Preparation and properties of monodispersed rifampicin-loaded poly(lactide-co-glycolide) microspheres.
Monodispersed rifampicin (RFP)-loaded poly(lactide-co-glycolide) (PLGA) microspheres were prepared by a solvent evaporation method. In order to control the sizes of the microspheres, a membrane emulsification technique using Shirasu porous glass (SPG) membranes was applied. RFP/PLGA microspheres with the average diameters of 1.3, 2.2, 5.2, and 9.0 microm were obtained. They were relatively monodisperse and the values of the coefficient of variation (CV) for the size distributions of the microspheres were in the range between 7.0 and 16.0%. The loading efficiency of RFP was in the range between 50.3 and 67.4% independent of the microsphere size. The release ratio of RFP from RFP/PLGA microspheres was measured in pH 7.4 PBS at 37 degrees C. From RFP/PLGA microspheres with average diameters of 1.3 and 2.2 microm, almost 60% of RFP loaded in the microspheres was released in the initial day and the release was terminated almost within 10 days. On the other hand, from those with average diameters of 5.2, and 9.0 microm, the release of RFP was observed even 20 days after the release started.


Fetal cardiac flow velocities in the late 1st trimester of pregnancy: a transvaginal Doppler study.
In 30 normal women with a singleton pregnancy, transvaginal Doppler ultrasound was used to record flow velocity at the fetal atrioventricular (AV) valve and outflow tract levels (ascending aorta and pulmonary artery) at 11 to 13 weeks of gestation. Technically acceptable flow velocity waveforms were recorded at the AV valve level in 19 fetuses and in the ascending aorta and pulmonary artery in 15 and 17 fetuses, respectively. Successful documentation of both transmitral and transtricuspid flow velocity waveforms was achieved in six fetuses only. Peak velocities during atrial contraction (A wave) were nearly twice as high as those during early diastolic filling (E wave), reflecting low ventricular compliance. Peak and time-averaged flow velocities in the outflow tract were lower than those observed in 2nd and 3rd trimester pregnancies with mean values of 32.1 +/- 5.4 (+/- SD) and 11.2 +/- 2.2 cm/s, respectively, in the ascending aorta and 29.6 +/- 5.1 and 10.8 +/- 2.1 cm/s in the pulmonary artery.


Diagnosis and management of gastrointestinal perforations in childhood dermatomyositis with particular reference to perforations of the duodenum.
Four children with dermatomyositis were recently seen with gastrointestinal perforations. The sites of perforation in the four cases were: (1) the duodenum, esophagus, and colon; (2) the duodenum; (3) the distal stomach; and (4) the traverse colon. The gastric and transverse colon perforations were intraperitoneal and easily diagnosed. The gastric perforation was treated successfully by partial gastrectomy. The patient with the colon perforation underwent exteriorization; death occurred from cerebral complications possibly related to vasculitis. Both duodenal perforations were posterior in the distal descending portion. Enzymatic dissection into the right lower quadrant produced confusing clinical and radiographic signs and extensive retroperitoneal necrosis. Successful treatment was obtained by partial gastrectomy, sump drainage of the perforation, and parenteral nutrition. Gastrointestinal perforation is a well-recognized complication of vasculitis in childhood dermatomyositis. In particular, perforations of the distal duodenum, as reported by others, are associated with delay in diagnosis and high mortality.


Electrode-Electrolyte Interfacial Chemistry Modulation for Ultra-High Rate Sodium-Ion Batteries.
Sodium-ion batteries capable of operating at rate and temperature extremes are highly desirable, but elusive due to the dynamics and thermodynamics limitations. Herein, a strategy of electrode-electrolyte interfacial chemistry modulation is proposed. The commercial hard carbon demonstrates superior rate performance with 212 mAh g-1 at an ultra-high current density of 5 A g-1 in the electrolyte with weak ion solvation/desolvation, which is much higher than those in common electrolytes (nearly no capacity in carbonate-based electrolytes). Even at -20 °C, a high capacity of 175 mAh g-1 (74 % of its room-temperature capacity) can be maintained at 2 A g-1 . Such an electrode retains 90 % of its initial capacity after 1000 cycles. As proven, weak ion solvation/desolvation of tetrahydrofuran greatly facilitates fast-ion diffusion at the SEI/electrolyte interface and homogeneous SEI with well-distributed NaF and organic components ensures fast Na+ diffusion through the SEI layer and a stable interface.


Annual risk of tuberculous infection in rural areas of Uttar Pradesh, India.
Rural areas in Uttar Pradesh, the most populous state in India. 1) To estimate the average annual risk of tuberculous infection (ARI), 2) to study ARI trends with age, and 3) to compare tuberculin reactions among children with and without BCG scar. A cross-sectional tuberculin survey was conducted among children aged 1-9 years residing in Rae Bareli, Hardoi and Jaunpur districts, Uttar Pradesh. Tuberculin testing was performed using 1TU of PPD RT23 with Tween 80, and indurations were measured 72 hours later. Prevalence of infection was estimated in children without BCG scar based on the cut-off point identified on the frequency distribution of reaction sizes. The ARI was computed from the estimated prevalence. The proportion of children with BCG scar varied from 25% to 31% in the study districts. Using a cut-off of 14 mm among children without BCG scar, the ARI was estimated at 2.3% in Rae Bareli, 1.9% in Hardoi and 1.5% in Jaunpur, and was observed to increase with age. Tuberculin test results among children with BCG scar suggest that they may be included in tuberculin surveys to estimate ARI. High rates of transmission of tuberculous infection suggest that tuberculosis control measures need to be intensified.


High levels of heat labile Escherichia coli enterotoxin in bacterial cell sonicates of agar grown cultures.
Escherichia coli heat-labile enterotoxin from 5 strains of human and animal origin was detected in broth cultures and agar-plate culture sonicates by using CHO and Y-1 adrenal cells and rabbit intestinal loop assay. Cell sonicates possessed higher levels of heat-labile enterotoxin than supernatants of broth cultures. Highest levels of heat-labile (LT) enterotoxin were detected in the sonicates of cultures grown on blood agar, followed by those grown on MacConkey, and lactose agar respectively.


Interleukin-6 production by peripheral blood monocytes in patients with chronic liver disease and acute viral hepatitis.
The in vitro production of the acute-phase mediator interleukin-6 by peripheral blood monocytes derived from patients with various liver diseases was studied. Compared with healthy controls (n = 45; 860 +/- 92 U/ml, mean +/- SEM), monocytes from patients with chronic hepatitis B produced significantly lower amounts of interleukin-6 (n = 14; 424 +/- 126 U/ml) after stimulation with lipopolysaccharide (p = 0.02), whereas monocytes from patients with chronic hepatitis non-A, non-B secreted normal amounts of interleukin-6 (n = 13; 672 +/- 151 U/ml; n.s.). In contrast, monocytes of patients suffering from alcoholic liver cirrhosis (n = 22; 1310 +/- 153 U/ml) or primary biliary cirrhosis (n = 6; 1450 +/- 186 U/ml) produced higher amounts of interleukin-6 than healthy control individuals (p = 0.03, respectively). Lipopolysaccharide-stimulated monocytes derived from patients with acute hepatitis A, B and non-A, non-B showed an interleukin-6 production not different from that seen in healthy control individuals and did not experience a discernible change during the course of the acute disease. These results suggest that the production of the acute-phase mediator interleukin-6 varies in chronic liver disease in accordance with various etiologies with a reduced lipopolysaccharide-inducible interleukin-6 response in chronic hepatitis B and an enhanced response in alcoholic liver cirrhosis and primary biliary cirrhosis.


New antifungal xanthones from the seeds of Rhus coriaria L.
Phytochemical investigations of the ethanolic extract of the seeds of Rhus coriaria L. (Anacardiaceae) led to the identification of four new xanthones, characterized as 2,3-dihydroxy-7-methyl xanthone (1), 2,3,6-trihydroxy-7-hydroxymethylene xanthone-1-carboxylic acid (2), 2-methoxy-4-hydroxy-7-methyl-3-O-beta-D-glucopyranosyl xanthone-1,8-dicarboxylic acid (4), and 2-hydroxy-7-hydroxymethylene xanthone-1,8-dicarboxylic acid 3-O-beta-D-glucopyranosyl-(2'-->3")-3"-O-stigmast-5-ene (5), along with the known steroidal glucoside beta-sitosterol-beta-D-glucoside (3). The structures of the isolated compounds have been identified on the basis of spectral data analysis and chemical reactions. All xanthones were active against Aspergillus flavus.


Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial.
Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.


Physicians' perceptions of shared decision-making for implantable cardioverter-defibrillators: Results of a physician survey.
Centers for Medicare and Medicaid Services has mandated the use of shared decision-making (SDM) for implantable cardioverter-defibrillator (ICD) implantation. SDM tools help facilitate quality SDM by presenting patients with balanced evidence-based facts related to risk and benefits. Perceptions of ICD implantation may differ based on patients' sex and race. To determine if and how physicians are incorporating SDM in counseling patients about ICD and if they are aware of sex- and race-based differences in patients' perception of ICDs. This was a pilot study involving an online survey targeting attending physicians who implant ICDs. Physicians were randomly selected by a computer-based program; 350 surveys were sent. Of the 124 (35%) respondents to the survey, 102 (84%) met the inclusion criteria, and of those, 99 (97%) were adult electrophysiologists. Most physicians (90, 88%) stated they engaged in SDM during the general consent process. Sixty-three (62%) physicians discuss end of life issues while obtaining general consent. Forty-four (43%) physicians said they use an existing SDM tool with the Colorado SDM tool being the most common (39, 89%). The majority of physicians were unaware of sex- and race-based differences in perceptions related to ICD implantation (sex 64, 63% and race 63, 62%). A vast majority of physicians are engaging in SDM; however less than half are using a formal SDM tool, and a minority of physicians were aware of sex- and race-based differences in patients' perception of ICD implantation. Sex- and race-based tools might help address this gap.


