Succinylation and inactivation of 3-hydroxy-3-methylglutaryl-CoA synthase by succinyl-CoA and its possible relevance to the control of ketogenesis.
Succinyl-CoA (3-carboxypropionyl-CoA) inactivates ox liver mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (EC 22.214.171.124) in a time-dependent manner, which is partially prevented by the presence of substrates of the enzyme. The inactivation is due to the enzyme catalysing its own succinylation. Complete inactivation corresponds to about 0.5 mol of succinyl group bound/mol of enzyme dimer. The succinyl-enzyme linkage appears to be a thioester bond and is probably formed with the active-site cysteine residue that is normally acetylated by acetyl-CoA. Succinyl-CoA binds to 3-hydroxy-3-methylglutaryl-CoA synthase with a binding constant of 340 microM and succinylation occurs with a rate constant of 0.57 min-1. Succinyl-enzyme breaks down with a half-life of about 40 min (k = 0.017 min-1) at 30 degrees C and pH 7 and is destabilized by the presence of acetyl-CoA and succinyl-CoA. A control mechanism is postulated in which flux through the 3-hydroxy-3-methylglutaryl-CoA cycle of ketogenesis is regulated according to the extent of succinylation of 3-hydroxy-3-methylglutaryl-CoA synthase.


Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial.
Despite treatment advances, major depressive disorder (MDD) is still a significant cause of morbidity and mortality. Current therapies frequently fall short of providing full remission. In addition, physical symptoms are commonly seen in MDD patients, increasing overall morbidity and health care utilization. Duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, was evaluated for efficacy and tolerability/safety in the treatment of MDD and associated physical symptoms. In this multicenter, double-blind, parallel-group study, adult patients with DSM-IV MDD were randomly assigned to receive placebo (N = 122) or duloxetine (60 mg/day, N = 123) for 9 weeks. The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score. Painful physical symptoms were assessed using visual analog scales, and global illness and quality of life were evaluated using the Clinical Global Impressions-Severity scale, the Patient Global Impressions-Improvement scale, and the Quality of Life in Depression Scale. Safety and tolerability were determined by monitoring discontinuation rates, adverse events, vital signs, and laboratory results. Duloxetine was significantly superior to placebo (p < .001) in reducing HAM-D-17 total scores, starting at week 2. The estimated probability of remission for duloxetine-treated patients (44%) was almost 3 times that of placebo patients (16%). Duloxetine significantly reduced painful physical symptoms in comparison with placebo. Discontinuation due to adverse events for duloxetine-treated patients (13.8%) compared favorably with the rates reported for SSRIs in other studies. Nausea, dry mouth, and somnolence were the most common adverse events; no significant incidence of hypertension was seen. Duloxetine, 60 mg/day, is a well-tolerated and effective treatment for MDD that reduces painful physical symptoms. These findings suggest that duloxetine may be a first-line treatment for patients with MDD and associated painful physical symptoms.


Arsenic and birth outcomes in a predominately lower income Hispanic pregnancy cohort in Los Angeles.
Prenatal arsenic exposure has been associated with reduced fetal growth and increased risk for preterm birth, but most studies have been conducted in highly exposed populations outside the U.S. or in non-Hispanic populations in the rural U.S. The objectives of the current study were to: 1) examine the impact of early pregnancy exposure to arsenic on birth weight and gestational age at birth in a predominately lower income Hispanic pregnancy cohort in urban Los Angeles and 2) compare multiple biomarkers of arsenic exposure (blood, urine, and hair) assessed in early pregnancy (mean ± SD gestational age at biospecimen collection: 14 ± 4 weeks). Total arsenic (blood, hair) was measured by ICP-MS and speciated arsenic (urine) was measured by HPLC coupled to ICP-MS. Associations between log2-transformed arsenic measures and birth outcomes were evaluated using multivariable linear regression. A doubling in hair arsenic was associated with a 72.2 g (95% CI: -144.3, -0.1, P = 0.05) lower birth weight, after adjusting for potential confounders and gestational age at birth. A similar but non-significant trend was observed for blood arsenic, but not urine arsenic. The inverse association between hair arsenic and birth weight was more pronounced among infants whose mothers gained greater amounts of weight during pregnancy (Pinteraction = 0.02). The association between urinary monomethyl arsenic and GA at birth differed by pre-pregnancy BMI (Pinteraction<0.01). This study provides evidence that even at relatively low levels of exposure, arsenic exposure (measured in hair samples collected in early pregnancy) may adversely affect fetal growth in this understudied population, particularly in combination with greater gestational weight gain. Future studies with larger sample sizes are needed to confirm these findings and to further investigate some of the inconsistencies observed for the different arsenic biomarkers evaluated.


Correlations between gene expression and mercury levels in blood of boys with and without autism.
Gene expression in blood was correlated with mercury levels in blood of 2- to 5-year-old boys with autism (AU) compared to age-matched typically developing (TD) control boys. This was done to address the possibility that the two groups might metabolize toxicants, such as mercury, differently. RNA was isolated from blood and gene expression assessed on whole genome Affymetrix Human U133 expression microarrays. Mercury levels were measured using an inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA) was performed and partial correlations between gene expression and mercury levels were calculated, after correcting for age and batch effects. To reduce false positives, only genes shared by the ANCOVA models were analyzed. Of the 26 genes that correlated with mercury levels in both AU and TD boys, 11 were significantly different between the groups (P(Diagnosis*Mercury) ≤ 0.05). The expression of a large number of genes (n = 316) correlated with mercury levels in TD but not in AU boys (P ≤ 0.05), the most represented biological functions being cell death and cell morphology. Expression of 189 genes correlated with mercury levels in AU but not in TD boys (P ≤ 0.05), the most represented biological functions being cell morphology, amino acid metabolism, and antigen presentation. These data and those in our companion study on correlation of gene expression and lead levels show that AU and TD children display different correlations between transcript levels and low levels of mercury and lead. These findings might suggest different genetic transcriptional programs associated with mercury in AU compared to TD children.


Real-world effectiveness of rotavirus vaccines, 2006-19: a literature review and meta-analysis.
Since licensure in 2006, rotavirus vaccines have been introduced in more than 100 countries. The efficacy of rotavirus vaccines is variable in settings with different child mortality levels. We did an updated review of the published literature to assess the real-world effectiveness of rotavirus vaccines in a range of settings. In this literature review and meta-analysis, we included observational, post-licensure studies of rotavirus vaccines, published from Jan 1, 2006, to Dec 31, 2019, in English, with laboratory-confirmed rotavirus as the endpoint. In addition to product-specific results for Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) or RotaTeq (Merck, West Point, PA, USA), we included Rotarix and RotaTeq mixed series, and non-product-specific vaccine effectiveness estimates from countries where Rotarix and RotaTeq are both available. Studies of other infant rotavirus vaccines were excluded because little or no post-licensure data were available. We fitted random-effects regression models to estimate vaccine effectiveness among children younger than 12 months and aged 12-23 months. On the basis of 2017 UNICEF mortality estimates for children younger than 5 years, countries were stratified as having low (lowest quartile), medium (second quartile), or high mortality (third and fourth quartiles). We identified and screened 1703 articles, of which 60 studies from 32 countries were included. 31 studies were from countries with low child mortality, eight were from medium-mortality countries, and 21 were from high-mortality countries. Rotarix vaccine effectiveness against laboratory-confirmed rotavirus among children younger than 12 months old was 86% (95% CI 81-90) in low-mortality countries, 77% (66-85) in medium-mortality countries, and 63% (54-70) in high-mortality countries. Rotarix vaccine effectiveness among children aged 12-23 months was 86% (81-90) in low-mortality countries, 54% (23-73) in medium-mortality countries, and 58% (38-72) in high-mortality countries. RotaTeq vaccine effectiveness among children younger than 12 months was 86% (76-92) in low-mortality countries and 66% (51-76) in high-mortality countries. RotaTeq vaccine effectiveness among children aged 12-23 months was 84% (79-89) in low-mortality countries. There was no substantial heterogeneity (I2 range: 0-36%). Median vaccine effectiveness in low-mortality countries was similar for Rotarix (83%; IQR 78-91), RotaTeq (85%; 81-92), mixed series (86%; 70-91), and non-product-specific (89%; 75-91) vaccination. Rotavirus vaccines were effective in preventing rotavirus diarrhoea, with higher performance in countries with lower child mortality. None.


What can parasitoid wasps teach us about decision-making in insects?
Millions of years of co-evolution have driven parasites to display very complex and exquisite strategies to manipulate the behaviour of their hosts. However, although parasite-induced behavioural manipulation is a widespread phenomenon, the underlying neuronal mechanisms are only now beginning to be deciphered. Here, we review recent advancements in the study of the mechanisms by which parasitoid wasps use chemical warfare to manipulate the behaviour of their insect hosts. We focus on a particular case study in which a parasitoid wasp (the jewel wasp Ampulex compressa) performs a delicate brain surgery on its prey (the American cockroach Periplaneta americana) to take away its motivation to initiate locomotion. Following a brief background account of parasitoid wasps that manipulate host behaviour, we survey specific aspects of the unique effects of the A. compressa venom on the regulation of spontaneous and evoked behaviour in the cockroach host.


Malignant solitary fibrous kidney tumor with peritoneal disease: a case report.
We report a case of a large malignant solitary fibrous kidney tumor. A complete surgical resection of the primary tumor and peritoneal disease was carried out, and a histological examination confirmed the initial diagnosis. We describe and discuss the characteristics of this rare kidney neoplasm.


[Isolation of the thermolabile E. coli enterotoxin and the study of its biological properties].
Enterotoxin was obtained from the culture of E. coli O15 by salt precipitation and gel-chromatography. The toxic activity of the preparation increased during the isolation and purification: 60-fold according to the results of the method of ligated rabbit intestinal segment and 66-100-fold according to the skin test. The "plateau" and the second fraction obtained as a result of gel-chromatography were inactive according to the results of the method of ligated intestinal segment, but possessed PF-activity in the skin test. Two suppositions are put forward: 1) possibly the factor of vascular permeability and the diarrheal factor were two different substances ((molecules), or 2) the skin test was more sensitive for determination of the toxicity than the method of the ligated segment of rabbit intestine.


