Removal of Dust Microelectric Signal Based on Empirical Mode Decomposition and Multifractal Detrended Fluctuation Analysis.
Microcharge induction has recently been applied as a dust detection method. However, in complex environments, the detection device can be seriously polluted by noise. To improve the quality of the measured signal, the characteristics of both the signal and the noise should be analyzed so as to determine an effective noise removal method. Traditional removal methods mostly deal with specific noise signals, and it is difficult to consider the correlation of measured signals between adjacent time periods. To overcome this shortcoming, we describe a method in which wavelet decomposition is applied to the measured signal to obtain sub-band components in different frequency ranges. A time-lapse Pearson method is then used to analyze the correlation of the sub-band components and the noise signal. This allows the sub-band component of the measurement signal that has the strongest correlation with the noise to be determined. Based on multifractal detrended fluctuation analysis combined with empirical mode decomposition, the similarity between the signal sub-band components and the noise sub-band components is analyzed and three indices are employed to determine the multifractal characteristics of the sub-band components. The consistency between noise components and signal components is obtained and the main signal components are verified. Finally, the sub-band components are used to reconstruct the signal, giving the noise-free measured (microcharge induction) signal. The filtered signal presents smoother, multifractal features.


[Importance of stimulation of the areas involved in the mathematical processing: effects on neurodevelopment].
This paper aims to discuss and analyze the role of mathematics in neurodevelopment, for which discusses the historical, ontogenetic and physiological bases involved. The methodology of this paper is a deductive analysis, describing the use of mathematics in ancient cultures to the specialization of brain regions. Sensory perceptions are useful for the acquisition and development of cortical functions thus sensory stimulations is essential for the maturation of specialized neurologic functions.


LF 15-0195 generates synergistic tolerance by promoting formation of CD4+CD25+CTLA4+ T cells.
The purpose of the present study was to investigate the influence of 15-deoxyspergualin (LF) on the phenotypes and functions of dendritic cells (DCs) and T cells and to further illustrate the mechanism of LF-inducing immunologic tolerance. DCs from mice were cultured and treated with varying doses of LF at specific time-points. Fluorescence-activated cell sorting (FACS) was used to verify the changes of phenotypes in the cultured DCs labeled with fluorescent antibody. DCs were also used as stimulators in mixed leukocyte reaction to detect their ability to stimulate T-cell proliferation. DCs and T cells, treated with or without LF, were cultured together; phenotypes and cytokine profile of the T cells were identified and assayed by FACS and enzyme-linked immunosorbent assay. LF induced a dose- and time-dependent suppression of maturation of DCs and a dose-dependent suppression of T-cell proliferation in mixed leukocyte reaction when LF-treated DCs were used as stimulators. LF-treated DCs, cultured with naive T cells, could promote the formation of CD4+CD25+CTLA4+ T-cell subtypes and the production of higher levels of interleukin-10. It was suggested that the mechanism of LF-induced tolerance was inhibiting maturation and function of DC and inducing the formation of regulatory T-cell subtype by "suppressor DCs" to achieve a new immune balance.


A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics.
When analyzing the human plasma metabolome with Nuclear Magnetic Resonance (NMR) spectroscopy, the Carr-Purcell-Meiboom-Gill (CPMG) experiment is commonly employed for large studies. However, this process can lead to compromised statistical analyses due to residual macromolecule signals. In addition, the utilization of Trimethylsilylpropanoic acid (TSP) as an internal standard often leads to quantification issues, and binning, as a spectral summarization step, can result in features not clearly assignable to metabolites. Our aim was to establish a new complete protocol for large plasma cohorts collected with the purpose of describing the comparative metabolic profile of groups of samples. We compared the conventional CPMG approach to a novel procedure that involves diffusion NMR, using the Longitudinal Eddy-Current Delay (LED) experiment, maleic acid (MA) as the quantification reference and peak picking for spectral reduction. This comparison was carried out using the ultrafiltration method as a gold standard in a simple sample classification experiment, with Partial Least Squares-Discriminant Analysis (PLS-DA) and the resulting metabolic signatures for multivariate data analysis. In addition, the quantification capabilities of the method were evaluated. We found that the LED method applied was able to detect more metabolites than CPMG and suppress macromolecule signals more efficiently. The complete protocol was able to yield PLS-DA models with enhanced classification accuracy as well as a more reliable set of important features than the conventional CPMG approach. Assessment of the quantitative capabilities of the method resulted in good linearity, recovery and agreement with an established amino acid assay for the majority of the metabolites tested. Regarding repeatability, ~ 85% of all peaks had an adequately low coefficient of variation (< 30%) in replicate samples. Overall, our comparison yielded a high-throughput untargeted plasma NMR protocol for optimized data acquisition and processing that is expected to be a valuable contribution in the field of metabolic biomarker discovery.


Serum reference values for leptin in healthy infants.
Reports on leptin concentrations in pediatric populations lack reference values for infants in the first months of life. Our study was conducted on healthy full-term infants between 2002 and 2012 to determine serum leptin reference values in subjects less than 18 months old. Routine outpatient blood tests for serum leptin were performed on 317 infants using a radioimmunoassay method. The median and 10th-90th percentiles were calculated to obtain reference values using quantile regression. Values established in this study were compared with another independent cohort of 110 infants. The median (IQR) serum leptin concentration in the infants was 2.37 (3.26) ng/ml (n = 317). The median leptin concentration was 2.81 (3.49) ng/ml (n = 202) in infants younger than 6 months of age, 1.44 (2.27) ng/ml (n = 59) in infants between 6-12 months of age and 1.77 (2.05) ng/ml (n = 56) in infants between 12-18 months of age. We obtained leptin reference values based on age by estimating the lower and upper percentiles. In the entire cohort, the median (IQR) leptin concentration was 2.22 (3.11) ng/ml in males (n = 168) and 2.60 (3.32) ng/ml in females (n = 149). According to the type of feeding median serum leptin concentration was higher in breast-fed infants (n = 188) than in formula-fed infants (n = 129) (2.63 (3.34) ng/ml vs. 2.12 (2.77) ng/ml; p<0.05). Our data revealed no gender difference in leptin concentration in early infancy. After 6 months of life, leptin concentrations decreased slightly. We used a large cohort to confirm that breast-fed infants had significantly higher serum leptin levels than formula-fed infants during the first 6 months of life, although this difference disappeared later in life. In this study, we defined the leptin reference range in healthy infants in the first 18 months of life according to the Clinical and Laboratory Standards Institute (CLSI).


A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy.
Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4(+) and CD8(+) T cells bearing a chimeric T-cell receptor (CD4zeta) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular-zeta signaling chain of the CD3 T-cell receptor. CD4zeta-modified T cells can inhibit viral replication, kill HIV-infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4zeta gene-modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads <50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4(+) T-cell counts.


Inhibitor of ribosomal RNA synthesis in Xenopus laevis embryos. VII. Inhibition of 40s pre-rRNA synthesis in Xenopus neurula cells.
A fraction containing acid-soluble materials (PCA-extract) from Xenopus early blastulae preferentially inhibits the incorporation of [3H]uridine into 18S and 28S rRNA in Xenopus neurula cells. Pulse- laneling experiments revealed that whereas tubercidin, a known inhibitor of rRNA processing, produced a marked accumulation of the label in 40S pre-rRNA, Xenopus inhibitor suppressed labeling of the pre-rRNA. When tubercidin was added to cells whose activity for rRNA synthesis had been lowered by the Xenopus inhibitor, there was still an accumulation of label in the pre-rRNA. These results indicate that Xenopus inhibitor suppresses the synthesis of rRNA at transcription rather than at processing.


Correlations between morphology of cervical vertebrae and dental eruption.
The process of dental eruption is submitted to physiological and pathological variables. A series of discrepancies may occur, one of these being a disturbance between dental age and bone age. The assessment of bone age is best made with the cervical vertebral maturation (CVM) method, simplified by Baccetti et al. (2005). The sample studied consisted of 215 orthodontic patients. The dental age was assessed on the orthopantomograph radiographies and the bone age on the lateral cephalograms. For determining the bone age, CVM method was used. Considering dental age, most of the patients (50.2%) have a premature dental age compared to bone age, while patients with normal dental age (27.9%) and patients with late dental age (21.9%) have a lower frequency. The correlation between the dental age and the bone age of the patients shows that patients who have higher values of dental age also have higher values of bone age (p<0.001). The correlation between genders shows that female patients tend to have a higher average value of bone age in comparison to male patients (p<0.001). The authors conclude that assessing bone age based on the morphology of cervical vertebrae and correlating it with the dental age could be of great use in opting for a certain orthodontic treatment plan.


The effects of epidural anesthesia on the urethral closure pressure profile in patients with prostatic enlargement.
In 10 patients with obstructive manifestations of prostatic enlargement the urethral closure pressure profile was observed before and after the effective blockade of thoracolumbar sympathetic outflow by epidural anesthesia. While epidural anesthesia significantly decreased urethral closure pressure considerable profile responses still remained in these patients. This fact suggests that the bulk of the prostatic tissue is responsible for the bladder outlet obstruction, since urethral closure pressure persists despite urethral smooth and skeletal muscular relaxation as a result of epidural anesthesia. After transurethral resection of the prostatic tissue in these patients the urethral closure pressure did decrease to zero. The result of the prostatic resection is to decrease the urethral closure pressure and, thereby, increase the efficiency of voiding.


