Improving the effectiveness of ANT DBS therapy for epilepsy with optimal current targeting.
Deep brain stimulation of the ANT is a novel treatment option in refractory epilepsy with an established efficacy at the group level. However, data on the effect of individualized programming are currently lacking. We report the effect of programming changes on outcome in deep brain stimulation of anterior nucleus of thalamus (ANT DBS). Secondly, we investigated whether the effect differs between seizure types. Thirdly, we compared the response status between patients with stimulation contacts verified inside the ANT with patients with contacts located outside of ANT. The participants were 27 consecutive patients with ANT DBS implantation with at least two-year follow-up. Seizures were subdivided into focal aware (FAS), focal impaired awareness (FIAS), and focal to bilateral tonic-clonic seizures (FBTCS). The patients' seizure diaries were analyzed retrospectively to assess changes in different seizure types. Active contact locations for each patient were verified from preoperative MRI and postoperative CT fusion images using SureTune III (Medtronic Inc, Minneapolis, MN) software. A significant reduction in monthly mean seizure frequency occurred in FIAS: 56% at two-year and 65% at five-year follow-up. The effects on FAS and FBTCS were less pronounced. Patients with contacts inside the ANT or on the anterolateral border of ANT experienced a greater reduction in seizure frequency than patients with outside-ANT contacts. Ultimately, seven patients became responders due to changes in DBS programming or repositioning of contacts, increasing our responder rate from 44% to 70% as measured by a seizure reduction of at least 50%. ANT DBS appears to be especially effective in reducing FIAS, when the appropriately chosen contacts are activated.


Hypoxia augments TRPM3-mediated calcium influx in vagal sensory neurons.
Transient receptor potential melastatin 3 (TRPM3) channels contribute to nodose afferent and brainstem nucleus tractus solitarii (nTS) activity. Exposure to short, sustained hypoxia (SH) and chronic intermittent hypoxia (CIH) enhances nTS activity, although the mechanisms are unknown. We hypothesized TRPM3 may contribute to increased neuronal activity in nTS-projecting nodose ganglia viscerosensory neurons, and its influence is elevated following hypoxia. Rats were exposed to either room air (normoxia), 24-h of 10 % O2 (SH), or CIH (episodic 6 % O2 for 10d). A subset of neurons from normoxic rats were exposed to in vitro incubation for 24-h in 21 % or 1 % O2. Intracellular Ca2+ of dissociated neurons was monitored via Fura-2 imaging. Ca2+ levels increased upon TRPM3 activation via Pregnenolone sulfate (Preg) or CIM0216. Preg responses were eliminated by the TRPM3 antagonist ononetin, confirming agonist specificity. Removal of extracellular Ca2+ also eliminated Preg response, further suggesting Ca2+ influx via membrane-bound channels. In neurons isolated from SH-exposed rats, the TRPM3 elevation of Ca2+ was greater than in normoxic-exposed rats. The SH increase was reversed following a subsequent normoxic exposure. RNAScope demonstrated TRPM3 mRNA was greater after SH than in Norm ganglia. Incubating dissociated cultures from normoxic rats in 1 % O2 (24-h) did not alter the Preg Ca2+ responses compared to their normoxic controls. In contrast to in vivo SH, 10d CIH did not alter TRPM3 elevation of Ca2+. Altogether, these results demonstrate a hypoxia-specific increase in TRPM3-mediated calcium influx.


Comparison of coronary flow velocity reserve and aortic distensibility in diabetic versus non-diabetic patients with and without aortic atherosclerosis.
Coronary flow velocity reserve (CFR) and aortic distensibility are altered both in diabetes and in the presence of aortic atherosclerosis (AA). Transoesophageal echocardiography has been demonstrated to be a suitable method for simultaneous evaluation of these functional parameters. In the present study no significant difference could be observed in CFR and aortic distensibility in diabetic patients compared to non-diabetic subjects with or without AA.


Physical characterization of deoxyribonucleic acids of different human papilloma viruses (HPV).
Different types of human papilloma viruses (HPV) had been identified by the use of bacterial restriction endonucleases (Gissmann et al., 1977). The DNAs of HPV 1, 2, and 3 showing a similar restriction enzyme pattern can be purified in sufficient quantities to permit further characterization. These viruses appear not to be identical, as far as molecular weight (4.9 X 10(6) d), buoyant density (1.700 mu/ml), and sedimentation values of the different DNA components (Co I: 22--23S; Co II: 17S; Co III: 16S) are concerned. HPV 4 DNA, which is entirely different from HPV 1--3 in its restriction enzyme pattern, does not hybridize with cRNA transcribed in vitro from HPV 1 DNA. The cRNA was shown to represent the whole viral genome.


[The prognostic value of the laser-interference-fringe-test with cataract patients (author's transl)].
The retinal visual acuity of 198 cataractous eyes was tested with interference-fringes and compared with the post-operative visual acuity. A new method of creating interference-fringes was used. The interference-fringe technique showed its special clinical value with immature cataracts. It is of certain value also with premature cataracts. With mature and hypermature cataracts no results of clinical value could be obtained. The method seems to have its value with congenital and juvenile cataracts.


Surgical Management of Severe Epistaxis.
Many patients with severe epistaxis benefit from endoscopic intervention for control of bleeding. Critical maneuvers to improve endoscopic visualization during surgery include head-of-bed elevation, application of topical vasoconstrictors, and local injection of vasonstrictors. Controlled, hypotensive anesthesia may also decrease intraoperative blood loss and improve visualization during surgery. Intractable posterior epistaxis can be controlled with high rates of success with endoscopic sphenopalatine artery ligation. Although less common, intractable anterior epistaxis may be controlled by anterior ethmoid artery ligation once this artery is identified as the primary source. Less common sources of severe epistaxis are also discussed in this article.


Increased inhibitory action against adenosine 5'-triphosphate in the isolated taenia of the guinea-pig caecum by substitution in the A-ring of 2-phenylisatogen.
1 The ability of a series of 17 isatogen derivatives to relax smooth muscle, inhibit adenosine 5'-diphosphate (ADP)-stimulated respiration in isolated mitochondria and to antagonize the inhibitory effects of adenosine 5'-triphosphate (ATP) on smooth muscle was measured. 2 Substitution in the 4- and 7-positions of the A-ring gave compounds that were strong inhibitors of mitochondrial ATP synthesis and potent, non-specific smooth muscle relaxants. The compounds also possessed ATP-receptor blocking activity. 3 Substitution in the 5- and 6-positions of the A-ring decreased both the relaxant effect on smooth muscle and inhibition of ATP synthesis, whilst enhancing ATP-receptor antagonism. 4 In a series of 6-substituted 2-phenylisatogens, 6-methoxy-2-phenylisatogen was the most effective ATP-receptor antagonist. This compound also showed the greatest separation of the desired pharmacological activity (ATP-receptor blockade) from the other two activities (smooth muscle relaxation and inhibition of mitochondrial ATP synthesis).


1,1'-Methyl-enebis(4,4'-bipyridin-1-ium) dibromide.
The asymmetric unit of the title salt, C21H18N4 2+·2Br-, comprises half of the mol-ecule and a bromide ion. The chevron-shaped cations stack as columns in the [001] direction with suitable inter-molecular distance for π-π inter-actions. These cationic columns are further stabilized by inter-columnar C-H⋯N hydrogen bonding with the bromide ions distributed between them.


Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample.
Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide-significant (p < 5 × 10-8) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10-10), the AKAP6 gene (rs3784187, p = 1.2 × 10-8), and near the MFSD1 gene (rs340315, p = 4.5 × 10-8). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71). In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power.


Liquid chromatographic determination of daunorubicin and daunorubicinol in plasma from leukemic patients.
A method is given for the determination of daunorubicin and its main metabolite, daunorubicinol, in plasma from leukemic patients after administration of daunorubicin as the free drug or as a complex with DNA. Daunorubicin and daunorubicinol are extracted from 2 ml of plasma (pH 8.1) using a mixture of chloroform and 1-heptanol (9:1). After re-extraction into phosphoric acid (0.1 M), the separation is performed as reversed phase liquid chromatography on a LiChrosorb RP-2 (5 micrometer) column with a mobile phase of acetonitrile-water, acidified with phosphoric acid. The precision, by quantitation with a photometric detector, was better than 2% within the range 20 ng/ml to 200 ng/ml. Some determinations of plasma levels of daunorubicin and daunorubicinol are presented.


Characterization of Mycobacterium tuberculosis complex isolates from Greek patients with sarcoidosis by Spoligotyping.
Spoligotyping was undertaken with 38 Mycobacterium tuberculosis isolates from Greek sarcoidosis patients and 31 isolates from patients with tuberculosis. Fifty percent of the isolates from sarcoidosis patients and 16.13% of the isolates from patients with tuberculosis were represented by a unique pattern, whereas the remaining isolates belonged to seven shared types. Interestingly, half of the isolates from sarcoidosis patients did not resemble the spoligotypes of the isolates from patients with tuberculosis, most of which pertained to shared spoligotypes.


Affinity chromatography of antiserum to a gram negative organism.
An immunoadsorbent method is described for the purification of antibody directed against gram negative bacteria. Two anion exchange materials were compared for their ability to immobilize whole cells of Veillonella alcalescens, a gram negative oral bacterium. Purified antibody preparations were applied to the columns and subsequently eluted with various combinations of desorbing buffers. The quantity of recovered antibody was measured and its activity assayed, using a microagglutination technique. The highest levels of protein and specific antibody activity were recovered from Dowex-1-acetate columns desorbed by a combination of borate buffer pH 10 and 3 M KSCN pH 6, followed by levels of specific antibody activity obtained from a DEAE cellulose column desorbed by glycine--HC1, PBH 2.3.


Polybrominated diphenyl ethers in human serum and sperm quality.
Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants; currently, they are identified as ubiquitous environmental contaminants. Several studies indicate that PBDEs might affect male fertility. We present the results of a pilot study on the relationship between human serum PBDEs and sperm quality. The PBDE levels in Japan are comparable to those found in European countries. Strong inverse correlations were observed between the serum concentration of 2,2',4,4',5,5'-hexabromodiphenyl ether and sperm concentration (r = -0.841, p = 0.002) and testis size (r = -0.764, p = 0.01). Extensive studies on the relationship between PBDEs and sperm quality are required.