Sympathetic neural recruitment strategies following acute intermittent hypoxia in humans.
We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence (P < 0.01), AP incidence (P = 0.01), and AP content per burst (P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once (P < 0.01) and more than once (P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH (P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst (P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.


Prolactin protects against diabetes induced by multiple low doses of streptozotocin in mice.
In earlier studies it has been shown that prolactin (PRL) is a stimulating factor for the immune system, and it has been suggested that PRL might antagonize immunosuppressive effects of glucocorticoids. PRL has been reported to affect the cytokine secretion pattern, by elevating cytokine gene expression in macrophages, after the onset of sepsis. It also promotes the antibody response in mice where it increases the production of interferon-gamma (IFN-gamma) and inhibits interleukin-1 (IL-1) production. Due to these properties, PRL might influence the development of autoimmune type 1 diabetes. The aim of the present study was to examine the effects of two drugs; PRL and bromocriptine (BC) in vivo on the development of hyperglycemia and pancreatic insulitis in mice treated with multiple doses of streptozotocin (STZ) (40 mg/kg body weight, i.p.). The dopaminergic agonist BC is known to inhibit PRL secretion. In another set of experiments, the direct effects of PRL on the function of pancreatic islets exposed to STZ in vitro were studied. Mice treated with STZ became gradually hyperglycemic, and concomitant treatment with PRL (4 mg/kg body weight) for 21 days significantly reduced the elevation in blood glucose levels from day 10 onwards (P<0.05). Morphologic examinations of the pancreas on day 21 of mice receiving STZ injections revealed a marked insulitis, but only moderate insulitis in the STZ treated animals given PRL. BC administration (10 mg/kg body weight) in combination with STZ did not significantly affect the elevation in blood glucose levels or the insulitis. PRL or BC administration alone did not change the serum glucose concentration. This study indicates that PRL may affect hyperglycemia in the early phase of autoimmune diabetes. We suggest that it might be due to counteraction of autoimmune immunologic mechanisms and/or enhancement of beta-cell regeneration.


MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines.
The ideal vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. Recombinant adenoviral vectors induce potent Ab and CD8+ T cell responses against transgenic Ags within weeks of administration, and they are among the most potent and versatile Ag delivery vehicles available. However, the impact of chronic infections like HIV and hepatitis C virus underscore the need for further improvements. In this study, we show that the protective immune response to an adenovirus-encoded vaccine Ag can be accelerated, enhanced, broadened, and prolonged by tethering of the rAg to the MHC class II-associated invariant chain (Ii). Thus, adenovirus-vectored vaccines expressing lymphocytic choriomeningitis virus (LCMV)-derived glycoprotein linked to Ii increased the CD4+ and CD8+ T cell stimulatory capacity in vitro and in vivo. Furthermore, mice vaccinated with a single dose of adenovirus-expressing LCMV-derived glycoprotein linked to Ii were protected against lethal virus-induced choriomeningitis, lethal challenge with strains mutated in immunodominant T cell epitopes, and systemic infection with a highly invasive strain. In therapeutic tumor vaccination, the vaccine was as efficient as live LCMV. In comparison, animals vaccinated with a conventional adenovirus vaccine expressing unmodified glycoprotein were protected against systemic infection, but only temporarily against lethal choriomeningitis, and this vaccine was less efficient in tumor therapy.


Maximal negative dP/dt as an indicator of end of systole.
The maximal negative peak of the first derivative of left ventricular pressure was examined as an index of the end of ventricular ejection by comparing it with the end of aortic flow. Under varying heart rate and afterload situations in anesthetized dogs, a correlation coefficient of 0.982 was obtained with a mean error of less than 0.4 ms. This may be a useful end point for determining systolic time where only ventricular pressure is available.


Optical coherence tomography angiography analysis of the retina in patients recovered from COVID-19: a case-control study.
To quantify the density of the macular microvasculature and the area of the foveal avascular zone (FAZ) in patients recovered from coronavirus disease 2019 (COVID-19) using optical coherence tomography angiography (OCTA) analysis. In a comparative cross-sectional, observational study, patients recovered from COVID-19 were included in this study. All included subjects exhibited a reverse transcription-polymerase chain reaction-confirmed diagnosis of COVID-19. Spectral domain macular OCTA was performed at least 2 weeks after recovery from systemic COVID-19. Vessel density (VD) of the superficial (SCP) and deep retinal capillary plexus (DCP) and the area of the FAZ were measured in COVID-19 recovered patients versus age-matched normal controls. Thirty-one recovered COVID-19 patients and 23 healthy normal controls were studied. Mean quality scan index was 7.64 ± 0.66 in the COVID cases and 8.34 ± 0.71 in the normal controls (p = 0.001). Mean SCP VD and DCP VD of the COVID cohort were significantly lower than the SCP VD and DCP VD of the control group in the foveal and parafoveal regions. FAZ area was greater in the COVID cohort, but this difference was not statistically significant. In addition, in the COVID cohort, VD of the SCP was lower in patients with a history of COVID-19 hospitalization versus those without such a history, but this did not reach statistical significance. Patients recovered from COVID-19 displayed alterations in the retinal microvasculature, including a significantly lower VD in the SCP and DCP. Patients with coronavirus infection may be at risk of retinal vascular complications.


Effects of age on mechanical properties of dorsiflexor and plantarflexor muscles.
Redundancy in the human muscular system makes it challenging to assess age-related changes in muscle mechanical properties in vivo, as ethical considerations prohibit direct muscle force measurement. We overcame this by using a hybrid approach that combined magnetic resonance and ultrasound imaging, dynamometer measurements, muscle modeling, and numerical optimization to obtain subject-specific estimates of the mechanical properties of tibialis anterior, gastrocnemius, and soleus muscles from young and older adults. We hypothesized that older subjects would have lower maximal isometric forces, slower contractile and stiffer elastic characteristics, and that subject-specific muscle properties would give more accurate joint torque predictions compared to generic properties. Unknown muscle model parameters were obtained by minimizing the difference between simulated and actual subject torque-time histories under both isometric and isovelocity conditions. The resulting subject-specific models showed age- and gender-related differences, with older adults displaying reduced maximal isometric forces, slower force-velocity and altered force-length properties and stiffer elasticity. Tibialis anterior was least affected by aging. Subject-specific models gave good predictions of experimental concentric torque-time histories (10-14% error), but were less accurate for eccentric conditions. With generic muscle properties prediction errors were about twice as large. For maximum predictive power, musculoskeletal models should be tailored to individual subjects.


The relationship between obstructive sleep apnea and insomnia: a population-based cross-sectional polysomnographic study.
The relationship between insomnia and objectively measured obstructive sleep apnea (OSA) severity has not previously been investigated in both genders in the general population. The main aim of this population-based polysomnography (PSG) study was to evaluate the cross-sectional association between severity of OSA and DSM-V insomnia and insomnia severity. A random sample of 1200 participants in the third Nord-Trøndelag Health Study (HUNT3) was invited and 213 (18%) aged between 21 and 82 years underwent an ambulatory PSG, a semi-structured interview, and a sleep-specific questionnaire. A proxy DSM-V insomnia diagnosis as well as an Insomnia Symptom Score (ISS, range 0-12) were calculated from three insomnia questions and one daytime sleepiness symptom question. Participants were then divided into three groups according to their apnea-hypopnea index (AHI): AHI < 5 (without OSA), AHI 5-14.9 (mild OSA), and AHI ≥ 15 (moderate-to-severe OSA). Associations between prevalence of insomnia and OSA groups were assessed by logistic regression models adjusted for age and gender. Associations between ISS and OSA were assessed in a general linear model with contrasts. A total of 25.2% (29.1% women, 12.5% men) had insomnia. Insomnia prevalence did not differ between subjects with and without OSA, but ISS differed significantly between OSA categories (ANCOVA df 2, F = 6.73, p = 0.001). ISS was lower in the moderate-to-severe OSA-group compared to those without OSA (mean difference -2.68; 95% [CI -4.33, -1.04]; p = 0.002). In subjects with moderate-to-severe OSA, ISS correlated negatively with age (Pearson r = -0.66, p = 0.015). In this population-based PSG study, no overall statistical association between OSA and insomnia prevalence was found. However, participants with moderate-to-severe OSA reported less insomnia symptoms than subjects without OSA, in particular in older individuals.


Calcitonin messenger RNA encodes multiple polypeptides in a single precursor.
Recombinant DNA techniques were used to analyze the structure of the messenger RNA encoding a precursor of calcitonin, a small calcium-regulating hormone of 32 amino acids. Analyses of the nucleotide sequences of cloned complementary DNA's comprising the entire coding sequence of the messenger RNA revealed that calcitonin is flanked at both its amino and carboxyl termini by peptide extensions linked to the hormone by short sequences of basic amino acids. The location of glycine next to the carboxyl terminal prolinamide of calcitonin is consistent with indications that glycine is required for the enzymatic amidation of proline to the prolinamide. During cellular biosynthesis, calcitonin arises from a large precursor protein by cleavages at both amino and carboxyl terminal residues of the hormone. These findings raise questions concerning the regulation of these cleavages and the potential biological functions of the precursor extensions derived from these cleavages.


Comparison of fundamental, second harmonic, and superharmonic imaging: a simulation study.
In medical ultrasound, fundamental imaging (FI) uses the reflected echoes from the same spectral band as that of the emitted pulse. The transmission frequency determines the trade-off between penetration depth and spatial resolution. Tissue harmonic imaging (THI) employs the second harmonic of the emitted frequency band to construct images. Recently, superharmonic imaging (SHI) has been introduced, which uses the third to the fifth (super) harmonics. The harmonic level is determined by two competing phenomena: nonlinear propagation and frequency dependent attenuation. Thus, the transmission frequency yielding the optimal trade-off between the spatial resolution and the penetration depth differs for THI and SHI. This paper quantitatively compares the concepts of fundamental, second harmonic, and superharmonic echocardiography at their optimal transmission frequencies. Forward propagation is modeled using a 3D-KZK implementation and the iterative nonlinear contrast source (INCS) method. Backpropagation is assumed to be linear. Results show that the fundamental lateral beamwidth is the narrowest at focus, while the superharmonic one is narrower outside the focus. The lateral superharmonic roll-off exceeds the fundamental and second harmonic roll-off. Also, the axial resolution of SHI exceeds that of FI and THI. The far-field pulse-echo superharmonic pressure is lower than that of the fundamental and second harmonic. SHI appears suited for echocardiography and is expected to improve its image quality at the cost of a slight reduction in depth-of-field.