Anthocyanin absorption and antioxidant status in pigs.
The effect of a simultaneous intake of food or flavonoids on anthocyanins absorption and antioxidant status in pigs was investigated. Twelve male pigs at 27.1 +/- 0.7 kg BW fitted with jugular venous cannulae were maintained in individual metabolic crates. The animals were each given one of three dietary treatments in random order: blackcurrant powder (BC) to give a dose of 100 mg total ACNs/kg BW mixed either with water and sugar (Diet A), cereal (Weet-Bix), milk, and sugar (Diet B), or cereal, milk, sugar, and an additional flavonol (rutin, approximately 100 mg/kg BW) (Diet C). The four major anthocyanins of BC, delphinidin-3-glucoside, delphinidin-3-rutinoside, cyanidin-3-glucoside, and cyanidin-3-rutinoside, were identified and quantified by HPLC-PDA in all three diets. In the pig plasma, four peaks with a reversed pattern to those of anthocyanins in the BC extract were detected. The total amount of anthocyanins absorbed was not significantly different between the three diets, but the rate of absorption and subsequent decline was slower following administration of diet B and C than diet A. All three diets increased antioxidant capacity when measured by the FRAP assay but not when measured by the ORAC and non-protein ORAC assay. However, the increase was delayed and did not appear until 4 h after ingestion, at a time when plasma anthocyanin levels had returned to baseline. The present study demonstrates that the simultaneous intake of food or other flavonoids delays the absorption profile for anthocyanins. Our results also suggest that the increase in antioxidant capacity is not due to dietary anthocyanins but may be due to metabolites that result from anthocyanin consumption.


Long-term feed intake regulation in sheep is mediated by opioid receptors.
These experiments were conducted to determine if 1) syndyphalin-33 (SD33), a mu-opioid receptor ligand, affects feed intake; 2) SD33 effects on feed intake are mediated by actions on opioid receptors; and 3) its activity can counteract the reduction in feed intake associated with administration of bacterial endotoxin. In Exp. 1, 5 mixed-breed, castrate male sheep were housed indoors in individual pens. Animals had ad libitum access to water and concentrate feed. Saline (SAL; 0.9% NaCl) or SD33 (0.05 or 0.1 micromol/kg of BW) was injected i.v., and feed intake was determined at 2, 4, 6, 8, 24, and 48 h after the i.v. injections. Both doses of SD33 increased (at least P < 0.01) feed intake at 48 h relative to saline. In Exp. 2, SAL + SAL, SAL + SD33 (0.1 micromol/kg of BW), naloxone (NAL; 1 mg/kg of BW) + SAL, and NAL + SD33 were injected i.v. Food intake was determined as in Exp. 1. The SAL + SD33 treatment increased (P = 0.022) feed intake at 48 h relative to SAL + SAL. The NAL + SAL treatment reduced (at least P < 0.01) feed intake at 4, 6, 8, 24, and 48 h, whereas the combination of NAL and SD33 did not reduce feed intake at 24 (P = 0.969) or 48 h (P = 0.076) relative to the saline-treated sheep. In Exp. 3, sheep received 1 of 4 treatments: SAL + SAL, SAL + 0.1 micromol of SD33/kg of BW, 0.1 microg of lipopolysaccharide (LPS)/kg of BW + SAL, or LPS + SD33, and feed intake was monitored as in Exp. 1. Lipopolysaccharide suppressed cumulative feed intake for 48 h (P < 0.01) relative to saline control, but SD33 failed to reverse the reduction in feed intake during this period. These data indicate that SD33 increases feed intake in sheep after i.v. injection, and its effects are mediated via opioid receptors. However, the LPS-induced suppression in feed intake cannot be overcome by the opioid receptor ligand, SD33.


Surprising strength of silkworm silk.
Commercial silkworm silk is presumed to be much weaker and less extensible than spider dragline silk, which has been hailed as a 'super-fibre'. But we show here that the mechanical properties of silkworm silks can approach those of spider dragline silk when reeled under controlled conditions. We suggest that silkworms might be able to produce threads that compare well with spider silk by changing their spinning habits, rather than by having their silk genes altered.


Thermal Neuromodulation With Focused Ultrasound: Implications for the Technique of Subthreshold Testing.
During focused ultrasound ablation (FUSA), the presumed stereotactic target is tested with subthreshold sonications before permanent ablation. This testing relies on ultrasound-induced reversible clinical effects (thermal neuromodulation, TN). However, the thermal dose and spot size thresholds to induce TN are not yet defined. To define the thermal dose and spot size thresholds associated with TN. We performed a retrospective analysis of intraoperative FUSA data of essential tremor patients. Sonications with a thermal dose of less than 25 cumulative equivalent minutes (CEM) were classified as subthreshold. The intraoperative writing samples were independently rated by 2 raters using the clinical rating scale for tremor. The association between thermal dose and tremor scores was statistically analyzed, and the thermal dose and spot size thresholds for TN were computed using leave-one-out cross-validation analysis. A total of 331 pairs of sonications and writing samples were analyzed; 97 were classified as subthreshold sonications. TN was observed in 23 (24%) subthreshold sonications. The median tremor improvement during TN was 20% (interquartile range = 41.6). The thermal dose threshold for TN was 0.67 CEM (equivalent to 30 s thermal exposure at 43°C). The spot size threshold for TN was 2.46 mm. Ventral intermediate medial nucleus was exposed to TN thermal dose during subablative and ablative sonications. The TN thermal dose and spot size thresholds are significantly higher than the current FUSA standard of care. We recommend long duration (>30 s), subthreshold sonications for intraoperative testing during FUSA. Future investigations should test whether the thermal dose threshold is tissue-specific and determine the mechanisms underlying focused ultrasound TN.


Local vibrational excitation through extended electronic states at a germanium surface.
Atomic motion through excitation of extended surface electronic states on Ge(001) is studied using extraction of electrons by scanning tunneling microscopy and density functional theory. Single-electron excitation into the surface states nonlocally alters the tilting orientation of the surface Ge dimer, and the change rate depends on the excitation energy. Theoretical investigations identify the excited electronic states for the dimer motion, and clarify the strong coupling between the surface state electrons and a local vibrational mode of the dimer for changing the tilting orientation.


Risk preference and choice stochasticity during decisions for other people.
In several contexts, such as finance and politics, people make choices that are relevant for others but irrelevant for oneself. Focusing on decision-making under risk, we compared monetary choices made for one's own interest with choices made on behalf of an anonymous individual. Consistent with the previous literature, other-interest choices were characterized by an increased gambling propensity. We also investigated choice stochasticity, which captures how much decisions vary in similar conditions. An aspect related to choice stochasticity is how much decisions are tuned to the option values, and we found that this was higher during self-interest than during other-interest choices. This effect was observed only in individuals who reported a motivation to distribute rewards unequally, suggesting that it may (at least partially) depend on a motivation to make accurate decisions for others. Our results indicate that, during decision-making under risk, choices for other people are characterized by a decreased tuning to the values of the options, in addition to enhanced risk seeking.


Metabolic disposition of the cognition activator tacrine in rats, dogs, and humans. Species comparisons.
The metabolic fate of tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA)] was examined in rats, dogs, and humans. After administration of single oral doses of [14C]THA to rats, dogs, and humans, drug-derived material was well absorbed, with urinary excretion being the predominant route of radiolabel elimination. Metabolic profiling of plasma and urine from rats, dogs, and humans showed THA to be extensively metabolized with marked species differences in quantitative amounts of metabolites observed. Plasma profiles were similar to respective urinary profiles in all three species. Present in profiles of urine from rats were 1-hydroxy (OH)-THA (major), 2-OH-THA, and 4-OHA-THA, and unchanged THA. Also observed were trace amounts of more polar metabolites, presumably arising from sequential metabolism. Metabolic profiling of dog urine also showed 1-OH-THA to be the major metabolite, with trace amounts of the 2-OHA-THA and 4-OH-THA regioisomers and THA excreted. In dog urine, more of the radioactivity was associated with polar metabolites, including 1,3-dihydroxy-THA and a dihydrodiol metabolite. Human urinary metabolic profiles were more similar to that in dogs than in rats, with no single metabolite constituting > 10% of urinary radioactivity. Present in human urine were phenol glucuronide metabolites, of which 7-OH-THA was identified as an aglycone. Relevance of the marked quantitative differences in THA metabolism between rats, dogs, and humans to species differences in THA hepatotoxic potential remains to be established.


Phytophthora sojae effector PsCRN108 targets CAMTA2 to suppress HSP40 expression and ROS burst.
Oomycete pathogens secrete numerous crinkling and necrosis proteins (CRNs) to manipulate plant immune and promote infection. However, the functional mechanism of CRN effectors is still poorly understood. Previous research has shown that Phytophthora sojae effector PsCRN108 binds to the promoter of HSP90s and inhibits their expression, resulting in impaired plant immunity. In this study, we found that in addition to HSP90, PsCRN108 also suppressed other HSP family genes, including HSP40. Interestingly, PsCRN108 inhibited the expression of NbHSP40 through its promoter, but did not directly bind to its promoter. Instead, PsCRN108 interacted with NbCAMTA2, a negative regulator of plant immunity. NbCAMTA2 was a negative regulator of NbHSP40 expression, and PsCRN108 could promote such inhibition activity of NbCAMTA2. Our results elucidated the multiple roles of PsCRN108 in the suppression of plant immunity, and revealed a new mechanism by which CRN effector hijacked transcription factors to affect immunity.


Copolymerization of Norbornene and Styrene with Anilinonaphthoquinone-Ligated Nickel Complexes.
Poly(norbornene-co-styrene)s were synthesized by the use of anilinonaphthoquinone-ligated nickel complexes [Ni(C10H5O2NAr)(Ph)(PPh3): 1a, Ar = C6H3-2,6-iPr; 1b, Ar = C6H2-2,4,6-Me; 1c, Ar = C6H5] activated with modified methylaluminoxane (MMAO) or B(C6F5)3 in toluene. The effects of the cocatalysts were more significant than those of the nickel complexes, and MMAO gave higher activity than B(C6F5)3. The structural characterizations of the products indicated the formation of statistical norbornene copolymers. An increase of the styrene ratio in feed led to an increase in the incorporated styrene (S) content of the resulting copolymer. The molecular weight of the copolymer decreased with increasing the S ratio in feed at 70 °C. The copolymerization activity, using MMAO as a cocatalyst, decreased with lowering of the temperature from 70 to 0 °C, accompanied by an increase in the molecular weight of the copolymer. The S incorporation up to 59% with Mn of 78,000 was achieved by the 1b-B(C6F5)3 catalytic system. The glass transition temperatures of the norbornene (N)/S copolymers determined by differential scanning calorimetry, decreased from 329 to 128 °C according to the S content.