Salmonella enterica serotype Typhimurium DT 104 antibiotic resistance genomic island I in serotype paratyphi B.
We have identified Salmonella genomic island I (SGI1) in an isolate of Salmonella enterica serotype Paratyphi B. This antibiotic-resistance gene cluster, which confers multidrug resistance, has been previously identified in S. enterica serotype Typhimurium phage types DT 104 and DT 120 and in S. enterica serotype Agona.


Thalidomide inhibits adipogenesis of orbital fibroblasts in Graves' ophthalmopathy.
The expansion of orbital adipose tissue is a main pathophysiology of Graves' ophthalmopathy (GO), which is an inflammatory autoimmune disease in the orbital region. The effects of immunosuppressive drugs on adipogenesis of orbital fibroblasts have not been determined. Thalidomide, as an immunosuppressive drug, has recently been used in the therapy of many autoimmune diseases. In this study, we analyzed the effects of thalidomide on adipogenesis and found that adipocyte differentiation from preadipocytes in the orbital region was enhanced, which was demonstrated by enhanced expression of peroxisome proliferator activated receptor γ (PPARγ), ap2, and thyroid-stimulating hormone receptor (TSHR). The expression of inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) was also increased in GO. Thalidomide dose-dependently inhibited adipogenesis of 3T3-L1 preadipocytes and orbital fibroblasts from GO patients. Along with the inhibited adipogenesis, the expression of TSHR, TNFα, and IL-6 was also down-regulated. We discovered that the mechanism for thalidomide inhibiting adipogenesis was the down-regulation of PPARγ, rather than C/EBPβ and C/EBPδ. We suggest that, besides its canonical anti-TNFα effect, thalidomide plays a role in inhibiting adipogenesis of orbital fibroblasts in GO patients.


Methods to assess Drosophila heart development, function and aging.
In recent years the Drosophila heart has become an established model for many different aspects of human cardiac disease. This model has allowed identification of disease-causing mechanisms underlying congenital heart disease and cardiomyopathies and has permitted the study of underlying genetic, metabolic and age-related contributions to heart function. In this review we discuss methods currently employed in the analysis of the Drosophila heart structure and function, such as optical methods to infer heart function and performance, electrophysiological and mechanical approaches to characterize cardiac tissue properties, and conclude with histological techniques used in the study of heart development and adult structure.


Countering drug resistance, infectious diseases, and sepsis using metal and metal oxides nanoparticles: Current status.
One fourth of the global mortalities is still caused by microbial infections largely due to the development of resistance against conventional antibiotics among pathogens, the resurgence of old infectious diseases and the emergence of hundreds of new infectious diseases. The lack of funds and resources for the discovery of new antibiotics necessitates the search for economic and effective alternative antimicrobial agents. Metal and metal oxide nanoparticles including silver and zinc oxide exhibit remarkable antimicrobial activities against pathogens and hence are one of the most propitious alternative antimicrobial agents. These engineered nanomaterials are approved by regulatory agencies such as USFDA and Korea's FITI, for use as antimicrobial agents, supplementary antimicrobials, food packaging, skin care products, oral hygiene, and for fortifying devices prone to microbial infections. Nevertheless, detailed studies, on molecular and biochemical mechanisms underlying their antimicrobial activity are missing. To take the full advantage of this emerging technology selective antimicrobial activity of these nanoparticles against pathogens should be studied. Optimization of these nanomaterials through functionalization to increase their efficacy and biocompatibility is also required. Urgent in vivo studies on the toxicity of nanomaterials at realistic doses are also needed before their clinical translation.


Analysis of chlormethiazole, ethchlorvynol and trichloroethanol in biological fluids by gas-liquid chromatography as an aid to the diagnosis of acute poisoning.
A simple method has been developed whereby chlormethiazole, ethchlorvynol and trichloroethanol can be simultaneously detected and measured in biological fluids. The procedure is based upon the rapid extraction of a small (50-microliter) sample volume with an equal volume of chloroform containing an internal standard, followed by the gas-liquid chromatographic analysis of this extract. Specimens of blood plasma or serum, urine and gastric contents can be used, and no interference from either endogenous or exogenous sources has been observed. The method is suitable for the measurement of the plasma concentrations of these compounds attained after overdosage.


Pathogenic Variants in CHEK2 Are Associated With an Adverse Prognosis in Symptomatic Early-Onset Breast Cancer.
Checkpoint kinase 2 (CHEK2) is frequently included in multigene panels. We describe the associated outcomes among carriers of CHEK2 pathogenic variants in young patients with symptomatic breast cancer. Participants (N = 2,344) in the Prospective Outcomes in Sporadic Versus Hereditary Breast Cancer study had a diagnosis of primary invasive breast cancer at age ≤ 40 years. Summary statistics were used to compare tumor characteristics among CHEK2+ carriers with those who were CHEK2-. Kaplan-Meier curves were used to demonstrate overall survival (OS) and distant disease-free survival. Overall, 53 of the 2,344 participants (2.3%) had a pathogenic CHEK2 variant. CHEK2+-associated tumors were significantly more likely to be grade 2, estrogen receptor and progesterone receptor-positive compared with CHEK2- tumors (grade 2, n = 28 of 52 [53.8%] v n = 803 of 2,229 [36.0%]; P = .029). CHEK2-associated tumors were significantly more likely to have nodal involvement (N1, n = 37 of 53 [69.8%] v 1,169 of 2,253 [51.9%]; P = .0098) and demonstrated a trend toward multifocality. A higher proportion of participants with CHEK2+ variants with invasive breast cancer were obese than were those with CHEK2- variant (28.3% v 18.8%; P = .039). Univariate and multivariable analyses revealed that OS and distant disease-free survival were significantly worse in CHEK2+ versus CHEK2- carriers (OS hazard ratio, 1.58; 95% CI, 1.01 to 2.48; P = .043). This work highlights the adverse prognosis associated with breast cancer in carriers of CHEK2 pathogenic variants. It also identifies a potential association among obesity, family history, and breast cancer risk in young CHEK2 gene carriers.


Attosecond spectroscopy in condensed matter.
Comprehensive knowledge of the dynamic behaviour of electrons in condensed-matter systems is pertinent to the development of many modern technologies, such as semiconductor and molecular electronics, optoelectronics, information processing and photovoltaics. Yet it remains challenging to probe electronic processes, many of which take place in the attosecond (1 as = 10(-18) s) regime. In contrast, atomic motion occurs on the femtosecond (1 fs = 10(-15) s) timescale and has been mapped in solids in real time using femtosecond X-ray sources. Here we extend the attosecond techniques previously used to study isolated atoms in the gas phase to observe electron motion in condensed-matter systems and on surfaces in real time. We demonstrate our ability to obtain direct time-domain access to charge dynamics with attosecond resolution by probing photoelectron emission from single-crystal tungsten. Our data reveal a delay of approximately 100 attoseconds between the emission of photoelectrons that originate from localized core states of the metal, and those that are freed from delocalized conduction-band states. These results illustrate that attosecond metrology constitutes a powerful tool for exploring not only gas-phase systems, but also fundamental electronic processes occurring on the attosecond timescale in condensed-matter systems and on surfaces.


Penicillin inhibitors of purple acid phosphatase.
Purple acid phosphatases (PAPs) are binuclear metallohydrolases that have a multitude of biological functions and are found in fungi, bacteria, plants and animals. In mammals, PAP activity is linked with bone resorption and over-expression can lead to bone disorders such as osteoporosis. PAP is therefore an attractive target for the development of drugs to treat this disease. A series of penicillin conjugates, in which 6-aminopenicillanic acid was acylated with aromatic acid chlorides, has been prepared and assayed against pig PAP. The binding mode of most of these conjugates is purely competitive, and some members of this class have potencies comparable to the best PAP inhibitors yet reported. The structurally related penicillin G was shown to be neither an inhibitor nor a substrate for pig PAP. Molecular modelling has been used to examine the binding modes of these compounds in the active site of the enzyme and to rationalise their activities.


REM sleep deprivation inhibits LTP in vivo in area CA1 of rat hippocampus.
Rapid eye movement (REM) sleep deprivation has previously been shown to interfere with normal learning and memory and to inhibit long-term potentiation (LTP) in vitro. Previous studies on REM sleep deprivation and LTP have relied on in vitro analysis in isolated brain slices taken from animals following several days of sleep deprivation. LTP in the hippocampus in situ may differ from LTP in vitro due to modulatory inputs from other brain regions, which are altered after REM sleep deprivation. Here, we examined LTP in unanesthetized, behaving animals on the first and second recovery days following REM sleep deprivation to determine if similar effects are seen in vivo as previously reported in vitro. We found that LTP was significantly impaired in REM sleep-deprived animals on the second recovery day but not the first recovery day. Our results extend previous findings by showing that REM sleep deprivation continues to affect hippocampal function for more than 24h following the end of deprivation. Our results also suggest the presence of a modulatory process not present in vitro. Our findings are not explained by stress during REM sleep deprivation because equivalent circulating corticosterone levels (an index of stress) were found during both REM sleep deprivation and control treatment.


Brief report: a comparison of statistical learning in school-aged children with high functioning autism and typically developing peers.
Individuals with autism spectrum disorders have impairments in language acquisition, but the underlying mechanism of these deficits is poorly understood. Implicit learning is potentially relevant to language development, particularly in speech segmentation, which relies on sensitivity to transitional probabilities between speech sounds. This study investigated the relationship between implicit learning and current language abilities in school-aged children with high functioning autism and a history of language delay (n = 17) and in children with typical development (n = 24) using a well-studied artificial language learning task. Results suggest that high functioning children with autism (HFA) and TD groups were equally able to implicitly learn transitional probabilities from a lengthy stimulus stream. Furthermore, task performance was not strongly associated with current language abilities. Implications for implicit learning research in HFA are discussed.