A golden anniversary: highlights of the 50th annual meeting of the American Society of Clinical Oncology.
The 50th Annual Meeting of the American Society of Clinical Oncology showed a shift in the culture of cancer research, moving towards multidisciplinary, integrated, and patient-centric work. Hormone-sensitive cancers were particularly highlighted at this meeting, and impressive strides were made in the previously underserved areas of the lung and thyroid cancer. Interestingly, immunotherapy was one of the strongest themes to emerge.


A new concept for an integrated Healthcare Access Model.
The increase of population mobility has been promoting a crescent dispersion of patient clinical records in Healthcare Information Systems. In this scenario, it is mandatory that new services will be available for healthcare practitioners, namely web-based interfaces with strong control access mechanisms providing effective authentication and identification of persons, and the establishment of new access models to the disperse patient information. This paper proposes and describes a Healthcare Access Model that integrates a new set of functionalities coping with patient mobility and implements an innovative concept of a virtual unique Electronic Patient Record--EPR.


Effect of shaking speed on the secretion of enterotoxin B by Staphylococcus aureus.
The concentration of enterotoxin B secreted by four strains of Staphylococcus aureus was dependent upon the shaking speed. For the conditions established, each strain demonstrated an optimal shaking speed, and speeds in excess of the optimum resulted in decreased secretion of toxin. At the optimal shaking speed, maximum secretion occurred at 37 C. At 45 C, both growth and toxin secretion were absent. By using agar containing antienterotoxin B sera, studies with strain S-6 at optimal and suboptimal shaking speeds demonstrated that individual cells vary in their toxin-synthesizing ability and that the relative numbers of high and low producers change during the growth cycle. Although most of the toxin was secreted during the first 12 hr of growth, a portion was secreted during the subsequent 6 hr, even though growth as measured by colony-forming units per milliliter decreased and Klett units increased.


Tet1 facilitates hypoxia tolerance by stabilizing the HIF-α proteins independent of its methylcytosine dioxygenase activity.
Because of the requirement of oxygen (O2) to produce energy, aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen in both acute status and chronic status. To date, how organisms tolerate acute hypoxia and the underlying mechanisms remain largely unknown. Here, we identify that Tet1, one member of the ten-eleven translocation (TET) family of methylcytosine dioxygenases, is required for hypoxia tolerance in zebrafish and mice. Tet1-null zebrafish and mice are more sensitive to hypoxic conditions compared with their wild-type siblings. We demonstrate that Tet1 stabilizes hypoxia-inducible factor α (HIF-α) and enhances HIF-α transcription activity independent of its enzymatic activity. In addition, we show that Tet1 modulates HIF-2α and HIF-1α through different mechanisms. Tet1 competes with prolyl hydroxylase protein 2 (PHD2) to bind to HIF-2α, resulting in a reduction of HIF-2α hydroxylation by PHD2. For HIF-1α, however, Tet1 has no effect on HIF-1α hydroxylation, but rather it appears to stabilize the C-terminus of HIF-1α by affecting lysine site modification. Furthermore, we found that Tet1 enhances rather than prevents poly-ubiquitination on HIF-α. Our results reveal a previously unrecognized function of Tet1 independent of its methylcytosine dioxygenase activity in hypoxia signaling.


Female fertility: is it safe to "freeze?".
To evaluate the safety and risk of cryopreservation in female fertility preservation. The data analyzed in this review were the English articles from 1980 to 2013 from journal databases, primarily PubMed and Google scholar. The criteria used in the literature search show as following: (1) human; embryo; cryopreservation/freezing/vitrification, (2) human; oocyte/immature oocyte; cryopreservation/ freezing/vitrification, (3) human; ovarian tissue transplantation; cryopreservation/freezing/vitrification, (4) human; aneuploidy/DNA damage/epigenetic; cryopreservation/freezing/vitrification, and (5) human; fertility preservation; maternal age. The risk ratios based on survival rate, maturation rate, fertilization rate, cleavage rate, implantation rate, pregnancy rate, and clinical risk rate were acquired from relevant meta-analysis studies. These studies included randomized controlled trials or studies with one of the primary outcome measures covering cryopreservation of human mature oocytes, embryos, and ovarian tissues within the last 7 years (from 2006 to 2013, since the pregnancy rates of oocyte vitrification were significantly increased due to the improved techniques). The data involving immature oocyte cryopreservation obtained from individual studies was also reviewed by the authors. Vitrifications of mature oocytes and embryos obtained better clinical outcomes and did not increase the risks of DNA damage, spindle configuration, embryonic aneuploidy, and genomic imprinting as compared with fresh and slow-freezing procedures, respectively. Both embryo and oocyte vitrifications are safe applications in female fertility preservation.


Nonsteroidal adrenal feedback demarcates two types of pathways to CRF-ACTH release.
We have tested the relationship between corticosterone (B) and the number of adrenal glands on stimulated corticotropin (ACTH) levels in rats. Rats were supplied throughout the experiment with various doses of B in the drinking fluid beginning 15-20 h before adrenal surgery. Bilateral, unilateral, or sham adrenalectomy was followed on the 3rd day by the stimulus of ether vapor or ether and laparotomy with intestinal traction. Plasma ACTH levels 3 min after the stimuli were decreased by both the dose of B and adrenal number; the adrenal number of adrenals, although prestimulus ACTh and B levels were similar across groups. The decrease in ACTH after ether resulted from an interaction between the dose of B and the however there was no interaction between the inhibitors after laparotomy with intestinal traction. These results show that 1) in addition to B, some aspect of adrenal gland number or mass inhibits the ACTH response to stimuli; and 2) the adrenal number input serves as a marker to distinguish between stimuli to ACTH secretion that are inhibited by B at sites proximal and those that are inhibited by B at sites distal to this input.


Delayed treatment with alpha-phenyl-N-tert-butyl nitrone (PBN) attenuates secondary mitochondrial dysfunction after transient focal cerebral ischemia in the rat.
The present experiments were undertaken to explore the mechanisms of secondary brain damage in focal ischemia of long duration (2 h), followed by recirculation. Recirculation has previously been found to cause partial recovery and secondary deterioration of cellular bioenergetic state, the subsequent damage being ameliorated by a free radical spin trap, alpha-phenyl-N-tert-butyl nitrone (PBN), even when the drug was given 1 (or 3) h after the start of recirculation. Our objective was to assess whether the secondary deterioration of the cellular bioenergetic state is due to mitochondrial dysfunction and to study whether PBN acts by preventing secondary damage to mitochondria. Focal and perifocal ("penumbral") tissues were sampled after 2 h of ischemia and after 1, 2, and 4 h of recirculation; at the latter two times, vehicle- and PBN-injected animals were studied, PBN being given after 1 h of recirculation. Homogenates were prepared, and stimulated (+ADP), nonstimulated (-ADP), and uncoupled respiratory rates were measured polarographically. The results were similar in focus and penumbra, albeit more pronounced in the focus. Ischemia was associated with a decrease in ADP-stimulated and uncoupled respiration rates, with a marked fall in the respiratory control ratio, defined as ADP-stimulated divided by nonstimulated respiration. Recirculation (1 h) brought about partial recovery, but continued reflow (2 and 4 h) was associated with a secondary deterioration of respiratory functions. This deterioration was prevented by PBN, given 1 h after the start of recirculation. The results raise the question whether the secondary deterioration of the cellular bioenergetic state in focal ischemia-reperfusion is due to secondary mitochondrial dysfunction and whether the amelioration of the subsequent damage by PBN is partly or wholly due to the effect of the spin trap on the mitochondria.


Prednisolone inhibits PDGF-induced nuclear translocation of NF-kappaB in human pulmonary artery smooth muscle cells.
Pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH), is partially due to increased proliferation of pulmonary arterial smooth muscle cells (PASMC) in the media, resulting in vascular wall thickening. Platelet-derived growth factor (PDGF) is a potent mitogen that may be involved in the progression of PAH. Blockade of PDGF receptors has been demonstrated to have therapeutic potential for patients with severe pulmonary hypertension. Prednisolone is an immunosuppressant shown to have anti-inflammatory and antiproliferative effects on PASMC. This study was designed to investigate whether PDGF and prednisolone affect human PASMC proliferation by regulating the nuclear translocation of NF-kappaB (a transcription factor composed of 2 subunits, p50 and p65). Treatment of human PASMC with PDGF (10 ng/ml) significantly increased nuclear translocation of p50 and p65 subunits. Inhibition of NF-kappaB activation or nuclear translocation of p50/p65 significantly attenuated PDGF-induced PASMC proliferation (determined by [(3)H]thymidine incorporation). In the presence of prednisolone (200 microM), the PDGF-induced nuclear translocation of p50 and p65 subunits was markedly inhibited (P < 0.05 vs. the cells treated with PDGF alone). These results indicate that PDGF-induced nuclear translocation of NF-kappaB may play an important role in stimulating PASMC proliferation (and/or enhancing PASMC survival), whereas prednisolone may exert anti-inflammatory and antiproliferative effects on PASMC by inhibiting NF-kappaB nuclear translocation.


