal grey matter (PAG), an area known to control pain and autonomic functions, and to be involved in migraine pathogenesis. Fos-immunoreactive nuclei were counted in rostral PAG and Edinger-Westphal nuclei (PAG-EWn bregma -6.5 mm), and caudal PAG (bregma -8 mm) of 17 adult male Sprague-Dawley rats after KCl-induced CSD under chloral hydrate anesthesia. Being part of a pharmacological study, six animals had received, for the preceding 4 weeks daily, intraperitoneal injections of lamotrigine (15 mg/kg), six others had been treated with saline, while five sham-operated animals served as controls. We found that the number of Fos-immunoreactive nuclei in the PAG decreased after CSD provocation. There was no difference between lamotrigine- and saline-treated animals. The number of CSDs correlated negatively with Fos-immunoreactive counts. CSD-linked inhibition of neuronal activity in the PAG might play a role in central sensitization during migraine attacks and contribute to a better understanding of the link between the aura and the headache.


Antigen-specific immunity following hematopoietic stem cell transplantation.
Most studies evaluating immune reconstitution following hematopoietic stem cell transplantation (HSCT) have focused on immunophenotypic analysis and the capacity of the immune system to respond to mitogenic stimulation. However, protection against infectious pathogens and potentially anti-tumor responses correlate with the presence of antigen-specific immunity, not the immunophenotypic presence of T lymphocytes. Antigen-specific T lymphocytes present after HSCT can be derived from donor antigen-specific T lymphocytes present in the transplantation inoculum if it is not T cell depleted. Furthermore, the naive T lymphocytes contained in the HSCT inoculum have the potential to develop into antigen-specific T lymphocytes. If the transplantation inoculum is T cell depleted, then all antigen-specific T lymphocytes will have to be derived from the newly engrafted hematopoietic stem cells following their differentiation through the recipient thymus. Thus, defects in thymopoiesis will result in delays or the absence of naive T lymphocytes and ultimately defects in antigen-specific immunity.


CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway.
Lymph node (LN) metastasis confers gastric cancer (GC) progression, poor survival and cancer-related death. Aberrant activation of Wnt/β-catenin promotes epithelial-mesenchymal transition (EMT) and LN metastasis, whereas the constitutive activation mutation of Wnt/β-catenin is rare in GC, suggesting that the underlying mechanisms enhancing Wnt/β-catenin activation need to be further investigated and understood. Bioinformatics analyses and immunohistochemistry (IHC) were used to identify and detect LN metastasis-related genes in GC. Cellular functional assays and footpad inoculation mouse model illustrate the biological function of CCT5. Co-immunoprecipitation assays, western blot and qPCR elucidate the interaction between CCT5 and E-cadherin, and the regulation on β-catenin activity. CCT5 is upregulated in LN metastatic GCs and correlates with poor prognosis. In vitro assays prove that CCT5 markedly promotes GC cell proliferation, anti-anoikis, invasion and lymphatic tube formation. Moreover, CCT5 enhances xenograft GC growth and popliteal lymph node metastasis in vivo. Furthermore, CCT5 binds the cytoplasmic domain of E-cadherin and abrogates the interaction between E-cadherin and β-catenin, thereby releasing β-catenin to the nucleus and enhancing Wnt/β-catenin signalling activity and EMT. CCT5 promotes GC progression and LN metastasis by enhancing wnt/β-catenin activation, suggesting a great potential of CCT5 as a biomarker for GC diagnosis and therapy.


Epitope characterization of proteins and aptamers with mass spectrometry.
The way in which professor Michael Przybylski has combined the spirit of research with entrepreneurship has set an example for any and all scientists. He has made significant achievements in the fields of mass spectrometry, biochemistry and medicine, and has initiated important technological developments in the area of protein analysis. Between 2016 and 2023 professor Przybylski's scientific focus shifted on protein interactions with emphasis on aptamer-protein and antibody-protein analysis. This review focuses on professor Przybylski's achievements in the last few years highlighting his impact on the scientific community, on his students and colleagues.