Characterisation of the urinary steroid profile of patients with nonfunctioning adrenal incidentalomas: A matched controlled cross-sectional study.
To identify alterations in steroid metabolism in patients with nonfunctioning adrenal incidentalomas (NFAIs) through the analysis of their urinary steroid profile (USP). Cross-sectional study with one study group (NFAIs, cortisol post dexamethasone suppression test [DST] ≤ 1.8 µg/dl [49.7 nmol/L]) and 2 control groups: patients with autonomous cortisol secretion (ACS group, cortisol post-DST > 1.8 µg/dl (49.7 nmol/L) and patients without adrenal tumours (healthy-adrenal group). Twenty-four-hour urine collections for USP measurement (total and free fraction of 51 24 h-urine specimens) were obtained from 73 participants (24 with NFAIs, 24 without AIs, and 25 with ACS). USP was determined by gas chromatography coupled to mass spectrometry. Patients of the three groups were matched according to sex, age (±5 years-old) and body mass index (±5 kg/m2 ). Compared to healthy-adrenal controls, patients with NFAIs had a lower excretion of androgen metabolites (230.5 ± 190.12 vs. 388.7 ± 328.58 µg/24 h, p = .046) and a higher excretion of urinary free cortisol (UFC) (54.3 ± 66.07 vs. 25.4 ± 11.16 µg/24 h, p = .038). UFC was above the reference range in 20.8% of patients in the NFAI, compared to 0% in the healthy-adrenal group (p = .018). Patients with ACS had a higher prevalence of hypertension, dyslipidemia, and diabetes than patients with NFAIs or the control group. A lower excretion of androgen metabolites (218.4 ± 204.24 vs. 231 ± 190 µg/24 h, p = .041) and a nonsignificant higher excretion of glucocorticoid metabolites (2129.6 ± 1195.96 vs. 1550.8 ± 810.03 µg/24 h, p = .180) was found in patients with ACS compared to patients with NFAIs. NFAIs seem to secrete a subtle, yet clinically relevant, excess of glucocorticoids. Future studies are needed to confirm our findings; and to identify metabolic alterations associated with an increased cardiometabolic risk.


Long-term Outcomes in Down Syndrome Children After Cochlear Implantation: Particular Issues and Considerations.
The aim of the study was to analyze the long-term outcomes after cochlear implantation in deaf children with Down syndrome (DS) regarding age at the first implantation and refer the results to preoperative radiological findings as well as postoperative auditory and speech performance. Additionally, the influence of the age at implantation and duration of CI use on postoperative hearing and language skills were closely analyzed in children with DS. Retrospective analysis. Referral center (Cochlear Implant Center). Nine children with Down syndrome were compared with 220 pediatric patients without additional mental disorders or genetic mutations. Patients were divided into four categories depending on the age of the first implantation: CAT1 (0-3 yr), CAT2 (4-5 yr), CAT3 (6-7 yr), and CAT4 (8-17 yr). The auditory performance was assessed with the meaningful auditory integration scales (MAIS) and categories of auditory performance (CAP) scales. The speech and language development were further evaluated with meaningful use of speech scale (MUSS) and speech intelligibility rating (SIR). The postoperative speech skills were analyzed and compared between the study group and the reference group by using nonparametric statistical tests. Anatomic abnormalities of the inner ear were examined using magnetic resonance imaging (MRI) and high-resolution computed tomography of the temporal bones (HRCT). The mean follow-up time was 14.9 years (range, 13.1-18.3 yr). Patients with DS received a multichannel implant at a mean age of 75.3 months (SD 27.9; ranging from 21 to 127 mo) and 220 non-syndromic children from reference group at a mean age of 51.4 months (SD 34.2; ranging from 9 to 167 mo). The intraoperative neural response was present in all cases. The auditory and speech performance improved in each DS child. The postoperative mean CAP and SIR scores were 4.4 (SD 0.8) and 3.2 (SD 0.6), respectively. The average of scores in MUSS and MAIS/IT-MAIS scales was 59.8% (SD 0.1) and 76.9% (SD 0.1), respectively. Gathered data indicates that children with DS implanted with CI at a younger age (<6 years of age) benefited from the CI more than children implanted later in life, similarly in a control group. There were additional anomalies of the temporal bone, external, middle, or inner ear observed in 90% of DS children, basing on MRI or HRCT. The early cochlear implantation in children with DS is a similarly useful method in treating severe to profound sensorineural hearing loss (SNHL) as in non-syndromic patients, although the development of speech skills present differently. Due to a higher prevalence of ear and temporal bone malformations, detailed diagnostic imaging should be taken into account before the CI qualification. Better postoperative outcomes may be achieved through comprehensive care from parents/guardians and speech therapists thanks to intensive and systematic rehabilitation.


The metabolite 5-methyl-1,3-benzenediol and its derivative methyl-2,4-dihydroxy-6-methylbenzoate from the lichen Parmotrema tinctorum with potent apoptotic and anti-angiogenesis effects.
Nature has been a rich resource of novel anticancer agents, one such source being lichens, which represent the symbiosis between algae and fungi with diverse range of secondary metabolites having therapeutic significance. With respect to this, the present study evaluates the in vitro apoptogenic profile of secondary metabolites from the lichen Parmotrema tinctorum towards cancer cell lines. Treatment with TLC-purified fraction 1 from P. tinctorum resulted in significant reduction in the cell viabilities of cancer cells with IC50 values ranging between 1.2 and 12.8 μg/ml. The potential anticancer effect of the bioactive fraction was further supported by Trypan blue cell viability, LDH and DNA fragmentation assays. At the cellular level, induction of apoptosis was confirmed through the activation of the caspase cascade and apoptotic cells accumulating in the Sub-G1 phase of cell cycle. Angiogenesis being one of the major characteristics needed for cancer growth, the ability of the lichen fraction to inhibit angiogenesis was checked through in ovo Yolk Sac Membrane (YSM) assay and was found to be significant. The study also verified the non-toxic nature of the bioactive fraction towards normal human peripheral lymphocytes. HPLC analysis and GC-MS characterisation of the bioactive fraction indicated the presence of 5-methyl-1,3-benzenediol and its derivative methyl-2,4-dihydroxy-6-methylbenzoate.


Outcomes of Short-Term Tigecycline-Containing Regimens for Mycobacterium abscessus Pulmonary Disease.
Short-term intravenous tigecycline therapy during a 1-month initial phase may improve early microbiological response in patients with Mycobacterium abscessus pulmonary disease (PD). However, short-term use of tigecycline did not improve the long-term culture conversion rate of M. abscessus PD. Further studies on the efficacy of prolonged intravenous tigecycline-containing regimens are needed.


Beaded fluorescence pattern of FTA-ABS test associated with malignancy.
A beaded pattern of immunofluorescence (IF) occasionally occurs in routine FTA-ABS testing. This phenomenon strongly correlates with false-positive reactions in patients with SLE. We report on this IF finding in association with carcinoma of the colon.


Further study on the roles of the effector molecules of immunosuppressive macrophages induced by mycobacterial infection in expression of their suppressor function against mitogen-stimulated T cell proliferation.
Previously, we found that phospholipids and reactive nitrogen intermediates (RNI) collaborated in expression of the T cell mitogenesis-inhibitory activity of immunosuppressive macrophages induced by Mycobacterium avium-intracellulare complex (MAIC) infection. In this study, we examined the roles of free fatty acids (FFA) and prostaglandins (PG) as effectors of MAIC-induced macrophages, and moreover, their collaborating effects with RNI. First, treatment of MAIC-induced macrophages with quinacrine (phospholipase A2 (PLA2) inhibitor), dexamethasone (inhibitor of PLA2 and PG synthesis) or indomethacin (PG synthesis inhibitor) attenuated their suppressor activity against concanavalin A (Con A)-induced mitogenesis of splenocytes (SPC), indicating important roles of FFA liberated from membrane phospholipids and PG, as effectors. Second, oleic acid, PGE2, RNI generated from NOR 4 (a new nitric oxide (NO) donor), and phosphatidylserine (PS) exhibited suppressor activity against SPC mitogenesis without showing significant cytotoxicity, in an irreversible manner. Third, the suppressor activities of RNI and PGE2 were potentiated by combined use with oleic acid in a synergistic manner. Fourth, a dual-chamber experiment in which target SPC were separated from MAIC-induced macrophages by a Millipore filter revealed a requirement for cell-to-cell contact for expression of the suppressor function of MAIC-induced macrophages. These findings indicate that RNI, FFA, PG, and phospholipids (presumably PS) and their collaboration play central roles in expression of the T cell mitogenesis-inhibitory function of MAIC-induced suppressor macrophages.


TMF, a natural dihydroflavonoid isolated from Scutellaria javanica Jungh, stimulates anticancer activity of s180 cancer-bearing mice, induces apoptosis, inhibits invasion and migration on HepG-2 cells.
5-hydroxy-7,8,2',6'-tetramethoxy flavanone (TMF) is a dihydroflavonoid extracted from Scutellaria javanica Jungh. It is a species of genus Scutellaria, and a representative southern herb and Li nationality medicine. The plant has been used as an ethnic medicine in treating cancer and the main components are dihydroflavonoids. However, the underlying mechanisms are yet to be elucidated. The present study aimed at investigating the efficacy of TMF in cancer and the underlying mechanisms. The s180 cancer-bearing mice experiment in vivo was designed to study the tumor growth inhibition of TMF. Also, we investigated the latent mechanism of TMF induced apoptosis and the inhibitory action of TMF on the metastasis and proliferation in HepG-2 cells. The in vitro experimental groups were treated with TMF or hydroxycamptothecine (HCPT) for 24 h. Apoptosis was detected by flow cytometry. Caspase-3 activity was detected by ELISA. The expressions of PCNA, Bcl-2, Bax, p53, E-Cadherin, MMP-9, MMP-2, STAT3, p-STAT3, JAK2, p-JAK2, AKT, p-AKT, ERK1/2 and p-ERK1/2 were examined by Western blot. After oral administration of TMF in s180 cancer-bearing mice, tumor growth in vivo was suppressed significantly. The MTT assay result and the reduction of PCAN proved that TMF could inhibit HepG-2 cells proliferation. TMF also caused dose-dependent apoptosis on HepG-2 cells. The experimental results showed that the expression of Bcl-2 was reduced, and the expressions of caspase-3, Bax and p53 were increased. Therefore, we speculated that TMF-induced apoptosis might be achieved by regulating the p53-Bcl-2/Bax-caspase-3 pathways. Transwell cell migration and invasion assay showed that treatment with TMF inhibited the invasion and migration in HepG-2 cells. The expressions of MMP-9 and MMP-2 were decreased while that of E-cadherin was enhanced significantly by TMF. Additionally, the expressions of p-JAK2, p-STAT3, p-AKT and p-ERK1/2 were decreased, but those of JAK2, STAT3, AKT and ERK1/2 remained unchanged. Thus, it is indicated that TMF induced apoptosis and inhibited proliferation and metastasis on HepG-2 cells via JAK2/STAT3, MAPK/ERK and PI3K/AKT pathways. The present results demonstrated that TMF could stimulate anticancer activity of s180 cancer-bearing mice, induce apoptosis, and inhibit invasion and migration on HepG-2 cells. Our findings displayed a systematic insight into the mechanisms underlying anticancer action of TMF, and provided a better understanding of its use for cancer.