Fission yeast Cdk7 controls gene expression through both its CAK and C-terminal domain kinase activities.
Cyclin-dependent kinase (Cdk) activation and RNA polymerase II transcription are linked by the Cdk7 kinase, which phosphorylates Cdks as a trimeric Cdk-activating kinase (CAK) complex, and serine 5 within the polymerase II (Pol II) C-terminal domain (CTD) as transcription factor TFIIH-bound CAK. However, the physiological importance of integrating these processes is not understood. Besides the Cdk7 ortholog Mcs6, fission yeast possesses a second CAK, Csk1. The two enzymes have been proposed to act redundantly to activate Cdc2. Using an improved analogue-sensitive Mcs6-as kinase, we show that Csk1 is not a relevant CAK for Cdc2. Further analyses revealed that Csk1 lacks a 20-amino-acid sequence required for its budding yeast counterpart, Cak1, to bind Cdc2. Transcriptome profiling of the Mcs6-as mutant in the presence or absence of the budding yeast Cak1 kinase, in order to uncouple the CTD kinase and CAK activities of Mcs6, revealed an unanticipated role of the CAK branch in the transcriptional control of the cluster of genes implicated in ribosome biogenesis and cell growth. The analysis of a Cdc2 CAK site mutant confirmed these data. Our data show that the Cdk7 kinase modulates transcription through its well-described RNA Pol II CTD kinase activity and also through the Cdc2-activating kinase activity.


Increased RBP4 and Asprosin Are Novel Contributors in Inflammation Process of Periodontitis in Obese Rats.
There is a significant comorbidity between obesity and periodontitis, while adipokines are pivotal in the immunoinflammatory process, which may play a role in this special relationship. We aimed to assess the effect of adipokines as mediators in the progression of periodontitis in obese Sprague Dawley rats. Rats were divided into four groups: normal body weight with and without periodontitis and obesity with and without periodontitis. Experimental obesity and periodontitis were induced by a high-fat diet or ligaturing, and the effect was measured using metabolic and micro-computed tomography analysis and histological staining. Compared with the other three groups, the group of periodontitis with obesity (OP) had the heaviest alveolar bone absorption, the largest increase in osteoclasts, the utmost inflammatory cell infiltration and the highest expressions of pro-inflammatory cytokines and nuclear factor-kappa B ligand (RANKL); meanwhile, its expression of the osteogenesis-related gene was the lowest among the four groups. The expressions of leptin, visfatin, resistin, retinol-binding protein 4 (RBP4) and asprosin were upregulated, while adiponectin was decreased significantly in OP. The strong positive associations between the periodontal or circulating levels of RBP4 (or asprosin) and the degree of alveolar resorption in experimental periodontitis and obese rats were revealed. The upregulated expression of inflammation biomarkers, the corresponding degradation in connective tissue and the generation of osteoclasts in periodontitis were activated and exacerbated in obesity. The elevated level of RBP4/asprosin may contribute to a more severe periodontal inflammatory state in obese rats.


11beta-Hydroxysteroid dehydrogenase type 1 regulates insulin and glucagon secretion in pancreatic islets.
Exposure to excess glucocorticoid is associated with pancreatic beta cell damage and decreased glucose-stimulated insulin secretion (GSIS). Inactive glucocorticoids (cortisone, 11-dehydrocorticosterone) are converted to active cortisol and corticosterone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which requires NADPH as cofactor, which is generated by hexose-6-phosphate dehydrogenase (H6PDH). We investigated the localisation and activity of 11beta-HSD1 within pancreatic islets, and determined its functional role in the regulation of insulin and glucagon secretion. mRNA expression of 11beta-HSD1 (also known as HSD11B1), glucocorticoid receptor and H6PDH (also known as H6PD) in human pancreas and murine islets was examined by real-time PCR. 11beta-HSD1 protein levels were examined by immunohistochemistry and immunofluorescence. 11beta-HSD1 activity was assessed in intact tissue and isolated islets of wild-type (WT) and both 11beta-Hsd1- and H6pdh-null mice. Glucagon secretion and insulin secretion were analysed by RIA and ELISA respectively in isolated murine islets incubated with dexamethasone. 11beta-HSD1 co-localised with glucagon in the periphery of murine and human islets, but not with insulin or somatostatin. Dexamethasone, 11-dehydrocorticosterone and corticosterone induced a dose-dependent decrease in GSIS and glucagon secretion following low glucose stimulation. Reduction of 11beta-HSD1 activity with specific inhibitors or in experiments carried out in H6pdh-null mice reversed the effects of 11-dehydrocorticosterone, but had no effect following treatment with corticosterone. Local regeneration of glucocorticoid via 11beta-HSD1 within alpha cells regulates glucagon secretion and in addition may act in a paracrine manner to limit insulin secretion from beta cells.


Biophysical characterization of O-glycosylated CD99 recognition by paired Ig-like type 2 receptors.
Paired Ig-like type 2 receptors (PILRs) are one of the paired receptor families, which consist of two functionally opposite members, inhibitory (PILRalpha) and activating (PILRbeta) receptors. PILRs are widely expressed in immune cells and recognize the sialylated O-glycosylated ligand CD99, which is expressed on activated T cells, to regulate immune responses. To date, their biophysical properties have not yet been examined. Here we report the affinity, kinetic, and thermodynamic analyses of PILR-CD99 interactions using surface plasmon resonance (SPR) together with site-directed mutagenesis. The SPR analysis clearly demonstrated that inhibitory PILRalpha can bind to CD99 with low affinity (K(d) approximately 2.2 microm), but activating PILRbeta binds with approximately 40 times lower affinity (K(d) approximately 85 microm). In addition to our previous mutagenesis study (Wang, J., Shiratori, I., Saito, T., Lanier, L. L., and Arase, H. (2008) J. Immunol. 180, 1686-1693), the SPR analysis showed that PILRalpha can bind to each Ala mutant of the two CD99 O-glycosylated sites (Thr-45 and Thr-50) with similar binding affinity to wild-type CD99. This indicated that both residues act as independent and equivalent PILRalpha binding sites, consistent with the highly flexible structure of CD99. On the other hand, it is further confirmed that PILRbeta can bind the T50A mutant, but not the T45A mutant, indicating a recognition difference between PILRalpha and PILRbeta. Kinetic studies demonstrated that the PILR-CD99 interactions show fast dissociation rates, typical of cell-cell recognition receptors. Thermodynamic analyses revealed that the PILRalpha-CD99 interaction is enthalpically driven with a large entropy loss (-TDeltaS = 8.9 kcal.mol(-1)), suggesting the reduction of flexibility upon complex formation. This is in contrast to the entropically driven binding of selectins to sugar-modified ligands involved in leukocyte rolling and infiltration, which may reflect their functional differences.


An efficient iterative algorithm for computation of scattering from dielectric objects.
We have developed an efficient iterative algorithm for electromagnetic scattering of arbitrary but relatively smooth dielectric objects. The algorithm iteratively adapts the equivalent surface currents until the electromagnetic fields inside and outside the dielectric objects match the boundary conditions. Theoretical convergence is analyzed for two examples that solve scattering of plane waves incident upon air/dielectric slabs of semi-infinite and finite thicknesses. We applied the iterative algorithm for simulation of sinusoidally-perturbed dielectric slab on one side and the method converged for such unsmooth surfaces. We next simulated the shift in radiation pattern of a 6-inch dielectric lens for different offsets of the feed antenna on the focal plane. The result is compared to that of the Geometrical Optics (GO).


Home pharmacological therapy in an ultra-75 years old population in Troina (inner Sicily).
In a group of 365 subjects, 75 years old and ultra, living in Troina (Sicily), a study on prevalence of dementia has been carried out. In the questionnaire, used to collect information about subjects' health, one of the questions concerned the assumption of drugs. The interviewer transcribed the name of the drugs and then coded the related chemical-pharmacological classification, according to the 14 principal groups of the guide of the National Health Service. Up to 9 drugs, on a daily basis, were registered. The total amount of prescriptions was 889, equal to 2.4 per person, with a clear prevalence of the females. 26.1% of the sample did not take any drug. The mode of assumptions was 3 a day. The cardiovascular system is at the top of prescriptions, with 39% of the total, followed by the gastroenteric apparatus and metabolism (17.9%), the nervous system (16.7%), the haemopoietic system (8.4%), the musculo-skeletal system (6.2%), the respiratory apparatus (5.7%), and so on the others. For each principal group of drugs, those more represented are identified, obtaining other information about the practitioners' choices. Among the principal subgroups of cardiovascular system, it is worth mentioning anti-hypertensives, diuretics and antianginal, each of them with their own subgroups. In the gastroenteric apparatus and metabolism group, the latter comprises the drugs for the treatment of diabetes: oral hypoglicaemics and insulin. These drugs allow to identify 34 cases of diabetes: 29 NIDD and 5 IDD. Analogous evaluations for drugs of other groups and comparisons with a few data available in literature are carried out. Surveying the drugs used in a population is useful: (i) to evaluate the health state; (ii) to identify the dominant disease; (iii) to draw comparisons with other populations; (iiii) to follow the evolution of pharmacotherapy.


[Recent advances in antireflux surgery for gastroesophageal reflux diseases--from open surgery to laparoscopic surgery].
Gastroesophageal reflux diseases (GERD) are common in the western countries and have been well studied about diagnosis and treatment. Nissen technique (a complete wrap) and Toupet technique (a partial wrap) are usually transabdominal fundoplication. Hill technique is a transabdominal posterior gastropexy. Allison technique is a transthoracic reduction method of the herniated cardia back into the abdomen, but is not frequently employed today. Belsey Mark VI technique is a transthroacic anterior plication. Collis gastroplasty is an esophageal lenghening technique and is used with standard repairs (Nissen, Belsey, and Hill). Good result rate of above mentioned surgery are about 90%. Recently, laparoscopic Nissen/Toupet technique are a standard antireflex surgery because of minimal invasiveness and more than 90% of good results. After introducing laparoscopic surgery the indication of antireflex surgery for GERD can be changed because of quality of life of patients and medicoeconomical reasons.