Effects of Mitochondrial Dynamics in the Pathophysiology of Obesity.
Obesity has become an urgent and serious public health challenge with an overwhelming increase over the decades worldwide. The rate of obese children and adolescents has recently accelerated, especially in China. Obesity is closely related to unbalanced cellular energy metabolism. Mitochondria, as the main organelles of energy metabolism, play an important role in the pathophysiology of obesity. Recent researches have revealed that mitochondrial dynamics with constant fission and fusion, can alter mitochondrial structure, organelle connections, ROS production, neuronal activity, and OXPHOS system as well as adipose tissue thermogenesis, which ultimately lead to obesity. In this review, we will update the latest findings about mitochondrial fission/fusion related GTPase proteins and discuss the effects of mitochondrial dynamics in the pathophysiology of obesity.


Thermoelectricity in polymer composites due to fluctuation-induced tunneling.
Transport in heavily-doped polymer composites, characterized by localized charge regions, is examined in light of the recent interest in polymers for thermoelectric applications. The developed fundamental transport theory describes carrier tunneling between charged localizations by taking into account thermally induced fluctuations of the applied potential. A range of characteristic behaviors corresponding to experimental data are described. Deviations from the Wiedemann-Franz law are also identified. This novel theory enables the determination of factors dominating the transport in polymers and a comparison to tunneling without thermal fluctuations is also provided. The obtained asymptotic expressions for the conductivity, Seebeck coefficient, and carrier thermal conductivity are particularly useful for elucidating possible routes for thermoelectric transport control and optimization.


Baseline MDCT findings after prosthetic heart valve implantation provide important complementary information to echocardiography for follow-up purposes.
Recent studies have proposed additional multidetector-row CT (MDCT) for prosthetic heart valve (PHV) dysfunction. References to discriminate physiological from pathological conditions early after implantation are lacking. We present baseline MDCT findings of PHVs 6 weeks post implantation. Patients were prospectively enrolled and TTE was performed according to clinical guidelines. 256-MDCT images were systematically assessed for leaflet excursions, image quality, valve-related artefacts, and pathological and additional findings. Forty-six patients were included comprising 33 mechanical and 16 biological PHVs. Overall, MDCT image quality was good and relevant regions remained reliably assessable despite mild-moderate PHV-artefacts. MDCT detected three unexpected valve-related pathology cases: (1) prominent subprosthetic tissue, (2) pseudoaneurysm and (3) extensive pseudoaneurysms and valve dehiscence. The latter patient required valve surgery to be redone. TTE only showed trace periprosthetic regurgitation, and no abnormalities in the other cases. Additional findings were: tilted aortic PHV position (n = 3), pericardial haematoma (n = 3) and pericardial effusion (n = 3). Periaortic induration was present in 33/40 (83 %) aortic valve patients. MDCT allowed evaluation of relevant PHV regions in all valves, revealed baseline postsurgical findings and, despite normal TTE findings, detected three cases of unexpected, clinically relevant pathology. • Postoperative MDCT presents baseline morphology relevant for prosthetic valve follow-up. • 83 % of patients show periaortic induration 6 weeks after aortic valve replacement. • MDCT detected three cases of clinically relevant pathology not found with TTE. • Valve dehiscence detection by MDCT required redo valve surgery in one patient. • MDCT is a suitable and complementary imaging tool for follow-up purposes.


Coronary artery spasm: use of ergonovine in diagnosis.
Ergonovine maleate was administered to 69 patients with chest pain but without significant coronary artery disease (less than 10% luminal diameter obstruction) to determine whether coronary artery spasm could be provoked. Coronary artery spasm was seen at angiography, or inferred from ECG or thallium myocardial perfusion scan changes. The test was positive in 16 patients: all five patients with documented variant angina (Group A); ten of the 19 patients with suspected variant angina (Group B); one of the 11 patients with exercise-induced chest pain (Group C); and none of the 34 patients with atypical chest pain (Group D). Patients with a positive test usually smoked, complained of recurrent nocturnal or early morning chest pain, showed ST changes during spontaneous chest pain and had minot degrees of fixed coronary obstruction (30--70%), when compared to those with a negative test. The only major side effect of the test was transient ventricular tachycardia which occurred in three patients and was reverted by sublingual and parenteral nitroglycerine.


Is implant pacemaker a physicochemical cause triggering Kikuchi-Fujimoto disease?
A 64 year-old Caucasian female of Greek origin was admitted to hospital with painful cervical and axillary lymphodenitis accompanied by fever and night sweats for 10 days. The patient had undergone a pacemaker implantation six weeks before disease onset because of heart conduction abnormalities. A diagnosis of Kikuchi-Fujimoto disease was established after lymph node biopsy. The etiology of the disease is unknown but viral, bacterial, protozoal; and neoplastic as well as physicochemical agents may stimulate a particular immune response. Hereby, we hypothesize that the implant pacemaker can act as a physicochemical agent triggering Kikuchi-Fujimoto disease. We present this case and we discuss various disease aspects. A brief review of the literature is also given.


Cognitive prognosis of patients with tuberous sclerosis complex.
To assess cognitive outcome in patients with tuberous sclerosis complex (TSC) and identify predictive risk factors, we reviewed records of 107 patients who underwent comprehensive neuropsychiatric evaluation. Fifty-seven percent of patients with TSC had normal-range IQ/developmental quotient (DQ). Cognitive outcome was strongly associated with refractory seizures and TSC2 mutation. In TSC, IQ/DQ is bimodally distributed, and more than half of individuals are in the normal range.


Routine Blood Tests in Asymptomatic Patients With Indolent Lymphoma Have Limited Ability to Detect Clinically Significant Disease Progression.
Patients with indolent non-Hodgkin lymphoma (iNHL) undergo regular active surveillance in between treatment periods to detect disease relapse or progression. As part of surveillance, international guidelines recommend regular routine blood testing, which is based on consensus rather than evidence of utility. We conducted a retrospective analysis of all patients older than age 16 years diagnosed with grade 1-3A follicular or marginal zone lymphoma between 2008 and 2017 from 2 Australian cancer centers to assess the utility of full blood examination, lactate dehydrogenase, and β2-microglobulin in detecting progression events, defined as either disease relapse or progression of disease. One hundred eighty patients attended 1,757 outpatient appointments (median follow-up, 36 months). Routine blood tests (RBTs) were performed before 83% of appointments. Seventy-four progression events occurred in 62 patients. Only 2 events (3%) were detected by RBTs alone, both of which occurred in treatment-naïve patients who subsequently developed symptoms within 3 weeks. The remainder of progression events were suspected clinically (88%) or detected by imaging (9%). RBT results were frequently abnormal in asymptomatic patients (19%), with abnormal results leading to either additional investigations or an increased surveillance frequency in 8% of cases. The overall sensitivity and positive predictive value of abnormal RBT results in detecting progression events were 39% and 9%, respectively. RBTs have poor performance characteristics and rarely detect clinically significant disease progression or relapse in asymptomatic patients with iNHL.


The role of colleges of pharmacy in meeting the pharmacoeconomic needs of the pharmaceutical industry: a conference report.
To provide a forum for the exchange of ideas regarding the role of colleges of pharmacy in meeting the pharmaceutical industry's pharmacoeconomic needs, an invitational conference was conducted by the University of Arizona's Center for Pharmaceutical Economics on January 14 and 15, 1993, in Tucson, Arizona. This article represents the program design, program types, and consensus development portions of that conference. A description of current needs in pharmacoeconomics was obtained through transcripts of industry and university presentations, panel discussions, and question-and-answer sessions. Conference participants generally agreed that pharmacoeconomics holds great potential for making significant contributions to health care but that it will not flourish without deliberate and cooperative efforts. Participants from both industry and academia voiced the need for the two parties to work together to increase the visibility and understanding of pharmacoeconomics and to meet the training and staffing challenges facing the discipline.


Genetic and phenotypic heterogeneity in tropical calcific pancreatitis.
Tropical calcific pancreatitis (TCP) is a form of chronic non-alcoholic pancreatitis initially reported in the developing parts of the tropical world. The clinical phenotype of TCP has undergone marked changes since its first description in 1968. The disease is now seen in relatively older people with less severe symptoms. In addition, there are varying reports on the proportion of cases presenting with imaging abnormalities like calcification, ductal dilation, and glandular atrophy. Significant progress has also been made in understanding the etiopathology of TCP. The role of malnutrition and cassava toxicity in its pathogenesis is disproven and few studies have focused on the role of micronutrient deficiency and oxidative stress in the etiopathogenesis of TCP. Emerging evidence support an important role for genetic risk factors in TCP. Several studies have shown that, rather than mutations in trypsinogens, variants in serine protease inhibitor kazal type 1, cathepsin B, chymotrypsin C, cystic fibrosis transmembrane regulator, and carboxypeptidase A1, predict risk of TCP. These studies also provided evidence of mutational heterogeneity between TCP and chronic pancreatitis in Western populations. The current review summarizes recent advances that have implications in the understanding of the pathophysiology and thus, heterogeneity in genotype-phenotype correlations in TCP.


EFFECTS OF POPULATION STRUCTURE AND CONE PRODUCTION ON OUTCROSSING RATES IN ENGELMANN SPRUCE AND SUBALPINE FIR.
Variation in the mating systems of Engelmann spruce and subalpine fir was examined in two adjacent subpopulations in the Colorado Front Range. Multilocus outcrossing rates were estimated from analysis of allozyme variation in embryo and megagametophyte tissue. The overall multilocus outcrossing rate of 0.93 for spruce was significantly higher than the outcrossing rate of 0.89 for fir. Outcrossing rates varied from 0.73 to 0.97 for spruce and from 0.65 to 0.94 for fir when trees of each species were grouped according to age, size, spatial distribution, maternal heterozygosity, cone production, and year of sampling. In both spruce and fir, trees with higher levels of male-cone production and/or more clumped spatial distribution had lower outcrossing rates. Temporal variation in outcrossing rates within subpopulations, examined only in spruce, was less than variation between subpopulations. Male-cone production was significantly correlated with tree size, and regression analyses revealed that the highest outcrossing rates are expected on trees that are medium to large in size, rather than the largest trees in the forest. The results show that, while there is some temporal variation, patterns of male cone production and spatial distribution of individuals are the most important factors influencing outcrossing levels in these wind-pollinated forest trees.


