Visceral fat enhances blood pressure reactivity to physical but not mental challenges in male adolescents.
Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension. Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence. In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges. Males vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm(3) of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP. Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.


Guiding SPPs with PT-symmetry.
The concept of parity-time (PT) symmetry in SPPs is proposed and confirmed for the first time in this work. By introducing periodic modulation of the effective refractive index in SPP system, the asymmetric propagation is theoretically predicted and numerically demonstrated. After validation of this concept, we apply it in two applications: PT-waveguide and PT-cloak. Both two applications further illustrate the wide applicability of this concept in SPP system.


Analysis of the Sox gene family in the European sea bass (Dicentrarchus labrax).
Sox (SRY-related genes containing a HMG box) genes encode a family of transcription factors that are involved in a variety of developmental processes including sex determination. Twenty Sox genes are present in the genomes of humans and mice, but far less is known about the Sox gene family in other vertebrate types. We have obtained clones representing the HMG boxes of twelve Sox genes from European sea bass (Dicentrarchus labrax), a fish species whose farming is complicated by a heavily skewed sex ratio, with between 70% and 99% of offspring typically being male. The cloned Sox genes are members of the SoxB, SoxC, SoxE and SoxF groups. Sequence analysis shows that some of the clones represent genes duplicated in sea bass with respect to the mammalian Sox gene family.


Computer-assisted image analysis of temporal retinal vessel width and tortuosity in retinopathy of prematurity for the assessment of disease severity and treatment outcome.
To quantify the severity of retinopathy of prematurity (ROP) through temporal retinal vessel diameter and tortuosity by the use semiautomated analysis and to evaluate the effects of laser treatment on retinal vessel measurements. A total of 176 RetCam digital fundus images from 63 infants diagnosed with ROP between January 2005 and December 2008 were retrospectively analyzed with Retinal Vessel Measurement V5.8 software. Patients were classified into 1 of 3 groups: stage 1 and 2 (Group 1), stage 3 not requiring treatment (Group 2), and stage 3 requiring treatment (Group 3). Diameter and tortuosity of the 4 major temporal retinal arteries and veins close to the optic disk were quantified. Tortuosity was measured as central (within 2 disk diameters from the center of the optic disk) and paracentral (from 2 to 4 disk diameters). For Group 3, measurements of vessels immediately before treatment and all follow-up post-treatment measurements of vessels were analyzed. Differences in central and paracentral arteriolar tortuosity were pronounced. The average central arteriolar tortuosities were 1.12 ± 0.018 for Group 1, 1.13 ± 0.018 for Group 2, and 1.32 ± for Group 3; the paracentral arteriolar tortuosities were 1.11 ± 0.019 for Group 1, 1.12 ± 0.019 for Group 2, and 1.31 ± 0.02 for Group 3. In the post-treatment analysis of Group 3 patients, significant reductions in all vascular measurements were observed compared to pre-treatment, except for central and paracentral vein tortuosity. Computerized systems can be used to objectively assess differences in vascular parameters between ROP stages.


Lactose metabolism by Streptococcus mutans: evidence for induction of the tagatose 6-phosphate pathway.
Growth on lactose by strains of Streptococcus mutans resulted in the induction of the lactose-phosphoenolpyruvate-phosphotransferase system, phospho-beta-galactosidase, and the enzymes of the tagatose 6-phosphate pathway.


Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR.
Accumulating evidence suggests that various neurodegenerative diseases, including Alzheimer's disease (AD), are linked to cytotoxic diffusible aggregates of amyloid proteins, which are metastable intermediate species in protein misfolding. This study presents the first site-specific structural study on an intermediate called amylospheroid (ASPD), an AD-derived neurotoxin composed of oligomeric amyloid-β (Aβ). Electron microscopy and immunological analyses using ASPD-specific "conformational" antibodies established synthetic ASPD for the 42-residue Aβ(1-42) as an excellent structural/morphological analogue of native ASPD extracted from AD patients, the level of which correlates with the severity of AD. (13)C solid-state NMR analyses of approximately 20 residues and interstrand distances demonstrated that the synthetic ASPD is made of a homogeneous single conformer containing parallel β-sheets. These results provide profound insight into the native ASPD, indicating that Aβ is likely to self-assemble into the toxic intermediate with β-sheet structures in AD brains. This approach can be applied to various intermediates relevant to amyloid diseases.