Site-specific substitutions of the Tyr-165 residue in the catalytic chain of aspartate transcarbamoylase promotes a T-state preference in the holoenzyme.
The amino acid residue Tyr-165C of aspartate transcarbamoylase (EC 220.127.116.11) of Escherichia coli has been proposed to be involved in the transition from the T-state to the R-state upon binding of the bisubstrate analogue N-(phosphonacetyl)-L-aspartate. Site-specific mutagenesis has been used to substitute phenylalanine for tyrosine, thus maintaining the aromatic R-group but removing the charged hydroxyl moiety. This mutation dramatically altered the aspartate requirements for the holoenzyme but did not substantially affect the homotropic or heterotropic characteristics of the oligomer. The aspartate requirements for half-maximal saturation increased from 5.5 mM at pH 7.0 for the native holoenzyme to approximately 90 mM in the mutant enzyme. Nonetheless, estimates of the kinetic cooperativity index remained similar (Hill coefficients: Tyr-165C, n = 2.1; Phe-165C, n = 2.5). CTP inhibited both enzymes approximately 70% and ATP activated approximately 40% at the aspartate concentrations required for half-maximal saturation (5 and 90 mM, respectively). The maximal velocity of the mutant holoenzyme is almost identical to that of the wild-type enzyme. The phenylalanine substitution does not affect the stability of the holoenzyme to heat or mercurials, and the Vmax of the catalytic trimer was 444% greater than that of the holoenzyme. Upon dissociation of the wild-type native enzyme into catalytic trimers, the Vmax increased 450%. The Km for aspartate in the separated catalytic trimer is approximately 2-fold higher than for the native catalytic trimer (16.5 versus 8 mM at pH 7.0). It is clear from the data that although Tyr-165C is not directly involved in the active site of the enzyme, it does play a pivotal role in catalytic transitions of the holoenzyme. In addition, the homotropic and heterotropic characteristics of the enzyme do not seem to be altered by the substitution of phenylalanine for Tyr-165C in the E. coli aspartate transcarbamoylase, although other substitutions have been reported (Robey, E. H., and Schachman, H. K. (1984) J. Biol. Chem. 259, 11180-11183) which show more complex effects.


Facile preparation of a novel high performance benzoxazine-CNT based nano-hybrid network exhibiting outstanding thermo-mechanical properties.
Untreated multi-walled carbon nanotubes (MWCNTs) have been dispersed in two benzoxazine precursors following an easy procedure. The strong intrinsic interactions of CNTs with a selected precursor give rise to the formation of a reinforced network with outstanding thermo-mechanical properties.


Factors associated with changes in leisure time physical activity during early pregnancy.
To identify key factors involved in modifying leisure time physical activity (LTPA) during early pregnancy. A prospective study was conducted of 1175 pregnant women who attended a scheduled visit at Virgen de las Nieves University Hospital, Granada, Spain, at 20-22 weeks of pregnancy. The Paffenbarger Physical Activity Questionnaire was used to collect data regarding participation in any LTPA or physical activity performed according to society recommendations during early pregnancy and in the year before pregnancy. A polytomous regression model was used to identify factors associated with LTPA. Approximately 20.0% of the women did not engage in any LTPA, and 68.0% did not achieve the recommendations for exercise, either before or during pregnancy. Desirable changes related to performing any LTPA or the society recommendations for LTPA during pregnancy were associated with university level of education (aOR, 3.64 [95% CI, 1.54-8.56] and aOR, 1.75 [95% CI, 0.67-4.57], respectively) and smoking cessation at pregnancy (aOR, 2.05 [95% CI, 0.97-4.35] and aOR, 4.83 [95% CI, 1.31-17.83], respectively). Few women achieved the minimum recommendations for exercise before or during pregnancy. Nevertheless, adoption of healthy lifestyle choices during pregnancy seemed to promote other healthy habits, such as participation in LTPA.


Unusual structures of TTTA repeats in icaC gene of Staphylococcus aureus.
One and two TTTA repeat expansions have been found in the coding region of icaC gene of Staphylococcus aureus variants which influence the expression of IcaC protein and alter the phenotype. Yet, the mechanism of these small-size TTTA repeat expansions remains unclear. In this study, we performed high-resolution nuclear magnetic resonance spectroscopic studies on TTTA repeats. Our results show that a DNA sequence containing three TTTA repeats can fold into dumbbell structures with a 3' or 5'-overhang. Exchange of these dumbbells makes the sequence behave like a 2-nt TT mini-loop at 25°C. The occurrence of these mini-loop and dumbbell structures in the nascent strand during DNA replication provides possible mechanistic pathways which account for one and two repeat expansions.


Postprandial increase of plasma apoAV concentrations in Type 2 diabetic patients.
Postprandial hypertriglyceridemia is considered as a risk factor for cardiovascular disease in Type 2 diabetes. However, little is known about the underlying mechanisms. Since the recently discovered apolipoprotein (apo) AV was identified as a modulator of triglyceride (TG) metabolism, the aim of the study was to determine the postprandial apoAV profile of Type 2 diabetic patients. We compared data from 11 patients with Type 2 diabetes mellitus to that of 12 non-diabetic normolipidemic subjects following the ingestion of a lipid-rich cream. Postprandial apoAV was elevated in diabetic patients but no correlation was observed either with plasma TG concentration or with the intensity of lipoprotein lipase-dependent lipolysis. These data obtained in human subjects suggest that plasma apoAV concentration does not play an acute or a direct role in the regulation of plasma TG in the postprandial state.


Pharmacological profile of BR-931, a new hypolipidemic agent that increases high-density lipoproteins.
BR-931 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl)-acetamide], a new hypolipidemic agent of low toxicity, was evaluated in several tests of lipolysis and hyperlipidemia in rats, and in the cholesterol-induced atherosclerosis in rabbits. Significant hypolipidemic activity was observed in rats with doses of the agent at 12.5--50 mg/kg. In the Triton-induced hyperlipidemia, 50 mg BR-931 per kg was equieffective as 200 mg of clofibrate (CPIB) per kg. In contrast with CPIB, BR-931 exerted a powerful antilipolytic activity against epinephrine, ACTH, nicotine and cold exposure. BR-931 was particularly effective in diet-induced hyperlipidemias. Ethanol lipemia was totally prevented by the agent at 100 mg/kg. With Nath's diet, doses as low as 25 mg/kg significantly reduced hypercholesterolemia and hypertriglyceridemia. In these last two tests, the distribution of lipoprotein cholesterol was also determined. CPIB did not affect HDL cholesterol levels that had been decreased by the diets; in contrast, BR-931, already at doses of 50 mg/kg, brought the HDL/total cholesterol ratio back toward normal. A significant HDL cholesterol increase, together with some reduction of atheromatosis, was also observed in cholesterol-fed rabbits. BR-931, a potent inducer of liver peroxisones and of mitochondrial carmitine acetyltransferase, appears to be a hypolipidemic agent of high efficacy and low toxicity for the clinical treatment of hyperlipidemias and atherosclerosis.


DNA microarray analysis of changes in gene expression induced by 1,25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells.
Using a DNA microarray, we analyzed about 16,600 genes for changes in expression associated with the differentiation of human promyelocytic leukemia HL-60 cells induced by 1alpha,25-dihydroxyvitamin D3 (DVD). Many of the up-regulated genes could be correlated to differentiation-associated changes toward a monocyte/macrophage lineage, and many down-regulated genes could be correlated to repressed cell growth. The present study revealed the down-regulated gene expression of importins and exportins 1, 5, 7, and exportin-tRNA. Thus, the present results confirmed our previous findings of down-regulation of exportin 1 and exportin-tRNA by DVD. Gene expression of exportin 6 is suggested to be regulated differently from that of exportins 1, 5, 7, and exportin-tRNA. The down-regulation of nuclear transport factors may be deeply associated with the differentiation of HL-60 cells induced by DVD.


Frantz's tumor: a papillary and cystic tumor of the pancreas in girls.
Four girls with Frantz's tumor, a papillary and cystic tumor of the pancreas, are studied and discussed in comparison with 112 cases in the literature, including 58 Japanese cases. The neoplasms occur predominantly in girls and young women. Up to recently, the tumors have possibly been misclassified as nonfunctioning islet cell tumor or carcinoma, acinar cell carcinoma, papillary cystadenocarcinoma, or pancreatoblastoma according to microscopic findings and frequently have been managed with aggressive surgery such as pancreatoduodenectomy. The tumors are well encapsulated and the cut surfaces show characteristically solid and hemorrhagic-necrotic patterns. Ultrasonography and CT scan are the most useful tools for the diagnosis. The neoplasms usually behave like a very low-grade malignancy, so that complete removal is the treatment of choice for the tumor arising anywhere in the pancreas. Immunochemical and electron microscopic studies can differentiate Frantz's tumor from other neoplasms and also suggest that the tumors originate from primordial cells or multipotential stem cells capable of differentiating into both exocrine and endocrine lines.


Sterols in erg mutants of Phycomyces: metabolic pathways and physiological effects.
Phycomyces is a fungal producer of beta-carotene and other beneficial metabolites. Several erg mutants of Phycomyces, originally selected to study the effects of membrane alteration on physiological responses, have now been used to gain information about sterol biosynthesis in filamentous fungi. One mutant, H23, and its progeny were found to be blocked at episterol C-5 dehydrogenase and did not produce ergosterol or any other sterol with a conjugated Delta(5,7) diene system. This mutant showed abnormal phototropism, which was correlated with the altered sterol composition. Another mutant, H25, seems to be a regulatory mutant. All analyzed mutants synthesized ergosta-7,22,24(28)-trien-3beta-ol, demonstrating for the first time that the sterol C-22 dehydrogenase of Phycomyces is capable of recognizing sterols with a 24(28) unsaturated side chain. New evidence regarding the biogenesis of neoergosterol and phycomysterols, the potential sparking function of cholesterol, as well as the regulation of sterol biosynthesis in this fungus is also reported. Given these results, a pathway for sterol biosynthesis in Phycomyces is proposed.


FROM NASA TO HEALTHCARE: REAL-TIME DATA ANALYTICS (MISSION CONTROL) IS RESHAPING HEALTHCARE SERVICES.
This is a case study of the implementation of a data and analytics-enabled Mission Control at one of the largest healthcare service providers in the state of Washington. Using data analytics and artificial intelligence, CHI-Franciscan (one of the largest healthcare organizations in state of Washington) is able to coordinate patient care more effectively and efficiently, improving safety for all its patients. This case study demonstrates tangible evidence from quantitative and qualitative analysis for return on investment for such a large project.


Review and survey of medicaments used with gingival retraction cords.
Data from a survey of 495 dentists indicate that most dentists used the mechanical-chemical method of gingival-deflection; 79.39% of those used cord containing epinephrine. It can be concluded that potentially significant amounts of epinephrine can be absorbed systemically from the local anesthetic solution, that secretion of endogenous epinephrine in response to stress occurs, often at levels sufficient to cause measurable changes in hemodynamic variables, and that absorption of epinephrine from impregnated strings occurs. The amount of absorption will vary with the exposure of the vascular bed, the length and concentration of the impregnated cord, and the length of time of application. It is possible that the actual total amount of circulating catecholamine would be cumulative, and the corresponding cardiovascular response would be related to the total amount of epinephrine in the bloodstream, regardless of the source. When the fact that we usually have inadequate data on the cardiovascular status of our patients is considered, as well as the tendency to make impressions of multiple prepared teeth, the continued use of epinephrine cord in dentistry must be viewed with alarm. Equally effective astringent gingival deflection agents such as alum, aluminum sulfate, and aluminum chloride exert no systemic effects. Therefore, there is little indication for use of epinephrine-containing retraction cords. Adequate medical evaluation, careful use of anesthetics that contain epinephrine, and sedative techniques when indicated will assure the safety of our patients.


