Effect of docosahexaenoic acid on tissue targeting and metabolism of plasma lipoproteins.
We examined the effect of the docosahexaenoic acid (DHA) content of lipoproteins on their metabolism in vivo by a radioisotope labeling and tracking method. Purified HDL and LDL were labeled with (3)H-cholesteryl oleate tracer. To mimic dietary-related changes in fatty acid composition of lipoproteins, we incorporated lipids acylated with either DHA, arachidonic (AA) or oleic (OA) acid to phosphatidylcholine (didocosahexaenoylphosphatidylcholine (di22:6-PC), diarachidonoylphosphatidylcholine (di20:4-PC) and dioleoylphosphatidylcholine (di18:0-PC), respectively) into the purified particles. The lipids, at the amount added, did not cause detectable alterations in the morphology of the lipoproteins. Levels of radiotracers in blood and in several target tissues such as brain, heart, liver, muscle and adipose were determined at 1.5, 3 and 24h after intravenous injection into C57Bl/6J mice. No statistically significant differences were detected in the tissue distribution of tracers introduced into HDL enriched in DHA, compared to particles enriched with OA. In contrast, we found a significantly higher proportion of radiolabel associated with LDL enriched in DHA in heart, brown adipose and brain tissues. The uptake of labels associated with DHA containing LDL nearly doubled for heart and brown adipose tissues at 1.5 and 3h, and it was 30% higher for brain tissues at 24h. The tissue distribution of labels from the same particles enriched in AA or OA did not show a statistically significant difference from unaltered control lipoproteins. These findings point to the possible role of DHA in the regulation of LDL metabolism and involvement of the lipoproteins in transport of n-3 PUFA to target organs.


Canada: agreement between patient and proxy information about colorectal cancer therapies.
Proxies, such as next of kin, often provide information to healthcare professionals about a cancer patient they know, particularly when this information is not available from the patient. Understanding the extent to which proxies offer reliable information about patients is important for improving the quality of patient care and also for assessing the quality of research, evaluation, and administrative data when proxy response is utilized. This study determined Levels of agreement between information reported by colorectal cancer patients and by their proxies about complementary and alternative medicine obtained by questionnaire response. Patient-proxy agreement was also compared for conventional therapies, patient demographics, lifestyle, and symptoms.


Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study.
Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML-LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo-identical (n = 3) or matched unrelated donors (n = 2). The median cell dose infused was 9 × 106 CD34/kg (range 4.8-12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14-17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non-relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2-48), two patients have relapsed. Overall survival at 2 years is 80% while the disease-free survival is 75%. The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML-LBC.


Filters and congruences in sectionally pseudocomplemented lattices and posets.
Together with J. Paseka we introduced so-called sectionally pseudocomplemented lattices and posets and illuminated their role in algebraic constructions. We believe that-similar to relatively pseudocomplemented lattices-these structures can serve as an algebraic semantics of certain intuitionistic logics. The aim of the present paper is to define congruences and filters in these structures, derive mutual relationships between them and describe basic properties of congruences in strongly sectionally pseudocomplemented posets. For the description of filters in both sectionally pseudocomplemented lattices and posets, we use the tools introduced by A. Ursini, i.e., ideal terms and the closedness with respect to them. It seems to be of some interest that a similar machinery can be applied also for strongly sectionally pseudocomplemented posets in spite of the fact that the corresponding ideal terms are not everywhere defined.


Potentiation of opioid analgesia by the antidepressant nefazodone.
Nefazodone is a new antidepressant related structurally to trazodone. In addition to its activity in preclinical assays for antidepressant activity, nefazodone was a potent analgesic in the mouse hotplate assay. At 50 mg/kg s.c. nefazodone doubled baseline latencies in 40% of mice but was inactive in the tailflick test at any dose tested. The hotplate analgesia seen with nefazodone alone was not reversed by naloxone (10 mg/kg s.c.). In the tailflick assay, nefazodone (50 mg/kg s.c.) enhanced morphine's analgesic response, shifting morphine's ED50 from 3.1 mg/kg alone to 0.86 mg/kg in conjunction with nefazodone (P less than 0.05). Two days after implantation of a morphine pellet (75 mg) no mice remained analgesic in the tailflick assay. Administration of nefazodone (50 mg/kg s.c.) restored analgesia to 60% of mice (P less than 0.03). In selective analgesic assays, nefazodone enhanced mu 1, mu 2 and delta analgesia, but not kappa 1 or kappa 3 analgesia. Nefazodone did not affect morphine's LD50 and, in assays of gastrointestinal transit, nefazodone increased morphine's potency only slightly. In conclusion, nefazodone alone is analgesic in certain animal models. In conjunction with morphine, nefazodone potentiated analgesia with no effect on lethality and little effect on gastrointestinal transit, resulting in an increase in morphine's therapeutic index. These results suggest that nefazodone and similar agents may have a significant role in the management of pain.


Submandibular cavernous hemangiomas with multiple phleboliths masquerading as sialolithiasis.
Vasoformative tumors (almost exclusively hemangiomas) are the most common lesions of the major salivary glands during infancy and early childhood. They are more common in the parotid gland but are particularly rare in the submandibular gland. Changes in blood flow dynamics within hemangiomas result in thrombus formation and phleboliths. Hemangiomas of the salivary glands in adults are histologically unlike those in infants, the former being characteristically of the cavernous variant. Most cavernous hemangiomas require surgery since they do not show a tendency to regress. A case of an adult man with cavernous hemangioma affecting the submandibular salivary gland that clinically simulated sialolithiasis is presented to alert surgeons to the possibility of such a lesion. We describe the clinical course and review the literature.


Machine-learning predictive model of pregnancy-induced hypertension in the first trimester.
In the first trimester of pregnancy, accurately predicting the occurrence of pregnancy-induced hypertension (PIH) is important for both identifying high-risk women and adopting early intervention. In this study, we used four machine-learning models (LASSO logistic regression, random forest, backpropagation neural network, and support vector machines) to predict the occurrence of PIH in a prospective cohort. Candidate features for predicting the occurrence of middle and late PIH were acquired using a LASSO algorithm. The performance of predictive models was assessed using receiver operating characteristic analysis. Finally, a nomogram was established with the model scores, age, and nulliparity. Calibration, clinical usefulness, and internal validation were used to assess the performance of the nomogram. In the training set (2258 pregnant women), eleven candidate factors in the first trimester were significantly associated with the occurrence of PIH (P < 0.001 in the training set). Four models showed AUCs from 0.780 to 0.816 in the training set. For the validation set (939 pregnant women), AUCs varied from 0.516 to 0.795. The nomogram showed good discrimination, with an AUC of 0.847 (95% CI: 0.805-0.889) in the training set and 0.753 (95% CI: 0.653-0.853) in the validation set. Decision curve analysis suggested that the model was clinically useful. The model developed using LASSO logistic regression achieved the best performance in predicting the occurrence of PIH. The derived nomogram, which incorporates the model score and maternal risk factors, can be used to predict PIH in clinical practice. We develop a model with good performance for clinical prediction of PIH in the first trimester.


LSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice.
Mammalian oocytes are arrested at prophase I until puberty when hormonal signals induce the resumption of meiosis I and progression to meiosis II. Meiotic progression is controlled by CDK1 activity and is accompanied by dynamic epigenetic changes. Although the signalling pathways regulating CDK1 activity are well defined, the functional significance of epigenetic changes remains largely unknown. Here we show that LSD1, a lysine demethylase, regulates histone H3 lysine 4 di-methylation (H3K4me2) in mouse oocytes and is essential for meiotic progression. Conditional deletion of Lsd1 in growing oocytes results in precocious resumption of meiosis and spindle and chromosomal abnormalities. Consequently, most Lsd1-null oocytes fail to complete meiosis I and undergo apoptosis. Mechanistically, upregulation of CDC25B, a phosphatase that activates CDK1, is responsible for precocious meiotic resumption and also contributes to subsequent spindle and chromosomal defects. Our findings uncover a functional link between LSD1 and the major signalling pathway governing meiotic progression.


The Half RR Rule: A Poor Rule of Thumb and Not a Risk Assessment Tool for QT Interval Prolongation.
Measuring the QT interval on an electrocardiogram (ECG) is integral to risk assessment of Torsade de Pointes (TdP). This study aimed to investigate the accuracy of the 1/2 RR rule as a risk assessment tool for drug-induced TdP, comparing it to the QT nomogram, Bazett's corrected QT (QTcB), and Fridericia's corrected QT (QTcF). The authors calculated sensitivity and specificity of the 1/2 RR rule using a published data set of 129 cases of drug-induced TdP and 316 controls (noncardiotoxic overdoses), compared to the QT nomogram, QTcB > 500 msec and QTcF > 500 msec. To further determine the value of the 1/2 RR rule, its observed positive, and negative agreement were calculated when compared to the QT nomogram for determining an abnormal QT in eight samples of different drugs in overdose. The sensitivity and specificity of the 1/2 RR rule were 88% (95% confidence interval [CI] = 80% to 93%) and 53% (95% CI = 47% to 58%), respectively, compared to the QT nomogram (sensitivity = 97%, 95% CI = 92% to 99%; specificity = 99%, 95% CI = 97% to 100%). It was also less sensitive than QTcB > 500 msec and had a lower specificity than QTcB > 500 msec and QTcF > 500 msec. In drug overdose patients, the 1/2 RR rule had poor observed agreement averaging 41%, which was mainly due to poor positive agreement, except for amisulpride where there was good agreement. The 1/2 RR rule was not as sensitive as the QT nomogram or QTcB > 500 msec for drug-induced TdP. It had poor positive agreement in almost all overdose patients, resulting in over half of patients receiving unnecessary cardiac monitoring and repeat ECGs.


Antimicrobial mechanisms of spice essential oils and application in food industry.
Spice essential oils (SEOs) are commonly used in food flavoring and are considered an effective food preservative. It has a broad range of applications and promising development prospects. As a natural food additive, SEOs' antimicrobial effects have been widely studied and utilized towards food preservation. Many SEOs have exhibited significant antimicrobial activities against food-borne pathogenic and food spoilage microorganisms. We reviewed the antibacterial and antifungal properties of SEOs, the active components, their corresponding mechanisms of actions, as well as their application in the food industry, providing a theoretical basis for SEOs' further development and application as natural preservatives.