The Supporting Role of Mentees' Peers in Online Mentoring: A Longitudinal Social Network Analysis of Peer Influence.
Studies show that online mentoring is an effective measure to support girls in STEM (science, technology, engineering, and mathematics), especially if it also allows for networking with other participants on the mentoring platform. However, research is missing on peer influence. This topic seems especially crucial in programs for adolescents as peer influence plays an important role at this age. In our study, we investigated peer influence on mentoring outcomes - confidence in own STEM abilities and STEM-related activities - in an online mentoring program in STEM for secondary school girls (N = 124, M = 14.3 years, SD = 2.2 years, age range: 11-19 years). The program provides girls with at least 1 year of one-on-one interaction with a personal female mentor who has a college degree in a STEM subject. Participants can also interact with other participants on the platform. We used a longitudinal social network analysis approach to examine peer influence on mentoring outcomes. Our results indicate that both mentoring outcomes - mentees' confidence in own STEM abilities and STEM-related activities - are influenced by peers moderated by the mentees' own age. Younger mentees tended to become more similar to their peers regarding confidence in own STEM abilities and STEM-related activities, whereas older mentees tended to become more dissimilar over time. In addition, peer group size had a positive effect on confidence in own STEM abilities, but not on STEM-related activities. This effect was moderated by the mentee's age. Overall, peers have a positive influence on the measured mentoring outcomes, especially for young mentees.


Nile tilapia (Oreochromis niloticus) Nanog co-expression with Pou5f3, transcriptional regulation and biological activity in embyonic development and embryonic cells.
Mammalian Nanog is critical in pluripotency acquisition and maintenance. Nonetheless, a recent report from zebrafish (Danio rerio) suggests that Nanog is not required for embryonic cells which is not like the mammalian homologs, but is necessary for the proper formation of the extra-embryonic yolk syncytial layer (YSL). However, whether its biological function in other fishes is conservative remains to be investigated. Our previous work shows that Nanog from Nile tilapia (Oreochromis niloticus) (termed as Ong thereafter) displays differential spatiotemporal expression patterns from the other teleost fishes including zebrafish. In this study, Ong co-expression with Pou5f3 (another core pluripotent transcription factor), transcriptional regulation and its biological functions during embryonic development and in the survival and proliferation of embryonic cells were investigated. At the blastula stage, both Ong and Pou5f3 were highly expressed in embryonic cells and co-located in the nucleus. After that, the expression of both Ong and Pou5f3 began to decrease at the gastrula stage (24 haf) and then exhibited a differential expression profile at the segmentation stage (28-36 haf). Ong disappeared in embryonic cells and was limited to YSL, whilst Pou5f3 was highly expressed in embryonic cells even some with obvious cytoplasmic distribution. Luciferase assay indicated that Ong was negatively regulated by Pou5f3 and positively regulated by androgen and itself. Ong depletion in fertilized one-cell embryos through CRISPR/Cas9 led to blastula blockage or death, and the survival and proliferation of blastula-derived embryonic cells in vitro failed. Collectively, Ong has similar expression and biological function to Pou5f3 at the blastula stage, which is similar to mammalian homolog but different from zebrafish homolog. These data suggest that the expression patterns and functions of Nanog are not conservative in fishes and vary from species to species. This study enriches our understanding about Nanog and its evolution.