Chronic paronychia treatment: Square flap technique.
Chronic paronychia is an inflammatory process of the periungual folds that lasts longer than 6 weeks. It manifests as hypertrophy of the proximal and lateral nailfolds, absence of cuticle, progressive retraction of the proximal nailfold, and onychodystrophy. Surgical treatment is recommended if there has been insufficient response to 6 months of appropriate medical therapies. We describe a new surgical technique that removes the fibrotic tissue without complete excision of the proximal and lateral nailfold, minimizing nailfold retraction and recovery time. We present a case series of 34 fingers (9 patients) treated with this new technique. All nailfolds healed well without complications. At the end of the follow-up, all fingers, apart from 2, were relieved of the preoperative symptoms. The length of the ungual plate was maintained in all patients, with no retraction of the nailfolds. Follow-up period of 6 months and small sample size are limitations of this study. This surgical technique can provide an alternative treatment for chronic paronychia, with good prognosis during follow up-period and optimal cosmetic results.


Alloimmunity does not protect from challenge with the feline immunodeficiency virus.
Immune responses against polymorphic host molecules incorporated into lentiviral envelopes during cell budding have induced protection against primate immunodeficiency virus infection. Dendritic cells (DCs) express high levels of MHC molecules and are infectable by lentiviruses. Therefore, in this pilot study we addressed the hypothesis that immunization of cats with allogeneic DC would induce immune responses that protect against challenge with the feline immunodeficiency virus. Two groups of 3 cats each received 3 subcutaneous injections of allogeneic or autologous DC, and were then challenged with viruses propagated in the immunizing DC. Infection status and lymphocyte parameters of cats were assessed during 6 weeks after challenge. MHC II antigens were incorporated into viral particles as identified by Western blot; and antibodies reactive with MHC class II antigens were detected in the serum of cats immunized with allogeneic but not autologous DC. After challenge, all cats had proviral DNA in blood leukocytes from 2 weeks post-challenge onward and seroconverted. Cats immunized with allogeneic DC maintained higher total and CD21(+) lymphocyte concentrations, and higher CD4(+)/CD8(+) lymphocyte ratios; however, these differences were not significantly different from cats that received autologous DC immunizations. Plasma viral load was not significantly different between groups of cats (p=0.204). These results suggest that immunization of cats with allogeneic DC does not induce protective immunity against FIV infection.


Oligomers of hepatitis A virus (HAV) capsid protein VP1 generated in a heterologous expression system.
The quasi-enveloped picornavirus, Hepatitis A Virus (HAV), causes acute hepatitis in humans and infects approximately 1.5 million individuals a year, which does not include the asymptomatically infected population. Several severe outbreaks in developing nations in recent years have highlighted the reduction in HAV endemicity, which increases the risk of infections in the vulnerable population. The current HAV vaccines are based on growing wildtype or attenuated virus in cell culture, which raises the cost of production. For generation of cheaper, subunit vaccines or strategies for antibody-based diagnostics, production of viral structural proteins in recombinant form in easily accessible expression systems is a priority. We attempted several strategies for recombinant production of one of the major capsid proteins VP1, from HAV, in the E. coli expression system. Several efforts resulted in the formation of soluble aggregates or tight association of VP1 with the bacterial chaperone GroEL. Correctly folded VP1 was eventually generated in a discrete oligomeric form upon purification of the protein from inclusion bodies and refolding. The oligomers resemble oligomers of capsid proteins from other picornaviruses and appear to have the correct secondary and antigenic surface structure. VP1 oligomers generated in the bacterial expression system can be utilized for understanding the molecular pathway of HAV capsid assembly and may also have potential biomedical usages in prevention and diagnostics of HAV infections.


Association of four DNA polymorphisms with acute rejection after kidney transplantation.
Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50-6.67]; P=0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42-8.09]; P=0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52-14.55]; P=0.007) and twice as likely in patients with at least one A allele of TNF-alpha G-308A (OR: 2.18, 95% CI [1.08-4.41]; P=0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.


Validation of UK-BCIS CHIP Score to Predict 1-Year Outcomes in a Contemporary United States Population.
A complex high-risk indicated percutaneous coronary intervention (CHIP) score was recently developed from the British Cardiovascular Intervention Society (BCIS) database to define CHIP cases and their risk of in-hospital major adverse cardiac or cerebrovascular events (MACCE). The authors sought to apply this score to a contemporary U.S. population for the prediction of adverse events at 1 year following percutaneous coronary intervention (PCI). Consecutive patients undergoing PCI at a large tertiary care center between 2011 and 2020 were considered for inclusion. Patients were categorized into 4 groups based on their BCIS-CHIP score (0, 1-2, 3-4, ≥5). In each category, we assessed the 1-year risk of MACCE, a composite of all-cause death, myocardial infarction, and stroke. Secondary outcomes were the individual components of MACCE, and major bleeding at 1 year. Among 20,799 patients included, MACCE at 1 year occurred in 1.7% patients with score 0 (reference), 3.0% with score 1 or 2 (HR: 1.72; 95% CI: 1.32-2.24), 6.1% with score 3 or 4 (HR: 3.60; 95% CI: 2.78-4.66), and 12.0% with score ≥5 (HR: 7.40; 95% CI: 5.75-9.51). Each point increase of the BCIS-CHIP score conferred a 28.0% increase of MACCE risk. The BCIS-CHIP score demonstrated good discrimination for the prediction of 1-year MACCE (C-index 0.70). The risk of secondary outcomes also progressively increased with higher score values. In a large PCI registry, the BCIS-CHIP score had a good predictive value for MACCE at 1 year. The utilization of this score can facilitate an accurate risk stratification of patients undergoing PCI.


One year of COVID-19 pandemic: Health care workers' infection rates and economical burden in medical facilities for oral and maxillofacial surgery.
The aim of this study was to create an overview on the COVID-associated burdens faced by the oral and maxillofacial surgery (OMS) workforce during 1 year of the pandemic. OMS hospitals and private practices nationwide were surveyed regarding health care worker (HCW) screening, infection status, pre-interventional testing, personal protective equipment (PPE), and economic impact. Participants were recruited via the German Society for Oral and Maxillofacial Surgery. A total of 11 hospitals (416 employees) and 55 private practices (744 employees) participated. The HCW infection rate was significantly higher in private practices than in clinics (4.7% vs. 1.4%, p<0.01), although most infections in HCW occurred in private environment (hospitals 88.2%, private practice 66.7%). Pre-interventional testing was performed significantly less for outpatients in private practices than in hospitals (90.7% vs. 36.4%, p<0.01). Polymerase chain reaction (PCR) was used significantly more for inpatients in hospitals than in private practices (100.0% vs. 27.3%, p<0.01). FFP2/3 use rose significantly in hospitals (0% in second quarter vs. 46% in fourth quarter, p<0.05) and private practices (15% in second quarter vs. 38% in fourth quarter, p<0.01). The decrease in procedures (≤50%) was significantly higher in hospitals than in private practices (90.9% vs. 40.0%, p<0.01). Despite higher infection rates in private practices, declining procedures and revenue affected hospitals more. Future COVID-related measures must adjust the infrastructure especially for hospitals to prevent further straining of staff and finances.


Evidence for a signal peptide at the amino-terminal end of human mitochondrial aldehyde dehydrogenase.
A full-length cDNA clone coding for human mitochondrial aldehyde dehydrogenase (ALDH I) was isolated from a human fetal muscle cDNA library. Sequence analysis revealed structural similarities between the amino-terminal end of ALDH I and other known targeting sequences responsible for protein uptake into the mitochondria.


Dual-color quantum dots nanobeads based suspension microarray for simultaneous detection of dual prostate specific antigens.
Featured with high multiplexibility, suspension microarray technology usually involves the conjugation of second-antibody with organic dye based fluorescent proteins, which are inherently unsuitable for multicolor signaling under single wavelength excitation. In addition, application of single QDs-based fluorescent reporter in suspension microarray is dramatically hampered since its preparation often suffers from poor reproducibility and stability. Herein, a novel suspension microarray system based on dual color quantum dots (QDs) nanobead as fluorescence label was developed for simultaneous detection of prostate specific antigen (PSA) biomarkers. When both antigens are present in sera sample, free (f)-PSA antibody-conjugated green and complexed (c)-PSA antibody-conjugated red QDs nanobeads would be both specifically absorbed onto the surface of total PSA antibody-conjugated magnetic beads, leading to the formation of magnetic fluorescent hybrid that can be purified from the mixture by an external magnet prior to flow cytometry analysis. The proposed method demonstrates simultaneous detection ability for f- and c- PSA antigen assay with high detection sensitivity that is comparable to clinical approaches including ELISA and chemiluminescence assay. Furthermore, result of clinical application of the proposed method is consistency with clinical data, demonstrating its potential in suspension microarray for accurate prostate cancer diagnosis.


Prevention of reperfusion injury in the neonatal heart with leukocyte-depleted blood.
Activated leukocytes release oxygen free radicals and cause microvascular occlusion. This experiment tests the hypothesis that reperfusion with leukocyte-depleted blood reduces injury after extended ischemic preservation. An in vitro model consisting of an isolated, working neonatal piglet heart and an adolescent support pig was used. Hearts were arrested with a cold crystalloid cardioplegic solution, excised, and stored in 4 degrees C saline for 12 hours. Two groups were compared. In group 1 piglets (n = 8), reperfused with whole blood, the maximum stroke work index was 0.91 +/- 0.29 x 10(3) erg/gm (mean +/- standard error of the mean). Group 2 piglets (n = 6), reperfused with blood depleted of leukocytes by a polyester filter, had a maximum stroke work index of 11.6 +/- 1.0 x 10(3) erg/gm. This difference was highly significant (p less than 0.0001). Group 1 exhibited severe injury with myofibrillar necrosis, mitochondrial disruption, nuclear chromatin clumping, and moderate interstitial edema. Group 2 had normal ultrastructure on electron microscopic examination. We conclude that reperfusion with leukocyte-depleted blood prevents reperfusion injury and results in excellent myocardial function after long-term heart preservation.