Bovine Milk-Derived Extracellular Vesicles Inhibit Catabolic and Inflammatory Processes in Cartilage from Osteoarthritis Patients.
Data from the Osteoarthritis Initiative shows that females who drink milk regularly have less joint cartilage loss and OA progression, but the biologic mechanism is unclear. Bovine milk is a rich source of extracellular vesicles (EVs), which are small phospholipid bilayer bound structures that facilitate intercellular communication. In this study, the authors aim to evaluate whether these EVs may have the capacity to protect cartilage from osteoarthritis patients, ex vivo, by directly effecting chondrocytes. Human cartilage explants are exposed to cow's milk-derived EVs (CMEVs), which results in reduced sulfated glycosaminoglycan release and inhibition of metalloproteinase-1 expression. Incubation of articular chondrocytes with CMEVs also effectively reduces expression of cartilage destructive enzymes (ADAMTS5, MMPs), which play key roles in the disease progression. In part, these findings are attributed to the presence of TGFβ on these vesicles, and in addition, a possible role is reserved for miR-148a, which is functionally transferred by CMEVs. These findings highlight the therapeutic potential of local CMEV delivery in osteoarthritic joints, where inflammatory and catabolic mediators are responsible for joint pathology. CMEVs are carriers of both TGFβ and miR-148a, two essential regulators for maintaining chondrocyte homeostasis and protection against cartilage destruction.


Cleavage of pre-mRNA sequences by ribonucleases bound to nuclear RNP particles of rat liver.
The 30S nuclear RNP particles from rat liver have been shown to split the double-stranded- (ds) and single-stranded (ss) sequences of nuclear pre-mRNA. Experiments performed in vitro have demonstrated that 1) a 5'-exonuclease and an endonuclease specific for double-stranded pre-mRNA sequences exist in the 30S pre-mRNP particles; 2) in dsRNA monophosphorylated 5'-termini arose in the course of incubation with 30S RNP and most of the products remained double-stranded. The analysis of terminal pNp nucleotides revealed a relatively high ratio of pPyp in the cleaved dsRNA, whereas the nucleosides in 5'-terminal pNp of ssRNA showed nearly random distribution. Our results provide a possible explanation for the appearance of pNp termini during the processing of nuclear pre-mRNA of mammalian cells.


A series of typical and atypical cases of Bazex syndrome: Identifying the red herring to avoid delaying cancer treatment.
Bazex syndrome is a rare paraneoplastic dermatosis that precedes diagnosis of cancer. Awareness of this syndrome is important, as it allows early detection of underlying malignancy and may prevent misdiagnosis and delays in cancer treatment.


Glucose, glycogen and triglyceride metabolism, as well as prostaglandin production in uterine strips and in embryos from diabetic pregnant rats. Influences of the presence of substrate in the incubation medium.
"In vitro" isometric developed tension (IDT) and frequency of contractions (FC), glucose (Glu), glycogen (GLY) and triglyceride (TG) metabolism, as well as prostaglandin PGE2 and PGE1 production, were studied in uterine strips and in embryos isolated from controls and diabetic rats at day 10 of pregnancy. The IDT and the FC, at 0 time or after a 60 min incubation, were not different in controls and in preparations from diabetic animals when the uterine strips were incubated in glucose or in glucose-free medium (p > 0.05). The production of 14CO2 and 14C-lactate from 14C-glucose were lower in the diabetic group than in controls (p < or = 0.05). Indomethacin (10(-6) M), an inhibitor of prostaglandin synthesis, failed to modify these results. Labelled Glu metabolism by isolated embryos was similar (p > 0.05) in controls and in embryos obtained from diabetic mothers. On the other hand, the initial TG and GLY levels were higher (p < or = 0.05) in diabetic uterine tissues than in controls. However, the values of TG and GLY in embryos obtained from both experimental groups were similar (p > 0.05). TG levels in uterine strips suspended in Glu or in Glu-free medium did not differ (p > 0.05) at 0 time (postisolation) and at 60 min, either in controls or in diabetic rats. However, Gly levels in uterine strips from diabetic animals, decreased significantly at 60 min in tissues incubated in Glu or in Glu-free medium (p < or = 0.05). In controls, uterine Gly content decreased (p < or = 0.05) only at 60 min time when the strips were incubated in Glu-free medium. Finally, uterine tissue from controls as well as from diabetic pregnant rats release more PGE2 than PGE1 into the incubation medium (p < or = 0.001). Nevertheless, secretion of PGE2 and PGE1 was similar in both experimental groups and was not modified by the presence or absence of glucose. In summary, we found differences in uterine metabolism of glucose, glycogen and triglycerides in controls and in diabetic rats, but metabolic differences have not been detected between embryos obtained from controls and from diabetic mothers.


Psychological mediation of a type of oxidative DNA damage, 8-hydroxydeoxyguanosine, in peripheral blood leukocytes of non-smoking and non-drinking workers.
The present study investigates whether the formation of 8-hydroxydeoxyguanosine (8-OH-dG), a known oxidative DNA damage relevant to carcinogenicity, can be associated with psychological factors, in order to clarify the possible stress-cancer linkage from a genetic viewpoint. We performed a cross-sectional study in which we examined the relationships of the levels of 8-OH-dG in peripheral blood leukocytes to various psychological factors, including the Profile of Mood States (POMS) and the Center for Epidemiologic Studies Depression Scale (CES-D) in 38 non-smoking and non-drinking workers (19 males and 19 females). The levels of 8-OH-dG in male subjects were negatively correlated with the Tension-Anxiety scores of the POMS. In contrast, the levels of 8-OH-dG in female subjects were positively correlated with the Depression-Rejection scores of the POMS and the CES-D scores, and negatively associated with the Vigor scores of the POMS, respectively. Male subjects who had self-blame coping strategy displayed significantly high levels of 8-OH-dG. Moreover, the worse the subjective closeness to parents in childhood, the higher the levels of 8-OH-dG became in male subjects. The levels of 8-OH-dG increased reliably in subjects who had experienced the loss of a close family member within 3 years, when compared with non-bereaved subjects. Psychological distress may be associated with cancer risk, although sex difference influences them. Inadequate coping styles, possibly resulting from a poor interpersonal relationship with parents since childhood, and experience of a relatively recent loss of a close family member also appear to influence the pathogenesis of cancer.


Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus (jSLE).
Systemic lupus erythematosus (SLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Approximately 15-20% of SLE patients develop the disease during childhood or adolescence (juvenile-onset SLE/jSLE). Patients with jSLE exhibit more variable and severe disease when compared to patients with disease-onset during adulthood. Neuropsychiatric (NP) involvement is a clinically heterogenous and potentially severe complication. Published reports on the incidence and prevalence of NP-jSLE are scarce, and the exact pathophysiology is poorly understood.This manuscript provides a review of the existing literature, suggesting NP involvement in 13.5-51% of jSLE patients. Among patients with NP-jSLE affecting the CNS, we propose two main subgroups: (i) a chronic progressive, predominantly type 1 interferon-driven form that poorly responds to currently used treatments, and (ii) an acutely aggressive form that usually presents early during the disease that may be primarily mediated by auto-reactive effector lymphocytes. While this hypothesis requires to be tested in large collaborative international cohort studies, it may offer future patient stratification and individualised care.


Determination of the correction factors for different ionization chambers used for the calibration of the helical tomotherapy static beam.
To determine the machine-specific correction factors for three commercial ionization chambers (Exradin A1SL, PTW Semiflex and PTW PinPoint) to be applied in the dose calibration of a helical tomotherapy (HT) unit. Machine-specific reference (msr) conditions for HT unit involved a 10 × 5 cm(2) (IEC x×y) radiation field at 85 cm SSD with the ionization chamber (IC) positioned at 10 cm depth in Virtual Water. Each msr correction factor was determined using the formalism proposed by the AAPM Task Group 148 (i.e. k(Q[HT)(TG-51])) and was compared to direct calibration of the ICs against radiochromic films, calibrated in absolute dose at our institute, following the formalism proposed by the IAEA-AAPM joint committee (i.e. [Formula: see text] ). TPR(20,10) values under HT msr conditions were 0.608, 0.608 and 0.615 corresponding to %dd(10)(x[HT)(Ref]) of 0.606, 0.606 and 0.613 for A1SL, Semiflex and PinPoint ICs, respectively. Based on these findings, k(Q[HT)(TG-51]) determination resulted 0.998±0.001, 0.998±0.001 and 0.991±0.002 for A1SL, Semiflex and PinPoint ICs, respectively. The [Formula: see text] correction factors obtained through direct calibration were 1.000±0.010, 1.004±0.007 and 0.998±0.006 for A1SL, Semiflex and PinPoint ICs, respectively. Direct calibration of ICs versus radiochromic films provided correction factors equivalent to those obtained following the TG-148 formalism. This study showed that ICs calibrated for conventional linear accelerators can be used for the calibration of the static beam delivered by a HT unit taking into account the particular reference conditions.


Electrophysiologic features in patients with chronic neurolathyrism.
Neurolathyrism is a toxic nutritional disorder induced by the ingestion of the chick-pea "lathyrus sativus" and characterized by a pure motor spastic paraparesis. Eight patients with long-standing disease underwent nerve conduction and electromyographic studies. Two of them (25%) showed electrophysiological signs of lower motor neuron disease in their lower limbs. Subclinical affection of the anterior horn cells occurs probably more frequently than expected in chronic neurolathyrism.


Pinhole rupture of aortic root aneurysm with severe atherosclerotic change.
We report two cases of the rupture of calcified aortic root aneurysms that were successfully treated by emergency operations. One patient underwent Bentall's operation, and for the other, we performed a valve-sparing operation. Because their aneurysms revealed pear-like configurations with aortic regurgitation, the findings were consistent with annuloaortic ectasia (AAE). However, both cases were unlike typical AAE in that the aortic walls showed severe atherosclerotic change, with little sign of cystic medial necrosis. It was very interesting that each rupture point was a very small pinhole originating from one of the atherosclerotic ulcers.