The role of intraspecific variation in bumblebee body size and behavior on buzz pollination of a tropical legume species.
The outcomes of generalized mutualisms rely on partner trait variation. In pollination mutualisms, although less explored, intraspecific variation in pollinator traits can be pivotal for successful pollination. We investigated the role of intraspecific body size and behavioral trait variations of bumblebee Bombus morio on the pollination of a buzz-pollinated legume species, Chamaecrista latistipula. To explore the impact of body size and behavior of B. morio on the pollination of C. latistipula, we observed visits to virgin flowers and quantified the pollen removal and deposition (pollination performance) and fruit and seed production (reproductive fitness). By analyzing video and sound recordings, we measured B. morio body size and behavior on each flower, including bee vibration descriptors. We observed intraspecific behavioral differences among B. morio bumblebees associated with different body sizes. Larger bumblebees had half the handling time and vibrational pulses, less angular displacement within flowers, and larger relative peak amplitudes during vibrations than smaller bumblebees did. Regardless of their large variation in size and behavior, bumblebees were equally effective in removing pollen and pollinating flowers. The high female reproductive fitness was independent of bumblebee body size and behavior, likely due to the interaction between both. On the other hand, larger bumblebees visited flowers for shorter periods, probably promoting higher male reproductive fitness. This study is the first to highlight the large intraspecific variation of bumblebee body size and behavior in buzz-pollinated flowers in the field. Together, body size and behavior effects unexpectedly cancel each other, generating a high buzz pollination efficiency.


Characterization of muscles injured by forced lengthening. I. Cellular infiltrates.
Myofiber injury-repair was studied in rat soleus muscles to elucidate the role of infiltrating cells in the injury-repair process. Muscle injury was induced by forced muscle lengthening with the contralateral muscle serving as a control. The muscles were removed for histologic, histochemical and immunohistochemical procedures at varying periods (12-120 h) post-injury. All injured muscles were severely damaged with many cells present in the interstitial spaces between myofibers. Normal appearing myofibers demonstrated elevated lysosomal proteolytic activity, but no evidence of increased activity, indicative of phagocytic cells, was found in or between damaged myofibers. The esterase stain for macrophages and immunohistochemical techniques for mast cells also provided no support for either cell type predominating in the damaged area, although mast cell degranulation could be observed in the pericapillary regions. In contrast, the use of a specific antisera for a multicatalytic protease uniquely defined most of these cells as myogenic in origin. They appeared to be most numerous between the torn ends of a myofiber. Surprisingly, the remainder of the cells appeared to be of lymphoid origin.


Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA-Associated Pancreatic Cancer in the Clinical and Preclinical Setting.
Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions. glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.


Current indications for cochlear implantation in adults and children.
Surgical treatment of deafness by cochlear implants is used for more than 40 years, and during this period permanently, gradual and significant expansion of indications for this surgery has been observed. In our Department in the years 1994-2018 1480 cochlear implantations were performed, both in adults (647) and in children (883). In this study current indications and the rules for eligibility of patients based on 25 years of experience are presented. Indications for cochlear implantation in adults are: 1) bilateral postlingual deafness, 2) bilateral sensorineural hearing loss - in pure tone audiometry > 70 dB HL (average 500-4000 Hz) and in speech audiometry in hearing aids understanding < 50% of words for the intensity of the stimulus 65 dB, in the absence of the benefits of hearing aids, 3) bilateral profound hearing loss for high frequency with good hearing for low frequency, in the absence of the benefits of hearing aids, 4) some cases of asymmetric hearing loss with intensive tinnitus in the deaf ear. An indication in children is bilateral sensorineural hearing loss > 80dB HL confirmed by hearing tests, after about 6 months of rehabilitation with the use of hearing aids. Although cochlear implantation is used for more than 40 years, the indications for this treatment underlies constant modifications. They concern the age of eligible patients, implantation in patients with partially preserved hearing, as well as treatment for patients with difficult anatomical conditions. In many countries, bilateral implantations are commonly performed, and more and more centers recommend this treatment in the case of unilateral deafness or asymmetric hearing loss, especially with the accompanying tinnitus in the deaf ear.


[Effects of serum from normal and burned rats on the biological behavior of bone marrow stromal cells].
To investigate the effect of serum from normal and burned rats on the biological behaviors of bone marrow stromal cells (BMSCs). Bone marrow was extracted from sacrificed Wistar rats and BMSCs were then incubated in F-12 medium in the presence of fetal calf serum (FCS, group F), normal rat serum (group N), serum harvested from burned rats at 3 days (group B1) and 14 days (group B2) after burn injury. The growth curve, cell cycle, apoptosis rate and contents of DNA of BMSCs were investigated. The growth curves of cells incubated in different rat serum were similar, but were significantly different from that of cells incubated in FCS. The doubling time of cells incubated in rat serum from group N, B1 and B2 were 23.7, 18.6 and 20.2 hours, respectively, which were significantly shortened compared with that in group F. Compared with group F, the numbers of cells at platform phase in group N, B1 and B2 were greater. The ratios of cells at phase G0/G1 in group B1 and B2 were significantly lower than those in other groups (all P<0.01), but the ratios of cells at phase S were adverse (P<0.01). Contents of DNA in cells incubated in rat serum were greater than that in cells incubated in FCS (P<0.05 or P<0.01). Contents of DNA in cells incubated in serum from burned rats were greater than that in cells in normal rat serum (P<0.01). The rate of cell apoptosis in group B1 was higher than those in other groups (P<0.01). Rat serum is more effective to stimulate proliferation of BMSCs from rat in vitro than FCS. There are probably many factors affecting the growth of BMSCs, the contents of which changed with the time after burn injury. The effects of serum from burned rats on the growth of BMSCs are complex.


Restless Legs Syndrome Prevalence and Clinical Correlates Among Psychiatric Inpatients: A Multicenter Study.
There are only limited reports on the prevalence of restless legs syndrome (RLS) in patients with psychiatric disorders. The present study aimed to evaluate the prevalence and clinical correlates in psychiatric inpatients in Germany and Switzerland. This is a multicenter cross-sectional study of psychiatric inpatients with an age above 18 years that were diagnosed and evaluated face-to-face using the International RLS Study Group criteria (IRLSSG) and the International RLS severity scale (IRLS). In addition to sociodemographic and biometric data, sleep quality and mood were assessed using the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale (ESS), and the Patient Health Questionnaire (PHQ-9). In addition to univariate statistics used to describe and statistically analyze differences in variables of interest between patients with and without RLS, a logistic model was employed to identify predictors for the occurrence of RLS. The prevalence of RLS in a sample of 317 psychiatric inpatients was 16.4%, and 76.9% of these were diagnosed with RLS for the first time. RLS severity was moderate to severe (IRLS ± SD: 20.3 ± 8.4). The prevalences in women (p = 0.0036) and in first-degree relatives with RLS (p = 0.0108) as well as the body mass index (BMI, p = 0.0161) were significantly higher among patients with RLS, while alcohol consumption was significantly lower in the RLS group. With the exception of atypical antipsychotics, treatment with psychotropic drugs was not associated with RLS symptoms. Regarding subjective sleep quality and mood, scores of the PSQI (p = 0.0007), ISI (p = 0.0003), and ESS (p = 0.0005) were higher in patients with RLS, while PHQ-9 scores were not different. A logistic regression analysis identified gender (OR 2.67; 95% CI [1.25; 5.72]), first-degree relatives with RLS (OR 3.29; 95% CI [1.11; 9.73], ESS score (OR 1.09; 95% CI [1.01; 1.17]), and rare alcohol consumption (OR 0.45; 95% CI [0.22; 0.94] as predictors for RLS. Clinically significant RLS had a high prevalence in psychiatric patients. RLS was associated with higher BMI, impaired sleep quality, and lower alcohol consumption. A systematic assessment of restless legs symptoms might contribute to improve the treatment of psychiatric patients.


Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes.
The master circadian pacemaker of the suprachiasmatic nuclei coordinates behavioral and physiological rhythms via synchronization of subordinate peripheral oscillators in the central nervous system and organs throughout the body. Among these organs, the adrenal glands hold a prime position because of their regulatory influence on numerous physiological functions via rhythmic secretion of catecholamines and corticoid hormones into the bloodstream. In this report, the authors perform whole genome microarray hybridization to characterize the circadian transcriptome of the murine adrenal. They show that ~5% of the mouse genome is under circadian control in this gland. Using gene ontology analysis, they identify classes of transcripts that may synchronize adrenal hormone production. The authors' expression profiling also revealed that multiple histone genes implicated in either DNA replication or transcriptional regulation are clock controlled, suggesting a novel way by which the circadian clock may regulate the chromatin state.


Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH).
We have mapped the globin gene region in the DNA of two HPFH patients. In a patient homozygous for the G gamma A gamma type of HPFH at least 24 kb of DNA in the globin gene region has been deleted to remove most of the gamma-delta intergenic region and the delta and beta globin genes. The 5' break point of the deletion is located about 9 kb upstream from the delta globin gene. The 3' break point has not been precisely located but is at least 7 kb past the beta globin gene. DNA from an individual heterozygous for the Greek (A gamma) type of HPFH, however, shows no detectable deletion in the entire gamma delta beta-globin gene region. HPFH, therefore, appears to occur in different molecular forms. These results are discussed in terms of a model for the regulation of globin gene expression in man.


[Diseases associated with viruses of the California encephalitis serogroup, in Russia].
Studies of 1986-1995 revealed diseases etiologically connected with California serogroup viruses (Bunyaviridae, Bunyavirus) all over the country. Highly endemic zones are the tundra, taiga, and leafy forest. The disease occurs mainly in summer, the patients are mostly young: under 30 years of age. Analysis of 183 cases confirmed by laboratory findings enabled us to distinguish the following forms: influenza-like (70.9%) with the predominant involvement of the bronchopulmonary system (bronchitis and pneumonia) and neuroinfection (20.2%) (serous meningitis and meningoencephalitis).


