Assessment of the nitric oxide system in the heart, aorta and kidney of aged Wistar-Kyoto and spontaneously hypertensive rats.
To assess the nitric oxide (NO) system in the cardiovascular and renal systems of old Wistar-Kyoto (WKY) rats and old spontaneously hypertensive rats (SHR) compared with young rats of the same strains. The NO pathway was assessed: (i) in analytical studies measuring the concentration of nitrate in plasma and the activity of NO synthases in the left ventricle, renal cortex and renal medulla; and (ii) in functional studies, in which we measured the blood pressure effects of NO blockade with intravenous N-nitro-L-arginine methyl ester (L-NAME, 0.1 mg/kg) in anaesthetized rats. In addition, we studied NO production in the aorta comparing the force attained by isolated segments exposed to cumulative concentrations of L-NAME (10(-7)-10(-3) mol/l). Plasma nitrate was significantly higher in old rats of both strains. Calcium-dependent NO synthase activity was markedly upregulated in the left ventricle, renal cortex and renal medulla of the old rats, both in hypertensive and normotensive animals. Intravenous L-NAME elicited deeper pressor effects in the old rats of either blood pressure condition. Aortic segments from old WKY rats, but not those from SHR, achieved remarkably stronger tension in response to L-NAME compared with the young counterparts. These findings suggest that the NO system is upregulated in the cardiovascular system and the kidney in senescence, even in hypertension.


Arrhythmia inducibility and ventricular vulnerability in a chronic feline infarction model.
Ventricular tachyarrhythmias are the cause of sudden cardiac death in ischemic heart disease. Reliable animal models are necessary to study techniques for identifying individuals at risk and to develop effective modes of therapy. The purpose of the present study was to evaluate the inducibility of ventricular tachyarrhythmias and vulnerability to ventricular fibrillation and to correlate these findings with changes in ventricular refractoriness in a chronic feline model. Twelve conditioned cats were randomly divided into two groups: group A, sham-operated controls (n = 5); or group B, permanent occlusion of the left anterior descending coronary artery (n = 7). Two weeks later, the following measurements were made: (1) assessment of refractory periods at several ventricular sites; (2) inducibility to ventricular tachyarrhythmias; and (3) determination of ventricular fibrillation threshold. After electrophysiologic testing, the animals were killed and the hearts were studied histologically. Ventricular fibrillation thresholds were significantly lower in group B compared with group A (13 +/- 3 vs 46 +/- 9 mA; p less than 0.01). One of the sham-operated controls had induction of nonsustained ventricular tachycardia, while six of the group B animals had reproducible, inducible ventricular tachyarrhythmias (p less than 0.01). There was a significant dispersion in effective refractory periods between normal and infarcted sites in group B (46 +/- 6 msec) not seen in group A (12 +/- 2 msec, p less than 0.01). The group A cats demonstrated minimal damage to the myocardium or cardiac architecture. Group B cats demonstrated extensive, transmural, homogeneous infarcts of approximately 30% of the anterior wall of the left ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)


Birthweight is increasing in the United States.
The rates of obesity and diabetes mellitus have increased over the last several decades.1,2 This has resulted in a higher number of large-for-gestational-age (LGA) neonates.3 The US cesarean delivery rate has increased over the same period; LGA fetuses may be a contributing factor.4 This study aimed to establish whether birthweights in the United States have increased over time. This was a retrospective cohort study conducted using live birth data of singleton pregnancies from the US National Vital Statistics between January 1972 and December 2020. These data are deidentified and publicly available; therefore, the study was deemed exempt from our institutional review board. Singleton births between 37 0/7 and 42 6/7 weeks of gestation were included. Multiple pregnancies and deliveries which had unknown gestational age or birthweight, were excluded. The mean birthweight by each gestational age week for the years 1972-2020 was calculated at selected years (1972, 1982, 1992, 2002, 2012, 2018, and 2020). Of note, 2018 was included to account for differences in the dataset that might be due to the COVID-19 pandemic. Using R statistical software, a linear model was fit for each gestational age week. A t test was performed to determine whether the slope was statistically different from zero (indicating whether there was a trend of rising or decreasing birthweights over time). A total of 19,730,588 individuals met the inclusion criteria. However, <1% of the data were excluded because of missing data. Birthweight at 39, 40, 41, and 42 weeks of gestation showed a statistically significant increase over time (Figure). There was a significant decrease in birthweight at 37 weeks of gestation. Data on Hispanic ethnicity became available in 1992. After 1992, birthweight by race or ethnicity group was examined. Each race or ethnicity group echoes the overall trends observed. However, for 39, 40, 41, and 42 weeks of gestation, the non-Hispanic Black and Hispanic groups have higher increases in birthweight than the non-Hispanic White group. There were fluctuations in the overall combined mean for 37 to 42 weeks of gestation (Table). Although the overall mean birthweight did not increase over the study period, it increased for each gestational age week at ≥39 weeks of gestation. The birthweight at 37 weeks of gestation decreased. The reason for the decrease in birthweight is unclear. Contributing factors may include changes in guidelines on the timing of delivery and method of calculation of gestational age. Increases in the rates of obesity and diabetes mellitus could be contributing to the birthweight increase from 39 weeks of gestation.1,2 There was an increase in the rate of gestational diabetes mellitus from 3% to 8% in our study population from 1992 to 2020 and an increase in mean body mass index from 26.3 to 27.5 from 2012 to 2020. The publicly available birthweight data have limitations. Data collection evolved during the study period. The estimates for gestational age have become more accurate with first-trimester dating ultrasounds. In summary, birthweight is increasing among those born from 39 to 42 weeks of gestation. These increasing birthweights may be a factor in persistently high cesarean delivery rates despite national campaigns.5.


Percutaneous fine needle aspiration biopsy using a modified coaxial technique.
A modified coaxial technique for the biopsy of small or deeply situated lesions using computed tomographic (CT) guidance is described. A 22-gauge needle was passed coaxially through an outer 18-gauge introducing needle and aspiration biopsy was performed. This modified coaxial technique allows for multiple biopsies to be obtained safely, expeditiously, and repeatedly.


The effect of dihydroceramide desaturase 1 inhibition on endothelial impairment induced by indoxyl sulfate.
Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 μM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 μM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects.


MR imaging of sports-related groin pain.
With increasing participation in professional and recreational athletics, activity-limiting pelvic and groin pain presents a growing challenge for patients and health care providers. The causes of musculoskeletal-related groin pain among athletes are diverse, with considerable overlap in history and physical examination findings. Pubalgia is a clinical diagnosis invoked when no more specific cause ofa patient's symptoms can be determined on history and physical examination. In many cases, dedicated MR imaging of the hip and pelvis can provide a prompt and specific diagnosis, which allows for early treatment and return to participation.


Identification and characterization of integron-associated antibiotic resistant Laribacter hongkongensis isolated from aquatic products in China.
Laribacter hongkongensis is a recently discovered bacterium associated with gastroenteritis. In this study, a total of 199 isolates of this species obtained from aquatic products (n=462) in Guangzhou City, China, were examined for their susceptibility to 19 antimicrobial agents and the presence of antimicrobial resistance integrons. The genetic relatedness of the isolates with integrons was also evaluated. A PCR-based method was used to screen integrons and found that 13 (6.5%) of the isolates harbored class 1 integrons. The antimicrobial resistance rates of integron-positive isolates were significantly higher than integron-negative ones for cefepime, ciprofloxacin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole and rifampicin. Genetic sequence analysis revealed that these integrons contained various antimicrobial-resistance genes (dfrA1, dfrA14, dfrA17, dfrA32, aadA1, aadA2, aadA5, cmlA5, arr2, ereA and orfC) organized into different gene cassettes arrangements including a novel array of dfrA14-arr2-cmlA5. Pulsed-field gel electrophoresis (PFGE) yielded 13 different patterns among 13 integron-positive isolates, which could be grouped into four clusters. These indicate the dispersal of multi-resistant integrons among different molecular types. To the best of our knowledge, this is the first report showing distribution and characterization of class 1 integrons among L. hongkongensis isolates.


Enzyme variability in natural populations of Daphnia carinata king.
Fifteen populations of the cladoceran crustacean, Daphnia carinata, were examined for allozyme variation at sixteen gene loci. Individuals of this cyclic parthenogen were heterozygous at only 2.1 per cent of their loci. Large differences in gene frequencies existed among the populations. Within populations genotypic frequencies were in good agreement with Hardy-Weinberg expectations, and remained stable during annual cycles of population growth. Strong linkage disequilibrium was observed between the allelic variants at two leucine aminopeptidase loci in certain populations, suggesting that the loci are tightly linked and that populations of D. carinata are founded from few individuals.


Vitamin B12 status and peripheral neuropathy in patients with type 2 diabetes mellitus.
To assess the status of vitamin B12 in patients with type 2 diabetes, and to explore any association between its deficiency and diabetic peripheral neuropathy. This cross-sectional observational study was conducted from August, 2017, to April, 2018, at the Specialized Centre for Endocrinology and Diabetes in Baghdad, Iraq. Type 2 diabetics using metformin were subjected to clinical examination for retinopathy using fundoscopy, and peripheral neuropathy using the Michigan Neuropathy Screening Instrument. Additionally, patients were asked to fill a questionnaire and their medical records were reviewed. Blood samples were obtained for the measurement of biomarkers. Vitamin B12 deficiency was recorded at ≤187 pg/ml. Data was analysed using SPSS 25. Of the 66 patients, 39(59%) were males and 27(41%) were females. The overall mean age was 53.3}9.2 years and the mean duration of diabetes was 104}71.8 months. The mean dose of metformin was 1135}496 mg and the duration of metformin use was 72}62 months. Overall, 19(29%) patients suffered from vitamin B12 deficiency. However, no significant difference was found between normal and deficit groups regarding the parameters that may affect vitamin B12 level. Also, no significant correlations were found between vitamin B12 concentration and the dose (p=0.16) or the duration of metformin use (p=0.09). High prevalence of vitamin B12 deficiency was observed in metformin-treated patients with type 2 diabetes. However, the deficiency had no correlation with the rate of peripheral neuropathy.