[Total synthesis and properties of prostaglandins. XXIV. Synthesis of glycerides with prostaglandin acyl residues].
Synthesis of a number of model triglycerides and lysoglycerides bearing the acyl moieties of 11-deoxyprostaglandin E1, and palmitic acid residues has been carried out.


Improving interstitial transport of macromolecules through reduction in cell volume fraction in tumor tissues.
Interstitial transport of large molecules and nanoparticles is an important concern in nanomedicine-mediated cancer treatment. To that end, the current study was proposed to improve the transport through enlargement of extracellular space by treating tumors with hypertonic solution of mannitol and cytotoxic agents (e.g., ethacrynic acid [ECA]), which could effectively shrink and kill cells, respectively. In the study, the improvement in interstitial penetration of dextran was investigated ex vivo using rat fibrosarcoma tissues sectioned into 600 μm slices. Experimental data showed that the hypertonic solution was more effective than ECA for improving interstitial penetration of dextran with molecular weights ranging from 4000 to 2,000,000. The extent of improvement depended on the size of dextran molecules and the time when the treatment was applied. Results from the study suggested that increases in both size and connectedness of interstitial pathways were important for improvement of interstitial transport of large molecules and nanoparticles. This study reports on the optimization of interstitial transport both for large molecules and nanoparticles in nanomedicine-mediated cancer treatment. The study demonstrates that hypertonic solutions could efficiently lead to cancer cell shrinkage and more so than the applied cytotoxic agent thereby improving transport of chemotherapeutic entities.


Addressing the instability issue of dopamine during microdialysis: the determination of dopamine, serotonin, methamphetamine and its metabolites in rat brain.
Dopamine is a catecholamine neurotransmitter that degrades rapidly in aqueous solutions; hence, its analysis following brain microdialysis is challenging. The aim of the current study was to develop and validate a new microdialysis coupled LC-MS/MS system with improved accuracy, precision, simplicity and turnaround time for dopamine, serotonin, methamphetamine, amphetamine, 4-hydroxymethamphetamine and 4-hydroxyamphetamine analysis in the brain. Dopamine degradation was studied with different stabilizing agents under different storage conditions. The modified microdialysis system was tested in vitro, and was optimized for best probe recovery, assessed by %gain. LC-MS/MS assay was developed and validated for the targeted compounds. Stabilizing agents (ascorbic acid, EDTA and acetic acid) as well as internal and cold standards were added on-line to the dialysate flow. Assay linearity range was 0.01-100 ng/mL, precision and accuracy passed criteria, and LOQ and LLOQ were 0.2 and 1.0 pg, respectively. The new microdialysis coupled LC-MS/MS system was used in Wistar rats striatum after 4 mg/kg subcutaneous methamphetamine. Methamphetamine rapidly distributed to rat striatum reaching an average ~200 ng/mL maximum, ~82.5 min post-dose. Amphetamine, followed by 4-hydroxymethamphetamine, was the most abundant metabolite. Dopamine was released following methamphetamine injection, while serotonin was not altered. In conclusion, we proposed and tested an innovative and simplified solution to improve stability, accuracy and turnover time to monitor unstable molecules, such as dopamine, by microdialysis.


Elevated hematocrit in nonalcoholic fatty liver disease: a potential cause for the increased risk of cardiovascular disease?
Hematocrit is an important hemorheological parameter. Both hematocrit and nonalcoholic fatty liver disease (NAFLD) are strongly correlated with cardiovascular disease. However, there is no study to explore the direct relationship of hematocrit with NAFLD. Hematocrit levels were analyzed from 1,821 Chinese Han adults, and questionnaire and physical examination were administered to know and suspect the relationship with NAFLD. NAFLD morbidity was positively correlated with hematocrit levels in both male and female. Multivariate-adjusted odds ratio illustrated that, compared with the lowest quartile of hematocrit, the highest quartile subjects had a 185% and 386% increased risk for developing NAFLD in male and female, respectively. Further receiver operating characteristic analysis showed that the optimal cutoff value of hematocrit for detecting NAFLD was 42.75 in male and 37.55 in female. Unhealthy lifestyles had similar effects on NAFLD and hematocrit. The prevalence of NAFLD is positively associated with hematocrit levels. Though the cause-effect relationship between NAFLD and hematocrit still needs further investigation to clarify, the elevated hematocrit in NAFLD patients may be of significance to link NAFLD and cardiovascular disease.


Bleeding in cardiac surgery: the use of aprotinin does not affect survival.
The antifibrinolytic drug aprotinin has been the most widely used agent to reduce bleeding and its complications in cardiac surgery. Several randomized trials and meta-analyses have demonstrated it to be effective and safe. However, 2 recent reports from a single database have implicated the use of aprotinin as a risk for postoperative complications and reduced long-term survival. In this single-institution observational study involving 7836 consecutive patients (1998-2006), we assessed the safety of using aprotinin in risk reduction strategy for postoperative bleeding. Aprotinin was used in 44% of patients. Multivariate analysis identified aprotinin use in risk reduction for reoperation for bleeding (odds ratio, 0.51; 95% confidence interval, 0.36-0.72; P = .001) and need for blood transfusion postoperatively (odds ratio, 0.67; 95% confidence interval, 0.57-0.79; P = .0002). The use of aprotinin did not affect in-hospital mortality (odds ratio, 1.03; 95% confidence interval, 0.71-1.49; P = 0.73), intermediate-term survival (median follow-up, 3.4 years; range, 0-8.9 years; hazard ratio, 1.09; 95% confidence interval, 0.93-1.28; P = .30), incidence of postoperative hemodialysis (odds ratio, 1.16; 95% confidence interval, 0.73-1.85; P = .49), and incidence of postoperative renal dysfunction (odds ratio, 0.78; 95% confidence interval, 0.59-1.03; P = .07). This study demonstrates that aprotinin is effective in reducing bleeding after cardiac surgery, is safe, and does not affect short- or medium-term survival.


Navigator-triggered oxygen-enhanced MRI with simultaneous cardiac and respiratory synchronization for the assessment of interstitial lung disease.
To evaluate an optimized method for oxygen-enhanced MRI of the lung, using simultaneous electrocardiograph (ECG) and navigator triggering. To correlate oxygen-enhanced MRI with lung function tests assessing alveolar-capillary gas exchange. A total of 12 healthy volunteers (aged 20-32 years) and 10 patients (aged 37-87 years) with interstitial lung diseases (ILD) underwent oxygen-enhanced MRI and pulmonary functional tests (PFTs) assessing alveolar-capillary gas exchange. The paradigm room-air-oxygen-room-air was acquired with a nonselective inversion-recovery half-Fourier single-shot turbo spin-echo sequence (inversion time = 1200 msec; acquisition time = 134.5 msec; slice thickness = 20 mm; matrix size = 128 x 128), using simultaneous double triggering (navigator plus ECG trigger). Cross-correlation was performed in regions of interest (ROIs) encompassing both lungs. The number of oxygen-activated pixels over the total number of pixels in the ROIs (OAP%) of volunteers and patients was compared. OAP%s were correlated with PFTs. The mean OAP% of patients was significantly lower than that of volunteers (36.7 vs. 81.7, P = 0.001). OAP% correlated with the transfer lung factor for carbon monoxide (Tlco) (r = 0.64; P = 0.002), the transfer coefficient (Kco) (r = 0.75; P = 0.001), the arterial partial pressure (r = 0.77; P < 0.001), and the saturation (r = 0.70; P < 0.001) of oxygen. Navigator-triggered oxygen-enhanced MRI of the lung may have a potential role in the quantitative assessment of lung function in ILD.


How do patients develop trust in community pharmacists?
Pharmacists frequently self-describe as "the most trusted health care professional" in society. Beyond the rhetoric of such self-promoting statements, there is little empirical evidence regarding how trust between pharmacists and patients is formed, nurtured, and sustained. This exploratory qualitative study in Ontario, Canada was undertaken in early 2020 to characterize trust-enhancing factors in community pharmacy practice. Recruitment posters/handouts in purposively-selected pharmacies using a convenience sampling of people collecting prescriptions was used to recruit 28 patient-participants. Inclusion criteria included a minimum of six conversations with a pharmacist regarding health/medication use in the previous 12 months. A semi-structured interview protocol was used to elicit descriptions from patients regarding how experiences with community pharmacists shaped or influenced trust formation in both individual pharmacists and the profession as a whole. A total of 28 patients were interviewed for this study. Five trust-enhancing factors were identified: i) availability; ii) affability; iii) acknowledgement; iv) respect; and v) interpersonal chemistry. Within each factor, sub-factors or facets were also identified that focused on specific behaviours of community pharmacists that helped enhance trust. This study suggests that trust-enhancing factors include a series of interpersonal communication behaviours and skills that are within the control of pharmacists; leveraging these behaviours and skills in a more consistent and effective manner may support more trusting relationships between pharmacists and patients. For pharmacists to truly live up to the moniker of "most trusted health care professional" it is important to better understand how trust is built and sustained, and to consider opportunities to focus on specific trust-enhancing behaviours that ultimately support better patient care and outcomes.


Cellulose-supported bioadsorbent from natural hemp fiber for removal of anionic dyes from aqueous solution.
The aim of this study is to prepare an eco-friendly bioadsorbent by graft copolymerization and modification from hemp fiber including bio-macromolecules such as cellulose, hemicellulose and lignin for anionic dyes adsorption from aqueous solutions, and to investigate adsorptive properties. The prepared cellulose-supported bioadsorbent (TEPA-(GMA-g-HF)) was characterized in detail using SEM-EDX, STEM, FTIR, XRD, TGA and BET techniques and calculating the point of zero charge. It was used as an adsorbent to remove three different anionic dyes, Remazol Brilliant Blue R (RBBR), Reactive Red 120 (RR120) and Reactive yellow 160 (RY160) from the aqueous medium. The effects of adsorbent amount, pH, initial dye concentration, time and temperature on the adsorption were investigated. From the results, it was determined that the adsorption of all three dyes to the developed fibrous bioadsorbent was more compatible with the pseudo-second-order kinetic and the Langmuir isotherm model. It was found that the adsorption capacity increased with increasing temperature, and the adsorption capacity at 298 K was 91.70 mg/g for RBBR, 83.33 for RY160 and 76.34 mg/g for RR120, respectively. Dye removal efficiencies were provided as approximately 100 % at acidic pHs. This high removal efficiency has also achieved in the dense matrix medium, and even after five consecutive reused.