Contributions of aspartate 49 and phenylalanine 142 residues of a tight binding inhibitory protein of beta-lactamases.
beta-Lactamases are bacterial enzymes that hydrolyze beta-lactam antibiotics to render them inactive. The beta-lactamase inhibitor protein (BLIP) of Streptomyces clavuligerus, is a potent inhibitor of several beta-lactamases, including the TEM-1 enzyme (Ki = 0.6 nM). Evidence from the TEM-1/BLIP co-crystal suggests that two BLIP residues, Asp-49 and Phe-142, mimic interactions made by penicillin G when bound in the active site of TEM-1. To determine the importance of these two residues, a heterologous expression system for BLIP was established in Escherichia coli. Site-directed mutagenesis was used to change Asp-49 and Phe-142 to alanine, and inhibition constants (Ki) for both mutants were determined. Each mutation increases the Ki for BLIP inhibition of TEM-1 beta-lactamase approximately 100-fold. To address how these two positions effect the specificity of beta-lactamase binding, Ki values were determined for the interaction of wild-type BLIP, as well as the D49A and F142A mutants, with two extended spectrum beta-lactamases (the G238S and the E104K TEM variants). Positions 104 and 238 are located in the BLIP/beta-lactamase interface. Interestingly, the three BLIP proteins inhibited the G238S beta-lactamase mutant to the same degree that they inhibited TEM-1. However, wild-type BLIP has a higher Ki for the E104K beta-lactamase mutant, suggesting that interactions between BLIP and beta-lactamase residue Glu-104 are important for wild-type levels of BLIP inhibition.


Phenotypic characterization and analysis of complete genomes of two distinct strains of the proposed species "L. swaminathanii".
Recently, a new Listeria species, "Listeria swaminathanii", was proposed. Here, we phenotypically and genotypically characterize two additional strains that were previously obtained from soil samples and compare the results to the type strain. Complete genomes for both strains were assembled from hybrid Illumina and Nanopore sequencing reads and annotated. Further genomic analysis including average nucleotide identity (ANI) and detection of mobile genetic elements and genes of interest (e.g., virulence-associated) were conducted. The strains showed 98.7-98.8% ANI with the type strain. The UTK C1-0015 genome contained a partial monocin locus and a plasmid, while the UTK C1-0024 genome contained a full monocin locus and a prophage. Phenotypic characterization consistent with those performed on the proposed type strain was conducted to assess consistency of phenotypes across a greater diversity of the proposed species (n = 3 instead of n = 1). Only a few findings were notably different from those of the type strain, such as catalase activity, glycerol metabolism, starch metabolism, and growth at 41 °C. This study further expands our understanding of this newly proposed sensu stricto Listeria species.


Resistance risk assessment for a novel succinate dehydrogenase inhibitor pydiflumetofen in Fusarium asiaticum.
Fusarium asiaticum is one of predominant pathogens of Fusarium head blight (FHB) in China. Pydiflumetofen (Pyd) is a novel succinate dehydrogenase inhibitor (SDHI) which has been commercialized in China for the controlling of wheat FHB since 2019. In the current study, a risk assessment of the pydiflumetofen-resistance selected in Fusarium asiaticum was investigated. One PydMR mutant [resistance factor (RF) < 80] and four PydHR mutants (RF > 3000) were generated by fungicide-taming from 1000 mycelial discs of the wild-type strain 2021. Nucleotide sequences alignment results of FaSdh from the wild-type strain and resistant mutants showed that all the mutations were categorized into three genotypes, i.e. FaSdhBH248Y from PydMR mutant, both FaSdhC1 A64V and FaSdhC1 R67K from PydHR mutants. All the resistant mutants possessed no fitness penalty based on the data of mycelial linear growth, conidiation and virulence. In addition, the FaSdhC1 A64V mutants showed positive cross-resistance between pydiflumetofen and boscalid or thifluzamide, but no cross-resistance between pydiflumetofen and Y13149 or Y12196, while the FaSdhC1 R67K mutants exhibited positive cross-resistance between pydiflumetofen and boscalid, thifluzamide or Y12196, and no cross-resistance between pydiflumetofen and Y13149. Furthermore, positive cross-resistance between the five tested SDHIs was detected in the FaSdhBH248Y mutants. The results suggest a moderate to high resistance risk of F. asiaticum to pydiflumetofen, and provide essential data for monitoring the emergence of resistance and resistance management strategies for pydiflumetofen, which will be useful for scientific application of this fungicide in China.


A novel sol-gel-based amino-functionalized fiber for headspace solid-phase microextraction of phenol and chlorophenols from environmental samples.
A novel amino-functionalized polymer was synthesized using 3-(trimethoxysilyl) propyl amine (TMSPA) as precursor and hydroxy-terminated polydimethylsiloxane (OH-PDMS) by sol-gel technology and coated on fused-silica fiber. The synthesis was designed in a way to impart polar moiety into the coating network. The scanning electron microscopy (SEM) images of this new coating showed the homogeneity and the porous surface structure of the film. The efficiency of new coating was investigated for headspace solid-phase microextraction (SPME) of some environmentally important chlorophenols from aqueous samples followed by gas chromatography-mass spectrometry (GC-MS) analysis. Effect of different parameters influencing the extraction efficiency such as extraction temperature, extraction time, ionic strength and pH was investigated and optimized. In order to improve the separation efficiency of phenolic compounds on chromatography column all the analytes were derivatized prior to extraction using acetic anhydride at alkaline condition. The detection limits of the method under optimized conditions were in the range of 0.02-0.05ngmL(-1). The relative standard deviations (R.S.D.) (n=6) at a concentration level of 0.5ngmL(-1) were obtained between 6.8 and 10%. The calibration curves of chlorophenols showed linearity in the range of 0.5-200ngmL(-1). The proposed method was successfully applied to the extraction from spiked tap water samples and relative recoveries were higher than 90% for all the analytes.


Restoration of Life Expectancy After Transcatheter Edge-to-Edge Mitral Valve Repair.
Survival data after mitral transcatheter edge-to-edge repair (TEER) are scarce, and its impact on predicted life expectancy is unknown. The aim of this study was to estimate the impact of TEER on postprocedural life expectancy among patients enrolled in the MitraSwiss registry through a relative survival (RS) analysis. Consecutive TEER patients 60 to 89 years of age enrolled between 2011 and 2018 (N = 1140) were evaluated. RS was defined as the ratio between post-TEER survival and expected survival in an age-, sex- and calendar period-matched group derived from the Swiss national 2011 to 2019 mortality tables. The primary aim was to assess 5-year survival and RS after TEER. The secondary aim was to assess RS according to the etiology of mitral regurgitation, age class and sustained procedural success over time. Overall, 5-year survival after TEER was 59.3% (95% CI: 54.9%-63.4%), whereas RS reached 80.5% (95% CI: 74.6%-86.0%). RS was 91.1% (95% CI: 82.5%-98.6%) in primary mitral regurgitation (PMR) and 71.5% (95% CI: 63.0%-79.3%) in secondary mitral regurgitation (SMR). Patients 80 to 89 years of age (n = 579) showed high 5-year RS (93.0%; 95% CI: 83.3%-101.9%). In this group, restoration of predicted life expectancy was achieved in PMR with a 5-year RS of 100% (95% CI: 87.9%-110.7%), whereas sustained procedural success increased the RS rate to 90.6% (95% CI: 71.3%-107.3%) in SMR. Mitral TEER in patients 80 to 89 years of age is able to restore predicted life expectancy in PMR, whereas in SMR with sustained procedural success, high RS estimates were observed. Our analysis suggests that successful, sustained mitral regurgitation reduction is key to survival improvement, particularly in patients 80 to 89 years of age.


LncRNA H19 via miR-29a-3p is involved in lung inflammation and pulmonary fibrosis induced by neodymium oxide.
The occupational and environmental health safety of rare earths has attracted considerable attention. In China, the rare earth neodymium oxide (Nd2O3) is extensively refined and utilized. However, the mechanisms of Nd2O3-induced lung injury are elusive. In the present study, we found that exposure of mice to Nd2O3 caused an inflammatory reaction and fibrosis in lung tissues, which was in relation to the Nd2O3-induced higher levels of the lncRNA H19 (H19), tumor necrosis factor receptor 1 (TNFRSF1A), p-p65, and p-IKKβ and lower levels of miR-29a-3p. Further, in mouse monocyte macrophage leukemia cells (RAW264.7), Nd2O3 induced an inflammatory reaction, increases of H19 and TNFRSF1A levels, decreases of miR-29a-3p levels, and activation of the nuclear factor (NF)-κB signaling pathway. Further, we established that miR-29a-3p regulates TNFRSF1A expression. Up-regulation of miR-29a-3p and down-regulation of H19 blocked the Nd2O3-induced secretion of TNF-α, MIP-1α, and IL-6; the increases of TNFRSF1A levels; and activation of the NF-κB signaling pathway in RAW264.7 cells. Further, in Nd2O3-treated RAW26.4 cells, H19 inhibited the expression of miR-29a-3p, which targets TNFRSF1A, and activated the NF-κB signaling pathway to enhance the expression of TNF-α, MIP-1α, and IL-6. Moreover, for mice, up-regulation of miR-29a-3p reversed lung tissue inflammation, pulmonary fibrosis, and activation of the NF-κB signaling pathway induced by Nd2O3. In sum, the present investigation shows that H19 via miR-29a-3p is involved in lung inflammation and pulmonary fibrosis induced by Nd2O3, which is a mechanism for the Nd2O3-induced lung inflammatory response and pulmonary fibrosis. This information is useful for development of a biomarker of Nd2O3-induced lung injury.


Antioxidants can increase melanoma metastasis in mice.
Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.


Emerging technologies for genetic control systems in cellular therapies.
Progress in synthetic biology has enabled the construction of designer cells that sense biological inputs, and, in response, activate user-defined biomolecular programs. Such engineered cells provide unique opportunities for treating a wide variety of diseases. Current strategies mostly rely on cell-surface receptor systems engineered to convert binding interactions into activation of a transcriptional program. Genetic control systems are emerging as an appealing alternative to receptor-based sensors as they overcome the need for receptor engineering and result in cellular behaviors that operate over therapeutically relevant timescales. Genetic control systems include synthetic gene networks, RNA-based sensors, and post-translational tools. These technologies present fundamental challenges, including the requirement for precise integration with innate pathways, the need for parts orthogonal to existing circuitries, and the metabolic burden induced by such complex cell engineering endeavors. This review discusses the challenges in the design of genetic control systems for cellular therapies and their translational applications.


The Use of the Over the Scope Clips Beyond Its Standard Use: A Pictorial Description.
Despite major improvements in endoscopic devices and therapeutic endoscopy, closure of gastrointestinal perforations, dehiscence, and fistulae had remained problematic. However, since the advent of devices such as the over the scope clip and others, endoscopic closure of gastrointestinal defects has become a routine approach. Furthermore, because of its strong apposition force, the over the scope clip may also be used to anchor fully covered self-expanding metal stents. In addition, the over the scope clip is an effective rescue therapy for various types of gastrointestinal bleeding pathologies. It is frequently used as an additional tool in complex gastrointestinal leak cases requiring internal and external drains.