Localization of multidrug resistance-associated DNA sequences to human chromosome 7.
Multidrug resistance in several human cell lines correlates with amplification or increased expression of two related DNA sequences, designated mdr1 and mdr2. These DNA sequences were used as probes for hybridization with DNA with a panel of human-mouse somatic cell hybrids and from individual human chromosomes separated by fluorescence-activated chromosome sorting. By these assays, both mdr1 and mdr2 sequences were localized to chromosome 7.


Structural basis of receptor sulfotyrosine recognition by a CC chemokine: the N-terminal region of CCR3 bound to CCL11/eotaxin-1.
Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8–23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-p interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.


"Would You Rather Jump Out of a Perfectly Good Airplane or Develop Cardiovascular Disease?" Validity and Reliability of the Cardiovascular Risk Perception Survey Among Military Personnel.
Cardiovascular disease (CVD) is a major cause of death in the United States. The military are viewed as fit, ready to fight and that jumping out of perfectly good airplane or going to war is a greater risk than CVD. The purpose of this study was to determine reliability and validity of the Cardiovascular Risk Perception Survey (CRPS). A cross-sectional descriptive design was performed, supported by the Health Belief Model. Internal consistency reliability (Cronbach's alpha) and validity (principal component analysis) were examined. Fifty-five participants were included in this study. Construct validity of the CRPS was supported by principal component analysis; indicating one scale that measured cardiovascular risk perception. The Cronbach's alpha is reported .865. Initial psychometric testing of the CRPS provides evidence for construct validity and internal consistency reliability.


Regulation of glycerol phosphate dehydrogenase and lactate dehydrogenase activity by forskolin and dibutyryl cyclic AMP in the C6 glial cells.
We have compared the effects of norepinephrine, forskolin, and dibutyryl cyclic AMP (Bt2cAMP) on the regulation of the cytosolic enzyme glycerol phosphate dehydrogenase (GPDH) in the C6 rat glioma cell line. Forskolin and Bt2cAMP elicit a dose-dependent increase in the levels of the enzyme that was, however, unaffected by norepinephrine. The half-maximal effect of forskolin was obtained at 7-8 microM, and the effect was maximal at 30 microM. Dexamethasone at a 50 nM concentration produced a two- to sixfold induction of GPDH after 48 h. The combination of dexamethasone with forskolin or Bt2cAMP leads to an elevation in GPDH levels that is higher than that produced by one of the compounds alone. This potentiation is found when both agents are added together with or after the glucocorticoid. The increase in uninduced and dexamethasone-induced GPDH activity was blocked by cycloheximide and actinomycin D, indicating that de novo protein and RNA synthesis are required. The activity of cytosolic lactate dehydrogenase activity did not change after incubation with dexamethasone, but increased with forskolin or Bt2cAMP.


Pregabalin in severe burn injury pain: a double-blind, randomised placebo-controlled trial.
This randomised, double-blind, placebo-controlled trial assessed the efficacy and tolerability of pregabalin to alleviate the neuropathic component of moderate to severe burn pain. Patients aged 18 to 65 years admitted to a burns unit with a 5% or greater total body surface area burn injury were screened to participate in the trial. Using the Neuropathic Pain Scale (NPS), patients scoring 4 or higher on 'hot' pain or 'sharp' pain were invited to participate. Consenting patients were randomly assigned to receive pregabalin or placebo for 28 days with individual dose titration commencing at 75 mg twice daily to a maximum pregabalin dose of 300 mg twice daily. The primary outcome measure was the patients' daily response to the sharp and hot pain of the NPS. Secondary outcome measures included the remaining elements of the NPS, daily opioid requirement, length of hospital stay, pain at 6 months, and side effects of nausea, vomiting, drowsiness and giddiness. For patients administered pregabalin, the primary outcome measures hot (P = .01) and sharp (P = .04) pain were significantly reduced compared with those in patients administered placebo. Secondary outcome measures of itch, unpleasantness, surface pain, and procedural pain were significantly lower (P < .05) in the pregabalin group. Adverse effects were uncommon, with no difference between the treatment groups. There was no significant difference between the pregabalin and placebo treatment groups with respect to opioid consumption, duration of hospital stay, or pain at 6 months. Pregabalin was efficacious and well tolerated in patients after severe burn injury and whose pain was characterised by features of acute neuropathic pain. In this study, pregabalin was well tolerated and significantly reduced several elements of the neuropathic pain scale including hot pain, unpleasantness of the pain, surface pain, and itch, and also significantly reduced procedural pain.


Functional surgery of the temporomandibular joint with conscious sedation for "closed lock" using eminectomy as a treatment: a case series.
The purpose of this case series study was to evaluate the advantages and disadvantages of using local anesthesia and conscious sedation (CS) rather than general anesthesia (GA) for performing functional surgery on patients suffering from temporomandibular joint (TMJ) closed lock, using the eminectomy procedure. Performing this procedure using CS allows functional assessment of the TMJ meniscus at the time of surgery. The objectives of this study were to determine if this surgery is possible under CS, to determine the benefits of being able to see the meniscus in action, and to investigate the patients' acceptability for this form of anesthesia. Twenty-two patients who underwent this eminectomy procedure under either CS or GA on a day-case basis participated in this retrospective case series study. All the recruited patients had this procedure carried out after a course of nonsurgical conservative treatment that had failed to relieve the symptoms associated with their TMJ disorder--"closed lock." Objective results obtained were as follows: preoperative and postoperative mouth opening; preoperative investigations; preoperative treatments. Subjective results obtained were as follows: preoperative and postoperative pain; noises; clicks; hearing and deviation on opening; patient rating of operation success. Paired t testing showed a significant change in mouth opening for both groups. The mean mouth opening change in the CS group (n = 9) was 10.6 mm (P = .014) and in the GA group (n = 13) was 13.7 mm (P < .001). An unpaired t test showed there is no statistical difference between these groups (P = .467). The subjective data recorded showed comparable outcomes and acceptance for the 2 techniques in terms of pain and operation success. The use of local anesthesia and CS is an alternative to GA for performing TMJ procedures in appropriately selected patients. The advantage of direct visualization of the meniscus and its movements in the nonasleep patient requires further evaluation.


Multiomics Integrative Analysis Identifying EPC1 as a Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma.
Biomarker research in head and neck squamous cell carcinoma (HNSCC) is constantly revealing promising findings. An enhancer of polycomb homolog 1 (EPC1) was found to play a procancer role in nasopharyngeal carcinoma (NPC), but its role in HNSCC with strong heterogeneity is still unclear. Herein, we investigated the prognostic significance and related mechanisms of EPC1 in HNSCC. The Kaplan-Meier plotter was used to evaluate the prognostic significance of EPC1. Based on a range of published public databases, the multiomics expression of EPC1 in HNSCC was explored to investigate the mechanisms affecting prognosis. According to the clinical data, high EPC1 expression in HNSCC was a predictor of patient prognosis (hazard ratio (HR) = 0.64; 95% confidence interval (CI) 0.49-0.83; P < 0.01). EPC1 expression varied among clinical subtypes and was related to key factors, such as TP53 and human papillomavirus (HPV) (P < 0.05). At the genetic level, EPC1 expression level may be associated with protein phosphorylation, cell adhesion, cancer-related pathways, etc. For the noncoding region, a competing endogenous RNA network was constructed, and 6 microRNAs and 12 long noncoding RNAs were identified. At the protein level, a protein-protein interaction (PPI) network related to EPC1 expression was constructed and found to be involved in HPV infection, endocrine resistance, and multiple cancer pathways. At the immune level, EPC1 expression was correlated with a variety of immune cells and immune molecules, which together constituted the immune microenvironments of tumors. High EPC1 expression may predict a better prognosis in HNSCC, as it is more frequently found in HNSCC with HPV infection. EPC1 may participate in the genomics, transcriptomics, proteomics, and immunomics of HNSCC, and the results can provide a reference for the development of targeted drugs and evaluation of patient prognosis.


Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome.
Gain-of-function (GOF) mutations in CXCR4 cause WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, characterized by infections, leukocyte retention in bone marrow (BM), and blood leukopenias. B lymphopenia is evident at early progenitor stages, yet why do CXCR4 GOF mutations that cause B (and T) lymphopenia remain obscure? Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome characterized by a switch from an adipogenic to an osteolineage-prone program with limited lymphopoietic activity. We identify lymphotoxin beta receptor (LTβR) as a critical pathway promoting interleukin-7 (IL-7) down-regulation in MSCs. Blocking LTβR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice. LTβR blocking also increased production of IL-7 and B cell activating factor (BAFF) in secondary lymphoid organs (SLOs), increasing B and T cell numbers in the periphery. These studies revealed that LTβR signaling in BM MSCs and SLO stromal cells limits the lymphocyte compartment size.


Novel glucokinase gene mutation in the first Macedonian family tested for MODY.
We present a boy with mild hyperglycemia detected during an upper respiratory infection. Novel splicing mutation in the intron 1 of the GCK gene (c.45+1G>A) was detected, and was subsequently confirmed in his father. This is the first case of genetically confirmed Macedonian family with MODY.