Active site architecture of an acetyl xylan esterase indicates a novel cold adaptation strategy.
SGNH-type acetyl xylan esterases (AcXEs) play important roles in marine and terrestrial xylan degradation, which are necessary for removing acetyl side groups from xylan. However, only a few cold-adapted AcXEs have been reported, and the underlying mechanisms for their cold adaptation are still unknown because of the lack of structural information. Here, a cold-adapted AcXE, AlAXEase, from the Arctic marine bacterium Arcticibacterium luteifluviistationis SM1504T was characterized. AlAXEase could deacetylate xylooligosaccharides and xylan, which, together with its homologs, indicates a novel SGNH-type carbohydrate esterase family. AlAXEase showed the highest activity at 30 °C and retained over 70% activity at 0 °C but had unusual thermostability with a Tm value of 56 °C. To explain the cold adaption mechanism of AlAXEase, we next solved its crystal structure. AlAXEase has similar noncovalent stabilizing interactions to its mesophilic counterpart at the monomer level and forms stable tetramers in solutions, which may explain its high thermostability. However, a long loop containing the catalytic residues Asp200 and His203 in AlAXEase was found to be flexible because of the reduced stabilizing hydrophobic interactions and increased destabilizing asparagine and lysine residues, leading to a highly flexible active site. Structural and enzyme kinetic analyses combined with molecular dynamics simulations at different temperatures revealed that the flexible catalytic loop contributes to the cold adaptation of AlAXEase by modulating the distance between the catalytic His203 in this loop and the nucleophilic Ser32. This study reveals a new cold adaption strategy adopted by the thermostable AlAXEase, shedding light on the cold adaption mechanisms of AcXEs.


Surgical repair of a right coronary artery fistula to the left ventricle.
A 17-year-old male complained of exertional dyspnea and was referred to our hospital after he was diagnosed with a right coronary artery fistula into the left ventricle. Surgical repair was considered to improve the symptoms. We identified the distal end of the right coronary artery entering the left ventricle under cardiopulmonary bypass with cardiac arrest. The fistula was transected at the distal end of the right coronary artery and closed at both ends without incision of the left ventricle. Coronary angiography revealed the patency of the right coronary artery and the peripheral branches four months after surgery. The coronary computed tomography four years and four months after operation showed no pseudoaneurysm formation, no thrombosis, and subsequent regression of the dilated right coronary artery. The coronary artery fistula is a rare congenital anomaly, and the treatment strategies of the coronary fistula are controversial. We performed ligation of the coronary fistula under cardiac arrest on cardiopulmonary bypass without incision of the left ventricle. This strategy may contribute to the accurate identification and ligation of the fistula without pseudoaneurysm formation.


Characterization of TonB interactions with the FepA cork domain and FecA N-terminal signaling domain.
The mechanism of TonB dependent siderophore uptake through outer membrane transporters in Gram-negative bacteria is poorly understood. In an effort to expand our knowledge of the interaction between TonB and the outer membrane transporters, we have cloned and expressed the FepA cork domain (11-154) from Salmonella typhimurium and characterized its interaction with the periplasmic C-terminal domain of TonB (103-239) by isotope assisted FTIR and NMR spectroscopy. For comparison we also performed similar experiments using the FecA N-terminal domain (1-96) from Escherichia coli which includes the conserved TonB box. The FepA cork domain was completely unfolded in solution, as observed for the E. coli cork domain previously [Usher et al. (2001) Proc Natl Acad Sci USA 98, 10676-10681]. The FepA cork domain was found to bind to TonB, eliciting essentially the same chemical shift changes in TonB C-terminal domain as was observed in the presence of TonB box peptides. The FecA construct did not cause this same structural change in TonB. The binding of the FepA cork domain to TonB-CTD was found to decrease the amount of ordered secondary structure in TonB-CTD. It is likely that the FecA N-terminal domain interferes with TonB-CTD binding to the TonB box. Binding of the FepA cork domain induces a loss of secondary structure in TonB, possibly exposing TonB surface area for additional intermolecular interactions such as potential homodimerization or additional interactions with the barrel of the outer membrane transporter.