Ethanol-induced death and lipid composition of Saccharomyces cerevisiae: a comparative study of the role of sterols.
Ethanol tolerance of four Saccharomyces cerevisiae strains characterized by different amounts of delta 5,7-sterols was tested. The individual tolerances did not correlate with the strains sterol levels. The highly and medium-accumulating strains exhibited the highest and lowest ethanol tolerances, respectively.


Solar maculopathy: prognosis over one year follow up.
To document the visual acuity, spectral domain optical coherence tomography (SD-OCT) findings and prognosis in10 eyes of 6 patients with foveal damage from solar retinopathy in 1 year. This was a prospective, observational case series of patients presented by solar maculopathy at Ophthalmology department, Sohag University. All patients underwent visual acuity (VA) testing, refraction, dilated fundus examination fluorescein angiography (FA) and SD-OCT (spectral Domain ocular coherence Tomography) imaging and follow up for 1 year. The mean age was 16.5 years (range 9-27 years, both eyes are affected in 4 patients. The mean spherical equivalent (SE) was - 0.25 ± 0.50 D. The visual acuity of the affected eyes ranged from 0.4 to 0.9 on presentation. At presentation Significant foveal pathology was identified on SD-OCT in 10 eyes, All eyes showed disruption of the photoreceptor ellipsoid zone and the interdigitation zone on SD-OCT, Follow up of the cases continued for 1 year.100% of cases showed improvement in VA: 20% eyes regained 1, 50% eyes with VA of 0.9; two eyes 20% 0.8 and one eyes (10%) with 0.4. The improvement began after 1 week and reached its maximum and became stationary after the 6th month of follow up, the outer retinal hole persist in OCT in 80% of cases. Solar maculopathy has a good prognosis yet shows no improvement after 6 months. Young age might pose as a risk factor.


New cold-fiber headspace solid-phase microextraction device for quantitative extraction of polycyclic aromatic hydrocarbons in sediment.
A new automated headspace solid-phase microextraction (HS-SPME) sampling device was developed, with the capability of heating the sample matrix and simultaneously cooling the fiber coating. The device was evaluated for the quantitative extraction of polycyclic aromatic hydrocarbons (PAHs) from solid matrices. The proposed device improves the efficiency of the release of analytes from the matrix, facilitates the mass transfer into the headspace and significantly increases the partition coefficients of the analytes, by creating a temperature gap between the cold-fiber (CF) coating and the hot headspace. The reliability and applicability of previously reported cold-fiber devices are significantly enhanced by this improvement. In addition, it can be easily adopted for full automation of extraction, enrichment and introduction of different samples using commercially available autosampling devices. Sand samples spiked with PAHs were used as solid matrices and the effect of different experimental parameters were studied, including the extraction temperature, extraction time, moisture content, and the effect of sonication and modifier under optimal experimental conditions, linear calibration curves were obtained in the range of 0.0009-1000 ng/g, with regression coefficients higher than 0.99 and detection limits that ranged from 0.3 to 3 pg/g. Reproducible, precise and high throughput extraction, monitoring and quantification of PAHs were achieved with the automated cold-fiber headspace solid-phase microextraction (CF-HS-SPME) device coupled to GC-flame ionization detection. Determination of PAHs in certified reference sediments using the proposed approach exhibited acceptable agreement with the standard values.


Mouse Models of Intestinal Fibrosis.
Mouse models are essential for investigation of underlying disease mechanisms that drive intestinal fibrosis, as well as assessment of potential therapeutic approaches to either prevent or resolve fibrosis. Here we describe several common mouse models of intestinal inflammation and fibrosis, including chemically driven colitis models, a bacterially triggered colitis model, and spontaneous intestinal inflammation in genetically susceptible mouse strains. Detailed protocols are provided for dextran sodium sulfate (DSS) colitis, 2,4,6-trinitro-benzene sulfonic acid (TNBS) colitis, adherent-invasive Escherichia coli (AIEC)-triggered colitis, the interleukin-10 knockout (IL-10KO) mouse model of spontaneous colitis, and the SAMP/YitFc model of spontaneous ileocolitis.


Reversible metabolism and pharmacokinetics: application to prednisone-prednisolone.
The simplest three pharmacokinetic models which apply in cases of reversible metabolism are described. Area under the curve (AUC) relationships are described which allow one to make a choice of which one of the three models may apply in a particular case. Expressions for clearances and other pharmacokinetic parameters are given. It is shown that biexponential time courses are expected after bolus intravenous administration although distribution is not involved in the models. In some cases dose/AUC or infusion rate/steady-state concentration yield simple clearances, while in other cases they are complex. AUC data obtained following oral administration of 5 mg doses of prednisone and prednisolone to 16 normal volunteers were analyzed with the new concepts and one of the models was found to apply. This new interpretation of such data results in some significant changes from application of classical pharmacokinetics.


Functional polysaccharides from Grifola frondosa aqueous extract inhibit atopic dermatitis-like skin lesions in NC/Nga mice.
Grifola frondosa (GF), distributed widely in far east Asia including Korea, is popularly used as traditional medicines and health supplementary foods, especially for enhancing the immune functions of the body. To extend the application of GF polysaccharides (GFP) for atopic dermatitis (AD), we investigated the effects of GFP on the 2,4-dinitrochlorobenzene-induced AD-like skin lesion in NC/Nga mice. GFP treatment significantly reduced the dorsa skin dermatitis score and combination treatment with GFP, and dexamethasone has a synergistic effect in AD-like skin lesion by reduced Serum IgE, mast cells infiltration, and cytokines expression. These results indicate that GFP suppressed the AD-like skin lesions by controlling the Th-1/Th-2-type cytokines in NC/Nga mice. These findings strongly suggest that GFP can be useful for AD patients as a novel therapeutic agent and might be used for corticosteroids replacement or supplement agent.


Evidence for regulatory control of canine platelet phosphodiesterase.
Forskolin, epinephrine, and prostaglandin I2 were used to examine the adenylate cyclase-phosphodiesterase system of intact thrombopathic and normal canine platelets. The results provide indirect support for the hypothesis that the elevation of intraplatelet c-AMP in this unique hereditary defect is due to impaired phosphodiesterase activity. The inhibitory (Nj) and stimulatory (Ns) components of adenylate cyclase appeared functionally intact. Cytosolic fractions of normal and thrombopathic platelets had similar cAMP hydrolytic activities. The failure of intact forskolin-stimulated thrombopathic platelets to return elevated cAMP to non-stimulated levels after 15 min, despite significant phosphodiesterase activity in cytosolic fractions, implies that the platelet isoenzymes are under regulatory control.


3D reconstruction of brain section images for creating axonal projection maps in marmosets.
The brain of the common marmoset (Callithrix jacchus) is becoming a popular non-human primate model in neuroscience research. Because its brain fiber connectivity is still poorly understood, it is necessary to collect and present connection and trajectory data using tracers to establish a marmoset brain connectivity database. To visualize projections and trajectories of axons, brain section images were reconstructed in 3D by registering them to the corresponding block-face brain images taken during brain sectioning. During preprocessing, autofluorescence of the tissue was reduced by applying independent component analysis to a set of fluorescent images taken using different filters. The method was applied to a marmoset dataset after a tracer had been injected into an auditory belt area to fluorescently label axonal projections. Cortical and subcortical connections were clearly reconstructed in 3D. The registration error was estimated to be smaller than 200 μm. Evaluation tests on ICA-based autofluorescence reduction showed a significant improvement in signal and background separation. Regarding the 3D reconstruction error, the present study shows an accuracy comparable to previous studies using MRI and block-face images. Compared to serial section two-photon tomography, an advantage of the proposed method is that it can be combined with standard histological techniques. The images of differently processed brain sections can be integrated into the original ex vivo brain shape. The proposed method allows creating 3D axonal projection maps overlaid with brain area annotations based on the histological staining results of the same animal.


Oxidative stress in diabetic retina.
The authors describe the alterations usually associated with diabetic retinopathy. They concern the classical thickening of the basal membrane of retinal capillaries and the associated modification of retinal vessel permeability. These alterations correspond to the blood-retinal barrier disruption. The authors then discuss the participation of oxygenated free radicals in the pathogenesis of diabetic retinopathy. They report several experimental studies establishing such a participation and finally describe their own results obtained on a model of retinas isolated from alloxan-induced diabetic rats. After one month of evolution, the electroretinograms (ERG) recorded on isolated retinas from diabetic rats had an amplitude about 20% lower than the controls, whereas after two months of diabetes, this decrease was about 60%. Under these conditions, the authors tested the protective properties of Ginkgo biloba extract (EGb 761) on their model. They observed that in EGb-treated animals (100 mg/kg/day), the ERG had a significantly (p less than 0.001) greater amplitude than untreated animals after two months of diabetes evolution. In conclusion, the authors discuss the possible utilization of a free radical scavenger, such as EGb 761, in the prevention of the retinal impairment in diabetes.


Diagnosis of ocular sarcoidosis.
Sarcoidosis is a chronic inflammatory disorder with an unknown etiology characterized by noncaseating granulomas. The disorder is a multisystemic disease and affects many organs, including most often the lung, lymph nodes, skin, heart, liver, muscles, and the eye. [corrected] Based on a review of the literature and on an algorithm generated in an international workshop on sarcoidosis, this article provides the reader with a schematic and simple approach to the diagnosis of ocular sarcoidosis. In a considerable proportion of cases it is the ophthalmologist who first sees patients presenting with the ocular expression of sarcoidosis. In countries where the incidence of sarcoidosis is common, like Japan, a complete workup should be performed, whereas in countries where the incidence of the disease is less high, a noninvasive approach may be warranted at first.