Effects of trazodone on aggressive behavior in seven patients with organic mental disorders.
Seven patients with organic mental disorders and physically aggressive behavior were treated with trazodone. Three ceased demonstrating aggressive behavior within 4-6 weeks after starting trazodone treatment. Three had no discernible reduction in aggressiveness. One was unable to complete the trial.


A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers.
The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a "dormant" TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.


Transcriptional activation of the alpha-1 acid glycoprotein gene by YY1 is mediated by its functional interaction with a negative transcription factor.
Regulation of alpha-1 acid glycoprotein (AGP) gene expression involves both positive and negative transcription factors. We have previously identified two dominant factors: positive and negative transcription factors, AGP/EBP and factor B, respectively, involved in the transcription of AGP and other acute-phase response genes. In this report, we present evidence showing that the transcription of the AGP gene is positively regulated by a transcription factor, YY1. The activation of AGP gene by YY1 is mediated by a negative element B in the AGP promoter region. YY1 can also activate the B motif linked to a heterologous promoter. However, YY1 does not bind directly to the B motif per se. Rather, our data suggest that the activation of AGP gene by YY1 may be mediated by its functional interaction with factor B, which recognizes the B motif.


The effect of online collaborative writing instruction on enhancing writing performance, writing motivation, and writing self-efficacy of Chinese EFL learners.
This study investigates the influence of online collaborative writing instruction on the writing performance, writing self-efficacy, and writing motivation of Chinese English as a foreign language (EFL) learners. The research was conducted at a language school in mainland China with 58 participants divided into an experimental group (n=30) and a control group (n=28). The experimental group utilized Tencent Docs, an online platform, for collaborative writing and peer-editing activities outside the classroom, while the control group received traditional in-class instruction. The study spanned a duration of 13 weeks, during which writing tasks, writing motivation scales, and writing self-efficacy scales were employed to collect data. The findings revealed that the experimental group exhibited significantly greater improvement in writing performance, motivation, and self-efficacy compared to the control group. These results indicate the positive impact of incorporating Tencent Docs into collaborative writing instruction. The outcomes of this study provide valuable insights for language educators regarding the benefits of integrating online tools into EFL instruction to enhance writing skills. By leveraging platforms like Tencent Docs for collaborative writing, instructors can foster improved performance, increased motivation, and enhanced self-efficacy among EFL learners. Overall, this research highlights the effectiveness of online collaborative writing instruction and its potential as a valuable tool for language educators seeking to optimize EFL learners' writing abilities.


Measure health, not care.
Effective and meaningful measurement of health is vitally important if we are to improve the health and experience of patients and reduce costs. We need to take an entirely different approach to measurement than we have in the past. Patient-reported outcomes measures provide more meaningful information than process and patient satisfaction measures and are easier for researchers and clinicians to implement.


[Treatment of ovarian cancer cell line SKOV3 with IL-24 gene under the control of ovarian-specific promoter-1].
To explore the in vitro antitumor effect of interleukin-24 (IL-24) gene regulated by ovarian-specific promoter-1 (OSP-1) on human ovarian cancer cell line SKOV3. An expression vector (pcDNA3.0-OSP-1-IL-24) containing IL-24 gene under ovarian-specific promoter-1 was constructed by molecular biological methods and then transfected into human ovarian cancer cell SKOV3, human hepatoma cell HepG2 and human fibroblast BJ by cationic liposome. Reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the IL-24 gene in cells and supernatants. The antitumor effects of IL-24 gene were investigated by direct cell count, flow cytometry and methyl thiazolyl tetrazolium (MTT) assay. After transfections with pcDNA3.0-OSP-1-IL-24, the expression of IL-24 gene was detected only in SKOV3 cells. And only the growth of SKOV3 cells was inhibited significantly while those of HepG2 and BJ cells were not affected. The culture supernatant of SKOV3 cells transfected with pcDNA3.0-OSP-1-IL-24 could significantly inhibit the growth of SKOV3 cells. But the antitumor efficiency in SKOV3 cells of OSP-1 system was significantly lower than that of CMV promoter system. With a high specificity, IL-24 gene therapy under the control of ovarian-specific promoter-1 is a novel target for the treatment of ovarian cancer.


Relationship between dental caries experience (DMFS) and dental fluorosis in 12-year-old Puerto Ricans.
Examine the relationship between (1) DMFS and community fluorosis index (CFI) scores, and (2) between individual DMFS and NIDR/Dean Index fluorosis scores. Population-based, cross-sectional study. Public and private schools of Puerto Rico. 1435, 12-year old students. A probabilistic stratified sample was selected from 11 regions of Puerto Rico, according to type of school (public and private), and setting (urban and rural). Children were examined using NIDR criteria for DMFS and fluorosis. Regressions examined the relationship between DMFS means and CFI scores. Individual level DMFS was regressed on NIDR/Dean Index scores to test for linear and deviation from linear trends. (1) There was no statistically significant relationship between regional DMFS and CFI scores, and (2) individual level fluorosis scores when dichotomized as 0-2 as the referent level to level 3-4 demonstrated a statistical significant higher DMFS with the higher fluorosis level. Gender and school setting were statistically significant in all models: females and public school attendance were associated with increased DMFS. No ecological relationship between CFI and DMFS scores was found in 12-year-old children in Puerto Rico. Moderate and severe fluorosis were associated with higher DMFS levels relative to lower fluorosis scores, though this finding may be associated with restorations placed for cosmetic reasons. While controlling severe fluorosis is desirable, this will have little impact on overall high caries in Puerto Rican children. These findings suggest caution when interpreting caries experience using the DMFS index in populations with differing fluorosis levels.


Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Children and adolescents with classical congenital adrenal hyperplasia have been shown to be at risk for obesity associated with higher insulin and leptin levels. Because these factors are also known to cause hypertension, the aim of this study was to analyze 24-h blood pressure profiles and their relation to different clinical and laboratory parameters. Fifty-five subjects, aged between 5.3 and 19.0 yr, were enrolled in a prospective, cross-sectional study. All patients had genetically proven 21-hydroxylase deficiency and underwent ambulatory 24-h blood pressure monitoring during a period off school/work. RESULTS (MEDIAN, RANGE): The median body mass index of the cohort was significantly elevated [1.09 sd score (SDS), -2.45 to 3.77]. Daytime and nighttime systolic blood pressures were also significantly elevated (0.67 SDS, -1.5-4.1; 0.63 SDS, -0.91 to 3.3), whereas daytime diastolic blood pressure was significantly lowered (-0.81 SDS, -2.6 to 3.2) and normal during the night (0.11 SDS, -2.0 to 2.0). Overall, there was a normal nocturnal drop of systolic (12.8%, 2.1-22.8) but not diastolic blood pressure (17.2%, 0.90-25.8). The different parameters of systolic and diastolic blood pressures were significantly correlated with body mass index and skinfold thickness (r(s) = 0.271-0.486). There was no correlation with equivalent hydrocortisone and fludrocortisone dosage and laboratory parameters except for serum leptin and insulin. Our data show altered 24-h blood pressure profiles with elevated systolic levels correlated with the degree of overweight and obesity, whereas normal-weight patients tended to diastolic hypotension.


The structure and duplex context of DNA interstrand crosslinks affects the activity of DNA polymerase η.
Several important anti-tumor agents form DNA interstrand crosslinks (ICLs), but their clinical efficiency is counteracted by multiple complex DNA repair pathways. All of these pathways require unhooking of the ICL from one strand of a DNA duplex by nucleases, followed by bypass of the unhooked ICL by translesion synthesis (TLS) polymerases. The structures of the unhooked ICLs remain unknown, yet the position of incisions and processing of the unhooked ICLs significantly influence the efficiency and fidelity of bypass by TLS polymerases. We have synthesized a panel of model unhooked nitrogen mustard ICLs to systematically investigate how the state of an unhooked ICL affects pol η activity. We find that duplex distortion induced by a crosslink plays a crucial role in translesion synthesis, and length of the duplex surrounding an unhooked ICL critically affects polymerase efficiency. We report the synthesis of a putative ICL repair intermediate that mimics the complete processing of an unhooked ICL to a single crosslinked nucleotide, and find that it provides only a minimal obstacle for DNA polymerases. Our results raise the possibility that, depending on the structure and extent of processing of an ICL, its bypass may not absolutely require TLS polymerases.


Emergency management of acute congestive glaucoma using an anterior chamber microsyringe and needle.
A microsyringe-needle assembly is described for use in aspiration and microinfusion procedures in the anterior chamber. Assets of a lancet pointed 30-gauge needle, surface anesthesia, and fine control of ocular pressure and aqueous humor volume are stressed. Use of the assembly for emergency treatment of acute congestive glaucoma, surgical paracentesis, aqueous sampling, and drug infusion are described. Drug volumes and concentrations must be maintained at levels which do not damage corneal endothelium.


Trauma-induced schwannoma of the recurrent laryngeal nerve after thyroidectomy.
Laryngeal schwannomas are rare, benign tumors, most often arising from the superior laryngeal nerve. We describe a case of a 68-year-old female with a laryngeal schwannoma of the recurrent laryngeal nerve after traumatic injury. We postulate that trauma to the recurrent laryngeal nerve during thyroidectomy or thyroplasty incited growth of a nerve sheath tumor. This is the first reported case of a trauma-induced schwannoma of the recurrent laryngeal nerve and second case of a recurrent laryngeal nerve schwannoma. Although rare, this case demonstrates that these tumors should be considered during workup of vocal cord paresis after surgery or failed thyroplasty. Laryngoscope, 126:1408-1410, 2016.