Technical Note: Virtual phantom analyses for preprocessing evaluation and detection of a robust feature set for MRI-radiomics of the brain.
The purpose of the paper was to use a virtual phantom to identify a set of radiomic features from T1-weighted and T2-weighted magnetic resonance imaging (MRI) of the brain which is stable to variations in image acquisition parameters and to evaluate the effect of image preprocessing on radiomic features stability. Stability to different sources of variability (time of repetition and echo, voxel size, random noise and intensity non-uniformity) was evaluated for both T1-weighted and T2-weighted MRI images. A set of 107 radiomic features, accounting for shape and size, first order statistics, and textural features was used. Feature stability was quantified using intraclass correlation coefficient (ICC). For each source of variability, stability was evaluated before and after preprocessing (Z-score normalization, resampling, gaussian filtering and bias field correction). Features that have ICC > 0.75 in all the analysis of variability are selected as stable features. Last, the robust feature sets were tested on images acquired with random simulation parameters to assess their generalizability to unseen conditions. Preprocessing significantly increased the robustness of radiomic features to the different sources of variability. When preprocessing is applied, a set of 67 and 61 features resulted as stable for T1-weighted and T2-wieghted images respectively, over 80% of which were confirmed by the analysis on the images acquired with random simulation parameters. A set of MRI-radiomic features, robust to changes in TR/TE/PS/ST, was identified. This set of features may be used in radiomic analyses based on T1-weighted and T2-weighted MRI images.


Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome.
X chromosome inactivation represents one of the most dramatic examples of mono-allelic gene expression and long-term gene-silencing in mammals. The key regulatory molecule that triggers silencing is the Xist transcript, but little is known about its repressive action. Some progress has been made in deciphering the epigenetics of the inactive state that it triggers, however. During pre-implantation development, the inactive state is relatively labile. Later on, in the soma, the inactive state is highly stable and clonally heritable. This is ensured by the panoply of epigenetic modifications that characterize the inactive X and, presumably, is also a result of its spatio-temporal segregation. The inactive X chromosome has been associated with an increasing number of histone modifications, and several recent studies have implicated Polycomb group proteins in laying down some of these marks. Thanks to genetic and biochemical approaches to analyse these proteins, the epigenetic tapestry of the inactive X is just beginning to be unravelled. Lineage-specific differences provide a glimpse into the developmental complexity of the epigenetic marks that ensure the inactive state.


Influence of the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO-1) trial on the use of thrombolytics in Germany. ALKK Study Group. Arbeitsgemeinschaft der Leitenden Kardiologischen Krankenhausärtze.
Our results show significant and independent influence of the GUSTO-1 trial on the use of recombinant tissue plasminogen activator in acute myocardial infarction in Germany. This influence started soon after the publication of the trial and was not restricted to subgroups who benefitted most from recombinant tissue plasminogen activator.


Association between insulin resistance and risk of complications in children and adolescents with type 1 diabetes.
It has been hypothesized that insulin resistance may be involved in the development of type 1 diabetes complications and early diagnosis would be important for their prevention. Our aim was to study insulin resistance in our population of children with type 1 diabetes and to identify associated early risk factors for micro- and macrovascular complications. A descriptive, cross-sectional study was conducted including 150 children with type 1 diabetes. Anthropometric, bioelectric impedance, carotid Doppler ultrasonography, electromyography, and conduction velocity studies were performed. Baseline plasma glucose, lipid profile, uric acid, plasma thyrotropin, glycosylated hemoglobin A1C, and microalbuminuria were assessed. More insulin-resistant patients were defined as those having an estimated glucose disposal rate (eGDR) value below the first quartile. Clinically manifest microvascular complications were not found in any of the patients. More insulin-resistant patients had a greater sub scapular fold thickness, a higher incidence of obesity (12% vs. 1.7% p 0.007), higher fructosamine levels (496 vs. 403 p<0.00019, and a higher incidence of altered lipid metabolism (70% vs. 39% p 0.0007). In the subgroup of patients with lower eGDR there were more children with lipid disorders, obesity, and worse diabetic control, which, if not corrected, may lead to development of micro- and macrovascular complications.