Ankrd2 is a modulator of NF-κB-mediated inflammatory responses during muscle differentiation.
Adaptive responses of skeletal muscle regulate the nuclear shuttling of the sarcomeric protein Ankrd2 that can transduce different stimuli into specific adaptations by interacting with both structural and regulatory proteins. In a genome-wide expression study on Ankrd2-knockout or -overexpressing primary proliferating or differentiating myoblasts, we found an inverse correlation between Ankrd2 levels and the expression of proinflammatory genes and identified Ankrd2 as a potent repressor of inflammatory responses through direct interaction with the NF-κB repressor subunit p50. In particular, we identified Gsk3β as a novel direct target of the p50/Ankrd2 repressosome dimer and found that the recruitment of p50 by Ankrd2 is dependent on Akt2-mediated phosphorylation of Ankrd2 upon oxidative stress during myogenic differentiation. Surprisingly, the absence of Ankrd2 in slow muscle negatively affected the expression of cytokines and key calcineurin-dependent genes associated with the slow-twitch muscle program. Thus, our findings support a model in which alterations in Ankrd2 protein and phosphorylation levels modulate the balance between physiological and pathological inflammatory responses in muscle.


Facial Danger Zones: Techniques to Maximize Safety during Soft-Tissue Filler Injections.
Given the short recovery and immediate results, facial fillers have become a popular alternative to surgical rejuvenation of the face. Reported complications arising from facial filler injections include erythema, tissue loss, blindness, stroke, and even death. In this article, the authors describe their anatomically based techniques to minimize risk and maximize safety when injecting in the facial danger zones, including the glabella/brow, temporal region, perioral region, nasolabial fold, nose, and infraorbital region. Complications generally arise secondary to vasculature injury and/or cannulation with filler. The authors have outlined their preferred injection techniques in the facial danger zones with respect to the pertinent anatomy in an attempt to minimize risk and maximize results. Most importantly, the practitioner should be able to recognize complications and address them immediately.


Effect of Transcranial Direct Current Stimulation Combined With Virtual Reality Training on Balance in Children With Cerebral Palsy: A Randomized, Controlled, Double-Blind, Clinical Trial.
The authors' aim was to investigate the effects of continuous transcranial direct current stimulation (tDCS) combined with virtual reality training on static and functional balance in children with cerebral palsy (CP). Twenty children with CP (6 girls and 14 boys; M age = 7 years 6 months ± 2 years) were randomly allocated to two groups. The experimental group received active tDCS and the control group received sham stimulation during the 10 sessions of virtual reality mobility training protocols. The children were evaluated on 3 occasions (preintervention, postintervention, and 1-month follow-up). Static balance was evaluated using a force plate under 4 conditions: feet on force plate with (a) eyes open and (b) with eyes closed, and feet on foam mat with (c) eyes open and (d) with eyes closed. Functional balance was evaluated using the Pediatric Balance Scale and the Timed Up and Go Test. The analyses demonstrated statistically significant postintervention and follow-up effects favoring the experimental group over the control group with regard to the Pediatric Balance Scale, Timed Up and Go Test, and area of oscillation of the center of pressure when standing on the force plate with eyes open. The present findings suggest that tDCS can potentiate the effects of virtual reality training on static and functional balance among children with CP.


Growth retardation and neonatal lethality in mice with a homozygous deletion in the C-terminal domain of RNA polymerase II.
The C-terminal domain (CTD) of the largest subunit of RNA polymerase II consists of tandem repeats of the consensus heptapeptide YSPTSPS. Deletion studies in tissue culture cells have indicated that the CTD plays an essential role in transcription, although the nature of this essential function remains unclear. About half of the CTD can be deleted without affecting the viability of cells in tissue culture. Paradoxically, the dispensable CTD repeats are precisely conserved among all mammals whose CTD sequences are known. To determine whether the mammalian CTD is important in transcription during mouse development, we developed a gene targeting approach to introduce deletions into the CTD coding region of mouse embryonic stem (ES) cells. To maintain a functional Rpo2-1 gene, the neo marker in the targeting vector was positioned outside of the Rpo2-1 transcribed region, 1.2 kb from the site of the CTD deletion. G418-resistant clones were screened for co-integration of the CTD deletion, and the resulting ES lines were used to create germline chimeric mice. Stable heterozygous lines were established and mated to produce animals homozygous for the CTD deletion. We show here that mice homozygous for a deletion of thirteen of the 52 heptapeptide repeats are smaller than wild-type littermates and have a high rate of neonatal lethality. Surviving adults, although small, appear morphologically normal and are fertile. This result suggests that the CTD plays a role in regulating growth during mammalian development. The gene targeting approach described here should be useful for making further deletions in the CTD and may be of general applicability where it is desirable to engineer specific mutations in the germline of mice.


Application of Computer Modeling in Systemic VAD Support of Failing Fontan Physiology.
Although the Fontan procedure has been enormously successful in palliation of single-ventricle patients, many seem to experience progressive failure of the Fontan circulation over time. Ventricular assist devices (VADs) have developed into stable platforms for long-term support of adult patients with heart failure. Given the success of axial flow devices, it was hypothesized that the technology could provide clinical benefit to failing Fontan patients. The aim of this study was to use a computer model to evaluate VAD support in failing Fontan physiology. A computer model of Fontan circulation with heart failure was developed and the HeartMate II (HM II) (Thoratec Corp) axial flow ventricular assist device was connected to this model in a systemic configuration to examine its impact. Cardiac catheterization data from 7 patients (8 catheterization studies) with failing Fontan physiology were applied to this model to evaluate the impact of using the HM II in this manner. When the HM II was used in a systemic configuration at 8000 rpm, there was a 35% decrease in the systemic venous pressure in the Fontan circuit and a 63% decrease in pulmonary capillary wedge pressure with a resultant 41% increase in CI. The model also predicted patient-specific parameters where the VAD may not benefit the patient, such as fixed elevated pulmonary vascular resistance, low systemic ventricular end-diastolic pressure, and high unresponsive systemic vascular resistance. These data suggest a potential benefit from application of axial flow VAD technology in the management of failing Fontan physiology. Clinical correlation will allow for refinement of this model as a predictive tool in discerning which patients may benefit from placement of a VAD and what issues must be addressed prior to implanting the device.


D-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia.
The hypothesis of N-methyl-D-aspartate receptor (NMDAR) dysfunction for cognitive impairment in schizophrenia constitutes the theoretical basis for the translational application of NMDAR co-agonist D-serine or its analogs. However, the cellular mechanism underlying the therapeutic effect of D-serine remains unclear. In this study, we utilize a mouse neurodevelopmental model for schizophrenia that mimics prenatal pathogenesis and exhibits hypoexcitability of parvalbumin-positive (PV) neurons, as well as PV-preferential NMDAR dysfunction. We find that D-serine restores excitation/inhibition balance by reconstituting both synaptic and intrinsic inhibitory control of cingulate pyramidal neurons through facilitating PV excitability and activating small-conductance Ca2+-activated K+ (SK) channels in pyramidal neurons, respectively. Either amplifying inhibitory drive via directly strengthening PV neuron activity or inhibiting pyramidal excitability via activating SK channels is sufficient to improve cognitive function in this model. These findings unveil a dual mechanism for how D-serine improves cognitive function in this model.


Targeting Duchenne muscular dystrophy by skipping DMD exon 45 with base editors.
Duchenne muscular dystrophy is an X-linked monogenic disease caused by mutations in the dystrophin gene (DMD) characterized by progressive muscle weakness, leading to loss of ambulation and decreased life expectancy. Since the current standard of care for Duchenne muscular dystrophy is to merely treat symptoms, there is a dire need for treatment modalities that can correct the underlying genetic mutations. While several gene replacement therapies are being explored in clinical trials, one emerging approach that can directly correct mutations in genomic DNA is base editing. We have recently developed CRISPR-SKIP, a base editing strategy to induce permanent exon skipping by introducing C > T or A > G mutations at splice acceptors in genomic DNA, which can be used therapeutically to recover dystrophin expression when a genomic deletion leads to an out-of-frame DMD transcript. We now demonstrate that CRISPR-SKIP can be adapted to correct some forms of Duchenne muscular dystrophy by disrupting the splice acceptor in human DMD exon 45 with high efficiency, which enables open reading frame recovery and restoration of dystrophin expression. We also demonstrate that AAV-delivered split-intein base editors edit the splice acceptor of DMD exon 45 in cultured human cells and in vivo, highlighting the therapeutic potential of this strategy.


Does body growth impair immune function in a large herbivore?
According to the principle of allocation, trade-offs are inevitable when resources allocated to one biological function are no longer available for other functions. Growth, and to a lesser extent, immunity are energetically costly functions that may compete with allocation to reproductive success and survival. However, whether high allocation to growth impairs immune system development during the growing period or immune system performance during adulthood is currently unknown in wild mammals. Using three roe deer (Capreolus capreolus) populations experiencing contrasting environmental conditions, we tested for potential costs of growth on immune phenotype over both the short-term (during growth), and the long-term (during adulthood) over the course of an individuals' life. We investigated potential costs on a set of 12 immune traits that reflect both innate and adaptive responses, and compared them between sexes and populations. Although fast growth tended to be associated with low levels of some humoral traits (globulins) during the growing period and some cellular immune traits (i.e. eosinophil and neutrophil counts) during adulthood, evidence for a trade-off between growth and other immune components was limited. Unexpectedly, no detectable growth costs on immunity were found in females from the population experiencing the least favourable environment. We discuss our findings in the light of the complex interplay between resource allocation strategies among reproduction, maintenance and immunity, in relation to local environmental conditions experienced by roe deer.


Older people--recipients but also providers of informal care: an analysis among community samples in the Republic of Ireland and Northern Ireland.
Data on both the provision and receipt of informal care among populations of older adults are limited. Patterns of both informal care provided and received by older adults in the Republic of Ireland (RoI) and Northern Ireland (NI) were evaluated. A cross-sectional community-based population survey was conducted. Randomly selected older people (aged 65+, n = 2033, mean age (standard deviation): 74.1 years (6.8), 43% men, 68% response rate) provided information on the provision and receipt of care, its location, and the person(s) who provided the care. Twelve per cent of the sample (251/2033) identified themselves as informal caregivers (8% RoI and 17% NI). Caregivers were more likely to be women, married, have less education and have less functional impairment. Forty-nine per cent (1033/2033, 49% RoI and 48% NI) reported receiving some form of care in the past year. Care recipients were more likely to be older, married, have more functional impairment, and poorer self-rated health. Receiving regular informal care (help at least once a week) from a non-resident relative was the most common form of help received [28% overall (578/2033); 27% RoI and 30% NI]. Five per cent (n = 102/2033) of the sample reported both providing and receiving informal care. Levels of informal care provided by community-dwelling older adults were notably higher than reported in single-item national census questions. The balance of formal and informal health and social care will become increasingly important as populations age. It is essential, therefore, to evaluate factors facilitating or impeding informal care delivery.