First trimester serum PIGF is associated with placenta accreta.
In this retrospective study, we investigated whether first trimester serum placental growth factor (PIGF) differed amongst pregnancies with placenta previa-accreta and non-adherent placenta previa and healthy pregnancies. In 1 January 2017-30 September 2019, a total of 177 pregnant females were included in the study, as follows: 35 cases of placenta previa-accreta, 30 cases of non-adherent placenta previa, and 112 cases of age and BMI-matched, healthy pregnant controls. PIGF multiples of the median (MoM) were acquired from laboratory data files. The predictor of placenta accreta was analyzed by using multiple logistic regression analysis. PIGF MoM of placenta previa-accreta group was significantly higher than those of the non-adherent placenta previa group and control group (p = 0.0098 < 0.01, p = 0.0002 < 0.01). Serum PIGF was found to be significantly positively associated with placenta accreta after adjusted gestational week at time of blood sampling, BMI, and age (OR: 4.83; 95% CI: 1.91-12.24;p = 0.0009 < 0.01). In addition, previous cesarean section history (OR: 2.75; 95% CI: 1.23-6.17; p = 0.014 < 0.05) and smoking (OR: 9.17; 95% CI: 1.69-49.62; p = 0.010 < 0.05) were also significantly associated with placenta accreta. Increased first trimester serum PIGF was significantly positively associated with placenta accreta, suggesting that the potential role of PIGF in identifying pregnancies at high risk for placenta accreta. Previous cesarean section history and smoking may be the risk factors for accreta in placenta previa patients.


[Results of electrocoagulation of Gasser's ganglion in 250 patients with idiopathic trigeminal neuralgia].
In 250 patients with tic doulourex an percutaneous radiofrequency coagulation of the gasserian ganglion has been performed. In 92.2% of the cases the patients were post-operatively painfree. The follow-up extended in 122 cases over 7 years. In these patients a pain recurrency was noted in 27%. On behalf of low invasivity of the procedure the radio-frequency coagulation of the gasserian ganglion is a recommendable operation with low risk and high efficiency especially in old patients.


Facilitators and barriers to elders' practice of t'ai chi. A mind-body, low-intensity exercise.
Research has documented the positive effects that t'ai chi has on the well-being of elders. However, the reasons that elders practice t'ai chi have not been explored. The purpose of this study was to describe the facilitators and barriers to t'ai chi practice in elderly populations. Taiwanese community-dwelling elders (40 of whom practiced t'ai chi and 40 who did not) aged 65 and older, matched on age and gender, were interviewed. Results showed that encouragement from others was the most important factor for elders to practice t'ai chi, whereas positive health outcomes were the reason they continued to practice it. Most of the non-t'ai chi group participants had never thought about practicing t'ai chi because they felt they were too weak to practice. Because t'ai chi can be helpful in promoting the well-being of elders, it is essential for health care professionals to overcome the barriers to its uses in elderly populations.


Generation of an ultra-short electrical pulse with width shorter than the excitation laser.
We demonstrate experimentally a rare phenomenon that the width of an electrical response is shorter than that of the excitation laser. In this work, generation of an ultrashort electrical pulse is by a semi-insulating GaAs photoconductive semiconductor switch (PCSS) and the generated electrical pulse width is shorter than that of the excitation laser from diode laser. When the pulse width and energy of the excitation laser are fixed at 25.7 ns and 1.6 μJ respectively, the width of the generated electrical pulse width by 3-mm-gap GaAs PCSS at the bias voltage of 9 kV is only 7.3 ns. The model of photon-activated charge domain (PACD) is used to explain the peculiar phenomenon in our experiment. The ultrashort electrical pulse width is mainly relevant to the time interval of PACD from occurrence to disappearance in the mode. The shorter the time interval is, the narrower the electrical pulse width will become. In more general terms, our result suggests that in nonlinear regime a response signal can have a much short width than the excitation pulses. The result clearly indicates that generating ultrashort electrical pulses can be achieved without the need of ultrashort lasers.


Comparative assessment of the resistance of the unstirred water layer to solute transport between two different intestinal perfusion systems.
The resistance of the unstirred water layer to solute transport was estimated in two different intestinal single-pass perfusion systems for a comparative study, using D-glucose as a model compound. One is a well established perfusion system in anesthetized rats as a standard (system A). The other is the one in unanesthetized rats for comparison (system B). It was demonstrated that in system B as well as in system A the resistance of the unstirred water layer to D-glucose transport should be taken into account and this resistance, accordingly, the effective thickness of the unstirred water layer (delta) which is assumed to be in proportion to its resistance, could be described as a function of the perfusion rate by using a film model. The delta decreased with increasing perfusion rate and was larger in system A than in system B at each perfusion rate; 785 microns in system A versus 319 microns in system B at the perfusion rate of 0.16 ml/min and 337 microns versus 184 micron at that of 2.95 ml/min. Thus in system B the effective thickness, accordingly, the resistance, of the unstirred water layer was reduced to about 50% of that in system A, but the resistance of the unstirred water layer could still account for 85% of the total resistance at the maximum as far as D-glucose absorption was concerned, while 93% in system A. These results suggest that, compared with perfusion experiments in anesthetized rats (system A), the resistance of the unstirred water layer is reduced but cannot be left out of consideration even if perfusion experiments are performed in unanesthetized rats (system B). And the lower resistance of the unstirred water layer in system B was attributed to a turbulent flow in contrary to a laminar flow in system A.


Membrane destabilization and pore formation induced by the Synechocystis IM30 protein.
The inner membrane-associated protein of 30 kDa (IM30) is essential in chloroplasts and cyanobacteria. The spatio-temporal cellular localization of the protein appears to be highly dynamic and triggered by internal as well as external stimuli, mainly light intensity. The soluble fraction of the protein is localized in the cyanobacterial cytoplasm or the chloroplast stroma, respectively. Additionally, the protein attaches to the thylakoid membrane as well as to the chloroplast inner envelope or the cyanobacterial cytoplasmic membrane, respectively, especially under conditions of membrane stress. IM30 is involved in thylakoid membrane biogenesis and/or maintenance, where it either stabilizes membranes and/or triggers membrane-fusion processes. These apparently contradicting functions have to be tightly controlled and separated spatiotemporally in chloroplasts and cyanobacteria. IM30's fusogenic activity depends on Mg2+ binding to IM30; yet, it still is unclear how Mg2+-loaded IM30 interacts with membranes and promotes membrane fusion. Here, we show that the interaction of Mg2+ with IM30 results in increased binding of IM30 to native, as well as model, membranes. Via atomic force microscopy in liquid, IM30-induced bilayer defects were observed in solid-supported bilayers in the presence of Mg2+. These structures differ dramatically from the membrane-stabilizing carpet structures that were previously observed in the absence of Mg2+. Thus, Mg2+-induced alterations of the IM30 structure switch the IM30 activity from a membrane-stabilizing to a membrane-destabilizing function, a crucial step in membrane fusion.


Challenges in Diagnosing and Reporting Cholangiocarcinoma.
Intrahepatic cholangiocarcinoma is a challenge to the practicing surgical pathologist for several reasons. It is rare in many parts of the world, and thus practical exposure may be limited. Related to the fact of its rarity is the fact that more common tumors which frequently metastasize to the liver can be morphologically indistinguishable (eg, pancreatic ductal adenocarcinoma). Immunohistochemical testing is generally non-contributory in this context. Other difficulties arise from the protean morphologic manifestations of cholangiocarcinoma (ie, small duct vs. large duct) and the existence of combined cholangiocarcinoma and hepatocellular carcinoma. These, and other issues of concern to the practicing diagnostic pathologist are discussed herein.


Mechanistic insights on impact of Adenosine monophosphate-activated protein kinase (AMPK) mediated signalling pathways on cerebral ischemic injury.
Cerebral ischemia is the primary cause of morbidity and mortality worldwide due to the perturbations in the blood supply to the brain. The brain triggers a cascade of complex metabolic and cellular defects in response to ischemic stress. However, due to the disease heterogeneity and complexity, ischemic injury's metabolic and cellular pathologies remain elusive, and the link between various pathological mechanisms is difficult to determine. Efforts to develop effective treatments for these disorders have yielded limited efficacy, with no proper cure available to date. Recent clinical and experimental research indicates that several neuronal diseases commonly coexist with metabolic dysfunction, which may aggravate neurological symptoms. As a result, it stands to a reason that metabolic hormones could be a potential therapeutic target for major NDDs. Moreover, fasting signals also influence the circadian clock, as AMPK phosphorylates and promotes the degradation of the photo-sensing receptor (cryptochrome). Here, the interplay of AMPK signaling between metabolic regulation and neuronal death and its role for pathogenesis and therapeutics has been studied. We have also highlighted a significant signaling pathway, i.e., the adenosine monophosphate-activated protein kinase (AMPK) involved in the relationship between the metabolism and ischemia, which could be used as a target for future studies therapeutics, and review some of the clinical progress in this area.


Social Determinants and Health Equity in Functional Medicine.
The functional medicine matrix provides us with an opportunity to understand how social determinants of health (SDOH) and health related social needs may be root causes and contributors to current health and illness among patients. The matrix also allows us to map and recognize the intersectionality of SDOH on exposures and behaviors that influence antecedents, triggers, mediators, lifestyle factors, and clinical imbalances. Incorporating SDOH into clinical evaluations helps uncover and address the complex factors that lead to health disparities in order to provide more optimal patient-centered care.


Sulfobetaine as a zwitterionic mediator for 3D hydroxyapatite mineralization.
Both positively and negatively charged residues play pivotal roles in recruiting precursor ions or ion clusters, and lowering interfacial energy in natural biomineralization process. Synergistic utilization of opposite charges, however, has rarely been implemented in the design of cytocompatible synthetic scaffolds promoting hydroxyapatite (HA)-mineralization and osteointegration. We report the use of cytocompatible zwitterionic sulfobetaine ligands to enable 3-dimensional in vitro mineralization of HA across covalently crosslinked hydrogels. The overall charge-neutral zwitterionic hydrogel effectively recruited oppositely charged precursor ions while overcame excessive swelling exhibited by anionic and cationic hydrogels under physiological conditions, resulting in denser and structurally well-integrated mineralized composites. Further controls over the size, content, and spatial distribution of the mineral domains within the zwitterionic hydrogel are accomplished by facile adjustments of hydrogel crosslinking densities and the supersaturation rate governing heterogeneous mineral nucleation and growth. These findings should inspire many creative uses of zwitterionic polymers and polymer coatings for skeletal tissue repair and regeneration.