More extensive genetic alterations in unmutated than in hypermutated cases of chronic lymphocytic leukemia.
B-cell chronic lymphocytic leukemia (CLL) is not a uniform disease entity; approximately half of the CLL cases have undergone immunoglobulin V(H) gene hypermutation, whereas the other half display unmutated V(H) genes. We investigated genome changes in 12 hypermutated cases (M-CLL) and 22 unmutated cases (UM-CLL) by use of comparative genomic hybridization, G-banding, and multicolor fluorescence in situ hybridization (m-FISH) after optimal mitogen stimulation and FISH analysis of typical CLL aberrations: 11q deletion, 13q deletion, and trisomy 12. Very high frequencies of aberrations were found in both groups: 82% in UM-CLL and 83% in M-CLL. Deletions of 11q and 13q were equally distributed in M-CLL and UM-CLL. However, larger aberrations detectable by CGH, trisomy 12, and complex aberrations were less frequent in M-CLL than in UM-CLL. These observations led to a hypothesis that unmutated and mutated CLL have different biological Backgrounds, given that large and/or complex chromosomal aberrations and hypermutation of the CLL progenitor cells tend to be mutually exclusive.


Cancellous bone-like tissue replacement from calcinosis in patients with systemic sclerosis with multiple external root resorption.
Calcinosis is frequently observed in patients with systemic sclerosis (SSc). The fundamental treatment of calcinosis has not yet been established. During follow-up, calcinosis in the subcutaneous surface is often spontaneously extracted or remains confined by fibrous tissues. We previously identified a new symptom in SSc patients, multiple external root resorption (MERR), and these patients had calcifications in the nasal spine. Here, we report for the first time that calcinosis at the nasal spine in patients with MERR can be replaced by cancellous bone-like tissue. Patients 1 and 2 were a 62-year-old Japanese female and a 45-year-old Japanese female (respectively) with MERR who had been previously treated for SSc (Patient 1: limited type, positive for anti-centromere antibody; Patient 2: diffuse type, positive for anti-Scl70 and anti-SS-A antibodies). Patient 3 was a 57-year-old female with MERR who had been previously treated for SSc (diffuse type, positive anti-Scl-70 antibody) and underwent denosumab injection for osteoporosis. Cone-beam computed tomography (CBCT) and CT images in the calcifications at the nasal spine in Patient 1 and 2 were replaced with cancellous bone-like tissue, but not in Patient 3. Serum laboratory examination was performed to assess the systemic bone disease. All three patients had normal clinical data within the references, apart from slightly higher 1,25-dihydroxyvitamin D levels in Patient 1. SSc patients with calcinosis in the maxillofacial area need to be examined carefully for bone replacement using CBCT or CT.


Advisory Committee: A Powerful Tool for Helping Decision Makers inEnvironmental Issues
/ It has been suggested that the general public should be moreinvolved in environmental policy and decision making. It is important forthem to realize that they will have to live with the consequences ofenvironmental policies and decisions. Consequently, policy makers shouldconsider the concerns and opinions of the general public before makingdecisions on environmental issues. This raises questions such as: How can weintegrate the perceptions and reactions of the general population inenvironmental decisions? What kind of public participation should weconsider? In the present study, using a new regional ecosystem model, weattempted to integrate these aspects in its decision making model byincluding the formation of an advisory committee to resolve problems relatedto waste management. The advisory committee requested the activeparticipation of representatives from all levels of the community: economic,municipal, and governmental intervenors; environmental groups; and citizens.Their mandates were to examine different management strategies available inthe region, considering all the interdisciplinary aspects of each strategy,elaborate recommendations concerning the management strategies that are mostsuitable for all, and collaborate in communication of the information to thegeneral population. The results showed that at least in small municipalitiessuch an advisory committee can be a powerful tool in environmental decisionmaking. Conditions required for a successful consultation process, such aseveryday lay language and the presence of a facilitator other than ascientific expert, are discussed.KEY WORDS: Public consultation; Environmental policies;Interdisciplinary aspects; Municipal sewage sludge management; Generalpopulation; Decision-making process


The collection and determination of ethylene glycol dinitrate, nitroglycerine, and trinitrotulene explosive vapors.
The method presented in this paper demonstrated that minute quantities of explosives such as EGDN, NG, and TNT can be easily detected and determined in relatively large amounts of debris after collecting their vapors on porous polymer beads. The method of collecting explosive vapors is simple, inexpensive, sensitive, and relatively fast compared to microscopic and physical methods of analysis.


[Endoscopic extraperitoneal patch-plasty of inguinal and femoral hernias without suture or staple fixation of the polypropylene patch].
The operative technique of endoscopic extraperitoneal inguinal and femoral hernia repair without fixation of the polypropylene patch is presented. The results of 725 inguinal and femoral hernia repairs are demonstrated and discussed.