Preparation and Characterization of Docetaxel-PLGA Nanoparticles Coated with Folic Acid-chitosan Conjugate for Cancer Treatment.
The conjugation of chitosan (CS) and folic acid (FA) was prepared and used to coat PLGA nanoparticles (NPs) that are loaded with Docetaxel (DTX) to target cancer cells that have lower pH and overexpression of folate receptors in comparison to normal cells. Three formulations had been prepared to reach the highest loading capacity (LC%) and encapsulation efficiency (EE%) and to study the effect of the amount of FA-CS on the drug release. The sizes, charges, homogeneity, surface morphology, LC% and EE% of the NPs were determined. The NPs were characterized using FTIR and XRD. In vitro release profiles of DTX from PLGA NPs, at pH 5.5 and 7.4 were determined. Finally, in vitro cytotoxicity assay on three cancer cell lines (RPMI 2650, Calu-3, and A549) was studied. The sizes of the three formulations ranged between 250.3±1.7 and 356.3±17.7. All prepared formulations showed acceptable monodispersity with highly positive charges. The EE% was above 85% and the LC% ranged between 6-35%. The in vitro release of DTX show an inverse relation to the amounts of FA-CS used and the pH of the dissolution medium. Coated PLGA NPs showed a significant difference in RPMI 2650, Calu-3, and A549 cell viability in comparison to free DTX. The NPs components were safe and non-toxic to human cells. In conclusion, coating PLGA NPs with FA-CS may be used as a good carrier for chemotherapeutic agents that selectively target carcinogenic tissues.


Rapid, cool sintering of wet processed yttria-stabilized zirconia ceramic electrolyte thin films.
Here we report a photonic annealing process for yttria-stabilized zirconia films, which are one of the most well-known solid-state electrolytes for solid oxide fuel cells (SOFCs). Precursor films were coated using a wet-chemical method with a simple metal-organic precursor solution and directly annealed at standard pressure and temperature by two cycles of xenon flash lamp irradiation. The residual organics were almost completely decomposed in the first pre-annealing step, and the fluorite crystalline phases and good ionic conductivity were developed during the second annealing step. These films showed properties comparable to those of thermally annealed films. This process is much faster than conventional annealing processes (e.g. halogen furnaces); a few seconds compared to tens of hours, respectively. The significance of this work includes the treatment of solid-state electrolyte oxides for SOFCs and the demonstration of the feasibility of other oxide components for solid-state energy devices.


[Features of contraction of various sections of the left ventricle of an intact heart upon the action of inotropic factors].
In anesthetized dogs, the effects of adrenaline and CaCl2 were studied by means of measuring intramural tension in the left ventricle wall (LV) and in the apex. The inotropic effect involved an increase in the ratio between the velocity of the tension growth in isovolumic phase and the maximum tension of this contraction, the ratio increasing more slowly in the apex than in the LV. This can be due to that the inotropic factors induce a greater growth of intramural tension in the apex than in the LV.


Supplementation with different protein profiles for grazing beef cattle supplemented in tropical grass during the rainy-dry transition season.
The objective of this study was to evaluate increasing levels of inclusion of dry distillery grains (DDGs) in substitution of corn and urea in multiple supplements for beef cattle of Urochloa brizantha cv. Marandu on the consumption, digestibility, and efficiency of microbial synthesis and use of nitrogen. We used four Nellore bulls cannulated in the rumen with an average age of 24 months and 445.12 ± 34.4 kg of body weight (BW), in a 4 × 4 Latin square design. Supplements differed by the inclusion level of DDG (0%, 31.5%, 63.0%, and 94.5%). Increasing levels of DDG inclusion decreased dry matter intake (DMI) (P = 0.002), forage (P = 0.002), organic matter (OM) (P = 0.001), crude protein (CP) (P = 0.037), and total digestible nutrients (TDN) (P < 0.001) and had a quadratic effect on the intake of non-fibrous carbohydrates (NFC) (P = 0.002). It was observed an increase in the digestibility of ether extract (EE) (P = 0.005), however a decrease in the digestibility of NFC (P = 0.001). Inclusion of DDG did not influence ruminal pH. There was a quadratic effect at collection times for ruminal ammoniacal nitrogen (P < 0.05), except for the supplement with 94.5% DDG where the effect was linear (P = 0.002). Nitrogen intake was 10.9% higher when there was no DDG in the supplement, compared with the supplement with 94.5% DDG (P = 0.039). The excretion of N by feces was greater when there was a greater amount of DDG in the supplement (P = 0.027), the opposite occurred with urine excretion of N, being higher when there was less amount of DDG in the supplement (P = 0.027). Increasing levels of DDG did not affect ruminal microbial protein yield (P > 0.05). Replacing corn and urea with up to 94.5% DDGs in multiple supplements resulted in no adverse effect efficiency of microbial synthesis, although nutrient intake, total digestible nutrients, and use of nitrogen were reduced at 94.5% DDG inclusion.