The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing.
The heterodimeric transcription factor HIF (hypoxia-inducible factor), consisting of a labile alpha-subunit and a stable beta-subunit, is a master regulator of genes involved in acute or chronic adaptation to low oxygen. Studies performed over the past 5 years revealed that HIFalpha-subunits are enzymatically hydroxylated in an oxygen-dependent manner. Hydroxylation of either of two conserved prolyl residues targets HIFalpha for destruction by a ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein whereas hydroxylation on a C-terminal asparagine affects HIF transactivation function. Pharmacological manipulation of HIF activity might be beneficial in diseases characterized by abnormal tissue oxygenation including myocardial infarction, cerebrovascular disease, and cancer.


Biophysical Reviews special issue call: LAFeBS-highlighting biophysics in Latin America.
This Commentary describes a call for contributions to an upcoming Special Issue (SI) of Biophysical Reviews on the Latin American Federation of Biophysical Societies (LAFeBS). It details the reason for the SI, the SI Editors contact information and the relevant submission details for those wishing to contribute.


Accumulation of polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (OPAHs) in organic and mineral soil horizons from four U.S. remote forests.
We characterized distributions of 23 polycyclic aromatic hydrocarbons (Σ23PAH) and nine oxygenated PAHs (Σ9OPAH) in four remote forests. We observed highest Σ23PAH and Σ9OPAH concentrations in a coniferous forest in Florida, particularly in organic layers which we attributed to frequent prescribed burning. Across sites, Σ23PAH and Σ9OPAH concentrations strongly increased from surface to humidified organic layers (+1626%) where concentrations reached up to 584 ng g(-1). Concentrations in mineral soils were lower (average 37 ± 8 ng g(-1)); but when standardized per unit organic carbon (OC), PAH/OC and OPAH/OC ratios were at or above levels observed in organic layers. Accumulation in litter and soils (i.e., enrichment factors with depth) negatively correlated with octanol-water partition coefficients (Kow) and therefore was linked to water solubility of compounds. Concentrations of Σ9OPAHs ranged from 6 ± 6 ng g(-1) to 39 ± 25 ng g(-1) in organic layers, and from 3 ± 1 ng g(-1) to 11 ± 3 ng g(-1) in mineral soils, and were significantly and positively correlated to Σ23PAHs concentrations (r(2) of 0.90) across sites and horizons. While OPAH concentrations generally decreased from organic layers to mineral soil horizons, OPAH/OC ratios increased more strongly with depth compared to PAHs, in particular for anthrone, anthraquinone, fluorenone, and acenaphthenequinone. The strong vertical accumulation of OPAH relative to OC was exponentially and negatively correlated to C/N ratios (r(2)=0.67), a measure that often is used for tissue age. In fact, C/N ratios alone explained two-thirds of the variability in OPAH/OC ratios suggesting particularly high retention, sorption, and persistency of OPAHs in old, decomposed carbon fractions.


Xanthine oxidase inhibitory peptides derived from tuna protein: virtual screening, inhibitory activity, and molecular mechanisms.
There has been growing interest in the use of xanthine oxidase (XO) as a therapeutic agent to prevent gout and hyperuricemia. In the present study, XO inhibitory peptides were identified from tuna protein by virtual screening, and molecular docking was used to elicit the interaction mechanism between XO and peptides. A novel tetrapeptide, EEAK, exhibited high XO inhibitory activity with an IC50 of 173.00 ± 0.06 μM. Molecular docking analysis revealed that EEAK bound with the pivotal residues of XO's active sites (i.e., Glu802, Arg880, Glu1261) through two conventional hydrogen bond interactions, two attractive charge interactions, and one salt bridge. EEAK could also bind with the residues Phe649, Leu648, Lys771, Ser876, Phe914, and Thr1010 of XO. This study suggested that conventional hydrogen bond interactions and electrostatic interactions play an important role in XO inhibition. The novel XO inhibitory peptide EEAK from tuna protein could be used as potential candidate for controlling gout and hyperuricemia. © 2020 Society of Chemical Industry.


Outcomes of consecutive patients referred for consideration for transcatheter aortic valve implantation from an encompassing health-care region.
Procedural outcomes for transcatheter aortic valve implantation (TAVI) are well described. However, limited information exists regarding patient screening and selection. Thus, the purpose of the study was to review consecutive patients referred for TAVI from an inclusive-defined population. The Mazankowski Alberta Heart Institute TAVI program has maintained a prospective database on all referred patients. Patients are reviewed in outpatient clinic attended by a nurse, cardiologist, cardiac surgeon, and administrative assistant. After workup is complete, a TAVI Heart Team conference occurs to accept or reject each patient. Since November 2009, 276 patients (145 men and 131 women) have been referred with a steady increase in the number of referrals annually. Mean age was 82.2 years (men 81.6 and women 82.8), with 13% aged <70 years. Mean EuroSCORE was 13.8 and mean STS score was 5.7. Of the referred patients, 34% received TAVI, 17% were rejected, 12% underwent open AVR, 10% refused TAVI, and 27% are currently being assessed or followed. There were no differences in the mean EuroSCORE (13.4 vs 14.3; p = 0.64) or STS scores (5.2 vs 6.4; p = 0.13) of those accepted for TAVI versus those who were not. In conclusion, a team-based approach to assess this complex patient population is essential to ensure efficient and comprehensive evaluation, in turn determining appropriate care allocation. With expansion of clinical experience and the evidence supporting TAVI, the Heart Teams defined to assess this patient population will be burdened with increased clinical commitment and require appropriate support.


Shape Detection using Semi-parametric Shape-Restricted Mixed Effects Regression Spline with Applications.
Linear models are widely used in the field of epidemiology to model the relationship between placental-fetal hormone and fetal/infant outcome. When researchers suspect curvilinear relationship exists, some nonparametric techniques, including regression splines, smoothing splines and penalized regression splines, can be used to model the relationship (Korevaar et al. 2016; Wu and Zhang 2006). By applying these nonparametric techniques, researchers can relax the linearity assumption and capture scientifically meaningful or appropriate shapes. In this paper, we focus on the regression spline technique and develop a method to help researchers select the most suitable shape to describe their data among increasing, decreasing, convex and concave shapes. Specifically, we develop a mixed effects regression spline to model hormonal data described in this paper. The proposed methodology is general enough to be applied to other similar problems. We illustrate the method using a state-wide prenatal screening program data set.


Chsy1 deficiency reduces extracellular matrix productions and aggravates cartilage injury in osteoarthritis.
Osteoarthritis (OA) is a kind of degenerative joint disease marked by the destruction of articular cartilage due to the degeneration of chondrocytes. CHSY1, one of the glycosyltransferases, is involved in the synthesis of chondroitin sulfate. Herein, we found that the expression of Chsy1 was decreased in the knee cartilage of OA rats. In order to investigate the role of CHSY1 in chondrogenesis and OA, we established a Chsy1 stable knockdown cell line in mouse ATDC5 chondrocytes by lentivirus. It was found that Chsy1 deficiency resulted in a reduction of extracellular matrix production in chondrocytes and a promotion of endochondral osteogenesis, which was indicated by the decreased expression of early chondrocytes genes (Col2a1, Sox9), and the increased expression of cartilage hypertrophy genes (Col10a1, Runx2, Mmp13, Mmp3). The expression trend of these genes is considered to be the characteristic of osteoarthritis. In addition, knockdown of Chsy1 could upregulate BMP signaling in differentiated chondrocytes, whereas Chsy1 overexpression had opposite effects. The reduction of extracellular matrix production and the promotion of endochondral osteogenesis by Chsy1 knockdown could be rescued by BMP signaling inhibitor LDN193189. Furthermore, the abnormally enhanced BMP signaling and the high expression of OA biomarker Mmp3 in primary cells of OA rats could be rescued by either LDN193189 or Chsy1 overexpression. These results implicate a role for Chsy1 in regulating extracellular matrix production and endochondral osteogenesis through BMP signaling; and a lack of Chsy1 could aggravate the cartilage damage of osteoarthritis.


Percutaneous Impella Recover circulatory support in high-risk coronary angioplasty.
Due to the increased life expectancy derived from better conditions of life and improved medical technology, interventional cardiologists are facing challenging procedures in older and much more delicate patients, in whom percutaneous coronary intervention is generally considered less dangerous than cardiac surgery. We present two recent cases of high-risk complete myocardial revascularization in patients older than 80 years assisted by the Impella Recover 2.5. In our initial experience this device proved to be relatively easy to set up and hemodynamically useful for patients with left ventricular dysfunction and end-stage coronary atherosclerosis.


Population structure and genetic variation of fragmented mountain birch forests in Iceland.
Betula pubescens Ehrh. (mountain birch) is the only forest-forming tree in Iceland. Since human settlement (874 AD), the continuous 25,000 to 30,000 km2 forest has shrunk to 1.200 km2 of fragmented patches, making it a good object to study population genetic consequences of habitat fragmentation and disturbance. Further, genetic studies have also shown that hybridization between the tetraploid (2n = 56) B. pubescens and the diploid (2n = 28) Betula nana L. (dwarf birch) occurs among Iceland's natural populations. This study assessed the genetic variation within and among 11 birch forests remaining across Iceland. Genotype-by-sequencing methodology provided a total of 24,585 single nucleotide polymorphisms (SNP´s), with a minor allele frequency >5% for genetic analyses. The analysis showed similar diversity within forests, suggesting that fragmentation and hybridization have had a limited effect on the genetic variation within sites. A clear genetic divergence is found among forests from the different regions of Iceland that may reflect historical isolation; the differentiation between forests increased with geographic distances reflecting isolation by distance. Information on the distribution of genetic variation of birch in Iceland is essential for its conservation and to establish genotype-phenotype associations to predict responses to new environmental conditions imposed by climate change and novel biotic/abiotic stressors.


Lymphoma simulating Crohn's colitis.
A patient with lymphomatous colitis whose disease mimicked Crohn's colitis has been presented. The diagnosis was not made despite multiple endoscopic biopsies. Lymphomatous colitis may produce a clinical and colonoscopic picture similar to Crohn's colitis.