Targeted immunomodulation of the NF-kappaB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa.
We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-kappaB activation in the lungs that was primarily localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-kappaB activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-kappaB before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-kappaB activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-kappaB. The TNF-alpha concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-kappaB up-regulation were abrogated in TNF-alpha-deficient mice. In contrast, NF-kappaB inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-kappaB pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa.


Adenylosuccinate lyase deficiency in a Malaysian patient, with novel adenylosuccinate lyase gene mutations.
Most cases of adenylosuccinate lyase (ADSL OMIM 103050) deficiency reported to date are confined to the various European ethnic groups. We report on the first Malaysian case of ADSL deficiency, which appears also to be the first reported Asian case. The case was diagnosed among a cohort of 450 patients with clinical features of psychomotor retardation, global developmental delay, seizures, microcephaly and/or autistic behaviour. The patient presented with frequent convulsions and severe myoclonic jerk within the first few days of life and severe psychomotor retardation. The high performance liquid chromatography (HPLC) profile of the urine revealed the characteristic biochemical markers of succinyladenosine (S-Ado) and succinyl-aminoimidazole carboximide riboside (SAICAr). The urinary S-Ado/SAICAr ratio was found to be 1.02 (type I ADSL deficiency). The patient was compound heterozygous for two novel mutations, c.445C > G (p.R149G) and c.774_778insG (p.A260GfsX24).


Is teenage parenthood associated with early use of disability pension? Evidence from a longitudinal study.
Over the past decades the number of young people using disability pensions (DP) has gradually increased in Europe but the reasons for this change are poorly understood. We hypothesize that teenage parenthood could be associated with an increased risk of receiving early DP. The aim of this study was to examine the association between having a first child at age 13-19 and receiving DP at age 20-42 (here called early DP). A longitudinal cohort study was undertaken based on national register data obtained from 410,172 individuals born in Sweden in 1968, 1969, and 1970. Teenage mothers and fathers were followed until age 42 and compared to non-teenage parent counterparts to examine their early receipt of DP. Descriptive analysis, Kaplan-Meier curves, and Cox regression analyses were performed. The proportion of teenage parents was more than twice higher in the group that received early DP (16%) compared to the group that did not receive early DP (6%) during the study duration. A higher proportion of teenage mothers and fathers started to receive DP at 20-42 years old compared to non-teenage parents, and the difference between the two groups increased during the observation period. A strong association was observed between being a teenage parent and receiving early DP, significant both independently and after adjusting for the year of birth and the father's level of education. From the age of 30 to 42 years, teenage mothers used early DP more often than teenage fathers or non-teenage parents, and this difference also increased during the follow-up period. A strong association was found between teenage parenthood and the use of DP between 20 and 42 years of age. Teenage mothers used DP more than teenage fathers and non-teenage parents.


Pharmacological treatment of gastro-oesophageal reflux in children.
Gastro-oesophageal reflux (GOR) is characterised by the regurgitation of gastric contents into the oesophagus. GOR is a common presentation in infancy, both in primary and secondary care, affecting approximately 50% of infants under three months old. The natural history of GOR in infancy is generally of a self-limiting condition that improves with age, but older children and children with co-existing medical conditions can have more protracted symptoms. The distinction between gastro-oesophageal reflux disease (GORD) and GOR is debated. Current National Institute of Health and Care Excellence (NICE) guidelines define GORD as GOR causing symptoms severe enough to merit treatment. This is an update of a review first published in 2014. To assess the effects of pharmacological treatments for GOR in infants and children. For this update, we searched CENTRAL, MEDLINE, Embase, and Web of Science up to 17 September 2022. We also searched for ongoing trials in clinical trials registries, contacted experts in the field, and searched the reference lists of trials and reviews for any additional trials. We included randomised controlled trials (RCTs) that compared any currently-available pharmacological treatment for GOR in children with placebo or another medication. We excluded studies assessing dietary management of GORD and studies of thickened feeds. We included studies in infants and children up to 16 years old. We used standard methodology expected by Cochrane. We included 36 RCTs involving 2251 children and infants. We were able to extract summary data from 14 RCTs; the remaining trials had insufficient data for extraction. We were unable to pool results in a meta-analysis due to methodological differences in the included studies (including heterogeneous outcomes, study populations, and study design). We present the results in two groups by age: infants up to 12 months old, and children aged 12 months to 16 years old. Infants Omeprazole versus placebo: there is no clear effect on symptoms from omeprazole. One study (30 infants; very low-certainty evidence) showed cry/fuss time in infants aged three to 12 months had altered from 246 ± 105 minutes/day at baseline (mean +/- standard deviation (SD)) to 191 ± 120 minutes/day in the omeprazole group and from 287 ± 132 minutes/day to 201 ± 100 minutes/day in the placebo group (mean difference (MD) 10 minutes/day lower (95% confidence interval (CI) -89.1 to 69.1)). The reflux index changed in the omeprazole group from 9.9 ± 5.8% in 24 hours to 1.0 ± 1.3% and in the placebo group from 7.2 ± 6.0% to 5.3 ± 4.9% in 24 hours (MD 7% lower, 95% CI -4.7 to -9.3). Omeprazole versus ranitidine: one study (76 infants; very low-certainty evidence) showed omeprazole may or may not provide symptomatic benefit equivalent to ranitidine. Symptom scores in the omeprazole group changed from 51.9 ± 5.4 to 2.4 ± 1.2, and in the ranitidine group from 47 ± 5.6 to 2.5 ± 0.6 after two weeks: MD -4.97 (95% CI -7.33 to -2.61). Esomeprazole versus placebo: esomeprazole appeared to show no additional reduction in the number of GORD symptoms compared to placebo (1 study, 52 neonates; very low-certainty evidence): both the esomeprazole group (184.7 ± 78.5 to 156.7 ± 75.1) and placebo group (183.1 ± 77.5 to 158.3 ± 75.9) improved: MD -3.2 (95% CI -4.6 to -1.8). Children Proton pump inhibitors (PPIs) at different doses may provide little to no symptomatic and endoscopic benefit. Rabeprazole given at different doses (0.5 mg/kg and 1 mg/kg) may provide similar symptom improvement (127 children in total; very low-certainty evidence). In the lower-dose group (0.5 mg/kg), symptom scores improved in both a low-weight group of children (< 15 kg) (mean -10.6 ± SD 11.13) and a high-weight group of children (> 15 kg) (mean -13.6 ± 13.1). In the higher-dose groups (1 mg/kg), scores improved in the low-weight (-9 ± 11.2) and higher-weight groups (-8.3 ± 9.2). For the higher-weight group, symptom score mean difference between the two different dosing regimens was 2.3 (95% CI -2 to 6.6), and for the lower-weight group, symptom score MD was 4.6 (95% CI -2.9 to 12). Pantoprazole: pantoprazole may or may not improve symptom scores at 0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg pantoprazole in children aged one to five years by week eight, with no difference between 0.3 mg/kg and 1.2 mg/kg dosing (0.3 mg/kg mean -2.4 ± 1.7; 1.2 mg/kg -1.7 ± 1.2: MD 0.7 (95% CI -0.4 to 1.8)) (one study, 60 children; very low-certainty evidence). There were insufficient summary data to assess other medications. There is very low-certainty evidence about symptom improvements and changes in pH indices for infants. There are no summary data for endoscopic changes. Medications may or may not provide a benefit (based on very low-certainty evidence) for infants whose symptoms remain bothersome, despite nonmedical interventions or parental reassurance. If a medication is required, there is no clear evidence based on summary data for omeprazole, esomeprazole (in neonates), H₂antagonists, and alginates for symptom improvements (very low-certainty evidence). Further studies with longer follow-up are needed. In older children with GORD, in studies with summary data extracted, there is very low-certainty evidence that PPIs (rabeprazole and pantoprazole) may or may not improve GORD outcomes. No robust data exist for other medications. Further RCT evidence is required in all areas, including subgroups (preterm babies and children with neurodisabilities).


Different dietary protein sources in low protein diets regulate colonic microbiota and barrier function in a piglet model.
Protein fermentation has an adverse effect on colonic health; high-quality proteins and reducing the protein level (protein restriction) can effectively decrease the amount of proteins flowing into the colon for microbial protein fermentation. The study is aimed at determining the effects of different protein sources on colonic microbial composition and barrier function in nursery pigs with a low protein diet. A total of 264 weaned pigs were randomly divided into 4 dietary groups and each group had 6 pens with 11 pigs. Four low protein, amino acid (AA)-supplemented diets containing either 4% Palbio 50 RD (P50), Soyppt-50% (S50), concentrated degossypolized cottonseed protein (CDCP), or fish meal (FM) were prepared, and all the diets had similar digestible energy (DE), crude protein content (CP, about 18%), and equal amount of standardized ileal digestible (SID) lysine, methionine, tryptophan, and threonine. After 28 days of feeding trial, CDCP decreased the Desulfovibrio abundance but increased the Parabacteroides abundance. S50 elevated the Bacteroides and CF231 abundance. P50 and FM reduced the Clostridium and Ruminococcus abundance. CDCP upregulated the Occludin mRNA expression and tended to increase the amount of mixed neutral-acidic mucins in the colon. FM and CDCP declined the serum DAO and endotoxin contents. S50 and CDCP decreased the levels of serum IL-1α, and P50 lowered the serum IL-8 content. We concluded that plant protein (CDCP and S50) had advantages over animal protein (P50 and FM) in maintaining the colonic health via the regulation of colonic microbiota and barrier function.