Effect of vitreoscilla hemoglobin and culture conditions on production of bacterial L-asparaginase, an oncolytic enzyme.
L-asparaginase is a widely used cancer chemotherapy enzyme. The source for the enzyme with this property is mainly bacterial and its synthesis is strongly regulated by oxygen. In this study, we utilized two recombinant systems: one carried the gene (vgb) for the Vitreoscilla hemoglobin (VHb), a protein of prokaryotic origin which confers a highly efficient oxygen uptake to its host and the other carried the L-asparaginase gene (ansB). The host bacteria were Escherichia coli, Enterobacter aerogenes, and Pseudomonas aeruginosa. Of these three bacteria, all gram-negative, E. coli and its recombinant strain showed up to sevenfold higher L-asparaginase activity in lactose than in other carbon sources. Although, in this bacterium glycerol was the poorest source for L-asparaginase synthesis, it supported the highest biomass production. In glucose medium, L-asparaginase activity of E. aerogenes was about threefold higher than its vgb and ansB recombinants. ansB recombinant showed significantly higher enzyme levels than both host and vgb recombinants in glycerol and lactose media. In this bacterium, VHb/vgb clearly caused a decrease in the enzyme synthesis under all conditions. As seen for E. aerogens, glycerol was the most favorable carbon source for P. aeruginosa and its vgb strain in terms of both L-asparaginase synthesis and biomass production. The cultures grown in glycerol had more than two- and threefold biomass than in glucose and lactose, respectively, and up to elevenfold than in mannitol. Indeed, the highest biomass production for all bacteria and their recombinants was in glycerol. The VHb/vgb system is clearly advantageous for production of L-asparaginase in P. aeruginosa. The same, however, does not hold true for E. aerogenes.


Cardiac output measurements with electrical velocimetry in patients undergoing CABG surgery: a comparison with intermittent thermodilution.
The purpose was to study the agreement between cardiac output measurements with electrical velocimetry vs. intermittent thermodilution before and after coronary artery bypass graft surgery. Cardiac output was measured simultaneously with electrical velocimetry and intermittent thermodilution before and immediately after coronary artery bypass graft surgery, and in the intensive care unit. Measurements were performed in three different body positions. The results were analysed according to Bland and Altman. The mean bias of all 150 paired measurements in 16 patients was 0.21 +/- 0.78 L min(-1), and the mean error was 40%. Before skin incision the mean bias was 0.04 +/- 0.41 L min(-1), and the mean error was 25%. After skin closure the mean bias was 0.57 +/- 0.92 L min(-1), and the mean error was 42%. In the intensive care unit the mean bias was 0.26 +/- 0.68 L min(-1), and the mean error was 32%. The agreement between cardiac output measurements with electrical velocimetry and intermittent thermodilution was clinically acceptable only before skin incision in coronary artery bypass graft surgery. The mean error was unacceptably high immediately after skin closure and was at a borderline level in the intensive care unit. Thus, the overall accuracy of cardiac output measurements with the electrical velocimetry technique during coronary artery bypass graft surgery is not clinically unacceptable.


Descriptive analysis of workflow variables associated with barcode-based approach to medication administration.
Bedside barcode technology is used during medication administration to ensure patient safety. This study evaluated the workflow variables related to a bedside barcode technology-based medication administration process. A time-and-motion technique was used to assess the observational episodes related to medication administration conducted by registered nurses. In an observational episode, nurses spent adequate time in "documenting medications" and "giving medications." Nurses were primarily engaged in tasks at the patient's bedside.


Dual inhibitors of phosphodiesterase-4 and serotonin reuptake.
A new class of multitarget compounds was synthesized by linking a novel selective serotonin reuptake inhibitor (SSRI) to a PDE4 inhibitor. The new dual PDE4 inhibitor/SSRI showed antidepressant-like activity in the forced swim test in mice The SSRIs 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine (14) and 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamine (15) were both individually linked to the PDE4 inhibitor 4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (19), via a five-carbon chain. The dual PDE4 inhibitor/SSRI 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine)-pentyl]-4,5,8,8a-tetrahydro-2H-phthalazin-1-one (21) showed potent and selective serotonin reuptake inhibition (IC(50) value of 127 nM). The dual PDE4 inhibitor/SSRI 21 also inhibited PDE4D3 with a K(i) value of 2.0 nM. The dual PDE4 inhibitor/SSRI was significantly more effective than the individual SSRI alone or fluoxetine in the forced swim test at standard doses. On a molar basis, the antidepressant-like effect of the dual PDE4 inhibitor/SSRI 21 showed a 129-fold increase in in vivo efficacy compared to fluoxetine.


Clinical and Imaging Profile of Patients with Joubert Syndrome.
Joubert syndrome (JS) is a rare syndrome characterized by ataxia and the molar tooth sign (MTS) on imaging. The present study aims to explore the clinical and radiological features in a cohort of patients with JS. This was a retrospective chart review of patients with JS evaluated by movement disorder specialists. Nine patients were included in the study. All patients had facial dysmorphism and ocular abnormalities, and 4 patients had dystonia. Ocular tilt reaction and alternate skew deviation (66%) were the most common ocular abnormalities. Horizontally aligned superior cerebellar peduncles were observed in all four patients with diffusion tensor imaging, with a lack of decussation in three. Exome sequencing performed in four patients revealed novel variants in the MKS1, CPLANE1, and PIBF1 genes. Facial dysmorphism, ocular abnormalities and classical imaging findings were observed in all patients with JS. Apart from ataxia, dystonia and myoclonus are other movement disorders observed in JS.


The low prevalence rate of vitamin E deficiency in urban adults of Wuhan from central China: findings from a single-center, cross-sectional study.
Vitamin E is an essential nutrient in human body famous for its antioxidant and non-antioxidant functions. However, little is known about vitamin E deficiency status in urban adults of Wuhan from central China. Our aim is to describe the distribution of both circulating and lipid-adjusted serum vitamin E concentration in urban adults of Wuhan. We hypothesized that the prevalence rate of vitamin E deficiency would be low in Wuhan in consideration of the Chinese food composition. A cross-sectional study with 846 adults was performed in a single-center. Concentrations of vitamin E were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The median (interquartile range, IQR) of serum vitamin E concentration was 27.40 (22.89-33.20) μmol/L while that of serum vitamin E concentration adjusted by total cholesterol or the sum of cholesterol (TC) and triglyceride (TG) (the sum of cholesterol and triglyceride, TLs) were 6.20 (5.30-7.48) and 4.86 (4.10-5.65) mmol/mol, respectively. No significant difference of the circulating and TC-adjusted vitamin E concentration was found between male and female except for vitamin E/TLs. However, concentrations of vitamin E increased significantly (r = 0.137, P < 0.001) with age, but lipid-adjusted concentrations of vitamin E did not. On analysis of risk factors, the subjects characterized by hypercholesterolemia are more likely to exhibit higher circulating but lower lipid-adjusted vitamin E level due to adequacy of the serum carriers for delivery of vitamin E. Only 0.47% of the population were below 12 μmol/L of vitamin E defined as functional deficiency. The prevalence rate of vitamin E deficiency in urban adults of Wuhan is low, which is important and useful to clinicians for clinical decision-making in public health practice.


Brain glucose metabolism in borderline personality disorder.
We searched for regional cerebral metabolic disturbances in patients with borderline personality disorder (BPD). Ten inpatients with BPD, no current DSM-IIIR Axis I diagnosis and free of any psychotropic substances, were compared with 15 age-matched control subjects using positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose and semiquantitative analysis of regional glucose metabolic activity. We found relative hypometabolism in patients with borderline personality disorder at the level of the premotor and prefrontal cortical areas, the anterior part of the cingulate cortex and the thalamic, caudate and lenticular nuclei. This study shows significant cerebral metabolic disturbances in patients with borderline personality disorder. These metabolic disturbances, which are similar to some of those described in other psychiatric entities, may help to understand the characteristic clinical aspects of this disorder.


RNA-directed DNA methylation.
DNA methylation is an important epigenetic mechanism for silencing transposons and other repetitive elements, and for stable repression of specific transgenes and endogenous genes. Plants can utilize small interfering RNAs (siRNAs) to guide de novo DNA methyltransferases for the establishment of sequence-specific DNA methylation. Genetic and biochemical approaches have identified many components involved in RNA-directed DNA methylation (RdDM). These components function in one or more of the following three aspects: biogenesis of siRNAs, production of scaffold RNAs, and the assembly of an effector complex that involves the complementary pairing between the guide siRNAs and nascent scaffold RNAs and that recruits the DNA methyltransferases. Recent studies not only unveiled new molecular players and novel interactions, but also suggested spatial and temporal segregation of the RdDM process within the nucleus.


Chemogenetic stimulation of proprioceptors remodels lumbar interneuron excitability and promotes motor recovery after SCI.
Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.


Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.
To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN. Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures. Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related. IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.


Identification of ligands targeting RGS proteins high-throughput screening and therapeutic potential.
Regulator of G protein signaling (RGS) proteins represent unique targets for the modulation of G protein-coupled receptor-mediated signal transduction cascades. Functionally, RGS proteins act to limit the duration of signaling of activated G proteins due to its ability to act as GTPase activating proteins (GAPs). This GAP activity catalyzes the intrinsic GTPase activity of G protein α subunits, such as those in the Gαo, Gαi, and Gαq families. Because of their unique regulatory properties, RGS proteins have emerged as an interesting target for development of both small molecule laboratory tools and potential future therapeutics. In this chapter, the utility of RGS modulators will be briefly reviewed, with a main focus on high-throughput screening methods and progress being made to discover new RGS ligands.


Aerobic granular sludge treating low-strength municipal wastewater: Efficient carbon, nitrogen and phosphorus removal with hydrolysis-acidification pretreatment.
Low organic load while high fraction of particulates still challenging the application of aerobic granular sludge process in low-strength municipal wastewater treatment. The feasibility of adopting short cycle length to increase organic load and hydrolysis-acidification pretreatment to enhance anaerobic COD uptake was evaluated. As the cycle length decreased from 4 h to 2 h, the organic loading rate increased from 0.98 to 1.3 g L-1 d-1 and granulation appeared after two weeks. Moreover, with the hydrolysis-acidification pretreatment, the average effluent TN and TP concentrations decreased respectively from 17.8 to 13.7 mg L-1 and 0.76 to 0.41 mg L-1, meeting the Grade IA of the effluent standards in China. Furthermore, cycle tests were conducted to reveal the underlying mechanism of the pretreatment effects. The results showed that the hydrolysis-acidification pretreatment enhanced the COD storage and phosphorus release in anaerobic phase, and improved the simultaneous nitrification-denitrification process, as well as the phosphorus uptake in aeration phase.


RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling.
RECK was first isolated as a transformation suppressor gene by cDNA expression cloning in a mouse fibroblast cell line transformed by an activated RAS oncogene. Subsequently, reduced expression of RECK in transformed cells and cancer cells were demonstrated. Moreover, in several types of tumors, positive correlation between RECK expression and survival of patients have been noted. RECK encodes a GPI-anchored glycoprotein harboring three protease inhibitor-like domains. The RECK protein regulates at least three members of the matrix metalloproteinase (MMP) family, MMP-2, MMP-9, and MT1-MMP, in vitro or in cultured cells. Restored expression of RECK in cancer cell lines results in strong suppression of invasion, metastasis, and tumor angiogenesis. Mice lacking RECK die in utero with reduced integrity of blood vessels, the neural tube, and mesenchymal tissues. In these mice, MMP activity is elevated, and the amount of collagen type I greatly reduced. The RECK null phenotype is partially rescued (half day delay of death and marked recovery of tissue integrity) by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo and involvement of other target(s) for RECK in the lethal phenotype. These findings indicate that (i) RECK is an important regulator of extracellular matrix remodeling and that (ii) down-regulation of RECK by oncogenic signaling leads to the excessive activation of MMPs thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis.


Quality of silages from Italian farms as attested by number and identity of microbial indicators.
This study evaluated the quality and possible hygiene risks related to farm-made silages by analysing the presence and number of micro-organisms that influence the preservation and safety in samples from four Italian regions. Lactic acid bacteria, clostridia, lactate-fermenting yeasts and propionibacteria (PAB) were isolated and identified by random amplified polymorphic DNA PCR, sequencing of the V2-V3 16S rRNA gene region, 5.8S-ITS rDNA RFLP and species-specific PCR. The Lactobacillus plantarum cluster was the most numerous and comprised strains mostly isolated from alfalfa silage. The Lactobacillus buchneri cluster, second in number, comprised isolates from both alfalfa and maize silage. Anaerobic spore formers were assigned to the species Clostridium baratii, Clostridium beijerinkii, Clostridium butyricum, Clostridium perfringens, Clostridium saccharolyticum, Clostridium tyrobutyricum and Paenibacillus macerans. Yeast isolates were identified as Candida apicola, Candida mesenterica and Pichia fermentans. PAB strains, detected only in unifeed, were all identified as Propionibacterium acidipropionici. The occurrence of spoiling micro-organisms was frequent and the possibility of contamination by potentially pathogenic clostridia was demonstrated. The results suggest the need for improved ensiling practices and appropriate control measures to safeguard the hygienic and nutritional quality of silages produced in farms.


Pinwheel inclusions in morphogenesis: a possible alternative to induction by viruses.
Pinwheel inclusions (PWs) were found in cells of callus tissue derived from explants of secondary phloem parenchyma of carrot (Daucus carota) storage root and grown on a basal medium containing zeatin and indoleacetic acid or coconut milk, naphthalene acetic acid, or combinations of these. Preliminary attempts to demonstrate the presence of viruses in the callus tissue failed. The possibility that the tissles were infected by a low titer or unstable conventional virus or by a defective mutant has not been ruled out. However, two lines of evidence suggest that the PWs in these tissues may be a result of culture conditions and not of virus infection. First, no PWs or other cytoplasmic inclusions were found in cells of otherwise similar tissue cultured on basal medium alone, and multifibrillar bundles (MFBs) but not PWs were found when the tissues were cultured on a medium that stimulates differentiation and morphogenesis. Second, culture stimulated to differentiate and containing MFBs only were returned to the supplemented basal medium and subsequently found to contain both PWs and MFBs.


Particulate methane monooxygenase from Methylosinus trichosporium OB3b.
Particulate methane monooxygenase (pMMO) catalyzes methane hydroxylation to methanol at ambient temperature and pressure. pMMO from Methylosinus trichosporium OB3b is one of the two pMMOs for which the protein structure was determined by X-ray crystallography. Because purified pMMO is inherently instable in vitro, it is difficult to use for time-consuming analysis. Therefore, investigations using crude enzyme preparations of pMMO are useful in some cases. In this chapter, methods for preparing pMMO from M. trichosporium OB3b to varying degrees of purity, including bacterial cells expressing pMMO, membrane fractions containing pMMO, and highly purified pMMO, are described.


Role of myocardial oxygen demand in the pathogenesis of silent ischemia during daily life.
The role of myocardial oxygen demand in the pathogenesis of silent ambulatory myocardial ischemia was evaluated by reviewing and assessing the methods and results of recent studies. The performance of simultaneous ambulatory electrocardiographic and blood pressure monitoring in 25 men with proven coronary artery disease (CAD) revealed significant increases in heart rate and blood pressure (p < 0.001) preceding most silent ischemic events. By plotting the mean heart rate obtained at 5-minute intervals during the 30 minutes before an ischemic event, the ischemic heart rate was shown to be significantly higher (95 +/- 15 vs 74 +/- 11 beats per minute [bpm]; p < 0.01) than the nonischemic heart rate. The evaluation of heart rate changes during ambulatory ischemia (in patients with CAD and ischemia induced by an exercise test using gradual work load increments) showed a significant heart rate increase (> 10 bpm) at 1-5 minutes preceding the onset of ST-segment depression. Heart rate increases during exercise testing according to the gradual work load increments of the National Institutes of Health protocol were compared with the heart rate preceding ischemic events during daily life monitored by ambulatory electrocardiography and were found to be closely related. In contrast, heart rate increases that occurred during exercise testing using the standard Bruce protocol were higher and correlated less with those preceding ischemia in daily life. Heart rate and blood pressure increased significantly in most silent ischemic episodes, indicating that increased myocardial oxygen demand plays a significant role in the pathogenesis of myocardial ischemia during daily life.


Sex-related differences in stressful events precipitating transient global amnesia - A retrospective observational study.
Physically or emotionally charged events have consistently been reported as precipitating an episode of transient global amnesia (TGA). In conjunction with evidence of hippocampal involvement from neuroimaging, this has promoted the hypothesis that TGA is a stress-related disorder. In this retrospective observational study, medical records of 389 patients with TGA were analysed regarding documented precipitating events, which were classified according to previously suggested criteria. Moreover, comorbidities and results of magnetic resonance imaging were collected. In our cohort of TGA patients, 231 were female (59.4%). A precipitating factor was identified in 266 patients (68.4%). Of these, 136 patients (51.1%) reported physical triggers, the most common being physical exertion (64.0%). Another 122 patients (45.9%) presented with an emotional trigger, most frequently classified as an interpersonal conflict (42.7%). In 8 cases (2.1%), TGA was preceded by a medical procedure. Emotional triggers were more often experienced by women (37.2% vs 22.8%, p = 0.003), while physical stressors were more often present in men (30.7% vs 41.1%, p = 0.035). Women had a significantly higher number of hippocampal MRI lesions than men (mean 1.13 vs 0.92; p = 0.042). Our data suggest a female predominance in TGA occurrence and a sex-related difference in susceptibility to certain triggering events in TGA patients. In light of recent research on sex-specific differences in vulnerability to stress, these findings support the hypothesis that this might be a significant contributing factor in the pathogenesis of TGA.


Favorable outcome after repeat resection for colorectal liver metastases.
The rate of recurrence after liver resection for colorectal liver metastases (CLM) is high, and repeat resection (RR) is reserved with curative intent in selected patients. This study evaluated the benefit of RR for recurrence after liver resection for CLM. Data were collected on 287 consecutive patients who underwent primary curative hepatectomy between January 1999 and October 2008 for CLM at our institution. After median follow-up of 63 months, 211 patients (73 %) developed recurrence and RR was conducted in 102 (48 %) patients. Five-year overall survival (OS) was significantly higher in the RR group than in those patients not selected for RR (70 vs. 45 %, P = 0.002). On multivariate analyses, RR was identified as an independent factor for good prognosis. According to the first recurrence sites, 5-year OS after recurrence was significantly better in patients with liver or lung only recurrence (55, 51 %, respectively) than in locoregional/lymph node metastases and other/multiple sites recurrence (33, 9.0 %, respectively). In patients with liver- or lung-only recurrence, 5-year OS after recurrence was significantly higher in RR patients than in those without RR (liver; 67 and 0 %, lung; 88 and 24 %, respectively; P < 0.001). Given similar indication criteria as the primary CLM, nearly half of all recurrence cases after liver resection for CLM could be salvaged by RR. In patients with liver-or lung-only recurrence, RR warrants a favorable outcome.


Robotic duodenal (D3) resection with Roux-en-Y duodenojejunostomy reconstruction for large GIST tumor: Step by step with video.
Duodenal gastrointestinal stromal tumors (GISTs) are uncommon, making up only 3-5% of all GISTs. [1,2] Historically, the treatment of choice for duodenal GIST tumors was pancreaticoduodenectomy. [3]Currently, newer surgical intervention methods including local resection via laparotomy, endoscopic resection, and robotic resection are feasible. When doing a local resection, the defect can be closed either primarily or via a Roux-en-Y duodenojejunostomy. [3] Case presentation: Our patient is a 64-year- old female who presented initially with shortness of breath and was found to have a pulmonary embolism. She then developed upper GI bleeding from anticoagulation and was found to have an ulcerated GIST tumor in the anti-mesenteric border of the third portion of the duodenum (D3). Initial surgery was postponed due to high pulmonary artery pressure from the pulmonary embolism. The patient underwent argon beam coagulation of the bleeding mass to control the bleeding, followed by localized radiotherapy plus Gleevec. Unfortunately, the tumor grew in size during follow-up. The patient was then taken to the OR for a robot-assisted partial duodenal resection (D3) with Roux-en-Y duodenojejunostomy to reconstruct the large defect. She did well post operatively and her final pathology showed a GIST tumor, c-kit and DOG1 positive, 3.5 cm in size, with negative margins. Robotic duodenal resection is a new technique currently being used to resect duodenal GIST tumors. Our video demonstrates the feasibility of D3 partial resection with Roux-en-Y duodenojejunostomy. Duodenal GIST tumor robotic resection offers both decreased morbidity and adequate oncologic outcomes.