Protocol of a patient randomized clinical trial to improve medication adherence in primary care.
Enhanced awareness of poor medication adherence could improve patient care. This article describes the original and adapted protocols of a randomized trial to improve medication adherence for cardiometabolic conditions. The original protocol entailed a cluster randomized trial of 28 primary care clinics allocated to either (i) medication adherence enhanced chronic disease care clinical decision support (eCDC-CDS) integrated within the electronic health record (EHR) or (ii) usual care (non-enhanced CDC-CDS). Enhancements comprised (a) electronic interfaces printed for patients and clinicians at primary care encounters that encouraged discussion about specific medication adherence issues that were identified, and (b) pharmacist phone outreach. Study subjects were individuals who at an index visit were aged 18-74 years and not at evidence-based care goals for hypertension (HTN), diabetes mellitus (DM), or lipid management, along with low medication adherence (proportion of days covered [PDC] <80%) for a corresponding medication. The primary study outcomes were improved medication adherence and clinical outcomes (BP and A1C) at 12 months. Protocol adaptation became imperative in response to major implementation challenges: (a) the availability of EHR system-wide PDC calculations that superseded our ability to limit PDC adherence information solely to intervention clinics; (b) the unforeseen closure of pharmacies committed to conducting the pharmacist outreach; and (c) disruptions and clinic closures due to the Covid-19 pandemic. This manuscript details the protocol of a study to assess whether enhanced awareness of medication adherence issues in primary care settings could improve patient outcomes. The need for protocol adaptation arose in response to multiple implementation challenges.


Methods for examination an explanted coronary sinus lead stabilized with a coronary stent.
The aim of our investigation was to test the suitability of a novel method for the analysis of the integrity of an explanted pacemaker lead stabilized by a stent. A coronary sinus lead has been explanted 27 months after implantation and has been examined by optical-, confocal-, x-ray-, and scanning electron microscopy. Several surface injuries were found on the insulation. Based on the surface characteristics, it is possible to define and differentiate the source of damages as well as to measure the extent of injuries. Impedance of the explanted lead has also been measured and electronic integrity has been verified.


Molecular assays for determining sulphadoxine-pyrimethamine drug resistance in India: a systematic review.
A plethora of studies analyse the molecular markers of drug resistance and hence help in guiding the evidence-based malaria treatment policies in India. For reporting mutations, a number of techniques including DNA sequencing, restriction-fragment length polymorphism and mutation-specific polymerase chain reaction have been employed across numerous studies, including variations in the methodology used. However, there is no sufficient data from India comparing these methods as well as report the prevalence of polymorphisms in SP drug resistance molecular markers independently using such methods. Therefore, all data from Indian studies available for molecular marker studies of Plasmodium falciparum drug resistance to sulphadoxine-pyrimethamine was gathered, and a systematic review was performed. This systematic review identifies the molecular methods in use in India and compares each method for detecting sulphadoxine-pyrimethamine drug resistance marker. To delay the spread of drug-resistant parasite strains, a simplified and standardized molecular method is much needed which can be obtained by analysing the performance of each method in use and answering the necessity of newer methodological approaches.


Molecular characterization of the insulin-like growth factor-I (IGF-I) gene in channel catfish (Ictalurus punctatus).
The insulin-like growth factor I (IGF-I) gene was characterized in channel catfish. Partial cDNA sequence, missing exon 1 and part of exon 2, was obtained in 5'- and 3'-RACE experiments. Direct sequencing of two bacterial artificial chromosome clones revealed gene structure and provided sequence from 640 bp upstream of the initiator methionine to 136 bp beyond the polyadenylation site. Genomic sequence contained a putative TATA box 506 bp upstream of the initiator methionine. The 477-bp reading frame within five exons encoded a 159-amino acid (aa) pre-propeptide highly similar to IGF-I in higher vertebrates. The sequence encoding the signal peptide was unique in catfish and contained 70% G+C content with the potential for a stable stem-loop structure. Full-length cDNA was only maintained in recombination-deficient (DH10B) strain E. coli. Levels of IGF-I mRNA were highest in liver, followed by brain and muscle, then heart and kidney (P<0.05). A CT/GA dinucleotide microsatellite in intron 1 was highly polymorphic in commercial channel catfish, and permitted placement of the IGF-I gene on the catfish genetic map. However, specific IGF-I alleles were not correlated with differences in growth rate from 100 to 130 days post-hatch in USDA103 line catfish.


Avoidance disruptive effect of clozapine and olanzapine is potentiated by increasing the test trials: further test of the motivational salience hypothesis.
Antipsychotic drugs suppress animals' ability to avoid an aversive stimulus in the conditioned avoidance response model (CAR). This behavioral effect is thought to reflect antipsychotic activity and is suggested to be mediated by a drug's action in attenuating the motivational salience of a conditioned stimulus (CS). In the present study, we tested whether atypical antipsychotic drugs clozapine and olanzapine act through this behavioral mechanism by manipulating the number of avoidance test trials. We reasoned that more CS trials in the presence of clozapine or olanzapine would afford the drug more opportunities to decrease the motivational salience of the CS, thus avoidance decline would be greater with the increase of CS trials in each test session. In two separate experiments, adult male Sprague-Dawley rats were tested under clozapine (5.0mg/kg, sc), olanzapine (0.5mg/kg, sc) or vehicle (sterile water) for 6 consecutive days in three CS trial conditions (i.e. 3, 10, and 40 CS trials per session). Two days later, all rats were tested under the same 40-trial session after receiving clozapine (5.0mg/kg, sc) or olanzapine (0.5mg/kg, sc). Results show that repeated clozapine and olanzapine treatment persistently decreased avoidance response, and this effect was potentiated by the increase of number of CS trials in the test sessions, as the clozapine-treated or olanzapine-treated rats tested under the 40-trial or 10-trial condition had significantly lower avoidance and faster decline across-sessions than those tested under the 3-trial condition. This potentiated effect was not only seen in the total avoidance percentage, but also observed in the within-session decline pattern in the last three drug test sessions and in the final 40-trial test session. These findings suggest that the clinical efficacy of a drug can be enhanced by increasing the exposure of symptoms in the presence of the drug.


Do patients think that dry powder inhalers can be used interchangeably?
As recognised in management guidelines, patients are the most important group of people in any prescribing decision. Despite their importance, few studies have asked what patients think about being switched between different inhalers. This paper reports two such studies, one involving interviews of a sample of patients and the other consisting of a quantitative survey of patients across five countries. In the qualitative study, four of the five patients interviewed reported that they would be confused, worried and unhappy about a switch in their dry powder inhaler and would revisit their physician to be shown how to use the inhaler or to ask for a new prescription for their old inhaler. In the quantitative survey of 499 patients with asthma, more than half (51%) were opposed to their current dry powder inhaler being replaced by a substitute device, with 83% reporting concerns. There was considerable concern about training in use of the new device and confusion about the need for change. Almost a quarter of patients (23%) would want training, and 23% of patients thought they would need information about the new inhaler. From limited information, it appears that patients would be concerned about switching of their existing dry powder inhaler for another, with the potential for confusion, need for additional consultations and need for training in the new device.


Acquired Robertsonian translocations in hematologic malignancy. A rare mechanism of clonal evolution.
We identified three patients with an acquired Robertsonian translocation among 1,200 patients with hematopoietic malignancy. In each case the translocation served to produce partial chromosomal trisomy or tetrasomy within the malignant clone. Acquired Robertsonian translocation represents another, although rare, mechanism of clonal evolution in malignant cells.


Phenotypic deconvolution in heterogeneous cancer cell populations using drug-screening data.
Tumor heterogeneity is an important driver of treatment failure in cancer since therapies often select for drug-tolerant or drug-resistant cellular subpopulations that drive tumor growth and recurrence. Profiling the drug-response heterogeneity of tumor samples using traditional genomic deconvolution methods has yielded limited results, due in part to the imperfect mapping between genomic variation and functional characteristics. Here, we leverage mechanistic population modeling to develop a statistical framework for profiling phenotypic heterogeneity from standard drug-screen data on bulk tumor samples. This method, called PhenoPop, reliably identifies tumor subpopulations exhibiting differential drug responses and estimates their drug sensitivities and frequencies within the bulk population. We apply PhenoPop to synthetically generated cell populations, mixed cell-line experiments, and multiple myeloma patient samples and demonstrate how it can provide individualized predictions of tumor growth under candidate therapies. This methodology can also be applied to deconvolution problems in a variety of biological settings beyond cancer drug response.


Contribution of Serendipita indica on growth improvement, antioxidative capacity of Dracocephalum kotschyi, and its resistance against cadmium stress.
Cadmium pollution is a severe issue worldwide which causes an elevated concern in agriculture. The utilization of plant-microbial interactions offers a promising approach for the remediation of cadmium-polluted soils. To elucidate the mechanism of Serendipita indica-mediated cadmium stress tolerance, a potting experiment was conducted to study the impact of S. indica on Dracocephalum kotschyi plants grown under different cadmium concentrations (0, 5, 10, and 20 mg/kg). The effects of cadmium and S. indica on plant growth, antioxidant enzyme activities, and accumulation of cadmium were investigated. The results showed that cadmium stress significantly decreases biomass, photosynthetic pigments, and carbohydrate content concomitantly with increasing antioxidant activities, electrolyte leakage, and hydrogen peroxide, proline, and cadmium content. Inoculation with S. indica alleviated the adverse effect of cadmium stress by enhancing shoot and root dry weight, photosynthetic pigments, and carbohydrate, proline, and catalase activity. Unlike cadmium stress, the presence of fungus led to a reduction in electrolyte leakage and hydrogen peroxide content as well as the content of cadmium in D. kotschyi leaf which mitigates cadmium-induced oxidative stress. Our findings demonstrated S. indica inoculation alleviates the adverse effects of cadmium stress in D. kotschyi plants which could prolong their survival under stressful conditions. Due to the importance of D. kotschyi and the effect of biomass increase on the amount of its medicinal substances, exploiting S. indica not only promotes plant growth, but also may be used as a potential eco-friendly method for relieving the phytotoxicity of Cd and remediating Cd-contaminated soil.


Multicenter phase II trial of brequinar sodium in patients with advanced melanoma.
Seventeen patients with advanced melanoma and no prior exposure to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given at a median weekly dose of 1200 mg/m2 intravenously. In 14 patients evaluable for efficacy, there were no objective responses. The toxicity was moderate. We conclude that, at this dose and schedule, brequinar has no activity in advanced melanoma.