Visual EEG reviewing times with SCORE EEG.
Visual EEG analysis is the gold standard for clinical EEG interpretation and analysis, but there is no published data on how long it takes to review and report an EEG in clinical routine. Estimates of reporting times may inform workforce planning and automation initiatives for EEG. The SCORE standard has recently been adopted to standardize clinical EEG reporting, but concern has been expressed about the time spent reporting. Elapsed times were extracted from 5889 standard and sleep-deprived EEGs reported between 2015 and 2017 reported using the SCORE EEG software. The median review time for standard EEG was 12.5 min, and for sleep deprived EEG 20.9 min. A normal standard EEG had a median review time of 8.3 min. Abnormal EEGs took longer than normal EEGs to review, and had more variable review times. 99% of EEGs were reported within 24 h of end of recording. Review times declined by 25% during the study period. Standard and sleep-deprived EEG review and reporting times with SCORE EEG are reasonable, increasing with increasing EEG complexity and decreasing with experience. EEG reports can be provided within 24 h. Clinical standard and sleep-deprived EEG reporting with SCORE EEG has acceptable reporting times.


Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial.
The bone marrow (BM) of breast cancer patients harbors tumor-reactive memory T cells (TCs) with therapeutic potential. We recently described the immunologic effects of adoptive transfer of ex vivo restimulated tumor-reactive memory TCs from the BM of 12 metastasized breast cancer patients in a clinical phase-I study. In this trial, adoptive T cell transfer resulted in the occurrence of circulating tumor antigen-reactive type-1 TCs. We here describe the long-term clinical outcome and its correlation with tumor-specific cellular immune response in 16 metastasized breast cancer patients, including 12 included in the original study. Sixteen metastatic breast cancer patients with preexisting tumor-reactive BM memory TCs were included into the study. The study protocol involved one transfusion of TCs which were reactivated in vitro with autologous dendritic cells pulsed with lysates of MCF-7 breast cancer cells as source of tumor antigens. The presence of tumor-reactive memory TCs was analyzed by IFN-γ ELISpot assays. Tumor-reactive memory TCs in the peripheral blood were induced de novo in 7/16 patients (44 %) after adoptive TC transfer. These patients were considered immunologic responders to the therapy. Positive adoptive immunotherapy (ADI) response was observed significantly more often in patients without bone metastases (p = 0.0051), in patients with high levels of tumor-reactive BM TCs prior to therapy (p = 0.036) and correlated significantly with the estimated numbers of transferred tumor-reactive TCs (p = 0.0021). After the treatment, we observed an overall median survival of 33.8 months in the total cohort with three patients alive at last follow-up and more than 7 years after ADI. Numbers of transferred tumor-reactive TCs correlated significantly with the overall survival of patients (p = 0.017). Patients with an immunologic response to ADI in the peripheral blood had a significantly longer median survival than nonresponders (median survival 58.6 vs. 13.6 months; p = 0.009). In metastasized breast cancer patients, adoptive transfer of BM TCs can induce the presence of tumor antigen-reactive type-1 TCs in the peripheral blood. Patients with immunologic response after ADI show a significantly longer overall survival. Patients with bone metastases significantly less frequently respond to the treatment and, therefore, might not be optimal candidates for ADI. Although the present study does not yet prove the therapeutic effect of ADI, these findings shed light on the relation between immune response and cancer prognosis and suggest that transfer of reactivated BM TCs might bear therapeutic potential.


Effect of nimodipine-associated hypotension on recovery from acute spinal cord injury in cats.
The effect of nimodipine on acute spinal cord trauma was studied in cats. Spinal evoked responses (SERs) were abolished after weight drop injury of 100 g-cm. All control animals showed spontaneous recovery of spinal cord function as measured by SERs. Treatment with a moderate intravenous dose of nimodipine resulted in a 32% drop in systemic blood pressure and delay in or failure of spinal cord recovery. We concluded that in this model, nimodipine treatment had deleterious effect on the spinal cord recovery due to the significant associated hypotension. It is likely that marked hypotension in the case of traumatic loss of autoregulation overrides the expected nimodipine-related increase in spinal cord blood flow with resultant additional ischemic damage.


Origin of malaria cases: a 7-year audit of global trends in indigenous and imported cases in relation to malaria elimination.
Countries in the different stages of pre-elimination, elimination, and prevention of reintroduction are required to report the number of indigenous and imported malaria cases to the World Health Organization (WHO). However, these data have not been systematically analysed at the global level. For the period 2007 to 2013, we aimed to report on 1) the proportion of countries providing data on the origin of malaria cases and 2) the origin of malaria cases in countries classified as being in the stages of pre-elimination, elimination and prevention of reintroduction. An observational study using annual data reported through routine health information systems to the WHO Global Malaria Programme between 2007 and 2013. For all countries classified as being in pre-elimination, elimination, and prevention of reintroduction in the year 2013, there has been a substantial decrease in the total number of indigenous malaria cases, from more than 15,000 cases reported in 2007 to less than 4,000 cases reported in 2013. However, the total number of imported malaria cases has increased over that time period, from 5,600 imported cases in 2007 to approximately 6,800 in 2013. Vigilant monitoring of the numbers of imported and indigenous malaria cases at national and global levels as well as appropriate strategies to target these cases will be critical to achieve malaria eradication.


Copper ligation to soluble oligomers of the English mutant of the amyloid-β peptide yields a linear Cu(I) site that is resistant to O2 oxidation.
Copper coordination to soluble oligomers of the English (AβH(6)R) mutant of the amyloid-β peptide is probed. Cu(II) coordination yields a square planar (N/O)4 coordination environment, while reduction yields an O2 inert linear bis-His Cu(I) centre.


Sampling Design and Mosquito Trapping for Surveillance of Arboviral Activity.
Mosquitoes are the most important vectors for arboviral human diseases across the world. Diseases such as Dengue Fever (DF), West Nile Virus (WNV), Yellow Fever (YF), Japanese Encephalitis (JE), Venezuelan Equine Encephalitis (VEE), and St. Louis Encephalitis (SLE), among others, have a deep impact in public health. Usually mosquitoes acquire the arboviral infection when they feed on viremic animals (birds or mammals), so their infection can be detected along the year or in short periods of time (seasons). All of this depends on the frequency and seasonality of the encounters between viremic animals and vectors.With the convergence of several phenomena like the increasing traveling of human populations, globalization of economy and more recently the global warming, the introduction of nonendemic arbovirus into new areas has become the current scenario. As examples of this new social and environmental frame we can mention the outbreak of West Nile Virus in North America in the late 1990s and more recently the outbreaks of chikungunya and Zika virus in the Americas. The present chapter deals with one of the first steps in the development of research studies and diagnosis programs, the surveillance of arboviruses in their vectors, the sampling design and mosquito trapping methods. The chapter also includes some important considerations and tips to be taken into account during the mosquito fieldwork.


Wellness, sexual health, and nonmotor Parkinson's.
Nonmotor symptoms of Parkinson's disease (PD) range from neuropsychiatric and cognitive to sleep, sensory, and genito-urinary disorders, and occur as a result of the disease process as well as due to side effects of drug treatment for PD. Sexual dysfunction is an important aspect of the nonmotor profile of Parkinson's but is rarely discussed. Sexual health is considered an integral element of holistic health, thus sexual dysfunction can also significantly impact quality of life in people with Parkinson's. The effect of sexual dysfunction of PD, both disease related and drug induced, on the concept of "wellness" of patients and their intimate partners is poorly understood, inadequately researched and a key unmet need in care and support. In this chapter we discuss the concept of "wellness" as applied to the treatment of PD, the ways in which nonmotor symptoms and other aspects of living may affect wellness in PD, and strategies for addressing sexual health utilizing a wellness model.


Association between preoperative statin use and acute kidney injury biomarkers in cardiac surgical procedures.
Acute kidney injury (AKI) is a serious complication of cardiac operations for which there remains no specific therapy. Animal data and several observational studies suggest that statins prevent AKI, but the results are not conclusive, and many studies are retrospective in nature. We conducted a multicenter prospective cohort study of 625 adult patients undergoing elective cardiac operations. All patients were taking statins and were grouped according to whether statins were continued or held in the 24 hours before operation. The primary outcome was AKI as defined by a doubling of serum creatinine or dialysis. The secondary outcome was the peak level of several kidney injury biomarkers. The results were adjusted for demographic and clinical factors. Continuing (vs holding) a statin before operation was not associated with a lower risk of AKI, as defined by a doubling of serum creatinine or dialysis (adjusted relative risk [RR] 1.09; 95% confidence interval [CI] 0.44, 2.70). However, continuing a statin was associated with a lower risk of elevation of the following AKI biomarkers: urine interleukin-18, urine neutrophil gelatinase-associated lipocalin, urine kidney injury molecule-1, and plasma neutrophil gelatinase-associated lipocalin (adjusted RR 0.34; 95% CI 0.18, 0.62), (adjusted RR 0.41; 95% CI 0.22, 0.76), (adjusted RR 0.37; 95% CI 0.20, 0.76), (adjusted RR 0.62; 95% CI 0.39, 0.98), respectively. Statins may prevent kidney injury after cardiac operations, as evidenced by lower levels of kidney injury biomarkers.


Surfactant displacement by meconium free fatty acids: an alternative explanation for atelectasis in meconium aspiration syndrome.
Meconium, an ether extract of meconium, and the major free fatty acids of meconium (palmitic, stearic, and oleic acids) were all found to increase the surface tension minimum of dog lung extract in a Wilhelmy balance. Each of these fractions was instilled into the lungs of dogs (15 experimental, eight saline solution controls), and cardiac output, venous and arterial blood gases, pulmonary, atrial, and systemic pressures, airway pressure, and static lung compliance were serially monitored for 2 hours. Mean airway pressure increased and static lung compliance decreased significantly in all of the experimental groups. Although arterial pH and PaCO2 and the various hemodynamic measurements did not change during the experiment, PaO2 decreased significantly and did not return to baseline in all experimental groups. Extracts from atelectatic portions of experimental dog lung had a surface tension minimum of greater than 20 dynes/cm, whereas airway foam had a surface tension minimum of less than 10 dynes/cm, suggesting that the free fatty acids of meconium are able to strip surfactant from the alveoli.