Application of the RealAudio package to computerized medical lectures.
We created a multimedia system to computerize past lectures using RealAudio software. Physicians, medical researchers and students can browse the contents of lecture slides and handouts with synchronous audio using the Internet. The audience can easily review the most interesting parts of lectures and medical students can listen to complete medical lectures from remote sites with narration and slide depiction, whenever convenient. We have created three multimedia programs; the memorial lecture of a professor's retirement, a new method of hand washing for surgical procedures and a lecture on medical informatics. The cost of this system and the results of the evaluation by medical students are described. The ease of using this application makes it a potentially valuable tool for clinicians and researchers.


Model organism data evolving in support of translational medicine.
Model organism databases (MODs) have been collecting and integrating biomedical research data for 30 years and were designed to meet specific needs of each model organism research community. The contributions of model organism research to understanding biological systems would be hard to overstate. Modern molecular biology methods and cost reductions in nucleotide sequencing have opened avenues for direct application of model organism research to elucidating mechanisms of human diseases. Thus, the mandate for model organism research and databases has now grown to include facilitating use of these data in translational applications. Challenges in meeting this opportunity include the distribution of research data across many databases and websites, a lack of data format standards for some data types, and sustainability of scale and cost for genomic database resources like MODs. The issues of widely distributed data and application of data standards are some of the challenges addressed by FAIR (Findable, Accessible, Interoperable, and Re-usable) data principles. The Alliance of Genome Resources is now moving to address these challenges by bringing together expertly curated research data from fly, mouse, rat, worm, yeast, zebrafish, and the Gene Ontology consortium. Centralized multi-species data access, integration, and format standardization will lower the data utilization barrier in comparative genomics and translational applications and will provide a framework in which sustainable scale and cost can be addressed. This article presents a brief historical perspective on how the Alliance model organisms are complementary and how they have already contributed to understanding the etiology of human diseases. In addition, we discuss four challenges for using data from MODs in translational applications and how the Alliance is working to address them, in part by applying FAIR data principles. Ultimately, combined data from these animal models are more powerful than the sum of the parts.


Thigh muscle MRI in immune-mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity.
The aims of this study were to define the pattern of muscle involvement in patients with immune-mediated necrotising myopathy (IMNM) relative to those with other inflammatory myopathies and to compare patients with IMNM with different autoantibodies. All Johns Hopkins Myositis Longitudinal Cohort subjects with a thigh MRI (tMRI) who fulfilled criteria for IMNM, dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) or clinically amyopathic DM (CADM) were included in the study. Muscles were assessed for intramuscular and fascial oedema, atrophy and fatty replacement. Disease subgroups were compared using univariate and multivariate analyses. Patients with IMNM with anti-signal recognition particle (SRP) autoantibodies were compared with those with IMNM with anti-HMG-CoA reductase (HMGCR) autoantibodies. The study included 666 subjects (101 IMNM, 176 PM, 219 DM, 17 CADM and 153 IBM). Compared with DM or PM, IMNM was characterised by a higher proportion of thigh muscles with oedema, atrophy and fatty replacement (p<0.01). Patients with IMNM with anti-SRP had more atrophy (19%, p=0.003) and fatty replacement (18%, p=0.04) than those with anti-HMGCR. In IMNM, muscle abnormalities were especially common in the lateral rotator and gluteal groups. Fascial involvement was most widespread in DM. Fatty replacement of muscle tissue began early during the course of disease in IMNM and the other groups. An optimal combination of tMRI features had only a 55% positive predictive value for diagnosing IMNM. Compared with patients with DM or PM, IMNM is characterised by more widespread muscle involvement. Anti-SRP-positive patients have more severe muscle involvement than anti-HMGCR-positive patients.


Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis [seecomments].
Leptin inhibits food intake and increases energy expenditure. Although the kidney expresses abundant transcripts of the short form of the leptin receptor (Ob-Ra), a role for this hormone in renal function remains unclear. Because individuals with massive obesity who may exhibit increased leptin serum concentrations develop renal glomerulosclerosis, we studied whether leptin can influence renal growth and profibrogenic processes. The effects of recombinant leptin on proliferation and synthesis of transforming growth factor-beta1 (TGF-beta1) was investigated in cultured glomerular endothelial cells of the rat (GERs) and syngeneic mesangial cells. Furthermore, leptin receptor expression and potential signal transduction pathways were evaluated in GERs. In addition, leptin was also infused for different time periods (72 hr and 3 weeks) into naive rats. Recombinant mouse leptin induced proliferation of GERs, but not of syngeneic mesangial cells. Coincubation with angiotensin II and leptin exerts additive proliferative effects in GERs. An antileptin-receptor antibody totally abolished this proliferation but did not influence serum-induced proliferation. GER expressed high affinity receptors of the Ob-Ra type (Kd, 4 nM; Bmax, 9700 receptors/cell). Leptin also stimulated phosphorylation of STAT1alpha, and kinase inhibitors attenuated proliferation, suggesting a pivotal role of phosphorylation in this process. Incubation of GERs with leptin also induced mRNA expression of TGF-beta1 and enhanced secretion of this profibrogenic cytokine. Short-term leptin infusion (72 hr) into naive rats induced a significant proliferation, mainly restricted to glomerular endothelial cells, and enhanced glomerular TGF-beta1 mRNA levels. In rats continuously infused for three weeks with leptin, glomerular TGF-beta1 expression was still enhanced, and an additional increase in glomerular collagen type IV mRNA and protein expression was detected. These animals revealed an increase in proteinuria compared with control-infused rats. Our findings are the first in vitro and in vivo demonstration that leptin is a renal growth and profibrogenic factor. These results may be an important contribution to our understanding of how leptin can contribute to renal damage, characterized by endocapillary proliferation and subsequent development of glomerulosclerosis, in pathophysiological situations with high circulating levels such as in diabetics or obese individuals. Although the effects of leptin itself are moderate, growth-promoting and profibrogenic effects may be enhanced in concert with other factors such as angiotensin II.


Bisphosphonates: mechanism of action and role in clinical practice.
Bisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. In addition to currently approved uses, bisphosphonates are commonly prescribed for prevention and treatment of a variety of other skeletal conditions, such as low bone density and osteogenesis imperfecta. However, the recent recognition that bisphosphonate use is associated with pathologic conditions including osteonecrosis of the jaw has sharpened the level of scrutiny of the current widespread use of bisphosphonate therapy. Using the key words bisphosphonate and clinical practice in a PubMed literature search from January 1, 1998, to May 1, 2008, we review current understanding of the mechanisms by which bisphosphonates exert their effects on osteoclasts, discuss the role of bisphosphonates in clinical practice, and highlight some areas of concern associated with bisphosphonate use.


Azygous Vein Aneurysm (AVA): A Case Report.
Azygous Vein Aneurysm (AVAs) is an uncommon cause of mediastinal mass. They are typically asymptomatic and do not commonly require treatment. They may mimic mediastinal adenopathy on chest radiographs. We present a case of AVAs found during evaluation of chest pain in a patient who was also found to have pulmonary thromboembolism. The mass was worked up with cross-sectional imaging techniques using both Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) and ultimately Positron Emission Tomography (PET). Due to recurrent symptomatology, the aneurysm was coiled.


Detection of antibodies to the SARS-CoV-2 spike glycoprotein in both serum and saliva enhances detection of infection.
Detecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect. We systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects. Using trimeric spike glycoprotein, rather than nucleocapsid enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike, but not nucleocapsid, IgG, IgA and IgM antibody responses were readily detectable in saliva from non-hospitalized symptomatic and asymptomatic individuals. Antibody responses in saliva and serum were largely independent of each other and symptom reporting. Detecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection. This work was funded by the University of Birmingham, the National Institute for Health Research (UK), the NIH National Institute for Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the University of Southampton.


The importance of early identification and intervention for children with or at risk for autism spectrum disorders.
There has been a dramatic rise in the number of children being diagnosed with autism spectrum disorders (ASD), which has led to increased attention paid to assessment and intervention issues. This manuscript agrees with Camarata (2014) that the evidence base for early assessment and intervention should be expanded. However, it disagrees with Warren et al.'s (2011) assumption that there are not empirically validated early interventions. Reliable diagnosis has been documented during infancy and toddlerhood, and evidence suggests that the earlier the onset of intervention, the greater likelihood of an improved developmental trajectory. It is argued that early intervention is more cost and time efficient than a "wait and see" approach. With regard to published studies, the large amount of heterogeneity in the ASD population supports the use of rigorous single case experimental design research. It is an error to limit empirical evidence for treatments to only randomized clinical trials, which have the weakness of masking individual differences. Single case experimental designs examine the effects of intervention beyond typical maturation by allowing for clear estimations of developmental trajectories prior to the onset of intervention, followed by evaluation of the impact of the intervention. This commentary discusses the short- and long-term benefits of early diagnosis and intervention.


Role of tachykinins in asthma.
The sensory neuropeptides substance P (SP) and neurokinin A (NKA) are localized to sensory airway nerves, from which they can be released by a variety of stimuli, including allergen, ozone, or inflammatory mediators. Sensory nerves containing these peptides are relatively scarce in human airways, but it is becoming increasingly evident that inflammatory cells such as eosinophils, macrophages, lymphocytes, and dendritic cells can produce the tachykinins SP and NKA. Moreover, immune stimuli can boost the production and secretion of SP and NKA. SP and NKA have potent effects on bronchomotor tone, airway secretions, and bronchial circulation (vasodilation and microvascular leakage) and on inflammatory and immune cells. Following their release, tachykinins are degraded by neutral endopeptidase (NEP) and angiotensin-converting enzyme. The airway effects of the tachykinins are largely mediated by tachykinin NK1 and NK2 receptors. Tachykinins contract smooth muscle mainly by interaction with NK2 receptors, while the vascular and proinflammatory effects are mediated by the NK1 receptor. In view of their potent effects on the airways, tachykinins have been put forward as possible mediators of asthma, and tachykinin receptor antagonists are a potential new class of antiasthmatic medication.