Medulloblastomas and other neural tumours in mice treated neonatally with N-ethyl-N-nitrosourea.
Newborn mice of four inbred strains were injected with a single dose of N-ethyl-N-nitrosourea. The wide range of tumours induced included a small number in the central and peripheral nervous systems. The 4 brain tumours all arose in the cerebellum. Three in one strain were medulloblastomas showing continuity with the internal granular layer. All three tumours showed diffuse infiltration through the molecular layer and continuity with densely-packed islets of cells that marginated immediately beneath the pia and closely resembled remnants of a persistent fetal external granular layer. The medulloblastomas are discussed with special relevance to the histogenesis of the equivalent tumour in man.


A double-blind comparison of the clinical tolerance of bacampicillin and pivampicillin. A preliminary report.
In this double-blind study, the clinical tolerance of high doses of bacampicillin hydrochloride (800 mg t. i. d.) and of pivampicillin base (700 mg t. i. d.) administered for ten days were compared in out-patients with acute urinary tract infections. The clinical response was comparable with that previously reported for those antibiotics. Upper gastrointestinal side-effects were more common after treatment with pivampicillin and were reported in 9/38 patients compared to 3/34 patients treated with bacampicillin. The duration of the symptoms of the side-effects was also more prolonged after pivampicillin than after bacampicillin.


Three-dimensional analysis of the gap space under forearm casts.
Secondary displacement represents a frequent complication of conservative treatment of fractures, particularly of the distal radius. The gap space between skin and cast may lead to a certain degree movements and this increased mobility might favor redisplacement. The aim of this study was to develop a new 3D method, to measure the gap space in all 3 geometrical planes, and to validate this new technique in a clinical setting of distal radius fractures. This study applies 3D imaging to measure the space between plaster and skin as a potential factor of secondary displacement and therefore the failure of conservative treatment. We developed and validated a new methodology to analyze and compare different forearm casts made of plaster of Paris and fiberglass. An unpaired t-test was performed to document differences between the investigated parameters between plaster of Paris and fiberglass casts. The significance level was set at p < 0.05. In a series of 15 cases, we found the width of the gap space to average 4 mm, being slightly inferior on the radial side. Comparing the two different casting materials, plaster of Paris and fiberglass, we found a significantly larger variance of space under casts made of the first material (p=0.39). A roughness analysis showed also a markedly significantly higher irregularity of the undersurface of plaster of Paris as compared with fiberglass. This study allows for a better understanding of the nature of the "gap space" between cast and skin and will contribute to develop and improve new immobilization techniques and materials.


Asymptomatic giant circumflex aneurysm in patient with a cisplatin treatment history.
We report a case of 62-years-old man with a previous history of squamocellular tumour at the jaw treated with cisplatin chemotherapy. Six years after the chemotherapy, a transthoracic echocardiography showed a large left atrial lateral wall mass causing mitral stenosis. The thoracic computed tomography angiography (CTA) scan confirmed the mass (66x88mm) with contrast enhancement and the coronary angiography defined it as a giant left circumflex aneurysm. The aneurysm was resected and bypass graft performed. The aetiology and the technique used to treat this aneurysm are worthy to be described.


Detection of myocardial perfusion in multiple echocardiographic windows with one intravenous injection of microbubbles using transient response second harmonic imaging.
The purpose of this study was to prove that transient response harmonic imaging could detect normal and abnormal myocardial perfusion in multiple echocardiographic windows with one intravenous injection of microbubbles in humans. Myocardial ultrasound contrast can be produced from intravenous perfluorocarbon-exposed sonicated dextrose albumin, and ultrasound can be significantly improved by briefly suspending the interval between frame rates. Whether this contrast can noninvasively quantify myocardial perfusion in humans is unknown. In 28 patients, harmonic transient response imaging was used to image the heart in multiple different imaging planes after one intravenous injection of ultrasound contrast agent. Twenty-five of these 28 patients had a repeat injection during dipyridamole stress. In the primary view, the ultrasound transmission rate was one frame per cardiac cycle; in secondary and tertiary views, the transmission rate was once every multiple cardiac cycles. Regional myocardial contrast was visually assessed and quantified off-line. Quantitative rest thallium and dipyridamole stress sestamibi imaging was also performed. Perfusion abnormalities were evident in the secondary and tertiary views only with one frame every multiple cardiac cycles. Regional peak myocardial videointensity (PMVI) correlated closely with regional tracer uptake in individual patients both at rest (r = 0.84) and during stress (r = 0.88). A PMVI ratio (abnormal region divided by the region with highest nuclear uptake) < 0.6 in any view had a 92% sensitivity and a 84% specificity in identifying a regional nuclear perfusion abnormality. Transient response imaging produces myocardial contrast in multiple views with one intravenous injection of contrast agent and can accurately identify regional myocardial perfusion abnormalities.


Biomarkers of Early Liver Graft Damage in Circulatory Death and Brain Death Donors: A Propensity Score Matching Analysis.
Donation after circulatory death (DCD) is related to a warm ischemia time and more complications compared with traditional donors (donation after brain death [DBD]). This study included biopsy samples retrospectively collected from November 2014 to December 2018 to compare histologic and biological markers of DCD and DBD liver grafts. The analysis includes marker of early apoptosis (p21), senescence (telomerase reverse transcriptase [TERT]), cell damage (caspase-3 active), endothelial damage (vascular endothelial growth factor), stem cell (CD90), hypoxia (HIF1A), inflammatory activation (COX-2), and cross-organ allograft rejection (CD44). A propensity score matching (PSM) was used to match patients receiving DCD livers to those receiving DBD livers. We analyzed the immunohistochemical initial liver damage-related warm ischemia time. Positive staining expression of liver damage biomarkers (COX-2, CD44, TERT, HIF1A, and CD90) was found, but no significant differences were found between DCD and DBD and with ischemic cholangiopathy. After PSM, there was a significant relationship between CD90 and male donors (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.07-0.91), TERT with donor sodium (OR, 1.11; 95% CI, 1.02-1.2), HIF1A with steatosis (OR, 0.33; 95% CI, 0.13-0.83), and CD44 with donor vasoactive drugs (OR, 0.36; 95% CI, 0.13-1) and glutamic oxaloacetic transaminase 1 week increase (OR, 1.01; 95% CI, 1-1.03). DCD immunohistochemical initial liver damage was found to behave similarly to DBD. The increase in complications and cholangiopathy associated with warm ischemia could be related to a different later phenomenon.


Sizing Prenatal mPHRs using COSMIC Measurement Method.
This paper presents an empirical evaluation of the COSMIC Function Points method (e.g., ISO 19761) through measuring the functional size of 33 prenatal mobile Personal Health Records (mPHRs) apps. This evaluation compares the functional size of each mobile app measured using the COSMIC method to the score of the app obtained in a previous evaluation that relied on functions extraction using a quality assessment questionnaire. It includes as well an investigation of the relationships between the functional sizes of these apps, their ratings in the apps stores, as well as the number of installs. As results, it was noticed that there is a considerable shift between the rankings of the functional sizes and the functionality scores obtained in the opinion-based questionnaire, for most of the apps assessed. Moreover, the study of the relationship between the functional sizes and the ratings, as well as the number of installs indicated that these variables are not linked, since they are impacted by external factors. The findings support the use of the COSMIC method for these apps in regard to measuring the functional size for further updates or improvements, which can also help developers to have an overview about the existing apps on the market and compare between them. Moreover, COSMIC is more effective since it covers all the features and functionalities of prenatal mPHRs.


Low conductivity on electrical properties tomography demonstrates unique tumor habitats indicating progression in glioblastoma.
Tissue conductivity measurements made with electrical properties tomography (EPT) can be used to define temporal changes in tissue habitats on longitudinal multiparametric MRI. We aimed to demonstrate the added insights for identifying tumor habitats obtained by including EPT with diffusion- and perfusion-weighted MRI, and to evaluate the use of these tumor habitats for determining tumor treatment response in post-treatment glioblastoma. Tumor habitats were developed from EPT, diffusion-weighted, and perfusion-weighted MRI in 60 patients with glioblastoma who underwent concurrent chemoradiotherapy. Voxels from EPT, apparent diffusion coefficient (ADC), and cerebral blood volume (CBV) maps were clustered into habitats, and each habitat was serially examined to assess its temporal change. The usefulness of temporal changes in tumor habitats for diagnosing tumor progression and treatment-related change was investigated using logistic regression. The performance of significant predictors was measured using the area under the curve (AUC) from receiver-operating-characteristics analysis with 1000-fold bootstrapping. Five tumor habitats were identified, and of these, the hypervascular cellular habitat (odds ratio [OR] 5.45; 95% CI, 1.75-31.42; p = .02), hypovascular low conductivity habitat (OR 2.00; 95% CI, 1.45-3.05; p < .001), and hypovascular intermediate habitat (OR 1.57; 95% CI, 1.18-2.30; p = .006) were predictive of tumor progression. Low EPT and low CBV reflected a unique hypovascular low conductivity habitat that showed the highest diagnostic performance (AUC 0.86; 95% CI, 0.76-0.96). The combined habitats showed high performance (AUC 0.90; 95% CI, 0.82-0.98) in the differentiation of tumor progression from treatment-related change. EPT reveals low conductivity habitats that can improve the diagnosis of tumor progression in post-treatment glioblastoma. • Electrical properties tomography (EPT) demonstrated lower conductivity in tumor progression than in treatment-related change. • EPT allowed identification of a unique hypovascular low conductivity habitat when combined with cerebral blood volume mapping. • Tumor habitats with a hypovascular low conductivity habitat, hypervascular cellular habitat, and hypovascular intermediate habitat yielded high diagnostic performance for diagnosing tumor progression.


Measurement of persistence in YAG:Ce(3+)scintillator with pulsed synchrotron X-rays.
The decay time of YAG:Ce(3+) phosphor was studied using a CMOS camera with a frame rate of 1302000 s(-1) and pulsed X-rays from SPring-8. A high-resolution X-ray detector with YAG:Ce(3+) was used with the camera to view the focused beam from the helical undulator. Mismatch between the ring circulation time and the frame time gave rise to a periodic variation of beam intensity in successive frames. Analysis of data obtained with two bunch modes showed that the decay time of YAG:Ce(3+) was 60 ns. The variation of the beam positions in isolated bunches was small enough to be neglected in experiments using the focused beam. The results also show the possibility of an X-ray diffraction study at high time and space resolution.