Impacts of heavy metals and medicinal crops on ecological systems, environmental pollution, cultivation, and production processes in China.
Heavy metals are widely distributed in the environment due to the natural processes and anthropogenic human activities. Their migration into no contaminated areas contributing towards pollution of the ecosystems e.g. soils, plants, water and air. It is recognized that heavy metals due to their toxicity, long persistence in nature can accumulate in the trophic chain and cause organism dysfunction. Although the popularity of herbal medicine is rapidly increasing all over the world heavy metal toxicity has a great impact and importance on herbal plants and consequently affects the quality of herbal raw materials, herbal extracts, the safety and marketability of drugs. Effective control of heavy metal content in herbal plants using in pharmaceutical and food industries has become indispensable. Therefore, this review describes various important factors such as ecological and environmental pollution, cultivation and harvest of herbal plants and manufacturing processes which effects on the quality of herbal plants and then on Chinese herbal medicines which influence human health. This review also proposes possible management strategies to recover environmental sustainability and medication safety. About 276 published studies (1988-2021) are reviewed in this paper.


Baicalin protects LPS-induced blood-brain barrier damage and activates Nrf2-mediated antioxidant stress pathway.
The integrity of the BBB is closely related to brain microvascular endothelial cells and TJs, and its dysfunction can lead to stroke, multiple sclerosis, extracranial injury and neurodegenerative diseases. Baicalin is one of the main bioactive extracts from Scutellaria Baicalensis Georgi, which has anti-inflammatory and anti-oxidation pharmacological functions. Preventive protection with baicalin for seven consecutive days can significantly improve the appearance of cell apoptosis and Fluorescein sodium infiltration in the brain tissue of BALB/C mice. In addition, baicalin can inhibit the production of pro-inflammatory cytokines induced by LPS in mice and bEnd.3 cells, including IL-1β and TNF-α. At the same time, LPS caused a decrease in tight junction proteins in the blood-brain barrier, but baicalin can alleviate the damage of the blood-brain barrier by up-regulating Claudin-5 and ZO-1 protein expression. In addition, the results showed that baicalin reduced the production of ROS and MDA in bEnd.3 cells and promoted the production of SOD, and up-regulated the expression of Nrf2, HO-1 and NQO1. The mechanism of this change was mediated by activating the Nrf2 signaling pathway. All in all, Baicalin protected LPS-induced blood-brain barrier damage and activateed Nrf2-mediated antioxidant stress pathway.


Mechanism of citrinin-induced dysfunction of mitochondria. V. Effect on the homeostasis of the reactive oxygen species.
The effects of citrinin in the maintenance of the homeostasis of the reactive oxygen species in rat liver cells were evaluated. Citrinin (CTN) modifies the antioxidant enzymatic defences of cells through the inhibition of GSSG-reductase and transhydrogenase. No effect was observed on GSH-peroxidase, catalase, glucose 6-phosphate and 6 phosphogluconate dehydrogenases, and superoxide dismutase. The mycotoxin increased the generation of reactive oxygen species, stimulating the production of the superoxide anion in the respiratory chain. The results suggest that oxidative stress is an important mechanism, side by side with other effects previously shown, in the establishment of the cytotoxicity and cellular death provoked by CTN in several tissues.


The accuracy of fitness watches for the measurement of heart rate and energy expenditure during moderate intensity exercise.
As new technology emerges and updated fitness watches are released to the market, it is important to examine their accuracy. The aim of the current study was to examine the accuracy of three commercially available activity trackers in assessing heart rate (HR) and energy expenditure (EE) during moderate intensity exercise. Twenty healthy participants (Age: 20.5±0.7 yrs., Ht: 173.4±10.8 cm, BM: 72.8±13.9 kg, BMI: 24.0±2.5 kg/m2) wore two fitness watches (FB: Fitbit VersaTM, San Francisco, CA, USA; and PI: Polar IgniteTM, Polar Electro Oy, Kempele, Finland) and a chest-worn HR monitor (PTP: Polar TeamPro SensorTM, Polar Electro) during a 12-minute exercise protocol at incremental speeds. An electrocardiogram (ECG) and indirect calorimetry were used as criterion measures for HR and EE. Mean absolute percentage error (MAPE) was calculated to determine measurement error. The MAPE values for HR were 11.6±8.7% for the FB, 11.0±10.0% for the PI, and 6.3±5.2% for the PTP. For EE, MAPE values were 9.6±7.2% for the FB, 16.7±19.6% for the PI and 13.8±13.0% for the PTP. Fitness watches relying on optical measures of HR underestimate HR compared to criterion measures during moderate intensity exercise. Despite providing a more accurate measure of HR, a chest-worn monitor does not provide a more accurate estimate of EE compared to fitness watches. The Fitbit provided the most accurate measure of EE when compared to the Polar Ignite watch and chest-worn device.


A hidden break in the 28.0S rRNA from Diphyllobothrium dendriticum.
Nondenatured and denatured total RNA from the tapeworm Diphyllobothrium dendriticum (Cestoda) was analysed by agarose gel electrophoresis. It was found that the large subunit ribosomal RNA (lrRNA) is 28.0S and the small subunit ribosomal RNA (srRNA) is 19.5S. Following denaturation the 28.0S rRNA was disrupted into a 19.5S subfragment and a 20.7S subfragment due to the presence of a centrally located hidden break. By hybridization of Northern blot membranes with oligonucleotide probes specific for the 5'- and 3'-ends of the lrRNA respectively, we have shown that the 19.5S subfragment is from the 5'-end (the alpha-subfragment) and the 20.7S subfragment from the 3'-end (the beta-subfragment) of the 28.0S rRNA of D. dendriticum.


What Do Neonatal Intensive Care Unit Policies Tell Us About Kangaroo Care implementation? A Realist Review.
Kangaroo care (KC) is recommended for infants during their stay in the neonatal intensive care unit (NICU) due to the benefits to infant growth, stabilized vital signs, and parental bonding; however, literature primarily explores the physiologic benefits, barriers, and facilitators to KC practice. Little is known about the context and mechanisms of KC implementation. This realist review is to explore what NICU policies tell us about practices to implement KC in the NICU. Policies were obtained via email, database, and search engines. Criteria were established to review each policy. Data were entered into a database then exported for frequency counts of identified characteristics. Fifty-one policies were reviewed, which revealed inconsistencies in the implementation of KC practices. Inconsistencies include variability in infant postmenstrual ages and weight criteria, infant medical equipment in place during participation, duration and frequency of KC, KC documentation, and ongoing monitoring requirements. KC implementation varies widely across NICUs, even with similar infant populations. Exclusion of some infants from receiving KC may decrease the potential beneficial outcomes known to result from KC. More research to understand KC best practice recommendations and implementation in the NICU is needed. Studies are needed to evaluate the duration and frequency of KC, as well as the benefits to infants and families to optimize KC in the NICU setting.


Resveratrol attenuates excessive ethanol exposure-induced β-cell senescence in rats: A critical role for the NAD+/SIRT1-p38MAPK/p16 pathway.
Resveratrol has been found to improve ethanol-induced diabetes. Although pancreatic β-cell senescence-induced β-cell mass loss plays a critical role in the progression of diabetes, the exact mechanism by which resveratrol improves ethanol-triggered β-cell senescence and its role in ethanol-induced diabetes remains unknown. Male Sprague-Dawley rats were fed either control or ethanol liquid diets containing 2.4 g/kg·bw ethanol with or without 100 mg/kg·bw resveratrol for 22 weeks. Resveratrol decreased the ethanol-induced augmentation in senescence-associated β-galactosidase (SA-β-gal)-positive area and attenuated reduction in β-cell mass, which were based on elevated levels of SIRT1 and proliferation marker Ki67 and reduced levels of senescence-associated markers (p-p38MAPK and p16INK4a). Similarly, resveratrol rescued the reduction in NAD+/NADH ratio and SIRT1 and inhibited the upregulation of p-p38MAPK and p16INK4a in ethanol-treated INS-1 cells. Furthermore, supplementation with NAD+ inducer nicotinamide mononucleotide, SIRT1 activator SRT1720 or p38MAPK inhibitor SB203580 effectively reversed ethanol-induced β-cell senescence, while supplementation with SIRT1 inhibitor Ex527 or NAD+ inhibitor FK866 abrogated resveratrol-mediated antisenescence effects in INS-1 cells. Together, our results indicate that resveratrol improves ethanol-triggered β-cell senescence and consequently recovers β-cell mass loss by inhibiting p38MAPK/p16 pathway through an NAD+/SIRT1 dependent pathway.


Lymphocyte subpopulations and development of immune functions in the newborn baby.
The distribution and dynamics of T, B and O cell populations were investigated in healthy term and preterm babies of 22-38 weeks gestational age, in relation to gestational age and birth weight, using the single slide method. Children 1-14 years old served as controls.