Enhanced binding and inhibition of SARS-CoV-2 by a plant-derived ACE2 protein containing a fused mu tailpiece.
Infectious diseases such as Coronavirus disease 2019 (COVID-19) and Middle East respiratory syndrome (MERS) present an increasingly persistent crisis in many parts of the world. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The angiotensin-converting enzyme 2 (ACE2) is a crucial cellular receptor for SARS-CoV-2 infection. Inhibition of the interaction between SARS-CoV-2 and ACE2 has been proposed as a target for the prevention and treatment of COVID-19. We produced four recombinant plant-derived ACE2 isoforms with or without the mu tailpiece (μ-tp) of immunoglobulin M (IgM) and the KDEL endoplasmic reticulum retention motif in a plant expression system. The plant-derived ACE2 isoforms bound whole SARS-CoV-2 virus and the isolated receptor binding domains of SARS-CoV-2 Alpha, Beta, Gamma, Delta, and Omicron variants. Fusion of μ-tp and KDEL to the ACE2 protein (ACE2 μK) had enhanced binding activity with SARS-CoV-2 in comparison with unmodified ACE2 protein derived from CHO cells. Furthermore, the plant-derived ACE2 μK protein exhibited no cytotoxic effects on Vero E6 cells and effectively inhibited SARS-CoV-2 infection. The efficient and rapid scalability of plant-derived ACE2 μK protein offers potential for the development of preventive and therapeutic agents in the early response to future viral outbreaks.


Analysis of class 1 residual solvents in pharmaceuticals using headspace-programmed temperature vaporization-fast gas chromatography-mass spectrometry.
A sensitive method is presented for the fast screening and determination of residual class 1 solvents (1,1-dichloroethene, 1,2-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride and benzene) in pharmaceutical products. The applicability of a headspace (HS) autosampler in combination with GC equipped with a programmed temperature vaporizer (PTV) and a MS detector is explored. Different injection techniques were compared. The benefits of using solvent vent injection instead of split or splitless-hot injection for the measurement of volatile compounds are shown: better peak shapes, better signal-to-noise ratios, and hence better detection limits. The proposed method is extremely sensitive. The limits of detection ranged from 4.9 ppt (benzene) to 7.9 ppt (1,2-dichloroethane) and precision (measured as the relative standard deviation) was equal to or lower than 12% in all cases. The method was applied to the determination of residual solvents in nine different pharmaceutical products. The analytical performance of the method shows that it is appropriate for the determination of residual class 1 solvents and has much lower detection limits than the concentration limits proposed by the International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use. The proposed method achieves a clear improvement in sensitivity with respect to conventional headspace methods due to the use of the PTV.


Microbial production of amphotericin B-3H and the synthesis of its sodium desoxycholate (carboxyl-14C) complex and methyl-14C-ester.
Amphotericin B-3H with a specific radioactivity in excess of 4 muCi/mg was produced by fermentation of Streptomyces nodosus IMRU 3694 in a complex medium, using acetate-3H as a precursor. The medium employed gave a production yield of 2.5 approximately 3.5 mg/ml of amphotericin B. The most efficient incorporation of acetate-3H occurred when the precursor was added at 24 hours after inoculation. It was observed, that the amount of amphotericin A co-produced in the fermentation broth with amphotericin B was significantly reduced by the addition of ethanol to the production medium. Complete inhibition of amphotericin A production was achieved at a level of 2% ethanol in the fermentation medium without an appreciable effect on the yield of amphotericin B. Methanol, 1-propanol, 2-propanol and 1-butanol lowered the yield of both antibiotics indiscriminately. The syntheses of amphotericin B-3H-Na desoxycholate (carboxyl-14C) complex and amphotericin B-3H methyl-14C-ester are also described.


Diversity and evolution of Ty1-copia and Ty3-gypsy retroelements in the non-photosynthetic flowering plants Orobanche and Phelipanche (Orobanchaceae).
We present the first study on the diversity and evolution of Ty1-copia and Ty3-gypsy retroelements in a group of non-photosynthetic flowering plants. To this end partial sequences of the reverse transcriptase (rt) gene were obtained from 20 clones for each retroelement type from seven and six accessions of Orobanche and Phelipanche (Orobanchaceae), respectively. Overall sequence similarity is higher in Ty3-gypsy elements than in Ty1-copia elements in agreement with the results from other angiosperm groups. Higher sequence diversity and stronger phylogenetic structure, especially of Ty1-copia sequences, in Orobanche species compared to Phelipanche species support the previously suggested hypothesis (based on karyological and cytological data) that genomes of Orobanche species are more dynamic than those of Phelipanche species. No evidence was found for intraspecific differences of retroelement diversity nor for differences between pest taxa and their putative wild relatives, e.g., O. crenata and O. owerini. The occurrence of a few sequences from Phelipanche species in clades otherwise comprising sequences from Orobanche species might be due to horizontal gene transfer, but the alternative of vertical transmission cannot be rejected unambiguously.


The shifting sands of research ethics and governance: effect on research in paediatrics.
Basic principles governing the ethical conduct of research have not changed but recent years have seen the burgeoning of bureaucracy to support and monitor research ethics and governance. More changes are planned, and the effect of the proposed changes on paediatric research are examined and broadly welcomed.


The trafficking of prosaposin (SGP-1) and GM2AP to the lysosomes of TM4 Sertoli cells is mediated by sortilin and monomeric adaptor proteins.
Prosaposin (SGP-1) and GM2 activator protein (GM2AP) are soluble sphingolipid activator proteins (SAPs) that are targeted to the lysosomal compartment of Sertoli cells to aid hydrolases in the breakdown of glycosphingolipids. To reach the lysosome, most soluble proteins must interact with the mannose 6-phosphate receptor (MPR). To be sorted from the Golgi, the MPR must bind to the Golgi associated, gamma-adaptin homologous, ARF binding proteins (GGAs), a group of monomeric adaptor proteins responsible for the recruitment of clathrin. It is well established, however, that the lysosomes of I-cell disease (ICD) patients have near normal levels of several lysosomal proteins, including prosaposin and GM2AP. ICD results from a mutation in the phosphotransferase that adds mannose 6-phosphate to hydrolases. Thus, prosaposin and GM2AP can traffic to lysosomes in a MPR independent manner. Previous work has demonstrated that an interaction with sphingomyelin in the Golgi membrane is necessary for the targeting of prosaposin by an unknown receptor. Using a TM4 Sertoli cell line, we tested the hypothesis that prosaposin and GM2AP are targeted to the lysosomal compartment via the sortilin receptor, which has been recently shown to have a GGA binding motif. Interestingly, dominant-negative GGAs, unable to bind clathrin to shuttle from the Golgi, prevented the trafficking of prosaposin and GM2AP to lysosomes. A dominant negative construct of sortilin lacking the GGA binding domain retained prosaposin and GM2AP in the Golgi. In conclusion, our results showed that the trafficking of prosaposin and GM2AP to the lysosome is dependent on sortilin.


Relations of biomarkers of manganese exposure and neuropsychological effects among welders and ferroalloy smelters.
The objective of present study was to assess relationship between biomarkers of Manganese (Mn) and neuropsychological effects. The study was carried out on 27 welders and 31 ferroalloy smelters as Mn-exposed groups and 30 office workers as unexposed controls. Air Mn concentrations were determined according to NIOSH method 7300. The biological samples were prepared using microwave assisted acid digestion and all samples were analyzed by graphite furnace- atomic absorption spectroscopy (GF-AAS) in order to determine manganese. Questionnaire 16 (Q16) and Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to evaluate the neuropsychological effects. The mean concentrations of air Mn for the welder and ferroalloy smelter groups were 0.023 ± 0.012 mg/m(3) and 0.008 ± 0.005 mg/m(3), respectively. Manganese concentrations in blood, urine, and toenail samples of exposed workers ranged between 1.80-32.60 (µg/l), 1.00-42.50 (µg/l), and 0.10-6.08 (µg/g), respectively. Mean Mn concentrations in all biological samples of cases were significantly higher than unexposed controls (p<0.05). A moderate relationship was observed between biomarkers of Mn exposure, air Mn, Q16 as well as some neurocognitive outcome measures. The present study shows that blood Mn, urine Mn and toenail Mn could be used to distinguish Mn-exposed workers from unexposed population at the group level.


Two-photon microscopy of dermal innervation in a human re-innervated model of skin.
When skin is injured, innervation can be severely disrupted. The subsequent re-innervation processes are poorly understood notably because of the inability to image the full meandering course of nerves with their ramifications and endings from histological slices. In this letter, we report on two-photon excitation fluorescence (TPEF) microscopy of entire human skin explants re-innervated by rodent sensory neurons labelled with the styryl dye FM1-43. TPEF imaging of nerve fibres to a depth up to roughly 300 μm within the dermis was demonstrated, allowing three-dimensional reconstruction of the neural tree structure. Endogenous second-harmonic imaging of type I fibrillar collagen was performed in parallel to TPEF imaging using the same nonlinear microscope, revealing the path of the nerves through the dermis.


Abdominal adiposity distribution in diabetic/prediabetic and nondiabetic populations: a meta-analysis.
Excess fat in the abdomen can be classified generally as visceral and subcutaneous adiposity. Evidence suggests that visceral adiposity has greater implications for diabetes than other fat depots. The purpose of this study is to explore the disparities in the distribution of abdominal adiposity in diabetic/prediabetic and nondiabetic populations and to identify moderators that influence the pattern of central obesity via a meta-analysis technique. The Hedges' g was used as a measure of effect size and 95% confidence interval was computed. A total of 41 relevant studies with 101 effect sizes were retrieved. Pooled effect sizes for visceral and subcutaneous adiposity were 0.69 and 0.42, respectively. Diabetic/prediabetic populations exhibited greater visceral and subcutaneous adiposity compared to nondiabetic populations (Z = 10.35, P < 0.05). Significant moderator effects of gender (Z = -2.90) and assessment method of abdominal adiposity (Z = -2.17) were found for visceral fat (P < 0.05), but not for subcutaneous fat. Type of health condition influenced both visceral (Z = -5.10) and subcutaneous (Z = -7.09) abdominal adiposity volumes (P < 0.05). Abdominal adiposity distributions were significantly altered in the diabetic/prediabetic population compared to the nondiabetic population. Gender, assessment method of abdominal adiposity, and type of health conditions (diabetic/prediabetics) were identified as crucial moderators that influence the degree of abdominal adiposity.