The exposome in rheumatoid arthritis.
The exposome integrates the variety and accumulation of exposures (external and internal) to which an individual is submitted to from conception to death. Exposome may therefore be a useful tool for understanding the diversity of these factors and their role in the pathophysiology of rheumatoid arthritis (RA). Life is perceived as a continuum of cumulative changes, with key periods of disruption (e.g. birth, adolescence, pregnancy, prolonged treatment). The combination of these changes and the external signals that cause them constitute an individual's exposome, which is constantly changing and expanding throughout life. Thus, measuring the exposome requires specific tools and approaches as well as a global perspective. RA, a complex, heterogeneous, pro-inflammatory autoimmune disease with a genetic component and for which a large number of environmental factors have already been incriminated is an appropriate field of application for the exposome. The aim of this review is to define the exposome concept, outline the different analytic tools available for its study and finally apply them to the field of RA.


Asiatic acid as a leading structure for derivatives combining sub-nanomolar cytotoxicity, high selectivity, and the ability to overcome drug resistance in human preclinical tumor models.
Amides and rhodamine B conjugates of different pentacyclic triterpene acids have been shown outstanding cytotoxicity for human tumor cells. Starting from asiatic acid, a new rhodamine B hybrid has been synthesized, and its cytotoxic activity was investigated employing several human tumor cell lines (A375 (melanoma), HT29 (colorectal carcinoma), MCF7 (breast adenocarcinoma), A2780 (ovarian carcinoma), HeLa (cervical carcinoma), (NIH 3T3 (non-malignant murine fibroblasts). For these conjugates of this kind it has been established that the spacer attached to the carboxyl group at ring E governs the magnitude of the cytotoxicity. These asiatic acid - rhodamine B conjugates were highly cytotoxic for human tumor cell lines but also selective. For example, 7, an acetylated homopiperazinyl spacered rhodamine B conjugate, held an EC50 = 0.8 nM for A2780 ovarian carcinoma cells. Additional staining experiments showed the rhodamine B conjugates to act as mitocans and to effect apoptosis. In further tests using 3D spheroid models of colorectal- and mamma carcinoma, 7 demonstrated activity in the lower nanomolar range and the ability to overcome resistance to clinically used standard chemotherapeutic drugs. Therefore 7 induces cytotoxic effects leading to an equal response in the chemotherapy of both sensitive and resistant tumor models. Analyses of mitochondrial function and glycolysis and respiration derived ATP production confirmed compound 7 to act as mitocan but also revealed a rapid perturbation of the cellular energy metabolism as the primary mechanism of action, which is completely different to conventional chemotherapeutic drugs and thereby explains the ability of compound 7 to overcome chemotherapeutic drug resistance.


Elective neck dissection versus observation in patients with head and neck cutaneous squamous cell carcinoma.
The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.


Food procurement and the nutritional adequacy of diets in low-income families.
Seventy-six white and black low-income families were interviewed weekly during 1 month to determine how much they spent on food using Food Stamps, WIC coupons, and cash and how much additional food they obtained from different food and meals programs. After families had received their public assistance and Food Stamp allotments for the month, a 24-hour recall was obtained each week from each family member so that food intake could be monitored from the recalls as food-buying resources were depleted. Although families bought most of their food the first 2 weeks, they maintained a relatively constant food intake through the last week of the month. However, when nutrient intakes were compared with Recommended Dietary Allowances, the diets were found to be well supplied in protein, ascorbic acid, thiamin, niacin, riboflavin, vitamin B-12, vitamin A, and phosphorus, and inadequately supplied in vitamin B-6, vitamin D, vitamin E, iron, calcium, magnesium, zinc, and pantothenic acid. Since that finding was true not just at the end of the month but from the beginning, it indicated that the nutrition problems of low-income families are not intermittent, but continuous.


[Cyclosporin A in therapy of chronic uveitis in childhood].
Four children, 4 to 10 years old, with chronic uveitis were treated with cyclosporin A (CsA; starting dosage 2 mg/kg per day) and prednisolone. All children had previously received systemic steroids and/or cytotoxic agents, which resulted either in a poor therapeutic effect or in intolerable side effects. In one child, suffering from uveitis in combination with juvenile rheumatoid arthritis, a complete reduction of intraocular inflammation was achieved. In a second child treatment resulted in a marked reduction of inflammatory activity with stabilization of visual function, although a temporary increase in the steroid dosage was necessary at one stage. In the remaining two cases therapy failed to improve the intraocular inflammation. During the time of treatment, ranging from 11 to 26 months, no serious side effects were observed. All patients developed moderate hypertrichosis and one child gingival hyperplasia. In our experience, cyclosporin A (CsA) combined with low-dose systemic steroids is useful as a therapeutic alternative to steroids alone and to other immunosuppressive agents in severe cases of chronic uveitis in childhood.


Cerebral blood flow in migraine with aura: a transcranial Doppler sonography study.
Transcranial Doppler sonography examination was performed on 44 patients with migraine with aura and 88 controls. All patients were investigated in headache-free periods and 10 of them also during a migraine attack. During the headache-free period a not significant increase of mean flow velocity in patients compared to controls was obtained. The pulsatility index (PI) mean values were also higher in patients than in controls and the differences were significant in the MCA (p < 0.05). No difference between right and left side was observed. During the attack the mean flow velocity (MFV) decreased in all arteries but the decrease was significant only in MCA and ACA (p < 0.05). The mean PI increased in all arteries but not significantly. These variations were observed both on the headache and contralateral side. Nevertheless, the MFV decrease in all arteries was observed in four patients only. In four patients the MFV decrease was found in the anterior arteries and the MFV increase in the posterior arteries, while in two patients the MFV increase was observed both in the anterior and posterior arteries. The correlation between the variations of MFV values during the attacks and the time interval from the onset of attacks showed that the PCA and BA flow velocities were increased in patients examined between 0.5 and 3 hours, while an increase in MCA and ACA flow velocities were observed only in patients examined after 1.5 hours.


Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis.
Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not assume linear relationships between variables and outcomes and that may account for higher order interactions to make individualized outcome predictions. To evaluate the performance of machine learning models compared to traditional risk stratification methods for the prediction of major adverse cardiovascular events (MACE) and bleeding in patients with acute coronary syndrome (ACS) that are treated with antithrombotic therapy. Data on 24,178 ACS patients were pooled from four randomized controlled trials. The super learner ensemble algorithm selected weights for 23 machine learning models and was compared to traditional models. The efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The safety endpoint was a composite of TIMI major and minor bleeding or bleeding requiring medical attention. For the MACE outcome, the super learner model produced a higher c-statistic (0.734) than logistic regression (0.714), the TIMI risk score (0.489), and a new cardiovascular risk score developed in the dataset (0.644). For the bleeding outcome, the super learner demonstrated a similar c-statistic as the logistic regression model (0.670 vs. 0.671). The machine learning risk estimates were highly calibrated with observed efficacy and bleeding outcomes (Hosmer-Lemeshow p value = 0.692 and 0.970, respectively). The super learner algorithm was highly calibrated on both efficacy and safety outcomes and produced the highest c-statistic for prediction of MACE compared to traditional risk stratification methods. This analysis demonstrates a contemporary application of machine learning to guide patient-level antithrombotic therapy treatment decisions.Clinical Trial Registration ATLAS ACS-2 TIMI 46: https://clinicaltrials.gov/ct2/show/NCT00402597. Unique Identifier: NCT00402597. ATLAS ACS-2 TIMI 51: https://clinicaltrials.gov/ct2/show/NCT00809965. Unique Identifier: NCT00809965. GEMINI ACS-1: https://clinicaltrials.gov/ct2/show/NCT02293395. Unique Identifier: NCT02293395. PIONEER-AF PCI: https://clinicaltrials.gov/ct2/show/NCT01830543. Unique Identifier: NCT01830543.


Effect of antacid on the pharmacokinetics of extended-release formulations of tolterodine and oxybutynin.
In general, extended-release (ER) formulations are designed to prolong the duration of efficacy and reduce the adverse effects of a drug. These formulations often contain the entire daily dose in a single tablet. Therefore, failure of the ER mechanism not only diminishes the desired benefits, but may temporarily expose the patient to drug concentrations higher than those released from a conventional tablet. In this study we determined whether pH has an effect on drug release from the ER formulations of oxybutynin (OROS technology) and tolterodine (membrane coated beads) in vitro and in vivo. In vitro studies were based on standardised dissolution experiments for each drug in media of different pH (artificial gastric fluid at pH 1.2, artificial intestinal fluid at pH 7.5, and water). In the two separate, identically designed in vivo studies, single doses of each drug were administered alone and with an antacid to male and female healthy volunteers aged 18-45 years. The randomised, crossover, open-label in vivo studies employed a validated assay to determine plasma concentrations of tolterodine and its metabolite 5-hydroxymethyl tolterodine (5-HM), or oxybutynin and its metabolite N-desethyloxybutynin. The in vitro study showed similar slow and steady drug release from ER-oxybutynin in each pH medium, with 64-71% released after 12 hours. Drug release from ER-tolterodine was steady and slow in artificial gastric fluid, with 72.5% of drug released after 12 hours. However, drug release was much faster in artificial intestinal fluid and water, where 69.8% and 69.1%, respectively, of the drug was released within 4 hours. These in vitro results were consistent with the findings of the in vivo studies. In vivo, the pharmacokinetic profile (peak plasma concentration [C(max)] and area under the concentration-time curve) of ER-oxybutynin was similar after administration with or without antacid, whereas C(max) values of both tolterodine and 5-HM increased significantly when ER-tolterodine was administered with antacid (p < or = 0.017 vs ER-tolterodine alone). Changes in pH affected the release of tolterodine from ER-tolterodine, while they had no effect on the release of oxybutynin from the proprietary ER technology used in ER-oxybutynin. The technology employed in ER formulations thus determines sensitivity of drug release to external factors.