Magnetic Properties of Ni-doped ZnO Nanocombs by CVD Approach.
The search for above room temperature ferromagnetism in dilute magnetic semiconductors has been intense in recent year. Arrays of perpendicular ferromagnetic nanowire/rods have recently attracted considerable interest for their potential use in many areas of advanced nanotechnology. We report a simple low-temperature chemical vapor deposition (CVD) to create self-assembled comb-like Ni-/undoped ZnO nanostructure arrays. The phases, compositions, and physical properties of the studied samples were analyzed by different techniques, including high-resolution X-ray diffraction/photoelectron spectroscopy/transmission electron microscopy, photoluminescence, and MPMS. In particular, the Ni-doped ZnO nanocombs (NCs) with ferromagnetic and superparamagnetic properties have been observed whereas undoped ZnO NCs disappear. The corresponding ferromagnetic source mechanism is discussed, in which defects such as O vacancies would play an important role.


Adolescent male bullies, victims, and bully-victims: a comparison of psychosocial and behavioral characteristics.
To determine among male adolescents whether bully-victims would report the poorest psychosocial health, the worst attitudes toward school, more problem behavior (delinquency, weapons possession, and substance use), and more physical injury compared with bullies, victims, and neutral students. We also assessed ethnic differences in bullying category membership. Employing multisample latent variable models, we contrasted 1,312 males in grades 7-12 classified as bullies (n = 299), victims (n = 180), bully-victims (n = 195), and neutral (n = 638) on school attitudes, psychosocial health, problem behaviors, and physical injury. Hypotheses were generally confirmed, especially contrasts between bully-victims and neutrals. However, bullies did not have better school attitudes than bully-victims, and victims only marginally reported better psychological health than bully-victims. The boys of mixed ethnicity were more likely to be victims. Greater awareness of the problems associated with boys who both bully and are victimized is necessary for improved intervention.


Infection with influenza A/Victoria virus in Houston families, 1976.
In 1976, an epidemic caused by infections with an influenza virus antigenically similar to A/Victoria/75 (H3N2) occurred in Houston, Texas. During this outbreak, 37 families (155 members) enrolled in the Houston Family Study were under observation. The families lived throughout the metropolitan area (Houston, Texas), and were representative of low income groups. The overall frequency of infection in family members was 27.7%. The frequency of infection was the highest for infants under one year of age and for their older siblings, 14 (37.8%) of 37 and 17 (33.3%) of 51, respectively. Eighteen (48.6%) of the 37 families had at least one infected member. Twelve of the 18 'infected' families had school aged children, whereas only three of the 19 'non-infected' families had school aged children (P less than 0.01). These infected families were also larger and had increased household density (persons/rooms). The levels of pre-existing HI antibodies to A/Victoria/75 and A/Port Chalmers/73 were inversely related to frequencies of infection and illness associated with A/Victoria/75 virus. Three children required hospitalization as direct consequence of their infection with this H3N2 influenza virus. Antibody response to infection was related to previous experience with antigenically-related influenza A (H3N2) viruses according to Francis', 'doctrine of original antigenic sin.'


A founder large deletion mutation in Xeroderma pigmentosum-Variant form in Tunisia: implication for molecular diagnosis and therapy.
Xeroderma pigmentosum Variant (XP-V) form is characterized by a late onset of skin symptoms. Our aim is the clinical and genetic investigations of XP-V Tunisian patients in order to develop a simple tool for early diagnosis. We investigated 16 suspected XP patients belonging to ten consanguineous families. Analysis of the POLH gene was performed by linkage analysis, long range PCR, and sequencing. Genetic analysis showed linkage to the POLH gene with a founder haplotype in all affected patients. Long range PCR of exon 9 to exon 11 showed a 3926 bp deletion compared to control individuals. Sequence analysis demonstrates that this deletion has occurred between two Alu-Sq2 repetitive sequences in the same orientation, respectively, in introns 9 and 10. We suggest that this mutation POLH NG_009252.1: g.36847_40771del3925 is caused by an equal crossover event that occurred between two homologous chromosomes at meiosis. These results allowed us to develop a simple test based on a simple PCR in order to screen suspected XP-V patients. In Tunisia, the prevalence of XP-V group seems to be underestimated and clinical diagnosis is usually later. Cascade screening of this founder mutation by PCR in regions with high frequency of XP provides a rapid and cost-effective tool for early diagnosis of XP-V in Tunisia and North Africa.


Composite outcomes in coronary bypass surgery versus percutaneous intervention.
Recent observational studies show that patients with multivessel coronary disease have a long-term survival advantage with coronary artery bypass grafting (CABG) compared with percutaneous coronary intervention (PCI). Important nonfatal outcomes may also affect optimal treatment recommendation. CABG was compared with percutaneous catheter intervention by using a composite of death, myocardial infarction (MI), or stroke. Medicare patients undergoing revascularization for stable multivessel coronary disease from 2004 through 2008 were identified in national registries. Short-term clinical information from the registries was linked to Medicare data to obtain long-term follow-up out to 4 years from the time of the procedure. Propensity scoring with inverse probability weighting was used to adjust for baseline risk factors. There were 86,244 CABG and 103,549 PCI patients. The mean age was 74 years, with a median 2.67 years of follow-up. At 4 years, the propensity-adjusted adjusted cumulative incidence of MI was 3.2% in CABG compared with 6.6% in PCI (risk ratio, 0.49; 95% confidence interval, 0.45 to 0.53). At 4 years, the cumulative incidence of stroke was 4.5% in CABG compared with 3.1% in PCI patients (risk ratio, 1.43; 95% confidence interval, 1.31 to 1.54). This difference was primarily due to the higher 30-day stroke rate for CABG (1.55% vs 0.37%). For the composite of death, MI, or stroke, the 4-year adjusted cumulative incidence was 21.6% for CABG and 26.7% for PCI (risk ratio, 0.81; 95% confidence interval, 0.78 to 0.83). The 4-year composite event rate of death, MI, and stroke favored CABG, whereas the risk of stroke alone favored PCI.


The Addition of EGFR Inhibitors in Neoadjuvant Therapy for KRAS-Wild Type Locally Advanced Rectal Cancer Patients: A Systematic Review and Meta-Analysis.
Patients with locally advanced rectal cancer (LARC) are at higher risk of local and distant recurrence and are thus more vulnerable to metastatic diseases. Neoadjuvant chemoradiotherapy (nCRT) and subsequent curative resection with total mesorectal excision (TME) followed by adjuvant chemotherapy have been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as standard of care for LARC patients. However, the efficacy of the addition of epidermal growth factor receptor (EGFR) inhibitors in kirsten rat sarcoma viral oncogene (KRAS)-wild type LARC patients remains uncertain. PubMed, Embase, and Web of Science were searched to retrieve records on the application of EGFR inhibitors in a neoadjuvant setting for LARC patients. pCR was used as surrogate endpoint to perform data synthesis in a single-arm setting. Ten cohorts covering 540 subjects were eligible in this systematic review. The pooled pCR rate for EGFR inhibitors was 15% (95% confidence interval (95% CI), 11-20%; I2 = 55.2%); the pooled estimates of Grade 3/4 diarrhea, Grade 3/4 hand-foot syndrome, Grade 3/4 acneiform rash were 17% (95% CI, 4-34%; I2 = 93.3%), 2% (95% CI, 0-5%; I2 = 13.7%), and 15% (95% CI, 9-22%; I2 = 65.4%), respectively. The addition of EGFR inhibitors in the nCRT for KRAS-wild type LARC patients provides comparable efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by more future studies.


Role of non-drainage of subretinal fluid in re-operation for retinal detachment.
In a study of 194 re-operations for retinal detachment in which one-third of the cases were managed without drainage of subretinal fluid, it was found that a number of failures occurred after non-drainage. Analysis of these failures shows that more than half could have been avoided if the correct choice of cases suitable for management without drainage of subretinal fluid had been made. It is felt that with careful attention to the criteria which are used to decide on the choice of surgical technique, the results obtained by the non-drainage method should be as good in the more complicated case as they have already been shown to be in the primary case. Because the drainage of subretinal fluid carries with it a risk of surgical complications and these complications may contribute to the development of massive preretinal retraction, management of the re-operation should be carried out without drainage of subretinal fluid whenever possible.


A layer-by-layer assembled MoS2 thin film as an efficient platform for laser desorption/ionization mass spectrometry analysis of small molecules.
A chip-based platform for laser desorption/ionization mass spectrometry (LDI-MS) analysis of small molecules was developed by utilizing layer-by-layer (LBL) assembly of MoS2 nanoflakes and polyallylamine on an arbitrary substrate. The LDI-MS efficiency of small molecules on MoS2 films increased as a function of LBL assembly cycles until reaching a saturation point. The optimized MoS2 nanoflake film exhibits high LDI-MS efficiency, salt tolerance, reusability and uniform ionic signal distribution, and its performance was further enhanced by surface modification with perfluoroalkanes mimicking a clathrate nanostructure.


Protein degradation in hepatocyte monolayers. Effects of glucagon, adenosine 3':5'-cyclic monophosphate and insulin.
1. Hepatocytes were isolated by collagenase perfusion of livers from fed rats and established in stationary monolayer culture. 2. Degradation of intracellular protein was measured in these monolayers after labelling for 16h with [3H]leucine followed by a 3h chase period in medium containing 2mM-leucine. 3. Proteolysis in this system was stimulated by physiological concentrations of glucagon and also by added dibutyryl cyclic AMP. The effects of these two agents were not additive, which is consistent with the view that they act by the same mechanism. 4. A close correlation was found between intracellular cyclic AMP concentrations generated by glucagon and the degree of stimulation of proteolysis elicited by the hormone. 5. Insulin reduced glucagon-stimulated proteolysis, but not glucagon-elevated intracellular cyclic AMP concentrations. 6. The continual presence of either insulin or glucagon was necessary for the full expression of their effects on proteolysis. 7. In the presence of cycloheximide, proteolysis was normally responsive to glucagon but not to insulin. In contrast, proteolysis was not responsive to either hormone in the presence of ammonia, an agent that blocks the final lysosomal step of protein breakdown. 8. We propose that in hepatocyte monolayers glucagon may act via cyclic AMP to increase cellular autophagy and thus increase proteolysis, whereas insulin inhibits these processes independently of cyclic AMP.