Immortalized fibroblasts from NF-kappaB RelA knockout mice show phenotypic heterogeneity and maintain increased sensitivity to tumor necrosis factor alpha after transformation by v-Ras.
Activation of the NF-kappaB pathway can either promote or block apoptosis and oncogenesis in different cell types and circumstances. In this report, we show that independently derived immortalized mouse embryonic fibroblast cell lines prepared from RelA knockout mice have different phenotypes, based on their sensitivity to tumor necrosis factor alpha (TNFalpha)-induced apoptosis, morphology, ability to form colonies in soft agar, and the presence of distinct kappaB site-binding complexes. In addition, these RelA-deficient cell lines appear to have distinct alterations in the p53 pathway, which correlate with the normal vs transformed status of individual cell lines. We have also infected mouse embryonic fibroblasts lacking RelA, c-Rel or p50 with a retrovirus for the expression of v-Ha-Ras to determine whether individual NF-kappaB family members are required for Ras-mediated transformation. All three NF-kappaB-deficient cell types could be transformed by v-Ha-Ras. However, v-Ras-infected RelA-deficient cells formed colonies in soft agar at an approximately fourfold reduced efficiency compared to v-Ras-transformed control mouse 3T3 and p50-deficient cells. Ras transformation did not alter the sensitivity of RelA-deficient cells to TNFalpha-induced apoptosis, and Ras transformation did not affect the general resistance of 3T3, c-Rel-deficient, and p50-deficient cells to TNFalpha-induced apoptosis. However, TNFalpha specifically and dose-dependently decreased the ability of v-Ras-transformed RelA-deficient cells to form colonies in soft agar. These results suggest that RelA is a potential protein target for human tumors driven by oncogenic Ras mutations, but caution that inhibition of RelA may promote tumorigenesis in some circumstances.


[The arthroscopic SLAP refixation].
Lesions of the superior glenoid labrum and the insertion of the biceps tendon are a common cause for shoulder pain in patients performing overhead sports. The therapeutic management depends on the type of lesion, and should be carried out using an arthroscopic procedure. While type I SLAP lesions should be treated conservatively or with simple debridement, SLAP II, IV, and V lesions, with a detachment of the labrumanchor- complex, should be refixed with suture anchors. Only in cases of type III lesions with a bucket handle-like lesion of the labrum, but stable insertion of the biceps tendon, a simple debridement can be performed. From the biomechanical point of view, large type III lesions should also be reconstructed. To improve the arthroscopic view for preparation of the glenoid neck, an intraarticular loop ("Imhoff-suspension sling") can prevent the posterosuperior labrum from falling into the joint. The arthroscopic SLAP refixation is a technically highly demanding procedure which provides good clinical results for the patient.


Effects of various microwave intensities collaborated with different cold plasma duration time on structural, physicochemical, and digestive properties of lotus root starch.
Lotus root starch was treated with single and combined microwave (300 and 700 W) and cold plasma (60, 90, and 120 s) treatments. Effects of treatments on multi-structural, physicochemical, and digestive properties of lotus root starch were investigated. The results revealed that a combination of cold plasma and microwave treatments significantly affected the morphology of starch granules and reduced the relative crystallinity of starch compared with a single treatment. However, no changes were found in the chemical functional groups of starch after single or combined treatments. Additionally, the amylose content, amylopectin branch chain length distribution, solubility, and swelling power of the starch significantly varied depending on cold plasma treatment duration and microwave power. Furthermore, the treated starch showed lower peak viscosity and higher pasting temperature than the native one. Moreover, the resistant starch content significantly decreased as cold plasma treatment was prolonged and microwave power increased.


A game-based approach for designing a collaborative evolution mechanism for unmanned swarms on community networks.
Intelligent and coordinated unmanned aerial vehicle (UAV) swarm combat will be the main mode of warfare in the future, and mechanistic design of autonomous cooperation within swarms is the key to enhancing combat effectiveness. Exploration of the essential features and patterns of autonomous collaboration in unmanned swarms has become the focus of scientific research and technological applications, in keeping with the evolving conceptions of the military theatre. However, given the unique attributes of the military and the novelty of the warfare mode of unmanned swarms, few achievements have been reported in the existing research. In this study, we analysed the military requirements of unmanned swarm operations and proposed an analytic framework for autonomous collaboration. Then, a literature review addressing swarm evolution dynamics, game-based swarm collaboration, and collaborative evolution on complex networks was conducted. Next, on the basis of the above work, we designed a community network for unmanned swarm cooperation and constructed a collaborative evolution model based on the multiplayer public goods game (PGG). Furthermore, according to the "network" and "model", the dynamic evolution process of swarm collaboration was formally deduced. Finally, a simulation was conducted to analyse the influence of relevant parameters (i.e., swarm size, degree distribution, cost, multiplication factor) on the collaborative behaviour of unmanned swarms. According to the simulation results, some reasonable suggestions for collaborative management and control in swarm operation are given, which can provide theoretical reference and decision-making support for the design of coordination mechanisms and improved combat effectiveness in unmanned swarm operation.


The effects of preferred provider organizations on costs and utilization of hysterectomy.
In this study, the costs and service utilization of preferred provider organizations (PPOs) were compared against traditional indemnity plans with similar benefits and utilization review for hysterectomy, a potentially overused procedure. PPOs were associated with significant cost savings, achieved primarily through lower utilization rates.


Integrated metabolomics and transcriptomics analysis reveals that the change of apoplast metabolites contributes to adaptation to winter freezing stress in Euonymus japonicus.
Euonymus japonicus, a common urban street tree, can withstand winter freezing stress in temperate regions. The apoplast is the space outside the plasma membrane, and the changes of metabolites in apoplast may be involved in plant adaptation to adverse environments. To reveal the molecular mechanism underlying the winter freezing stress tolerance in E. japonicus, the changes in physiological and biochemical indexes, apoplast metabolites, and gene expression in the leaves of E. japonicus in early autumn and winter were analyzed. A total of 300 differentially accumulated metabolites were identified in apoplast fluids in E. japonicus, which were mainly related to flavone and flavonol biosynthesis, and galactose metabolism, amino acid synthesis, and unsaturated fatty acid synthesis. Integrated metabolomics and transcriptomics analysis revealed that E. japonicus adjust apoplast metabolites including flavonoids such as quercetin and kaempferol, and oligosaccharides such as raffinose and stachyose, to adapt to winter freezing stress through gene expression regulation. In addition, the regulation of ABA and SA biosynthesis and signal transduction pathways, as well as the activation of the antioxidant enzymes, also played important roles in the adaptation to winter freezing stress in E. japonicus. The present study provided essential data for understanding the molecular mechanism underlying the adaptation to winter freezing stress in E. japonicus.


Masks or N95 Respirators During COVID-19 Pandemic-Which One Should I Wear?
Coronavirus Disease 2019 (COVID-19) has caused suffering and death around the world. Careful selection of facial protection is paramount for preventing virus spread among healthcare workers and preserving mask and N95 respirator supplies. This paper is a comprehensive review of literature written in English and available on Pubmed comparing the risk of viral respiratory infections when wearing masks and N95 respirators. Current international oral and maxillofacial surgery guidelines for mask and N95 respirator use, patient COVID-19 disease status, aerosol producing procedures were also collected and incorporated into a workflow for selecting appropriate facial protection for oral and maxillofacial surgery procedures during the current pandemic. Most studies suggest N95 respirators and masks are equally protective against respiratory viruses. Some evidence favors N95 respirators, which are preferred for high-risk procedures when aerosol production is likely or when the COVID-19 status of a patient is positive or unknown. N95 respirators may also be used for multiple patients or reused depending on the type of procedure and condition of the respirator after each patient encounter. N95 respirators are preferred over masks against viral respiratory pathogens, especially during aerosol-generating procedures or when a patient's COVID-19 status is positive or unknown.


Activation of Aptamers with Gain of Function by Small-Molecule-Clipping of Intramolecular Motifs.
Click reactions have the advantages of high reactivity, excellent orthogonality, and synthetic accessibility. Inspired by click reactions, we propose the concept of "clipped aptamers", whose binding affinity is regulated by the "clip"-like specific interaction between a synthetic DNA-mismatch-binding small molecule (molecular glue, Z-NCTS) and the preset CGG/CGG sequences in nucleic acid sequences. In this study, we investigated a Z-NCTS-mediated de novo selection of clipped aptamers against epithelial cell adhesion molecule. The generated clipped aptamers can achieve the efficient transition from a binding-inactive state to an active state by clipping of Z-NCTS with two CGG sites, which otherwise would not hybridize. The experimental and simulation results showed that the clipped aptamer had ideal binding thermodynamics and the ability to regulate cellular adhesion. Because of this superior activated mechanism and structural diversity, clipped aptamers hold great potential in biosensing, imaging, conditional gene- and cellular behavior-regulation, and drug delivery.


Implementation of a computerized management information system in an urban fire department.
An important aspect in the effective management of an emergency medical services system is the ability to monitor system performance. To provide this information on a timely basis, a comprehensive data collection system is required. We describe the design, implementation, use, and effect of a comprehensive, computerized data retrieval system within an urban fire department. Building on a data collection system already in place, it was possible to minimize the cost and accelerate the training process. A comparison is included between the different type of systems available for use with prehospital providers. Use of prehospital data collection systems results in more in-depth understanding of system operations and the status of prehospital medical care provided to the community.


Diagnostic accuracy of two-dimensional echocardiography for detection of left atrial thrombus in patients with mitral stenosis.
Two-dimensional echocardiograms of 56 patients with mitral stenosis, who subsequently underwent operation, were analyzed to evaluate the accuracy for the detection of left atrial thrombi. From left parasternal, apical, and subcostal cardiac windows, multiple planes (including standard planes and their derived scanning planes) were assessed for the presence or absence of mass echoes in the left atrium. The results showed 63% sensitivity, 95% specificity, 87% positive predictive value, 84% negative predictive value, and 83% overall diagnostic accuracy. Most of the false-negative cases had their thrombi confined to the left atrial appendage. We conclude that in patients with mitral stenosis, two-dimensional echocardiography is promising for the diagnosis of left atrial thrombi, particularly when they locate or extend to the main left atrial cavity (not confined to atrial appendage).