BET bromodomain-containing epigenetic reader proteins regulate vascular smooth muscle cell proliferation and neointima formation.
Recent studies revealed that the bromodomain and extra-terminal (BET) epigenetic reader proteins resemble key regulators in the underlying pathophysiology of cancer, diabetes, or cardiovascular disease. However, whether they also regulate vascular remodelling processes by direct effects on vascular cells is unknown. In this study, we investigated the effects of the BET proteins on human smooth muscle cell (SMC) function in vitro and neointima formation in response to vascular injury in vivo. Selective inhibition of BETs by the small molecule (+)-JQ1 dose-dependently reduced proliferation and migration of SMCs without apoptotic or toxic effects. Flow cytometric analysis revealed a cell cycle arrest in the G0/G1 phase in the presence of (+)-JQ1. Microarray- and pathway analyses revealed a substantial transcriptional regulation of gene sets controlled by the Forkhead box O (FOXO1)1-transcription factor. Silencing of the most significantly regulated FOXO1-dependent gene, CDKN1A, abolished the antiproliferative effects. Immunohistochemical colocalization, co-immunoprecipitation, and promoter-binding ELISA assay data confirmed that the BET protein BRD4 directly binds to FOXO1 and regulates FOXO1 transactivational capacity. In vivo, local application of (+)-JQ1 significantly attenuated SMC proliferation and neointimal lesion formation following wire-induced injury of the femoral artery in C57BL/6 mice. Inhibition of the BET-containing protein BRD4 after vascular injury by (+)-JQ1 restores FOXO1 transactivational activity, subsequent CDKN1A expression, cell cycle arrest and thus prevents SMC proliferation in vitro and neointima formation in vivo. Inhibition of BET epigenetic reader proteins might thus represent a promising therapeutic strategy to prevent adverse vascular remodelling.


Current intake levels of potatoes and all-cause mortality in China: A population-based nationwide study.
Current levels of potato consumption in relation to mortality in Chinese people remains unknown. The aim of this study was to investigate the intakes of total potatoes, fried potatoes, non-fried potatoes, and sweet potatoes as dietary carbohydrate sources in relation to all-cause mortality in the China Health and Nutrition Survey (CHNS). Overall 14 117 participants ≥20 y of age were included, with a median follow-up of 14 y. The cumulative average consumption of potatoes and other foods were calculated and validated using weighing methods in combination with 3-d, 24-h dietary recalls at both household and individual levels. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models after multivariate adjustment. We documented 1007 deaths among the participants. The low and moderate intakes of total potatoes, fried potatoes, and non-fried potatoes were inversely associated with mortality. Compared with non-consumers, the intakes of total potatoes (HR, 0.48; 95% CI, 0.38-0.59), fried potatoes (HR, 0.44; 95% CI, 0.34-0.56), and non-fried potatoes (HR, 0.47; 95% CI, 0.37-0.61) at low consumption levels were most significantly related to lower mortality. Sweet potato consumption was inversely associated with mortality after full adjustment (HR, 0.82; 95% CI, 0.69-0.96) compared with non-consumers. Substituting grains and mixed beans for potatoes with equal amounts at high consumption levels strengthened the inverse associations. In the CHNS, current low and moderate, but not high levels of total potato and fried/non-fried potato consumption as well as sweet potato consumption were inversely associated with all-cause mortality among Chinese people.


Cell Therapy for Type 1 Diabetes: Current and Future Strategies.
Type 1 diabetes (T1D) is defined by an autoimmune destruction of insulin producing β-cells located in the endocrine part of the pancreas, the islets of Langerhans. As exogenous insulin administration fails at preventing severe complications associated with this disease, cell replacement therapies are being considered as a means to treat T1D. The purpose of this manuscript is to review the challenges associated with current strategies and discuss the potential of stem cell therapy for the treatment of T1D. The most prominent therapy offered to T1D patients is exogenous insulin administration which, despite formulations improvement, remains a suboptimal treatment, due to the frequency of injections and the issues associated with precise dosing. As immunotherapy approaches have remained unsuccessful, the only cure for T1D is transplantation of donor-derived pancreas or islets. However, donor scarcity, graft loss, and immune response to the foreign tissue are issues challenging this approach and limiting the number of patients who can benefit from such treatments. In this review, we discuss the causes of T1D and the shortcomings of the current treatments. Furthermore, we summarize the cutting edge research that aims to tackle the current challenges in reaching a quality-controlled product with long-term effects, with a focus on regenerative medicine approaches using human pluripotent stem cells.


Terumo-Triplex grafts for total arch replacement: analysis of postoperative graft performance.
We evaluated the performance of Terumo-Triplex (TRP) with a large-diameter vascular graft sealed with non-biodegradable material in 48 patients who underwent total arch replacement under selective cerebral perfusion between 2004 and 2009. TRP grafts were used in 13 patients (T group), Gelseal graft in 15 (G group), Hemashield graft in 10 (H group) and Intergard graft in 10 (I group). The total tube drainage, time to tube removal, graft dilation ratio and inflammation were evaluated postoperatively. Cardiopulmonary bypass and selective cerebral perfusion times did not differ between groups. Two patients died in hospital. The total drain drainage was significantly lower in the T group (956 ± 156 ml) than in the H (2058 ± 403 ml, p = 0.001) or I (5959 ± 1027 ml, p = 0.01) groups. The time to tube removal was significantly lower in T group and G group than H and I group (T: 3.7 ± 0.4, G: 4.1 ± 0.4, H: 8.3 ± 1.6, I: 18.6 ± 3.6 days, T vs. H, I: p = 0.07, 0.0002, G vs. H, I: p = 0.004, <0.0001). The graft dilation ratio was significantly lower in T group than G group (T: 104 ± 4 vs. 130 ± 7 %, p = 0.001). The max C-reactive protein level was significantly lower in T group (16.2 ± 4.5 mg/dl) than in the G group (19.4 ± 3.2 mg/dl, p = 0.047), H (20.4 ± 4.1 mg/dl, p = 0.048), or I (20.5 ± 4.5 mg/dl, p = 0.013) groups. Maximum body temperature was also lower in the T group (38.2 ± 0.5 °C) than in the G (38.7 ± 0.4 °C, p = 0.011), H (38.9 ± 0.6 °C, p = 0.0087), and I (39.3 ± 0.7 °C, p = 0.0005). Thus, TRP graft might attenuate inflammatory response compared to the other sealed grafts for total arch replacement in patients with aortic arch aneurysm or dissection.


Wnt/β-catenin signaling induces axial elasticity patterns of Hydra extracellular matrix.
The extracellular matrix (ECM) plays crucial roles in animal development and diseases. Here, we report that Wnt/β-catenin signaling induces the ECM remodeling during Hydra axis formation. We determined the micro- and nanoscopic arrangement of fibrillar type I collagen along Hydra's body axis using high-resolution microscopy and X-ray scattering. Elasticity mapping of the ECM ex vivo revealed distinctive elasticity patterns along the body axis. A proteomic analysis of the ECM showed that these elasticity patterns correlate with a gradient-like distribution of metalloproteases along the body axis. Activation of the Wnt/β-catenin pathway in wild-type and transgenic animals alters these patterns toward low ECM elasticity patterns. This suggests a mechanism whereby high protease activity under control of Wnt/β-catenin signaling causes remodeling and softening of the ECM. This Wnt-dependent spatiotemporal coordination of biochemical and biomechanical cues in ECM formation was likely a central evolutionary innovation for animal tissue morphogenesis.


Neonatal acute ethanol intoxication during the epidemic of COVID-19: a case report.
After the outbreak of COVID-19, many families equip with 75% ethanol to inactivate the SARS-CoV-2, which increases the risk of exposure to ethanol. We reported a 25-day-old newborn who was diagnosed with neonatal acute ethanol intoxication with a presenting complaint of accidental consumption about 15 ml formula milk containing 75% ethanol. His main clinical manifestations were irritability, flushed skin, tachycardia, tachypnea, and toxicology analysis detected ethanol. After timely gastric lavage and intravenous fluid replacement, he was cured and discharged. During the COVID-19 epidemic, high concentration ethanol used for inactivating SARS-COV-2 should be placed reasonably and neonatal feeding safety should be emphasized. Timely diagnosis and symptomatic treatment are essential for the prevention and management of acute ethanol intoxication in newborns.


Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes.
Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare. Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥ 5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique. In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p<0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection. Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.


Evaluation of serological tests for diagnosis of Bordetella pertussis infection in adolescents and adults.
Bacterial agglutination antibodies against Bordetella pertussis, Yamaguchi and Tohama strains, are frequently measured for serodiagnosis of pertussis infection in Japan. To determine the serological criteria, the comparative titres of bacterial agglutination antibody and anti-pertussis toxin (PT) antibody were evaluated. Antibody titres were analysed in 36 definitive (fourfold increase in agglutination antibody) and 137 presumptive (high titre of single-antibody) cases of B. pertussis infection among adolescents and adults, and in a control group of 318 healthy volunteers. When a single Yamaguchi agglutinin titre of ≥ 1:1280 (> three SD above the geometric mean for the control group) was taken as diagnostic, the sensitivity and specificity at 4-5 weeks after onset of cough were 58% and 98%, respectively. Using this criterion, the clinical findings in presumptive cases were almost identical to those in definitive cases. When the two tests were compared using 318 control sera, there was no association between the Tohama agglutinin titre and the anti-PT antibody titre, whereas a weak association between the Yamaguchi agglutinin titre and the anti-PT antibody titre was observed. When the numbers of pertussis cases with high antibody titres in the two tests were compared, 60% of cases with a Yamaguchi agglutinin titre of ≥1:1280 showed an anti-PT antibody titre of ≥100 EU/mL. These results indicate that the bacterial agglutination test is a method with low sensitivity and specificity for the diagnosis of B. pertussis infection. Therefore, to yield an accurate diagnosis, anti-PT antibody levels should be measured instead of bacterial agglutination antibody.


Anatomical landmark localization via convolutional neural networks for limb-length discrepancy measurements.
Measurement of limb-length discrepancy (LLD) from a radiograph is a cognitively simple but time-consuming task. To develop a convolutional neural network (CNN) to localize anatomical landmarks from full-length lower-extremity radiographs in predicting LLD. The author searched a hospital's image database to identify studies performed between Feb. 1, 2016, and Sept. 30, 2019. Inclusion criteria were: (1) patients ≤21 years old, (2) study indication of LLD, (3) full-length lower-extremity anteroposterior radiographs performed on the EOS system, and (4) imaging field-of-view that included entire bilateral femurs and tibias. The six requisite ground truth anatomical landmarks for measuring LLD from each radiograph - bilateral top of femoral heads, medial femoral condyles, and center of tibial plafonds - were manually labeled by a pediatric radiologist. For each landmark, a two-dimensional heatmap was generated to encode the pseudo-probability of a landmark being at a particular spatial location. A CNN was developed that regressed across a collection of these heatmaps for landmark localization and bone length predictions. The study cohort consisted of 504 full-length lower-extremity radiographs from 359 patients with wide ranging skeletal deformities and in situ hardware. Evaluation of this CNN showed that the mean point-error for the predicted top of femoral head, medial femoral condyle, and center of tibial plafond were 0.37 cm, 0.39 cm and 0.42 cm, respectively. The mean absolute error for the predicted femoral, tibial and limb lengths, and LLD were 0.33 cm, 0.30 cm, 0.30 cm, and 0.36 cm, respectively. Predicted bone lengths correlated strongly with ground truth. This prototype CNN delivered promising results in predicting bone lengths from full-length lower-extremity radiographs and offers the potential use of a computer algorithm to predict LLD.