Comparison of resonance assisted and charge assisted effects in strengthening of hydrogen bonds in dipyrrins.
This paper deals with the study of two types of hydrogen bonding: a quasi-aromatic hydrogen bonding in dipyrromethene and the ionic one in dipyrromethane. The study focuses on two phenomena-the proton transfer process and tautomeric equilibrium. Metric parameters and spectroscopic assignments have been calculated; this allowed a further comparison of spectral features calculated with four methods (Car-Parrinello molecular dynamics (CPMD), ab initio, density functional theory (DFT), and numerical calculation of anharmonic vibrational levels via a solution of the corresponding 1D Schrödinger equation). A significant dynamics of the bridged proton and bent vibration of pyrrole fragments in dipyrromethane have been exposed by the CPMD calculations. The prevailing of the ionic effect over the π-electronic coupling in the strengthening of the hydrogen bonding has been shown on the basis of the calculated structural, electron-topological, and spectral data as well as potential energy surface (PES). The analysis of the aromaticity and electronic state of pyrrole and chelate moieties depending on the tautomeric equilibrium by the quantum theory of atoms in molecules (QTAIM) method was conducted. The principle divergence in the behavior of aromaticity of the chelate chains in the analyzed compounds was demonstrated.


Genetic changes during mouse skin tumorigenesis.
This paper describes specific genetic changes involving chromosome 7 in mouse skin tumors, the most important consequence of which appears to be an alteration in the allelic balance of normal and mutant H-ras genes. The use of restriction-fragment-length polymorphisms in F1 hybrid mice demonstrates that trisomy of chromosome 7 is an early event preceding papilloma formation, and further events, such as mitotic recombination, seem to occur during progression to malignant carcinomas. There is some evidence of a tumor-suppressor locus situated on chromosome 7.


Venous thrombosis: a multicausal disease.
The risk factors for venous thrombosis differ from those for arterial vascular disease. During the past 5 years, knowledge about the aetiology of venous thrombosis has advanced with the discovery of several factors that contribute to the incidence of thrombosis, particularly the role of coagulation abnormalities. These abnormalities are common in the general population and therefore will be present simultaneously in some individuals. The resultant gene-gene and gene-environment interactions between risk factors are the key to the understanding of why a certain person develops thrombosis at a specific point in time.


Nursing care system development for patients with cleft lip-palate and craniofacial deformities in operating room Srinagarind Hospital.
For a successful surgical outcome for patients with cleft lip/palate (CLP), the attending nurses must continuously develop their potential, knowledge, capacity and skills. The goal is to meet international standards of patient safety and efficiency. To assess and improve the nursing care system for patients with CLP and craniofacial deformities at the operating room (OR), Srinagarind Hospital, Khon Kaen University. Data were collected for two months (between March 1, 2011 and April 30, 2011). Part I was an enquiry regarding the attitude of OR staff on serving patients with CLP; and, Part 2.1) patient and caregiver satisfaction with service from the OR staff and 2.2) patient and caregiver satisfaction with the OR transfer service. The authors interviewed 28 staff in OR unit 2 of the OR nursing division and 30 patients with CLP and his/her caregiver. The respective validity according to the Cronbach's alpha coefficient was 0.87 and 0.93. The OR staff attitude visa-vis service provision for patients with CLP service was middling. Patient and caregiver satisfaction with both OR staff and the transfer service was very satisfactory. Active development of the nursing care system for patients with CLP and craniofacial deformities in the operating room, Srinagarind Hospital improved staff motivation with respect to serving patients with CLP. The operating theater staff was able to co-ordinate the multidisciplinary team through the provision of surgical service for patients with CLP.


An Insight into the Increasing Role of LncRNAs in the Pathogenesis of Gliomas.
Long non-coding RNAs (LncRNAs) are essential epigenetic regulators with critical roles in tumor initiation and malignant progression. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of gliomas are not fully understood. With the development of deep sequencing analyses, an extensive amount of functional non-coding RNAs has been discovered in glioma tissues and cell lines. Additionally, the contributions of several lncRNAs, such as Hox transcript antisense intergenic RNA, H19 and Colorectal neoplasia differentially expressed, previously reported to be involved in other pathogenesis and processes to the oncogenesis of glioblastoma are currently addressed. Thus, lncRNAs detected in tumor tissues could serve as candidate diagnostic biomarkers and therapeutic targets for gliomas. To understand the potential function of lncRNAs in gliomas, in this review, we briefly describe the profile of lncRNAs in human glioma research and therapy. Then, we discuss the individual lncRNA that has been under intensive investigation in glioma research, and the focus is its mechanism and clinical implication.


Rodents as intermediate hosts of Hepatozoon ayorgbor (Apicomplexa: Adeleina: Hepatozoidae) from the African ball python, Python regius?
Two experimental trials were performed to elucidate the role of rodents in the life cycle of Hepatozoon species using snakes as intermediate hosts. In one trial, two ball pythons, Python regius Shaw, 1802 were force fed livers of laboratory mice previously inoculated with sporocysts of Hepatozoon ayorgbor Sloboda, Kamler, Bulantová, Votýpka et Modrý, 2007. Transmission was successful in these experimentally infected snakes as evidenced by the appearance of intraerythrocytic gamonts, which persisted until the end of trial, 12 months after inoculation. Developmental stages of haemogregarines were not observed in histological sections from mice. In another experimental trial, a presence of haemogregarine DNA in mice inoculated with H. ayorgbor was demonstrated by PCR in the liver, lungs and spleen.


Behavioral responses to hypoxia and hyperoxia in Drosophila larvae: molecular and neuronal sensors.
The ability to detect changes in oxygen concentration in the environment is critical to the survival of all animals. This requires cells to express a molecular oxygen sensor that can detect shifts in oxygen levels and transmit a signal that leads to the appropriate cellular response. Recent biochemical, genetic and behavioral studies have shown that the atypical soluble guanylyl cyclases function as oxygen detectors in Drosophila larvae triggering a behavioral escape response when exposed to hypoxia. These studies also identified the sensory neurons that innervate the terminal sensory cones as likely chemosensors that mediate this response. Here I summarize the data that led to these conclusions and also highlight evidence that suggests additional, as yet unidentified, proteins are also required for detecting increases and decreases in oxygen concentrations.


Perinatal exposure to a low dose of bisphenol A impaired systemic cellular immune response and predisposes young rats to intestinal parasitic infection.
Perinatal exposure to the food contaminant bisphenol A (BPA) in rats induces long lasting adverse effects on intestinal immune homeostasis. This study was aimed at examining the immune response to dietary antigens and the clearance of parasites in young rats at the end of perinatal exposure to a low dose of BPA. Female rats were fed with BPA [5 µg/kg of body weight/day] or vehicle from gestational day 15 to pup weaning. Juvenile female offspring (day (D)25) were used to analyze immune cell populations, humoral and cellular responses after oral tolerance or immunization protocol to ovalbumin (OVA), and susceptibility to infection by the intestinal nematode Nippostrongylus brasiliensis (N. brasiliensis). Anti-OVA IgG titers following either oral tolerance or immunization were not affected after BPA perinatal exposure, while a sharp decrease in OVA-induced IFNγ secretion occurred in spleen and mesenteric lymph nodes (MLN) of OVA-immunized rats. These results are consistent with a decreased number of helper T cells, regulatory T cells and dendritic cells in spleen and MLN of BPA-exposed rats. The lack of cellular response to antigens questioned the ability of BPA-exposed rats to clear intestinal infections. A 1.5-fold increase in N. brasiliensis living larvae was observed in the intestine of BPA-exposed rats compared to controls due to an inappropriate Th1/Th2 cytokine production in infected jejunal tissues. These results show that perinatal BPA exposure impairs cellular response to food antigens, and increases susceptibility to intestinal parasitic infection in the juveniles. This emphasized the maturing immune system during perinatal period highly sensitive to low dose exposure to BPA, altering innate and adaptative immune response capacities in early life.


Polymer-induced bundling of F actin and the depletion force.
The inert polymer polyethylene glycol (PEG) induces a "bundling" phenomenon in F actin solutions when its concentration exceeds a critical onset value C(o). Over a limited range of PEG molecular weight and ionic strength, C(o) can be expressed as a function of these two variables. The process is reversible, but hysteresis is also observed in the dissolution of the bundles, with ionic strength having a large influence. Additional actin filaments are able to join the previously formed bundles. PEG polymers are not incorporated into the actin bundles. Estimates of the Asakura-Oosawa depletion force, Coulomb repulsion, and van der Waals potential are combined in order to explain the bundling effect and hysteresis. Conjectures are presented concerning the apparent limit in bundle size.


Outpatient parenteral antimicrobial therapy (OPAT) in the UK: a cross-sectional survey of acute hospital trusts and health boards.
This study reviews the current OPAT service provision in the UK and evaluates concordance with the national OPAT practice guidelines (standards of care). We conducted a survey of acute hospital trusts and health boards in the UK regarding OPAT practices between June and September 2017. 165 (93%) of the 178 acute hospital trusts/health boards that were contacted responded to the survey. 100 (61%) indicated they had an OPAT service. Ten (10%) OPAT services did not involve an infection specialist. Bone and joint infections, and skin and soft-tissue infections were the most common conditions treated. Most OPAT services (74%) hold weekly multidisciplinary meetings/virtual ward rounds to review patient's progress. 73% had a dedicated OPAT database. We identified variations in practice and concordance with the national OPAT good practice guidelines. In an era of increasing demand for home-based care, further studies are required to identify the optimal configuration of OPAT services with regards to quality and patient safety.