Myostatin auto-regulates its expression by feedback loop through Smad7 dependent mechanism.
Myostatin, a secreted growth factor, is a member of the TGF-beta superfamily and an inhibitor of myogenesis. Previously, we have shown that myostatin gene expression is regulated at the level of transcription and that myostatin is a downstream target gene of MyoD. Here we show that myostatin gene expression is auto-regulated by a negative feedback mechanism. Northern blot analysis indicated that there are relatively higher levels of myostatin mRNA in the biceps femoris muscle of cattle that express a non- functional myostatin allele (Belgian Blue) as compared to normal cattle. In contrast, addition of exogenous myostatin decreases endogenous myostatin mRNA. Consistent with this result, wild type myostatin protein is able to repress myostatin promoter activity via Activin type IIb receptor (ActRIIB) and ALK5 (P < 0.001). However, non-functional myostatin (Piedmontese) failed to repress the myostatin promoter suggesting that myostatin auto-regulates its promoter by negative feedback inhibition. Auto-regulation by myostatin appears to be signaled through Smad7, since the expression of the inhibitory Smad7 is induced by myostatin and the over-expression of Smad7 in turn inhibits the myostatin promoter activity (P < 0.001). In contrast down regulation of Smad7 by siRNA results in increased myostatin mRNA indicating that Smad7 is a negative regulator of myostatin gene expression. Consistent with these results, a decrease in Smad7 mRNA and concomitant increase in myostatin expression is seen in myotubes that express non functional myostatin. In addition, interference with myostatin signaling prevents the induction of Smad7 promoter activity by myostatin. Based on these results, we propose that myostatin auto-regulates its gene expression through a Smad7 dependent mechanism in myogenic cells.


Correction: Leptospiral LPS escapes mouse TLR4 internalization and TRIF-associated antimicrobial responses through O antigen and associated lipoproteins.
[This corrects the article DOI: 10.1371/journal.ppat.1008639.].


Proximate composition and spatio-temporal heterogeneity of phytochemicals in Agave sisalana Perrine (sisal) adapted in different agro-ecological zones of Punjab, Pakistan.
Exploring extractable phytochemicals from locally adapted sisal plant vegetation vary seasonally at different locations. This study elaborated proximate composition and phytochemical heterogeneity in sisal due to varying environmental conditions analyzed from five districts, i.e., Chakwal, Khushab, Rawalpindi, Faisalabad, and Layyah in Punjab, Pakistan. Extensive surveying and plant sampling across 2 years 2017-2018 and 2018-2019, during mid-spring, summer, autumn, and winter seasons were carried out for understanding the seasonal impact on sisal. The present study was designed in a randomized complete block design (RCBD) and analyzed considering seasonal, yearly, and locational impact. The spatial differences in phytochemicals concentration were strongly associated with environmental conditions prevailing in different seasons. Autumn season reflected saponins, tannins, and flavonoids in higher concentrations during 2018-2019 while steroids and terpenoids were higher during spring 2018-2019. Spatio-temporal variations in the proximate analysis were more apparent in different samples collected from different districts. Data recorded for the Khushab district and autumn season reflected the higher composition of a proximate analysis and phytochemical contents as compared to other seasons. Overall, the spatial differences in phytochemicals concentration were strongly associated with soils and environmental conditions prevailing in different seasons in selected districts.


Social-skills training to teach alcoholics to refuse drinks effectively.
Two alcoholics who received social-skills training in ways of refusing drinks reported some success in applying their new skills in actual social situations after they left the hospital.


Diagnosis-specific sickness absence and disability pension before and after multiple sclerosis diagnosis: An 8-year nationwide longitudinal cohort study with matched references.
Multiple sclerosis (MS) typically onsets when of working age and may reduce work capacity. Previous studies have examined the risk of sickness absence (SA) and disability pension (DP) among MS patients, however, limited knowledge is available on whether MS patients have an excess risk for SA/DP when compared with the general population in Sweden. Moreover, no information exists on the actual diagnoses for SA and DP among MS patients and whether the patterns of SA/DP diagnoses differs to those without MS. We aimed to explore diagnosis-specific SA and DP among working-aged MS patients both before and after MS diagnosis, in comparison to the levels and distributions of SA and DP diagnoses of a matched reference group and analyze the risk of diagnosis-specific DP. Longitudinal Swedish register data of the 2567 MS patients diagnosed with MS in 2009-2012 when aged 25-59 and 10,268 population-based matched references (matched on sex, age, educational level, type of living area, and country of birth) were analysed regarding annual diagnosis-specific SA and DP in the four years before and four years after MS diagnosis. Annual differences in the mean numbers of SA and/or DP net days were calculated with 95% confidence intervals (CI). Hazard ratios (HR) with 95% CI from Cox proportional hazard models were used to compare risks for new all-cause and diagnosis-specific DP after MS diagnosis among the MS patients and references. The mean SA/DP net days/year increased among MS patients over follow-up, due to both MS and other diagnoses. During follow-up, around 50% of MS patients had some SA/DP compared to 20% of references. The mean days of SA/DP among the MS patients compared to references increased from 10.3 more days (95% CI: 6.6-14.2) four years prior to MS diagnosis to 68.9 days (62.8-75.1) 4 years after MS diagnosis. Although most new DP among MS patients were due to MS, 15% were not. The adjusted HR for all-cause DP was 23.1 (18.1-29.5). MS patients also had higher risks of new DP due to all diagnoses except MS (HR 3.4; 2.4-4.8), musculoskeletal (HR 2.6; 1.1-6.0) and mental (HR 2.0; 1.1-3.6) diagnoses compared with references. MS patients had higher levels of SA/DP days/year than the references, already 4 years before the MS diagnosis, and increasingly so thereafter. The excess of SA/DP prior to MS diagnosis could be related to MS onset. However, the excess of SA/DP days were not all due to MS diagnoses, even after being diagnosed with MS. MS patients had a higher risk of having a new DP after being diagnosed with MS in total, but also for diagnoses other than MS.


Comparison of fascicle behaviors between superficial and deeper muscles of triceps brachii during isometric contractions.
We assessed fascicle behaviors of the upper extremities during isometric contractions at different joint angles in this study. Thirteen healthy men and women performed isometric elbow extension tasks at 50% and 75% of maximal voluntary contraction (MVC) at 60°, 90°, and 120° of elbow extension (full extension = 180°). Extended field-of-view B-mode ultrasonography was used to obtain sagittal plane panoramic images of the long head (TB-Long) and medial head (TB-Med) of the triceps brachii at rest and during contraction; fascicle length and pennation angle were measured. In the TB-Long, significant fascicle shortening from rest was found during 50% and 75%MVC at 60° and during 75%MVC at 90° of extension. There was no significant fascicle shortening in the TB-Med muscle under any conditions. There was no significant pennation angle change from rest in either muscle. The pennation angle of the TB-Long was significantly greater than that of the TB-Med under all conditions. These results suggest that fascicle shortening in the TB-Long muscle occurs in flexion; however, no change was found in the TB-Med. In the upper extremity muscle-tendon complex, the superficial and deeper muscles may have different force-transmission efficiency at flexed joint angles.


Oligovanadate binding to sarcoplasmic reticulum ATPase. Evidence for substrate analogue behavior.
Solutions of vanadate were controlled through concentration and pH adjustment to give specific compositions of mono- and oligovanadates. By monitoring the EPR spectrum of iodoacetamide spin-labeled ATPase, it is shown that decavanadate and the oligovanadate species present at neutral pH exhibit behavior typical of a substrate analogue. This is seen in terms of Ca2+ binding site affinity (microM), outward Ca2+ site orientation, and conformational effects on the enzyme normally associated with enzyme activation. In contrast, monovanadates exhibit behavior identical to that observed with Pi, with one exception: the vanadoenzyme is stable to Ca2+ in the concentration range of high affinity binding at the vanadate concentrations used here (200 microM). It is further demonstrated that Ca2+ binding in the 100 microM range directly induces enzyme devanadation of the monovanadate enzyme complex through Ca2+ binding to internal sites. Extensive array formation of dimeric ATPase units is found only with decavanadate in the absence of Ca2+, and then stoichiometric amounts are sufficient. Electron micrographs of dimeric arrays show evidence of increased penetration into the lipid bilayer, including freeze-fracture replicas which show evidence of corresponding "pits" in the inner leaflet of the bilayer. In turn, EPR spectra provide a means of following vanadate binding to the ATPase per se, as well as monitoring Ca2+-induced changes in the vanadoenzyme conformation, as only binding to specific sites on the enzyme affect the EPR spectrum.


Combined effects of bacterial-feeding nematodes and prometryne on the soil microbial activity.
Microcosm experiments were carried out to study the effects of bacterial-feeding nematodes and indigenous microbes and their interactions on the degradation of prometryne and soil microbial activity in contaminated soil. The results showed that soil indigenous microbes could degrade prometryne up to 59.6-67.9%; bacterial-feeding nematodes accelerated the degradation of prometryne in contaminated soil, and prometryne degradation was raised by 8.36-10.69%. Soil microbial biomass C (C(mic)), basal soil respiration (BSR), and respiratory quotient (qCO(2)) increased in the beginning of the experiment and decreased in the later stage of the experiment. Nematodes grew and reproduced quite fast, and did increase the growth of soil microbes and enhance soil microbial activity in prometryne contaminated soil during the incubation period.


Formulations combining CpG containing oliogonucleotides and poly I:C enhance the magnitude of immune responses and protection against pancreas disease in Atlantic salmon.
Both CpG oligodeoxynucleotides and double-stranded RNA (poly I:C) have documented effects as treatments against several viral diseases in fish. However, as stand-alone treatments their effects have been modest. We have tested here whether CpG and poly I:C, alone or in combination induce protection against Salmonid Alphavirus (SAV), the causative agent of pancreas disease in Atlantic salmon. Our results revealed a significant reduction of viraemia 2 weeks after ip injection of the combined treatment and 1 week after challenge with SAV subtype 3, followed by reduced SAV induced heart pathology 3 weeks later. The SAV titers in blood samples from the combination group were lower as compared to single treatments with either CpG or poly I:C. Surprisingly, reduced SAV levels could also be found in fish as long as 7 weeks after receiving the combination treatment. The expression of IFNγ and to a lesser extent IFNa and Mx was up-regulated in head kidney and spleen 5 days after the fish had been treated with CpG and poly I:C. Furthermore, the complement factor C4 was depleted in serum 8 weeks post treatment, suggesting complement activation leading to C4 consumption. We hypothesize that the CpG/poly I:C-induced protection against SAV3 is mediated by mechanisms involving type I and type II IFN induced antiviral activity and complement mediated protective responses.


Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine.
Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.


Failed labor induction in nulliparous women at term: the role of pelvic floor muscle strength.
The prolongation, protraction or complete cessation of labor is called failed labor. It is one of the leading indications for cesarean delivery. The goal of this study was to measure pelvic floor muscle strength and investigate its effect on labor in nulliparous pregnant women. A total of 88 patients were included in the study. The study was conducted in nulliparous pregnant women with a low Bishop score (≤ 7). A low-dose intravenous oxytocin protocol was used for labor induction in all patients. Evaluation of pelvic floor muscle (PFM) strength was performed using a vaginal pressure measurement device just before labor induction. The duration of labor stages and the rate of failed labor were considered the main outcomes. The study group consisted of patients whose labor failed and who subsequently underwent cesarean delivery. The control group consisted of patients who delivered vaginally. The pelvic floor muscle strength and main outcome measures of the two groups were compared. No differences were found in age, weight, height, body mass index (BMI), and neonatal birth weight between the study and control groups. The mean resting and maximum squeeze pressures in the study group were 29.6 ± 9.8 and 56.4 ± 12.1 cm H(2)O respectively, significantly higher than in the control group. The best predictor of failed labor was a maximum squeeze pressure value of 59 cm H(2)0 (51.6% sensitivity and 87.7% specificity). Pelvic floor muscle strength appears to play a role in predicting failed labor.


Pour des soins plus sécuritaires pour les patients : élaboration d'un programme de retour au travail en anesthésie fondé sur les besoins après un congé non relié au travail.
During anesthesiologists' careers, a leave of absence (LOA) is common. After prolonged leave, updating may be beneficial in reducing concerns about knowledge and skill decrements. Although formal return-to-work (RTW) courses and checklists assist UK practitioners, and Australia mandates a one-month RTW program for each year away from practice, no Canadian RTW programs exist. This project aimed to determine the needs of anesthesiologists for an RTW program. This quality improvement activity developed a needs analysis survey that was sent to all practicing anesthesiologists in Alberta. Respondents provided their opinions about the requirements necessary for an RTW program. Seventy-three of 350 eligible participants (21%) responded; one-third of respondents were female. Thirty-four respondents (47%) had taken at least one LOA, with a median [interquartile range] duration of 6 [3-12] months. Overall, respondents thought the duration of an LOA requiring formal RTW updating should be 12 [6-15] months, with a median updating period of 7 [5-20] days. Those who had previously taken an LOA thought updating should occur after a shorter absence (11 [6-12] vs 12 [6-24] months, P = 0.009) and be shorter (5 [3-12] vs 10 [5-26] days, P = 0.007). Comments indicated RTW updating should be flexible and individualized. Upgrades of computer systems and equipment plus specific skills retraining were identified. Leave of absences are common among anesthesiologists. Appropriate departmental support before, during, and after a gap in clinical practice could be provided by an RTW program to help endorse knowledge, skills, and confidence. Results identified the needs of Albertan anesthesiologists and provided initial guidance in the design of a user-centred RTW program.


Immunotherapy using BCG during remission induction and as the sole form of maintenance in acute myeloid leukaemia.
Thirty-two adults with acute myeloid leukaemia (AML) were randomized to receive, from the time of diagnosis, either chemotherapy alone (C group) or chemotherapy plus Bacille Calmette-Guérin vaccine (BCG) (C+I group). After remission induction and consolidation, chemotherapy was stopped in both groups but BCG was continued in the C+I group. The overall survival of the C+I group was significantly increased (P less than 0.05). There was no significant increase in the duration of first remission in the C+I group (0.05 less than P less than 0.1) nor in the time from first relapse to death (0.05 less than P less than 0.1). There was no significant difference in the incidence of first or second remissions, and the time taken to enter remission did not differ significantly between the two groups. Comparison with the results of other trials suggests that the use of maintenance chemotherapy in addition to immunotherapy produces longer remissions. Five patients in the C group developed leukaemic central-nervous-system (CSN) involvement, in comparison with none in the C+I group. CNS relapse did not produce a significant decrease in remission length (P greater than 0.1) but reduction in survival after CNS relapse was highly significant (P = 0.001). These results suggest that administration of BCG from an early stage in the treatment of AML may protect the CNS against leukaemic infiltration and therefore serve as a simple, innocuous form of CNS prophylaxis.


Shared-intermediates in the biosynthesis of thio-cofactors: Mechanism and functions of cysteine desulfurases and sulfur acceptors.
Cysteine desulfurases utilize a PLP-dependent mechanism to catalyze the first step of sulfur mobilization in the biosynthesis of sulfur-containing cofactors. Sulfur activation and integration into thiocofactors involve complex mechanisms and intricate biosynthetic schemes. Cysteine desulfurases catalyze sulfur-transfer reactions from l-cysteine to sulfur acceptor molecules participating in the biosynthesis of thio-cofactors, including Fe-S clusters, thionucleosides, thiamin, biotin, and molybdenum cofactor. The proposed mechanism of cysteine desulfurases involves the PLP-dependent cleavage of the C-S bond from l-cysteine via the formation of a persulfide enzyme intermediate, which is considered the hallmark step in sulfur mobilization. The subsequent sulfur transfer reaction varies with the class of cysteine desulfurase and sulfur acceptor. IscS serves as a mecca for sulfur incorporation into a network of intertwined pathways for the biosynthesis of thio-cofactors. The involvement of a single enzyme interacting with multiple acceptors, the recruitment of shared-intermediates partaking roles in multiple pathways, and the participation of Fe-S enzymes denote the interconnectivity of pathways involving sulfur trafficking. In Bacillus subtilis, the occurrence of multiple cysteine desulfurases partnering with dedicated sulfur acceptors partially deconvolutes the routes of sulfur trafficking and assigns specific roles for these enzymes. Understanding the roles of promiscuous vs. dedicated cysteine desulfurases and their partnership with shared-intermediates in the biosynthesis of thio-cofactors will help to map sulfur transfer events across interconnected pathways and to provide insight into the hierarchy of sulfur incorporation into biomolecules. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.


Development and validation of a magnetic resonance imaging-based nomogram for predicting invasive forms of placental accreta spectrum disorders.
The aim of the study was to develop and validate a magnetic resonance imaging (MRI)-based nomogram for predicting invasive forms of placental accreta spectrum (PAS) disorders (placenta increta and percreta) with "uncertain ultrasound diagnosis." This was a retrospective cohort study of a primary cohort of 118 patients and a validation cohort of 65 patients with "uncertain ultrasound diagnosis," who were further evaluated by MRI. MRI signs associated with PAS disorders were analyzed between invasive and noninvasive groups by both univariate and logistic regression to construct the nomogram. The accuracy and discriminative ability of the nomogram were measured by concordance index (C-index) and calibration curve internally and externally. The history of previous cesarean deliveries (odds ratio [OR], 3.27; 95% confidence interval [CI], 1.16-9.27), loss of double-line sign (OR, 9.49; 95% CI, 3.06-29.48), abnormal uterine bulging (OR, 4.05; 95% CI, 1.53-10.69), and disorganized abnormal placenta vascularity (OR, 3.38; 95% CI, 1.09-10.50) were imputed for the nomogram. The C-index of the nomogram was 0.85 for internal validation and 0.84 for external validation. Calibration curve showed good agreement with predicted risk and actual observation for both primary and validation cohort. MRI can be a useful adjunct for clinical staging of patients with "uncertain ultrasound diagnosis."


Vanadium complexes with polypyridyl ligands: Speciation, structure and potential medicinal activity.
This review focuses on the interaction between the essential element‑vanadium with 1,10-phenanthroline and polypyridyl ligands. It starts with a summary of the prior work on speciation studies for the binary systems vanadium-phenanthroline alongside several hydrolytic studies of the metal ion. It also includes a complete overview on the different X-ray structures known to date with discussions on the potential cytotoxic activity of several vanadium-polypyridyl complexes.


Icariin attenuates cardiac remodelling through down-regulating myocardial apoptosis and matrix metalloproteinase activity in rats with congestive heart failure.
In this study, the anti-heart failure effect of icariin, a natural flavonol glycoside, and the underlying mechanisms were investigated. Heart failure was induced by isoproterenol in male Sprague-Dawley rats. Matrix metalloproteinase activity was determined by gelatin zymography assay. The mRNA expression was determined by real-time PCR. The protein expression was determined by Western bolt. Mitochondria structure was examined by transmission electron microscopy. Isoproterenol administration resulted in a severe heart failure, as shown by the increased levels of left ventricular weight index, heart rate, left ventricular end diastolic pressure, maximal rate of left ventricular pressure decline (dp/dt(min) ), decreased levels of left ventricular systolic pressure and maximal rate of left ventricular pressure rise (dp/dt(max) ). Against these, icariin dose-dependently reversed the changes of these cardiac morphometric and haemodynamic parameters. In addition, icariin significantly inhibited serum levels of tumour necrosis factor-α, noradrenaline, angiotensin II and brain natriuretic peptide in rats with congestive hear failure and improved the histological changes, including cardiocyte hypertrophy, cardiocyte degeneration, inflammatory infiltration and cardiac desmoplasia. Furthermore, the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9, which regulate collagen production, were also blocked by icariin. Moreover, myocardial apoptosis was remarkably attenuated by icariin through regulating Bcl-2/Bax axle. Icariin ameliorates left ventricular dysfunction and cardiac remodelling through down-regulating matrix metalloproteinase-2 and 9 activity and myocardial apoptosis in rats with congestive heart failure.