Diet deficient in alpha-linolenic acid alters fatty acid composition and enzymatic properties of Na+, K+-ATPase isoenzymes of brain membranes in the adult rat.
The effects of dietary (n-6)/(n-3) polyunsaturated fatty acid balance on fatty acid composition, ouabain inhibition, and Na(+) dependence of Na(+), K(+)-ATPase isoenzymes of whole brain membranes were studied in 60-day-old rats fed over two generations a diet either devoid of alpha-linolenic acid [18:3(n-3)] (sunflower oil diet) or rich in 18:3(n-3) (soybean oil diet). In the brain membranes, the sunflower oil diet led to a dramatic decrease in docosahexaenoic acid [22:6(n-3)] membrane content. The activities of Na(+), K(+)-ATPase isoenzymes were discriminated on the basis of their differential affinities for ouabain and their sensitivity to sodium concentration. The ouabain titration curve of Na(+), K(+)-ATPase activity displayed three inhibitory processes with markedly different affinity [i.e., low (alpha1), high (alpha2), and very high (alpha3)] for brain membranes of rats fed the sunflower oil diet, whereas the brain membranes of rats fed the soybean oil diet exhibited only two inhibitory processes, low (alpha1) and high (alpha2' = alpha2 + alpha3). Regardless of the diet, on the basis of the Na(+) dependence of Na(+), K(+)-ATPase activity, three isoenzymes were found: alpha1 form displaying an affinity 1.5- to 2-fold higher that of than alpha2 and 3-fold higher that of alpha3. In rats fed the sunflower oil diet, alpha2 isoenzyme exhibited higher affinity for sodium (Ka = 8.8 mmol/L) than that of rats fed the soybean oil diet (Ka = 11.7 mmol/L). These results suggest that the membrane lipid environment modulates the functional properties of Na(+), K(+)-ATPase isoenzymes of high ouabain affinity (alpha2).


Metropolitan Detroit's network. "The scattered and competing parts...
The success of the union list of serials in the Detroit network interlibrary loan program played a part in the development of a union catalog of monographs. The procedures involved and the two bonuses of the catalog are mentioned in some detail.


Prevalence and Predictive Factors of Asymptomatic Spondylotic Cervical Spinal Stenosis in Patients with Symptomatic Lumbar Spinal Stenosis.
We performed a retrospective cohort study to investigate the prevalence of and risk factors for asymptomatic spondylotic cervical spinal stenosis (ASCSS) in the setting of lumbar spinal stenosis (LSS). A total of 114 patients with a diagnosis of LSS without cervical myelopathy and radiculopathy were grouped into ASCSS and non-ASCSS groups. The medical data and radiological parameters, including age, sex, body mass index, Charlson comorbidity index, symptom duration, redundant nerve roots, dural sac cross-sectional area (DCSA), facet joint angle, lumbar lordosis angle (LLA), pelvic incidence (PI), Torg-Pavlov ratio, and lumbosacral transitional vertebrae, were analyzed. The lumbar stenosis index and cervical stenosis index of the 114 patients were also analyzed. ASCSS occurred in 70 of the 114 patients with LSS (61.4%). The two groups showed significant differences in symptom duration, redundant nerve roots, LLA, DCSA, and PI. On multivariate logistic regression analysis, an LLA >35.85° (P < 0.001) and a DCSA <84.50 mm2 (P = 0.003) were independently associated with ASCSS. The multi-index receiver operating characteristic curve showed that the area under the curve for predicted probability was 0.805 (P < 0.001). Linear regression analysis revealed that cervical stenosis index significantly and positively correlated with the lumbar stenosis index (r = 0.430; P < 0.001). Our findings suggest that an LLA >35.85° and a DCSA <84.50 mm2 are risk factors for the development of ASCSS. For LSS patients with an enlarged LLA and reduced DSCA, a whole spinal magnetic resonance imaging examination should be performed.


Synthesis of Fluorophore Based Functional Material for Selective Detection of Al3+ Ion in Water and Decoding the AIEE Property of Its Hydrosol.
A designed aggregation-induced emission enhancement (AIEE) active fluorescence probe 2,3-Bis-[(2-hydroxy-napthalen-1-ylmethylene)-amino]-but-2-enedinitrile (L) was synthesized via one step condensation method. The probe shows swift sensitivity and selectivity toward Al3+over other relevant metal ions and also exhibits significant AIEE phenomena in methanol/water mixture. Significant enhancement of fluorescence intensity is triggered via chelation-enhanced fluorescence through complex (Al3+-L) formation. A 2:1 metal to ligand ratio is observed from Job's plot based on UV - Vis absorption titration and detection limit (LOD) is found as low as 31.14 nM. Moreover, 1H NMR titrations and fluorescence reversibility by adding Al3+ and EDTA sequentially had been performed to establish the binding site of sensor complex (Al3+-L). Time-resolved photoluminescence, dynamic light scattering, optical microscopy, and on-site visualization studies have been performed to understand the AIEE mechanism of L in different volume percentage of water and methanol mixture. An INHIBIT molecular logic gate has been constructed utilizing the fluorescence behavior of the probe, L in presence of Al3+ and strong chelating ligand EDTA.


Comprehensive molecular analysis of driver mutations in non-small cell lung carcinomas and its correlation with PD-L1 expression, An Indian perspective.
The understanding of molecular mechanisms involved in non-small cell lung carcinoma (NSCLC) has revolutionized significantly in the recent years. These have helped to develop personalized management strategies by identifying specific molecular alterations such as mutations in EGFR, ROS1, BRAF, ERBB2, MET, ALK, and KRAS genes. These mutations are targetable ensuring a better clinical outcome. Next-generation sequencing (NGS) methodology is the recommended technique for the identification of driver mutations in the five hot-spot genes (EGFR, ALK, ROS1, MET, and BRAF) involved in the NSCLC. NGS has numerous advantages including multiplexing, tissue conservation, identification of rare and novel variants, and reduced cost over the sequential single gene testing. Herein, we sought to demonstrate the mutational profile in NSCLC and their clinicopathologic correlation in a contemporary cohort of Indian NSCLC patients. Additionally, we studied the correlation of oncogenic driver mutations with PD-L1 status in these patients. Five fifty-two stage IV NSCLC patients (adenocarcinoma=490; squamous cell carcinoma=51; adenosquamous carcinoma=5; large cell carcinoma=2; sarcomatoid carcinoma=3; spindle cell carcinoma=1) underwent broad molecular profiling by a custom-made, targeted DNA- and RNA-based five hot-spot genes lung cancer panel (EGFR, ALK, ROS1, BRAF, and MET), compatible with the NGS Ion S5 system. The mutations were correlated with the clinicopathologic characteristics. Additionally, PD-L1 expression status, available on 252 tumors, was correlated with the oncogenic drivers. Validation of the 5 gene panel yielded the following results: a) specificity of 99.74%; b) sensitivity of 100% for single nucleotide variants (SNVs) (>5% variant allele frequency, VAF), indels (>10% VAF) and fusions; c) 100% intra- and inter-run reproducibility; d) 88% inter-laboratory agreement. Validated panel was then used to analyze clinical samples. Sixty percentage tumors harbored either one (54.71%) or multiple (3.26%) mutations. EGFR and BRAF V600E mutations, ALK and ROS1 rearrangements, and MET exon 14 skipping mutation were observed in 38.41% (n = 212) and 2.72% (n = 15) patients, 12.14% (n = 67) and 3.62% (n = 20) patients, and 1.09% (n = 6) patients, respectively. EGFR exon 19 deletion accounted for 52.83% of all mutations, followed by L858R (35.85%), T790M (5.19%), exon 20 insertions (6.6%), and other rare mutations (G719X, L861Q, S768I) (9.91%). Concurrent EGFR with ALK, EGFR with ROS1, EGFR with MET, and EGFR with BRAF were observed in 10, 4, 1, and 3 patients, respectively. PD-L1 was expressed in 134 patients (53.2%). Exon 19 deletion was more prevalent in PD-L1 negative tumors whereas exon 21 substitution (L858R) was seen more in PD-L1 positive tumors. This is one of the largest cohorts of NSCLC for comprehensive targeted mutational profiling and correlation with the PD-L1 expression. The mutations are more prevalent in non-smoker females for all genes, except ALK (non-smoker males). MET and BRAF mutations are more common in elderly population whereas EGFR mutations, and ALK and ROS1 genes rearrangements are more prevalent in younger population. The most common histopathologic subtype/feature associated with various mutations was as follows: acinar with EGFR, solid with ALK, macronucleoli with ROS1, signet ring with MET, and micropapillary with BRAF.


On the geochemistry of the Kyra eruption sequence of Nisyros volcano on Nisyros and Tilos, Greece.
The Kyra sequence is a volcanic eruption sequence originating from the eastern flank of Nisyros volcano, Greece. Its eruptions products can be found not only on Nisyros itself but also on the nearby non-volcanic island of Tilos. In an extensive sampling campaign, outcrops of the Kyra eruption products on Nisyros were sampled and corresponding samples on Tilos were taken. The clear stratigraphical relationship between the different units within in the individual outcrops, combined with the chemical information gained by the application of instrumental neutron activation analysis (INAA) to the samples, made a detailed chemo-stratigraphy of the complete eruption sequence possible. It can be shown that the sequence is separated into eight distinguishable eruptions. Furthermore, no eruption products of the caldera-forming eruptions from Nisyros (Lower- and Upper Caldera Pumice) or from Santorin were found on Tilos.