Effects of Postoperative Percutaneous Coronary Intervention, Pharmacologic Treatment, and Predisposing Factors on Clinical Outcomes in Patients With and Without Type 2 Diabetes Along With Critical Limb Ischemia.
Critical limb ischemia (CLI) has been identified as being connected to rates of cardiovascular mortality and lower extremity amputation (LEA). This prospective study investigated the effects of percutaneous coronary intervention (PCI), pharmacologic treatment, and predisposing factors on clinical outcomes in patients with and without type 2 diabetes mellitus (DM) along with CLI after endovascular intervention. 249 consecutive patients with CLI (Fontaine stages III-IV) received pharmacologic treatment after successful endovascular intervention. Their primary patency rates of infrapopliteal lesions and cardiovascular and amputation events during a 36-month follow-up period were assessed. Patients with DM were more likely to be younger (P = 0.026); 50% (n = 63), 42.9% (n = 54), 52.4% (n = 66), and 77% (n = 97) of DM patients had arterial calcification, end-stage renal disease, diabetic neuropathy, and Fontaine stage IV (P < 0.001, P < 0.001, P < 0.001, and P = 0.019, respectively). The primary patency rates were 61%, 48.8%, and 42.3% at 12, 24, and 36 months, in the patients without DM (P = 0.034, P = 0.013, and P = 0.005). Patients with DM had higher risks of 36-month coronary artery disease, cerebrovascular accident, mortality, and LEA (P = 0.005, P = 0.042, P = 0.042, and P < 0.001). Patients with CLI receiving long-term cilostazol treatment had a better primary patency and amputation-free survival, and a lower risk of mortality at 36 months (P < 0.001, P < 0.001, and P = 0.001). Statin use was associated with 36-month amputation-free survival but not with primary patency (P = 0.032 and P = 0.088). Subgroup multivariate Cox analyses showed that primary patency was independently associated with long-term cilostazol treatment, PCI in the first postoperative year, and direct revascularization in the DM group, whereas in the control group, long-term cilostazol treatment was the main independent factor. The risk of amputation was independently associated with a high high-sensitivity chronic reactive protein level, diabetic neuropathy, sole use of an oral hypoglycemic agent, and lack of supervised exercise. Long-term cilostazol treatment, aggressive management of dyslipidemia, and meticulous assessment and prevention of postoperative unstable coronary artery disease should be considered in CLI patients with and without DM to maximize clinical outcomes. PCI in the first postoperative year may be a predisposing factor for patency failure in patients with CLI, especially those with DM. A large-scale prospective randomized trial should be conducted to confirm these findings (TVGH IRB No. 2013-08-020B).


Role of sugars and organic acids in regulating the concentration and activity of the alternative oxidase in Poa annua roots.
Detached roots of Poa annua were used to study alternative oxidase protein expression upon the addition of sucrose, glucose, fructose, inositol, mannitol, citrate or malate, at a concentration of 1 or 10 mM for 24 h. After 24 h the capacity of cytochrome c oxidase was decreased equally in all treatments. Only citrate induced the expression of the alternative oxidase, especially at a concentration of 1 mM (15-fold). The activity of the alternative pathway (measured with the (18)O-fractionation technique) was not affected by the addition of sucrose for 24 h as compared with time zero. However, after the addition of citrate or mannitol the activity of the alternative pathway decreased to almost zero. The discrepancy between the large increase in alternative oxidase protein concentration when citrate was applied and the concomitant decrease in alternative pathway activity is discussed.


Use of dermograph for improvement of PpIX precursor's delivery in photodynamic therapy: Experimental and clinical pilot studies.
Photodynamic Therapy (PDT) is a treatment for non-melanoma skin cancer. One of the main challenges of topical PDT is to increase the precursor penetration when applied on the lesion. Protoporphyrin IX (PpIX) is an endogenous photosensitizer (PS) widely used, obtained by the administration of precursors such as aminolevulinic acid and methyl aminolevulinate. Aiming for the technique improvement by providing greater PS penetration in skin lesions, we tested a new approach for drug delivery with a minimally invasive technique. A dermograph is a device currently used in aesthetic procedures to promote skin rejuvenation or to micropigmentation. The use of dermograph for drug delivery has not been particularly explored for PDT so far, and the present study explores that approach as its main goal. This study evaluated the PpIX distribution and PDT damage in normal rat skin model; the response of dermograph application in a pilot clinical study was also investigated. The animal tests showed that more homogeneous PpIX distribution and greater penetration in the tissue was observed with dermograph when compared to the topical application. Six nodular basal cell carcinoma lesions were treated with PDT using intradermal delivery by dermograph, and no recurrence was observed after 28 months of follow-up. The precursor's penetration improvement and the consequent increase in PpIX distribution in-depth both favor PDT response, providing upgrades concerning problems that hinder the clinical practice acceptance.


US: court refuses to order disclosure of HIV status to police.
In February 2001, Massachusetts' highest court ruled that a man whose blood was splattered on police officers during his arrest is protected under that state's law from having to reveal his HIV status.


[Personality structure and subjective illness concepts of neurotically depressed patients. Qualitative comparison of 11 individual cases analyses of initial psychotherapy interviews].
Verbatim transcripts of 11 psychotherapeutic interviews with patients suffering from depressive neurosis were examined, focusing on subjective theories of illness, biography, and descriptions of the patient's own personality. The results of our qualitative content analysis allow reconstruction of some characteristic features of these patients, like over identification with social roles and norms (1), feeling of being dependent and injured by another person (2), problems of self-esteem (3), shyness (4), unfulfilled wishes to be loved and accepted (5). These findings are discussed in the context of psychopathological and psychoanalytic concepts of depression.


Cloning, expression and characterization of the putative nuclear transport factor 2 (NTF2) gene from moss Conocephalum conicum(L.) Dum.
Biomacromolecules import into the nucleus is a complex progress which requires the participation of several cytosolic factors, and nuclear transport factor 2 (NTF2) is one of essential components in nuclear trafficking. Its main role is to transport RanGDP from cytoplasm to nucleus by interacting with FxFG nucleoporin repeats. In the study a putative new gene, designated as CcNTF2, was obtained from the moss (Conocephalum conicum) cDNA library we have constructed. The full-length cDNA sequence is 913 bp in size contains a 372 bp open reading frame (ORF) flanked by a 195 bp 5'-untranslated sequence and a long 346 bp 3'-non-coding region, encoding 123 amino acids of 13,575.3 Da. Part of the genomic sequence was also cloned and sequenced, which is 1,602 bp long and possesses two exons and one intron. Alignment analysis showed that the CcNTF2 protein is high conserved among plant NTF2 and shares 81% similarity with the ones from Arabidopsis thaliana and Brassica rapa. The expression of wild-type CcNTF2 was detected by immunoblotting of extraction of C. conicum and it indicated the putative protein is integral. Through functional expression of CcNTF2-green fluorescent protein (GFP) in tobacco, it was demonstrated that CcNTF2 can accumulate at the nuclear rim. Site-directed mutagenesis analysis confirmed CcNTF2 P71K has influence on the protein import into nucleus. In addition, overexpression of CcNTF2 P71K was observed to be deleterious for the plant cell. It is the first illumination of NTF2 in moss, and our study established the primary foundation for further research on moss NTF2.


Concurrent validity of WAIS-III short forms in a geriatric sample with suspected dementia: verbal, performance and full scale IQ scores.
Evaluation of intellectual abilities using the WAIS-III is a common component of neuropsychological assessments. However, clinicians might be interested in administering reliable and valid short forms due to practical and clinical reasons. The present study examined the concurrent validity of eight short forms of the WAIS-III with full form IQ scores in a sample (n=43) of geriatric outpatients referred for assessment of suspected dementia. There were no significant differences between the short and full form VIQ scores at P<.01, while half of the short form PIQ and FSIQ scores were significantly different from their respective full form scores at P<.01. Correlations between short and full form IQ scores ranged from .89 to .99. Seven-subtest short forms were able to accurately estimate over 80% of scores within +/-2 S.E.M.s. This study supports limited use of WAIS-III short forms when conducting evaluations of older adults with suspected dementia.


Metatarsus adductus and hallux abducto valgus: their correlation.
Metatarsus adductus has long been suspected to contribute to hallux abducto valgus. This paper gives statistical evidence on the relationship between metatarsus adductus and hallux abducto valgus in an attempt to support this long held belief.


Evidence for a conceptual account of same-different discrimination learning in the pigeon.
We trained pigeons to peck two different buttons in response to 16-icon same arrays versus 16-icon different arrays. In the same arrays, the icons were all the same as one another, whereas in the different arrays, the icons were all different from one another. In Experiment 1, we upset the spatial regularities of the displays by disarranging the icons--randomly displacing each icon to reduce the degree of perceptual order. The pigeons' discriminative performance was unaffected by disarranging. In Experiment 2, spatial regularities were disturbed by varying the rotation of the icons within a display. Again, no disruption in discriminative performance was observed. These and other findings suggest that pigeons treat the 16 icons as either the same or different despite changes in the spatial organization or orientation of the icons, thus implicating a conceptual rather than a perceptual process in same-different discrimination.


Activation of cyclic AMP-dependent protein kinases in human gut adenocarcinoma (HT 29) cells in culture.
Vasoactive intestinal peptide, secretin, catecholamines and prostaglandin E1 stimulate the accumulation of cyclic AMP in HT 29 cells (see Laburthe, M. et al. (1978) Proc. Natl. Acad. Sci. U.S. 75, 2772-2775). In the present work maximal activation of protein kinases has been obtained at similar or even lower concentrations of the effectors. Maximal stimulation also requires a phosphodiesterase inhibitor. Type I and type II cyclic AMP-dependent protein kinases from basal and stimulated cells have been characterized by DEAE-Sepharose chromatography. Further identidication of the kinase has been carried out by gel electrophoresis and assay of the enzymes in the gel slabs. Comparison of the radioautography patterns of high speed supernatant lysate from basal and stimulated cells shows: First, that one type I and two type II cyclic AMP-dependent protein kinases plus one or two major and two minor cyclic AMP-independent protein kinases are present in HT 29 cells. Second, that all three holoenzymes are fully dissociated upon maximal stimulation, while the activity of the independent kinases appears unchanged.