Regulation of lactic acid production during exercise.
Lactic acid accumulates in contracting muscle and blood beginning at approximately 50-70% of the maximal O2 uptake, well before the aerobic capacity is fully utilized. The classical explanation has been that part of the muscle is O2 deficient and therefore lactate production is increased to provide supplementary anaerobically derived energy. Currently, however, the predominant view is that lactate production during submaximal dynamic exercise is not O2 dependent. In the present review, data and arguments in support of and against the hypothesis of O2 dependency have been scrutinized. Data underlying the conclusion that lactate production during exercise is not O2 dependent were found to be 1) questionable, or 2) interpretable in an alternative manner. Experiments in human and animal muscles under various conditions demonstrated that the redox state of the muscle is reduced (i.e., NADH is increased) either before or in parallel with increases in muscle lactate. Based on experimental data and theoretical considerations, it is concluded that lactate production during submaximal exercise is O2 dependent. The amount of energy provided through the anaerobic processes during steady-state submaximal exercise is, however, low, and the role of lactate formation as an energy source is of minor importance. It is proposed that the achievement of increased aerobic energy formation under conditions of limiting O2 availability requires increases of ADP, Pi, and NADH and that the increases in ADP (and therefore AMP via the adenylate kinase equilibrium) and Pi will stimulate glycolysis, and the resulting increase in cytosolic NADH will shift the lactate dehydrogenase equilibrium toward increased lactate production.


DNA damage induces cdk2 protein levels and histone H2B phosphorylation in SH-SY5Y neuroblastoma cells.
DNA damage and activation of the cell cycle have been implicated in numerous neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. To better understand the role of cell cycle proteins in DNA-damage induced neuronal cell death, we examined various cell cycle proteins during camptothecin-induced death of human neuroblastoma cells. We report a rapid induction of p53 and increased expression of p21, concurrent with reduced levels of many cell cycle proteins that regulate G1 to S phase cell cycle progression. However, we found increased levels of cdk2 and cyclin E, and formation of a cyclin E-cdk2-p21 protein complex. DNA damage failed to induce activation and progression of the cell cycle. Finally, camptothecin-induced neuronal cell death occurred concurrent with phosphorylation of histone H2B. Pretreatment of cells with cdk inhibitor olomoucine impeded cdk2-cyclin E accumulation, but not the induction of p53. Olomucine concurrently delayed histone H2B phosphorylation, caspase-3 activation and cell death. These findings suggest that DNA-damage of differentiated neuroblastoma cells induces a rapid p53-mediated inhibition of cell cycle progression and induction of cdk2-cyclin E, followed by caspase-3 activation, phosphorylation of histone and cell death.


Promoting Cell Migration in Tissue Engineering Scaffolds with Graded Channels.
Ideal bone scaffolds having good biocompatibility, good biodegradability, and beneficial mechanical properties are the basis for bone tissue engineering. Specifically, cell migration within 3D scaffolds is crucial for bone regeneration of critical size defects. In this research, hydroxyapatite scaffolds with three different types of architectures (tortuous, parallel, and graded channels) are fabricated using the freeze-casting (ice-templating) method. While most studies promote cell migration by chemical factors, it can be greatly enhanced by introducing only graded channels as compared with tortuous or parallel channels. The results provide insights and guidance in designing novel scaffolds to enhance cell migration behavior for bone tissue regeneration.


Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis.
Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Cyclooxygenase inhibitors (COX-I) may prevent PDA-related complications. Controversy exists on which COX-I drug is the most effective and has the best safety profile in preterm infants. To compare the effectiveness and safety of prophylactic COX-I drugs and 'no COXI prophylaxis' in preterm infants using a Bayesian network meta-analysis (NMA). Searches of Cochrane CENTRAL via Wiley, OVID MEDLINE and Embase via Elsevier were conducted on 9 December 2021. We conducted independent searches of clinical trial registries and conference abstracts; and scanned the reference lists of included trials and related systematic reviews. We included randomised controlled trials (RCTs) that enrolled preterm or low birth weight infants within the first 72 hours of birth without a prior clinical or echocardiographic diagnosis of PDA and compared prophylactic administration of indomethacin or ibuprofen or acetaminophen versus each other, placebo or no treatment. We used the standard methods of Cochrane Neonatal. We used the GRADE NMA approach to assess the certainty of evidence derived from the NMA for the following outcomes: severe intraventricular haemorrhage (IVH), mortality, surgical or interventional PDA closure, necrotizing enterocolitis (NEC), gastrointestinal perforation, chronic lung disease (CLD) and cerebral palsy (CP). We included 28 RCTs (3999 preterm infants). Nineteen RCTs (n = 2877) compared prophylactic indomethacin versus placebo/no treatment, 7 RCTs (n = 914) compared prophylactic ibuprofen versus placebo/no treatment and 2 RCTs (n = 208) compared prophylactic acetaminophen versus placebo/no treatment. Nine RCTs were judged to have high risk of bias in one or more domains.We identified two ongoing trials on prophylactic acetaminophen. Bayesian random-effects NMA demonstrated that prophylactic indomethacin probably led to a small reduction in severe IVH (network RR 0.66, 95% Credible Intervals [CrI] 0.49 to 0.87; absolute risk difference [ARD] 43 fewer [95% CrI, 65 fewer to 16 fewer] per 1000; median rank 2, 95% CrI 1-3; moderate-certainty), a moderate reduction in mortality (network RR 0.85, 95% CrI 0.64 to 1.1; ARD 24 fewer [95% CrI, 58 fewer to 16 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and surgical PDA closure (network RR 0.40, 95% CrI 0.14 to 0.66; ARD 52 fewer [95% CrI, 75 fewer to 30 fewer] per 1000; median rank 2, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic indomethacin resulted in trivial difference in NEC (network RR 0.76, 95% CrI 0.35 to 1.2; ARD 16 fewer [95% CrI, 42 fewer to 13 more] per 1000; median rank 2, 95% CrI 1-3; high-certainty), gastrointestinal perforation (network RR 0.92, 95% CrI 0.11 to 3.9; ARD 4 fewer [95% CrI, 42 fewer to 137 more] per 1000; median rank 1, 95% CrI 1-3; moderate-certainty) or CP (network RR 0.97, 95% CrI 0.44 to 2.1; ARD 3 fewer [95% CrI, 62 fewer to 121 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty) and may result in a small increase in CLD (network RR 1.10, 95% CrI 0.93 to 1.3; ARD 36 more [95% CrI, 25 fewer to 108 more] per 1000; median rank 3, 95% CrI 1-3; low-certainty). Prophylactic ibuprofen probably led to a small reduction in severe IVH (network RR 0.69, 95% CrI 0.41 to 1.14; ARD 39 fewer [95% CrI, 75 fewer to 18 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and moderate reduction in surgical PDA closure (network RR 0.24, 95% CrI 0.06 to 0.64; ARD 66 fewer [95% CrI, from 82 fewer to 31 fewer] per 1000; median rank 1, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic ibuprofen may result in moderate reduction in mortality (network RR 0.83, 95% CrI 0.57 to 1.2; ARD 27 fewer [95% CrI, from 69 fewer to 32 more] per 1000; median rank 2, 95% CrI 1-4; low-certainty) and leads to trivial difference in NEC (network RR 0.73, 95% CrI 0.31 to 1.4; ARD 18 fewer [95% CrI, from 45 fewer to 26 more] per 1000; median rank 1, 95% CrI 1-3; high-certainty), or CLD (network RR 1.00, 95% CrI 0.83 to 1.3; ARD 0 fewer [95% CrI, from 61 fewer to 108 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty). The evidence is very uncertain on effect of ibuprofen on gastrointestinal perforation (network RR 2.6, 95% CrI 0.42 to 20.0; ARD 76 more [95% CrI, from 27 fewer to 897 more] per 1000; median rank 3, 95% CrI 1-3; very low-certainty). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (network RR 1.17, 95% CrI 0.04 to 55.2; ARD 22 more [95% CrI, from 122 fewer to 1000 more] per 1000; median rank 4, 95% CrI 1-4; very low-certainty), mortality (network RR 0.49, 95% CrI 0.16 to 1.4; ARD 82 fewer [95% CrI, from 135 fewer to 64 more] per 1000; median rank 1, 95% CrI 1-4; very low-certainty), or CP (network RR 0.36, 95% CrI 0.01 to 6.3; ARD 70 fewer [95% CrI, from 109 fewer to 583 more] per 1000; median rank 1, 95% CrI 1-3; very low-certainty). In summary, based on ranking statistics, both indomethacin and ibuprofen were equally effective (median ranks 2 respectively) in reducing severe IVH and mortality. Ibuprofen (median rank 1) was more effective than indomethacin in reducing surgical PDA ligation (median rank 2). However, no statistically-significant differences were observed between the COX-I drugs for any of the relevant outcomes. Prophylactic indomethacin probably results in a small reduction in severe IVH and moderate reduction in mortality and surgical PDA closure (moderate-certainty), may result in a small increase in CLD (low-certainty) and results in trivial differences in NEC (high-certainty), gastrointestinal perforation (moderate-certainty) and cerebral palsy (low-certainty). Prophylactic ibuprofen probably results in a small reduction in severe IVH and moderate reduction in surgical PDA closure (moderate-certainty), may result in a moderate reduction in mortality (low-certainty) and trivial differences in CLD (low-certainty) and NEC (high-certainty). The evidence is very uncertain about the effect of acetaminophen on any of the clinically-relevant outcomes.


CD44v3,8-10 is essential for Slug-dependent vimentin gene expression to acquire TGF-β1-induced tumor cell motility.
CD44 is a widely expressed polymorphic adhesion molecule that has pleiotropic functions in development and tumor progression. Its mRNA undergoes alternative splicing to generate multiple variant (CD44v) isoforms, although the function of each CD44v isoform is not fully elucidated. Here, we show that CD44v plays an important role in the induction of vimentin expression upon transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT). Among multiple CD44v isoforms expressed in NUGC3 gastric cancer cells, CD44v8-10 and CD44v3,8-10 are involved in the acquisition of migratory and invasive properties associated with TGF-β1-induced EMT, and only CD44v3,8-10 induces the transcription of vimentin mediated by the EMT transcription factor Slug. In primary tumor specimens obtained from patients with gastric cancer, CD44-containing variant exon 9 (CD44v9) expression and EMT features [E-cadherin(-)vimentin(+)] were significantly correlated, and EMT features in the cells expressing CD44v9 were associated with tumor invasion depth, lymph node metastasis, and pStage, which indicate invasive and metastatic properties, and poor prognosis. These results indicate that certain CD44v isoforms promote tumor cell motility and metastasis in gastric cancer in association with EMT features, and CD44v3,8-10 may contribute to these clinical characteristics.