Siblings FORWARD: Development of a New Program to Engage Siblings of Autistic Adults in Future Planning.
The adult service system does not adequately meet the needs of autistic adults, prompting families to continue their supportive roles. Siblings frequently assume these roles when parents are no longer able to do so, often without preparation or planning. We received feedback on the proposed Siblings FORWARD (Focusing on Relationships, Well-being, and Responsibility aheaD) program concept, which would involve 6-7 individualized sessions over ~ 3 months and would facilitate siblings' proactive future planning involvement with their autistic family member. Siblings FORWARD would bolster siblings' skills, knowledge, and self-efficacy to engage in future planning with their family members. We report on perceived need for a sibling program and feedback on the proposed program goals, content, and design. Adult siblings (n = 13), autistic adults (n = 6), and service providers (n = 17) participated in individual interviews or focus groups. Data were systematically coded and analyzed using directed content analysis. Siblings, autistic adults, and service providers expressed high enthusiasm for the Siblings FORWARD concept. Participants indicated that the combination of skill-building and education would promote continued, collaborative future planning that persists after the formal program ends. They had positive impressions of the program concept, goals, content, and design, including the telehealth delivery model. Siblings and autistic adults reported wanting to participate in Siblings FORWARD. This uniform, strong enthusiasm for the Siblings FORWARD concept warrants moving forward to examine preliminary acceptability and feasibility. Ultimately, greater sibling involvement in family future planning may improve autistic adults' functioning through improved continuity of care and support across adulthood.


Association of interleukin-8 with inflammatory and innate immune components in bronchoalveolar lavage of children with chronic respiratory diseases.
The host inflammatory response and innate immunity play a complex role in respiratory diseases. We evaluated the levels of inflammatory mediators and antibacterial proteins in children who required bronchoscopy and bronchoalveolar lavage fluid (BALF) for clinical indications such as chronic tracheostomy (n=15) and chronic suppurative lung disease (n=8). Our results suggested the presence of interleukin-1beta (IL-1beta) and IL-8 as major inflammatory mediators in BALF samples. The level of the antibacterial protein sIgA was higher than lactoferrin and lysozyme. BALF IL-8 levels significantly correlated with the presence of IL-1beta, IL-6, IL-10, IL-16, sIgA and lysozyme. BALF IL-8 levels did not correlate with the levels of immunomodulatory and anti-inflammatory clara cell 10 kDa protein (CC10) or lactoferrin. This study suggests that patients with high levels of BALF IL-8 could potentially have high levels of IL-6, IL-10, IL-16, lysozyme and sIgA. Evaluating the inflammatory mediators (IL-8) in relation to other BALF protein components provides insight into understanding the role of inflammatory mediators in the regulation of host defense and the response to lung inflammation and injury.


Neuropeptidergic organization of the suprachiasmatic nucleus in the blind mole rat (Spalax ehrenbergi).
The blind mole rat, Spalax, is a subterranean rodent with atrophied, subcutaneous eyes. Whereas most of the visual system is highly degenerated, the retino-hypothalamic pathway in this species has remained intact. Although Spalax is considered to be visually blind, circadian locomotor rhythms are entrained by the light/dark cycle. In the present study we used anterograde tracing techniques to demonstrate retinal afferents to the suprachiasmatic nucleus (SCN) and immunohistochemistry to examine the distribution of neuropeptides that are known to be involved in the regulation or expression of circadian rhythmicity. Based on the localization of retinal afferents and neuropeptides, the SCN can be divided into two subdivisions. The ventral region, which receives retinal afferents, also contains vasoactive intestinal polypeptide (VIP)-containing neurons, and fibers that are immunopositive to neuropeptide Y (NPY) and serotonin (5-HT). The dorsal region contains vasopressinergic neurons, but this latter cell population is extremely sparse compared to that described in other rodents. The dorsal region is also characterized by numerous VIP-immunoreactive fibers. The presence of NPY and 5-HT fibers suggests that the SCN receives afferent projections from the intergeniculate leaflet and from the raphe nuclei, respectively. These neuroanatomical results, together with previous studies of behavior, visual tract tracing, and immediate early gene expression, confirm that an endogenous clock and the capacity for light entrainment of circadian rhythms are conserved in the blind mole rat.


Neonatal Dermatology: The Normal, the Common, and the Serious.
The objective of this review is to help practitioners of neonatal and pediatric medicine become more familiar with diagnosing and managing neonatal skin conditions. This article will discuss normal neonatal skin care and benign and common rashes, as well as some of the serious dermatologic conditions that require specialists for further evaluation and/or treatment.


Safety and Efficacy Studies of Vertebroplasty with Dual Injections for the Treatment of Osteoporotic Vertebral Compression Fractures: Preliminary Report.
To evaluate the clinical safety and efficacies of percutaneous vertebroplasty (PVP), percutaneous vertebroplasty with dual injections (PVPDI), and percutaneous kyphoplasty (PKP) for the treatment of osteoporotic vertebral compression fractures (OVCFs), a retrospective study of 90 patients with OVCFs who had been treated by PVP (n = 30), PVPDI (n = 30), and PKP (n = 30) was conducted in this work. The clinical efficacies of these three treatments were evaluated by comparing their PMMA cement leakages, cement patterns, height restoration percentages, wedge angles, visual analogue scales, and Oswestry disability index (ODI) at the pre- and postoperative time points. Ten percent, 6.7%, and 0% of patients had PMMA leakage in PVP, PVPDI, and PKP groups, respectively. Three (solid, trabecular, and mixed patterns), two (trabecular and mixed patterns), and two (solid and mixed patterns) types of cement patterns were observed in PVP, PVPDI, and PKP groups, respectively. PVP and PVPDI treatments had similar and less height restoration ability than PKP treatment. All the PVP, PVPDI, and PKP treatments had significant and similar ability in pain relief and functional recovery ability for the treatment of OVCFs. Microfractures after the surgery occurred after PVP and PKP treatments. These results indicate minimally invasive techniques were effective methods for the treatment of OVCFs. Moreover, these initial outcomes suggest PVPDI treatment has great value and is worth promoting vigorously in orthopedics clinics.


Manual therapy and ear pain: a report of four cases.
To report and discuss four cases of ear pain which were treated successfully with manual therapy. Report of four cases. Four patients with ear pain were referred for chiropractic consult. They were all treated with a combination of manual therapy and exercise with resolution of their ear symptoms. The mechanism of idiopathic ear pain that may be amenable to manual therapy is not fully known. Further research is needed to investigate the etiology of this disorder and to determine whether manual therapy and exercise are viable options in some patients with idiopathic ear pain. In the meantime, it may be advantageous for otolaryngologists to seek input from physicians skilled in assessment and treatment of the musculoskeletal system in cases ear pain for which an otolarygologic etiology cannot be found.


A randomized placebo controlled double blind crossover study of pioglitazone on left ventricular diastolic function in type 2 diabetes.
Thiazolidinediones (TZDs), such as pioglitazone, are widely used to treat type 2 diabetes but there is evidence that their use is associated with an increased risk of heart failure. We compared the effect of pioglitazone vs. placebo on left ventricular (LV) diastolic and systolic function in people with type 2 diabetes. 24 male or female patients with type 2 diabetes were randomized to pioglitazone (45 mg/day) or placebo in addition to current therapy for 12 weeks using a prospective double blind crossover protocol following a run-in period >1 week and a 2 week washout period at crossover. Tissue Doppler early peak velocity (e'), a measure of LV diastolic function, was the primary outcome. Pioglitazone significantly increased e' by 0.7(0.1, 1.3) cm/s (mean (95% confidence interval); p=0.02) compared with placebo. Pioglitazone also increased E/A and mitral deceleration index, ejection fraction, stroke volume and weight, whereas fasting glucose, HbA1c, total peripheral resistance and LV meridional end systolic stress were decreased. Treatment with pioglitazone for 12 weeks improves left ventricular diastolic and systolic function in people with type 2 diabetes.


Intractable digital neuroma pain; the ultimate solution?
A case is presented in which, following the failure of several surgical and non-surgical procedures to control the increasingly severe pain in an amputation thumb stump, a toe transfer was carried out, successfully relieving the symptoms without transfer of the pain to the donor site. The patient has remained pain-free for 3 years.


Detachment of the right coronary artery resulting in subsequent aneurysm of the ascending aorta and pulmonary artery fistula 7 years after a bentall procedure.
This report describes detachment of the right coronary artery, an extremely infrequent late complication of Bentall's procedure combined with Cabrol's maneuver for aneurysm of the ascending aorta. This resulted in subsequent formation of the progressive aneurysm of the ascending aorta and fistula entering the main pulmonary artery. Successful surgical treatment depended on meticulous echocardiographic investigation and careful physical examination.


Cysteine scanning mutagenesis and disulfide mapping analysis of arrangement of GspC and GspD protomers within the type 2 secretion system.
The type II secretion system (T2SS) secretes enzymes and toxins across the outer membrane of Gram-negative bacteria. The precise assembly of T2SS, which consists of at least 12 core-components called Gsp, remains unclear. The outer membrane secretin, GspD, forms the channels, through which folded proteins are secreted, and interacts with the inner membrane component, GspC. The periplasmic regions of GspC and GspD consist of several structural domains, HR(GspC) and PDZ(GspC), and N0(GspD) to N3(GspD), respectively, and recent structural and functional studies have proposed several interaction sites between these domains. We used cysteine mutagenesis and disulfide bonding analysis to investigate the organization of GspC and GspD protomers and to map their interaction sites within the secretion machinery of the plant pathogen Dickeya dadantii. At least three distinct GspC-GspD interactions were detected, and they involve two sites in HR(GspC), two in N0(GspD), and one in N2(GspD). None of these interactions occurs through static interfaces because the same sites are also involved in self-interactions with equivalent neighboring domains. Disulfide self-bonding of critical interaction sites halts secretion, indicating the transient nature of these interactions. The secretion substrate diminishes certain interactions and provokes an important rearrangement of the HR(GspC) structure. The T2SS components OutE/L/M affect various interaction sites differently, reinforcing some but diminishing the others, suggesting a possible switching mechanism of these interactions during secretion. Disulfide mapping shows that the organization of GspD and GspC subunits within the T2SS could be compatible with a hexamer of dimers arrangement rather than an organization with 12-fold rotational symmetry.