Ultrasensitive and affordable assay for early detection of primary liver cancer using plasma cell-free DNA fragmentomics.
Early detection of primary liver cancer (PLC), including HCC, intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC (cHCC-ICC), is essential for patients' survival. This study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell-free DNA (cfDNA) fragmentomic profiles. Whole-genome sequencings (WGS) were performed using plasma cfDNA samples from 192 patients with PLC (159 HCC, 26 ICC, 7 cHCC-ICC) and 170 noncancer controls (including 53 liver cirrhosis [LC] or HBV-positive) enrolled in the training cohort. An ensembled stacked model for PLC detection was constructed using the training cohort. The model performance was assessed in an independent test cohort (189 patients with PLC [157 HCC, 26 ICC, 6 cHCC-ICC], 164 noncancer controls [including 51 LC/HBV]). Our model showed excellent performance for cancer detection in the test cohort (AUC: 0.995, 96.8% sensitivity at 98.8% specificity). It showed excellent sensitivities in detecting early-stage PLC (I: 95.9%, II: 97.9%), small tumors (≤3 cm: 98.2%), and HCC (96.2%) or ICC (100%). The AUC for distinguishing PLC from LC/HBV reached 0.985 (96.8% specificity at 96.1% specificity). Promisingly, our model maintained consistent performances during the downsampling process, even using 1X coverage data (AUC: 0.994, 93.7% sensitivity at 98.8% specificity). A separate model showed potential for distinguishing ICC from HCC (AUC: 0.776). Our model, outperforming previous reports at a lower cost by solely using low-coverage WGS data, exhibits excellent clinical potential for ultrasensitive and affordable detection of PLC and its subtypes.


Thoracic and lumbar dural ectasia in a two-year-old boy.
A two year old boy, admitted for evaluation of failure to thrive was found to have multiple paraspinal masses and a widened spinal canal. The masses proved to be lateral meningoceles, present varying degrees at every thoracic and lumbar level.


The university/public health link in reducing infant mortality in a high-risk population.
The Greater Cleveland Healthy Family/Healthy Start (HF/HS) Project Consortium was established to combine various resources in the Cleveland community in an effort to reduce the infant mortality rate by 50% over five years. As part of HF/HS, an Infant Mortality Review Program (IMRP) was instituted. This program has two important facets: an in-depth review of the circumstances of each death, and the development of scientifically-based, community-oriented interventions based on these reviews. To conduct the IMRP, a "hot line" connection with each hospital and the coroner's office was established to provide prompt notification of infant deaths and to enable timely data collection. A core review group determines actual cause of death and preventability, and identifies appropriate interventions. Recommendations issued by a technical oversight panel are disseminated to groups with the authority to institute changes in an effort to foster continuous quality improvement. Complete reviews of 243 of 319 deaths reported to date have resulted in 11 recommendations for presentation to community groups. The public health department's cooperation with other agencies has facilitated a process which ensures timely implementation. Cleveland's strongly committed consortium was able to link university and public health expertise to activate community groups and health care providers to implement recommended solutions. Demonstration of a measurable decline in the community's infant mortality rate (IMR) should provide concrete evidence of the value of such linkages. We suggest that a similar review mechanism be considered for other communities with high infant mortality rates.


China's carbon emissions peaking pathway in the post-COVID-19 era.
Several countries have weakened the carbon emission objectives to immediately revive the economy in the post-COVID-19 era. Therefore, it is a challenge worth addressing to readjust the economic development and carbon emissions after the COVID-19 pandemic. From the perspective of China's carbon emissions, this study shapes a multi-objective dynamic optimization model based on the material capital input and R&D support aspects. The proposed model imitates China's economic development, energy consumption, and carbon dioxide (CO2) emissions. The model provides theoretical suggestion for the government to revive economic development and reduce carbon emissions. In addition, this research paper compares the evolutionary path of carbon peak under the two scenarios. The first scenario requires maintaining the pre-epidemic development state and pace of carbon emission reduction, referred to as the baseline scenario (BS). The second scenario is termed the optimal scenario (OS) based on the model calculation. The study findings exhibit that China is not able to accomplish the 2030 CO2 emission peak objective, under the BS. However, China under the OS shall expectedly accomplish the 2030 carbon peak objective ahead of schedule, while the peak CO2 emissions shall be around 11.28 billion tons. Reportedly, at least 788 million tons of CO2 reduction contrasted with the BS. Furthermore, there is an 80.35% decline in energy intensity as compared to 2005. Consequently, the study results contribute theoretical guidance for the "green recovery" of China's economy and the adjustment of carbon emission reduction's path after the COVID-19 epidemic. Consistent with this, the research method also contributes to the theoretical research on carbon emissions at the national level while extending a new research perspective for the economic and environmental fields.


Theta oscillations regulate the speed of locomotion via a hippocampus to lateral septum pathway.
Hippocampal theta oscillations support encoding of an animal's position during spatial navigation, yet longstanding questions about their impact on locomotion remain unanswered. Combining optogenetic control of hippocampal theta oscillations with electrophysiological recordings in mice, we show that hippocampal theta oscillations regulate locomotion. In particular, we demonstrate that their regularity underlies more stable and slower running speeds during exploration. More regular theta oscillations are accompanied by more regular theta-rhythmic spiking output of pyramidal cells. Theta oscillations are coordinated between the hippocampus and its main subcortical output, the lateral septum (LS). Chemo- or optogenetic inhibition of this pathway reveals its necessity for the hippocampal regulation of running speed. Moreover, theta-rhythmic stimulation of LS projections to the lateral hypothalamus replicates the reduction of running speed induced by more regular hippocampal theta oscillations. These results suggest that changes in hippocampal theta synchronization are translated into rapid adjustment of running speed via the LS.


Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
Hyperostosis cranialis interna (HCI) is an autosomal dominant sclerosing bone dysplasia affecting the skull base and the calvaria, characterized by cranial nerve deficits due to stenosis of neuroforamina. The aim of this study is to describe the value of several neurophysiological, audiometric and vestibular tests related to the clinical course of the disorder. Ten affected subjects and 13 unaffected family members were recruited and tested with visual evoked potentials, masseter reflex, blink reflex, pure tone and speech audiometry, stapedial reflexes, otoacoustic emissions, brainstem evoked response audiometry and electronystagmography. Due to the symmetrical bilateral nature of this disease, the sensitivity of visual evoked potentials (VEPs), masseter reflex and blink reflex is decreased (25-37.5%), therefore reducing the value of single registration. Increased hearing thresholds and increased BERA latency times were found in 60-70%. The inter-peak latency I-V parameter in BERA has the ability to determine nerve encroachment reliably. 50% of the patients had vestibular abnormalities. No patient had disease-related absence of otoacoustic emissions, because the cochlea is not affected. In patients with HCI and similar craniofacial sclerosing bone dysplasias we advise monitoring of vestibulocochlear nerve function with tone and speech audiometry, BERA and vestibular tests. VEPs are important to monitor optic nerve function in combination with radiological and ophthalmologic examination. We do not advise the routine use of blink and masseter reflex.


Metal complexes of phenobarbituric acid. Chelating behavior of the phenobarbiturate ring. Anticonvulsant properties of the K2[Cu(N-methylphenobarbiturato)]4.8H2O.
Na2Ni(phenobarbiturato)4.3H2O, Na2Ni3(phenobarbiturato)2(OH)6.4H2O, and NaZn(phenobarbiturato)2(OH).H2O derivatives were prepared from Ni(II) and Zn(II) and phenobarbital. The Na2Ni(phenobarbiturato)4.3H2O complex is diamagnetic and isostructural with the complex previously reported, Na2Cu(phenobarbiturato)4, suggesting a square-planar environment around the Ni(II) ion. The DMF solutions of this complex show the existence of two species. The EPR spectra of the Cu(II) doped complex show the hyperfine and superhyperfine structures. The covalence parameters Alpha2, Beta2, and Delta2 show a strong bonding in the equatorial plane and suggests the formation of a [CuN4] chromophore. The anticonvulsant properties of the K2Cu(N-methylphenobarbiturato)4.8H2O are reported.


Axillary Silicone Granulomas in Patients With Melanoma.
Subcutaneous lesions may be detected during follow-up of patients with melanoma. The main entities that should be contemplated in the differential diagnosis in such cases are in-transit and regional lymph node metastases. We describe 2 cases of women with breast implants who developed palpable subcutaneous lesions in the axillary region during follow-up of melanoma. In both cases, the ultrasound study showed diffuse hyperechoic signals forming the characteristic snowstorm sign in the subcutaneous tissue. Ultrasound proved to be a key diagnostic tool for ruling out melanoma-related disease, such as in-transit metastases and regional lymph node metastases.


Characterisation of liposomes containing aminolevulinic acid and derived esters.
Liposomes of different compositions have been designed to improve delivery of aminolevulinic acid (ALA) and its esterified derivatives ALA-Hexyl ester (He-ALA) and ALA-Undecanoyl ester (Und-ALA) for its use in photodynamic therapy (PDT). Egg yolk phosphatidyl choline (PC), phosphatidic acid (PA) and phosphatidyl glycerol (PG) were employed in the preparation of the liposomes. Sonicated vesicles composed of PC, PC-PG (80:20) or PC-PA (80:20) containing ALA or derivatives were obtained and purified by a minicolumn centrifugation method. PC liposomes presented encapsulation percentages around 6% for 2 mM ALA, 13% for 2 mM He-ALA and 51% for 2 mM Und-ALA. The addition of PG or PA to the formulation, resulted in an increased entrapment: 19% for 2 mM ALA, 69% for 2 mM He-ALA and 87% for 2 mM Und-ALA in PC-PG liposomes and 21% for 2 mM ALA, 60% for 2 mM He-ALA and 87% for 2 mM Und-ALA in PC-PA liposomes. Higher concentrations of ALA or derivatives resulted in lower percentages of entrapment. The three formulations containing ALA or derivatives were stable up to 1 week upon storage at 4 degrees C. However, upon dilution with medium, ALA leaked from the liposomes, while on the contrary, He-ALA was highly retained, being therefore a good choice for its use in PDT. The stability of Und-ALA upon dilution could not be tested, but Und-ALA proved to have the highest entrapment efficacy.


New antimicrobial terpenoids and phloroglucinol glucosides from Syzygium szemaoense.
Six new terpenoids (1-6) and two new phloroglucinol glucosides (7 and 8) were isolated from the extract of Syzygium szemaoense leaves. Among the isolates, compounds 1 and 2 (named syzygiumursanolides A and B) were unusual 28-norursane type triterpenoids with 19(18→17)-abeo spirocyclic skeleton. And syzygiumone B (8) was rare ascorbyl-modified phloroglucinol glucoside. Their structures were elucidated on the basis of comprehensive 1D and 2D NMR, HRESIMS spectroscopic data analysis, as well as experimental and calculated ECD spectra and acid hydrolysis. Antimicrobial bioassay revealed that syzygiumursanolide D (4) displayed the most potent antifungal activities with MIC values ranging from 6.25 to 25 μg/mL against a panel of fungi.