Radical radiation therapy of advanced lung cancer: evaluation of prognostic factors and results of continuous and split course treatment.
One hundred patients with inoperable (80) or unresectable (20) bronchogenic carcinoma without evidence of spread beyond the thorax and supraclavicular nodes were planned for radical radiotherapy. Seventy-six patients received continuous irradiation (6000 rads in 30 treatments in 6 weeks, TDF 99) and 24 received split course therapy (2 courses of 2500 rads in 10 treatments with a 3 week break between courses, TDF 88). Forty-three patients had squamous cell carcinoma or adenocarcinoma and were considered to have favorable prognostic factors, while 57 patients had unfavorable prognostic factors: undifferentiated large cell or small cell carcinoma, supraclavicular metastases, SVC obstruction, superior sulcus tumors, or bone erosion in continuity with the tumor. Ninety-two patients completed the planned course of treatment. In patients completing treatment, local control of cancer within the irradiated volume was achieved in 58.5% of continuously irradiated patients and 45.4% of patients receiving split course therapy. Median survival was 1.2 months in patients not completing treatment and 12 months for the patients who completed treatment; 19% of the total group survived 3 years. Median and 3 year survivals of 14 months and 20.4% and of 9 months and 11% were observed for patients treated continuously and by the split course techniques, respectively. Corresponding survival figures for patients with favorable and unfavorable prognostic signs were 21 months and 26%, and 4 months and 11%, respectively. Implications of these data for treatment planning and patient selection for radical radiotherapy in bronchogenic carcinoma are discussed.


Malondialdehyde concentration in plasma is inversely correlated to the proportion of linoleic acid in serum lipoprotein lipids.
It has been suggested that the susceptibility of low density lipoprotein (LDL) to oxidative stress depends on the balance between its contents of polyunsaturated fatty acids and antioxidants. In a healthy reference population (n = 103), the plasma concentration of malondialdehyde (MDA) (mean 0.86, range 0.50-1.27 mumol/l) was positively correlated to the serum concentrations of LDL cholesterol (r = 0.31, P = 0.001), very low density lipoprotein triglycerides (r = 0.25, P = 0.009) and apolipoprotein B (r = 0.23, P = 0.03), and negatively correlated to lipid corrected alpha tocopherol in serum (r = -0.22, P = 0.02) and lipoprotein(a) (Lp(a)) (r = -0.26, P = 0.01). Plasma MDA was negatively correlated to the content of linoleic acid in the serum lipoprotein phospholipids (r = -0.35, P = 0.0008). In a stepwise regression analysis 12% of the variation in plasma MDA was explained by variations in the content of linoleic acid and 27% after addition of Lp(a) and abdominal sagittal diameter. The significant negative relation between plasma MDA and the amount of linoleic acid in the lipoprotein lipids indicates that other factors, e.g. the availability of anti-oxidants and the lipoprotein metabolism, may be of greater importance for intravascular lipid peroxidation than the proportion of polyunsaturated fatty acids in the lipoprotein lipids.


Accelerated human epidermal turnover driven by increased hyaluronan production.
Hyaluronan (HA) is an essential component of extracellular matrix in the skin, but its functions in the epidermis remain elusive. We examined the interaction of increased HA production mediated by 1-ethyl-β-N-acetylglucosaminide (β-NAG2), a newly developed highly selective inducer of HA production which is intracellularly converted to UDP-N-acetylglucosamine, a substrate of HA, with epidermal proliferation and differentiation. The amount, molecular size and epidermal tissue distribution of HA and expression of CD44, a cell surface receptor for HA, were analyzed in β-NAG2-treated organ cultured human skin, reconstructed human skin equivalents or cultured human skin keratinocytes. The relationship between HA and epidermal proliferation or differentiation was examined. β-NAG2 significantly increased HA production in the epidermis of skin explants or skin equivalents without affecting molecular size of HA (>2000 kDa) or CD44 mRNA expression. Histochemical experiments revealed that β-NAG2 enhances HA signals in the basal to granular layers of the epidermis of skin equivalents, accompanying increased epidermal stratification. Immunohistochemical experiments demonstrated that signals of Ki67, transglutaminase 1 and filaggrin are increased in β-NAG2-treated skin equivalents, and these observations were confirmed by the data showing that mRNA expression of PCNA, transglutaminase 1 (TGM1) and filaggrin (FLG) is significantly up-regulated by β-NAG2 in skin equivalents. Importantly, blockade of HA production by inhibiting conversion of β-NAG2 to UDP-NAG abolished β-NAG2-mediated up-regulation of PCNA, TGM1 and FLG mRNA expression in cultured keratinocytes. These results suggest that increased epidermal HA production plays a key role in epidermal morphogenesis and homeostasis by accelerating keratinocyte proliferation and differentiation.


Integrating virtual and biochemical screening for protein tyrosine phosphatase inhibitor discovery.
Protein tyrosine phosphatases (PTPs) represent an important class of enzymes that mediate signal transduction and control diverse aspects of cell behavior. The importance of their activity is exemplified by their significant contribution to disease etiology with over half of all human PTP genes implicated in at least one disease. Small molecule inhibitors targeting individual PTPs are important biological tools, and are needed to fully characterize the function of these enzymes. Moreover, potent and selective PTP inhibitors hold the promise to transform the treatment of many diseases. While numerous methods exist to develop PTP-directed small molecules, we have found that complimentary use of both virtual (in silico) and biochemical (in vitro) screening approaches expedite compound identification and drug development. Here, we summarize methods pertinent to our work and others. Focusing on specific challenges and successes we have experienced, we discuss the considerable caution that must be taken to avoid enrichment of inhibitors that function by non-selective oxidation. We also discuss the utility of using "open" PTP structures to identify active-site directed compounds, a rather unconventional choice for virtual screening. When integrated closely, virtual and biochemical screening can be used in a productive workflow to identify small molecules targeting PTPs.


Changes of Early Sepsis Biomarker Presepsin Level during Hemodialysis: Influence of β2-Microglobulin Clearance of Dialysis Membrane: A Preliminary Study.
Although presepsin (P-SEP) is an early sepsis biomarker, sepsis is often suspected after starting hemodialysis (HD). To enhance the utility of P-SEP, we investigated whether pre-HD P-SEP levels could be predicted using the P-SEP levels from blood samples collected after starting HD. We observed P-SEP level changes due to HD and dialyzer passage in HD patients using a dialysis membrane with a β2-microglobulin (β2-MG) clearance of either ≥50 mL/min (high-flux) or < 30 mL/min (intermediate-flux). We calculated the removal ratios for the elimination of P-SEP or the predicted pre-HD P-SEP levels based on the correction of hemoconcentration. The P-SEP levels significantly decreased at 4 h after starting HD (n = 8) using membranes with a β2-MG clearance ≥50 mL/min; the removal ratios at 2 and 4 h were 42.8 ± 7.9% and 58.8 ± 18.4%, respectively. In contrast, the P-SEP levels did not decrease during the passage of dialyzer in 2 patients with a β2-MG clearance < 30 mL/min, and the P-SEP levels increased during HD in all patients (n = 10, including the abovementioned 2 patients) with a β2-MG clearance < 30 mL/min. The predicted pre-HD P-SEP levels (y) were strongly correlated with the actually measured pre-HD P-SEP levels (x) (R 2 = 0.9562) using the regression equation: y = 1.0987x. The levels of P-SEP with a molecular weight near that of β2-MG decreased similarly to those of β2-MG during HD using membranes with a β2-MG clearance ≥50 mL/min. On the contrary, the levels of P-SEP rather increased during HD with a β2-MG clearance < 30 mL/min, suggesting that P-SEP appeared not to be eliminated. Furthermore, the pre-HD P-SEP levels might be predictable by the correction of hemoconcentration using even blood samples collected after starting HD with a β2-MG clearance < 30 mL/min.


Combination chemotherapy for islet cell carcinoma and metastatic carcinoid tumors with 5-fluorouracil and streptozotocin.
The results of combination chemotherapy with intermittent courses of 5-fluorouracil and streptozotocin in ten patients with metastatic carcinoid tumors and in eight patients with islet cell carcinoma are reported. Objective responses occurred in two of ten and in two of seven evaluable patients respectively. Biochemical responses occurred in an additional two patients with carcinoid. No improvement over single-agent chemotherapy and no effects on survival were noted.


Simultaneous measurement of pure curvature and twist distribution fields by a five-aperture shearing and two-fourier filtering technique.
A five-aperture shearing and two-Fourier filtering technique to measure simultaneously pure curvature and twist distribution fields of a deformed object is proposed. In this method the slope fringes that are contained in the patterns of curvature and twist fringes can be completely eliminated. Thus patterns of pure curvature and twist fringes with a good contrast can be obtained. A theoretical analysis and experimental results are given.


Antitumour activity of coumarin in prostate and mammary cancer models.
The antineoplastic and antimetastatic activities of coumarin were evaluated in transplanted prostate tumours of the rat. The growth of Noble Nb-R prostate tumours was strongly inhibited by coumarin (40 mg/kg; administered three times per week), whereas the hormonally more sensitive Dunning R3327-G rat prostate carcinoma did not respond. Coumarin was also shown to possess antimetastatic activity in a Dunning R3327-MatLu tumour model. The number of lung metastases was reduced significantly by 40%-50% following the administration of coumarin (40 mg daily). Preliminary data from experiments with rats bearing DMBA-induced mammary carcinomas showed that these tumours are as sensitive to coumarin as Noble-R-prostate tumours.


Access, utilization, and awareness for clinical genetic testing in autism spectrum disorder in Sweden: A survey study.
Several medical professional societies recommend clinical genetic testing for autistic individuals as many genetic conditions are linked to autism. However, it is unclear to what extent autistic individuals and parents of autistic children are offered clinical genetic testing. We conducted a community-based survey to estimate the access, utilization, and awareness for clinical genetic testing in Sweden. In total, 868 parents of autistic children and 213 autistic adolescents or adults participated as respondents. The referral rate for clinical genetic testing after autism spectrum disorder diagnosis was low, with only 9.1% for the autistic children as reported by their parents and 2.8% for autistic adolescents/adults. The autistic children who got referrals were more likely to have intellectual disability and language disorder. We also report that awareness of the clinical genetic testing possibility was low in both respondent groups. We also highlight preferred communication means and needs for information before clinical genetic testing. Our results show that utilization and access are low in Sweden, and more studies should be conducted to report these rates in different countries to analyze the effects of clinical genetic testing on healthcare for autistic individuals. Our results highlight the most important information for the families and how the information should be communicated prior to clinical genetic testing.


Heat shock of porcine zygotes immediately after oocyte activation increases viability.
We evaluated the effect of different timing variations of an applied heat shock on parthenogenetically activated (PA) porcine embryos. PA embryos were heat shocked for 9 hr at 42 degrees C from either 0-9 hr post activation (hpa; 09HS), 13-22 hpa (1322HS), or 22-31 hpa (2231HS). Analysis of 24-hr cleavage rates (P < 0.0001), day 5 cell numbers (P < 0.005), day 7 blastocyst rates (P < 0.0001), and day 7 cell numbers (P < 0.05) showed that 09HS embryos developed more successfully in vitro than did all other treated and control embryos. In vitro fertilized (IVF) embryos were exposed to similar heat treatments as described for PA embryos, and embryos derived from somatic cell nuclear transfer (SCNT) were exposed only to the control and 09HS treatments to assess the effects of the different heat treatments on the timing of first cleavage and development to blastocyst. Embryos derived from both IVF and SCNT showed higher proportions of cleaved embryos on day 1 of development when heat shocked immediately after fertilization or fusion/activation as compared to NHS controls (P < 0.05). Blastocyst rates however, showed only modest (IVF; P = 0.089) or no (SCNT; P > 0.1) improvement as compared with control embryos. In summary, exposing PA embryos to elevated temperatures immediately after oocyte activation results in dramatically enhanced developmental potential. A thorough characterization of this phenomenon may yield findings that can serve to increase the efficiency with which PA, IVF, and SCNT embryos are produced in vitro.


Hypertrophic cardiomyopathy: two-dimensional echocardiographic score versus clinical and electrocardiographic findings.
The severity and site of hypertrophy is important in determining the clinical picture and the natural history of hypertrophic cardiomyopathy (HCM). We evaluated left ventricular hypertrophy by means of two-dimensional echocardiographic score and score index, and correlated these findings with symptoms, electrovector-cardiographic data, and ventricular arrhythmias. A total of 42 patients with HCM were studied by clinical examination, ECG, VCG, M-mode and 2D echocardiography, and 24-h Holter monitoring. The extent and severity of the hypertrophic process were calculated by a score system. The left ventricle was divided into 11 segments and a hypertrophic score (HS) was given to each segment. A hypertrophy score index (HSI) was also calculated by dividing the number of hypertrophied segments by 13. No correlation was found between symptoms and HS and HSI, nor ECG-VCG abnormalities and HS and HSI. A statistically significant relationship between the severity of ventricular arrhythmias and HS and HSI was found (p less than 0.01). The mechanism responsible for ventricular tachyarrhythmias in severe and diffuse hypertrophy might reside in the high intraventricular pressures which produce or worsen areas of myocardial ischemia.


New indene-derivatives with anti-proliferative properties.
Metabolites of the non-steroidal anti-inflammatory drug Sulindac inhibit cell proliferation by affecting several intracellular signaling pathways including the tumorigenic Ras/Raf/MAPK pathway. Here, we report the synthesis of eight new indene derivatives derived from the Sulindac structure, and present data on their anti-proliferative properties and their effects on the p21ras protein.


Decision optimization of emergency material support based on blockchain under major public health emergencies.
The work intends to relieve the pressure on the urban medical system and reduce the cross-infection of personnel in major public health emergencies. On the premise of an in-depth analysis of the utility risk entropy algorithm model and prospect theory, the decision-making of major health emergencies is proposed. Firstly, the utility risk entropy algorithm model is optimized, and the main decision-making members are subjected to utility perception according to the perceived utility values of different levels of risk, and the weights of decision-making members are calculated and revised according to the results of utility clustering. Secondly, the prospect theory is optimized. Taking the zero as the reference point to calculate the prospect value, and taking the maximization of the comprehensive prospect value as the objective to optimize the model, the comprehensive prospect value of each scheme is calculated and sorted. Finally, the proposed scheme is tested, and the test results show that in the optimal decision-making time of the scheme, the optimal decision-making time is 0 every day. When the epidemic situation is in the first cycle, the decision-making loss of the optimal scheme is 2.69, and the reduction ratio of the optimal scheme decision-making loss is 63.96%. When the epidemic situation is in the second cycle, the decision-making loss of the optimal scheme is 0.65, and the reduction ratio of the optimal scheme decision-making loss is 94.44%. When the epidemic situation is in the third cycle, the decision-making loss of the optimal scheme is 0.22, and the reduction ratio of the decision-making loss of the optimal scheme is 89.39%. The proposed scheme can improve the processing efficiency of major health emergencies and reduce the risk of accidents.


Acute depletion of telomerase components DKC1 and NOP10 induces oxidative stress and disrupts ribosomal biogenesis via NPM1 and activation of the P53 pathway.
Mutations in DKC1, NOP10, and TINF2 genes, coding for proteins in telomerase and shelterin complexes, are responsible for diverse diseases known as telomeropathies and ribosomopathies, including dyskeratosis congenita (DC, ORPHA 1775). These genes contribute to the DC phenotype through mechanisms that are not completely understood. We previously demonstrated in models of DC that oxidative stress is an early and independent event that occurs prior to telomere shortening. To clarify the mechanisms that induce oxidative stress, we silenced genes DKC1, NOP10, and TINF2 with siRNA technology. With RNA array hybridisation, we found several altered pathways for each siRNA model. Afterwards, we identified common related genes. The silenced cell line with the most deregulated genes and pathways was siNOP10, followed by siDKC1, and then by siTINF2 to a lesser extent. The siDKC1 and siNOP10 models shared altered expression of genes in the p53 pathway, while siNOP10 and siTINF2 had the adherens junction pathway in common. We also observed that depletion of DKC1 and NOP10 H/ACA ribonucleoprotein produced ribosomal biogenesis impairment which, in turn, promoted p53 pathway activation. Finally, we found that those enzymes responsible for GSH synthesis were down-regulated in models of siDKC1 and siNOP10. In contrast, the silenced cells for TINF2 showed no disruption of ribosomal biogenesis or oxidative stress and did not produce p53 pathway activation. These results indicate that depletion of DKC1 and NOP10 promotes oxidative stress and disrupts ribosomal biogenesis which, in turn, activates the p53 pathway.


Treatment outcomes of the patient with sinonasal mucosal melanoma: the role of endoscopic resection and postoperative radiotherapy.
The standard of care for sinonasal mucosal melanoma is surgery and postoperative radiotherapy (PORT). Our treatment strategy comprises endoscopic resection and PORT. We performed combined endoscopic and open resection or applied an external approach alone when sufficient resection was difficult to achieve endoscopically. The objective of this study was to evaluate the validity of our treatment strategy. We assessed 30 patients with sinonasal mucosal melanoma who underwent definitive therapy between January 2002 and April 2021, and conducted a retrospective analysis. The median follow-up period was 2.2 years. The primary endpoint was overall survival. The Kaplan-Meier method was used for the calculation of survival rates, the cumulative incidence of distant metastasis, and local recurrence. Twenty-eight patients underwent surgery. The other two patients were treated by definitive proton beam therapy. Twenty-one of 28 (75%) patients underwent resection by endoscopic approach alone. Postoperative radiotherapy was performed for all 28 patients who underwent surgery. Twenty-one patients (70%) experienced recurrence during the observation period. Overall, distant metastasis was observed in 19 patients. Twelve patients died during the observation period, with 10 of the 12 patients (83%) dying of distant metastasis. The overall survival rate at 2 and 5 years was 70% and 46%, respectively. The cumulative incidence rate of distant metastasis at 2 years was 63%, while the 2-year cumulative incidence rate of local recurrence was 6.7%. The local disease was controlled by our treatment strategy. To improve treatment outcomes, control of the distant metastasis is needed.


Gallstone recurrence after shock-wave therapy.
The long-term outcome of nonoperative gallstone therapy depends on both absence of stones and absence of biliary pain. The aim of the present study was to determine the rate of stone recurrence and the rate of symptoms within 5 years after successful shock wave lithotripsy combined with bile acid therapy. One hundred consecutive patients (single stones, n = 89; 2 or 3 stones, n = 11) were followed up for a median of 4.3 years after stone disappearance and discontinuation of bile acids. Twenty-three of the 100 patients developed recurrent stones. Calculated by actuarial analysis, the recurrence rate was 7% +/- 3%, 11% +/- 3%, 13% +/- 4%, 20% +/- 5%, and 31% +/- 7% (mean +/- SD) at 1, 2, 3, 4, and 5 years, respectively. The recurrent stones were small (6 +/- 5 mm) and were associated with recurrent biliary pain in 14 (61%) of the 23 patients. Repeated shock wave lithotripsy and/or bile acid medication resulted in stone disappearance in only 10 of 20 patients with recurrence. The long-term rate of stone recurrence after lithotripsy of primarily solitary gallbladder calculi is lower than expected from post-bile acid dissolution trials. Recurrence of stones frequently is associated with recurrence of biliary pain.


mTORC1 signaling-associated protein synthesis in porcine mammary glands was regulated by the local available methionine depending on methionine sources.
Mechanistic target of rapamycin complex1 (mTORC1) activation and protein synthesis varied with methionine sources; however, the related mechanisms are largely unknown. Porcine mammary epithelial cells (PMEC) and mammary tissue slices (MTS) were used to test whether methionine precursors differ in providing the available methionine and thus differ in mTORC1 signaling-associated protein synthesis. PMEC with methionine deprivation for 8 h and MTS from lactating sows were cultured for 24 and 2 h, respectively, with treatment media without methionine (negative control, NC) or supplemented with 0.6 mM (for PMEC) and 0.1 mM (for MTS) of L-methionine (L-MET), D-methionine (D-MET), DL-2-hydroxy-4-(methylthio) butyric acid (HMTBA), or keto-methyl(thio)butanoic acid (KMB). The measurements included: phosphorylation of mTORC1 signaling, fractional protein synthesis rate (FSR), amino acids (AA) profile, and enzyme activities. Compared with the NC treatment, activated mTORC1 signaling as manifested by higher (P < 0.05) protein abundance of phosphorylated-S6 Kinase 1 (P-S6K1) and phosphorylated-4E-binding Protein 1 (P-4E-BP1) in PMEC and MTS, and increased protein synthesis as indicated by higher (P < 0.05) FSR in MTS occurred in L-MET and HMTBA treatments rather than in D-MET treatment. Compared with the NC treatment, methionine concentration and ratio of methionine to lysine in MTS increased (P < 0.05) in L-MET and HMTBA treatments but not in D-MET treatment, and activities of enzymes responsible for conversion of D-MET and HMTBA to keto-methionine in mammary tissues were about 10 and 50%, respectively, of that in liver. Taken together, mTORC1 signaling-associated protein synthesis in porcine mammary glands was regulated by the local available methionine depending on methionine sources.