Anti-cytokine auto-vaccinations as tools for the analysis of cytokine function in vivo.
Braking B cell tolerance to generate antibodies against autologous cytokines or chemokines offers an alternative to gene inactivation for functional analysis of these factors in vivo. It is clearly less potent than the genetic approach but offers the advantage of extreme flexibility. The basic principle is to enable a self-reactive B cell to attract T cell help by presenting foreign peptides, a process we called "deceptive" antigen presentation. We here review the different auto-vaccine procedures that are currently used and provide several examples of functional information acquired by this procedure or by mAbs derived from auto-vaccinated mice.


The simultaneous presence and expression of human hepatitis C virus (HCV), human herpesvirus-6 (HHV-6), and human immunodeficiency virus-1 (HIV-1) in a single human T-cell.
We have developed a system that isolates and replicates HCV in vitro. These isolates are called CIMM-HCV. This system has made it possible to analyze the biology, nature, and extent of HCV variability, among other things. Individuals that are infected with HIV-1 are often also infected with HCV and HHV-6. In addition to HCV, our lab has systems for replicating HIV-1 and HHV-6. We asked whether all these viruses could infect the same cells. We report here the successful infection of a T-cell (CEM) by CIMM-HCV, HHV-6, and HIV-1. PCR analyses demonstrated that the CEM cells were productively infected by HHV-6A. RT-PCR showed that the same cell culture was positive for HCV and HIV-1. Co-infection of a T-cell by all three viruses was confirmed by transmission electron microscopy (TEM). All these viruses are highly cytolytic; therefore, triply-infected cells were short lived. However, HIV-1 and HCV co-infected cells unexpectedly lasted for several weeks. Viral replication was unhindered and the phenomenon of 'dominance' was not observed in our experiments. In addition, CIMM-HCV was present in the perinuclear space, suggesting their possible synthesis in the nucleus. This report is based entirely on viruses produced in vitro in our laboratories. As part of the determinations of host ranges of these viruses, studies were designed to demonstrate the infection of a single cell by these viruses and to study the consequences of this phenomenon. All measurements were made on cultured cells and cell culture supernatants.


Characterization of plasma protein binding dissociation with online SPE-HPLC.
A novel parameter of relative recovery (R re) was defined and determined by online SPE-HPLC to characterize plasma protein binding (PPB) kinetics of highly plasma binding drugs. The proportional relationship of R re with k off of PPB has been established with a new SPE model. A rapid, easy to use method could potentially be used to categorize PK properties of the drug candidates in the decision process of drug discovery and development.


HIV INFECTION IN HERPES ZOSTER.
The interaction of Herpes zoster and Human Immunodeficiency Virus (HIV) was evaluated in 120 cases of herpes zoster admitted to our hospital and in 157 HIV positive cases detected in the hospital during the same period. The incidence of HIV seropositivity was 22.5 per cent in cases of herpes zoster without AIDS defining disease conditions. Whereas the incidence of Herpes zoster in cases detected to be HIV positive in the same period was 17.2 per cent. A large number of herpes zoster cases found to be HIV positive were in the sexually active age group viz. 21-30 years. Thoracic dermatomal segments were most frequently involved. None of the cases had severe complications or showed evidence of progression to symptomatic HIV disease.


Effect of individual proton pump inhibitors on cardiovascular events in patients treated with clopidogrel following coronary stenting: results from the Ibaraki Cardiac Assessment Study Registry.
The aim of this study was to evaluate whether combination therapy of clopidogrel and proton pump inhibitors (PPIs) causes higher numbers of cardiovascular events than clopidogrel alone in Japanese patients. PPIs are often prescribed in combination with clopidogrel following coronary stenting. PPIs are reported to diminish the effect of clopidogrel because both are metabolized by CYP2C19. However, no reports address the effects of PPIs on cardiovascular events following coronary stenting in the Japanese population. A total of 1,887 patients treated with clopidogrel following coronary stenting were enrolled in the Ibaraki Cardiac Assessment Study (ICAS) registry. All subjects were classified into two groups according to treatment without (n = 819) or with (n = 1,068) PPI. Propensity score analysis matched 1:1 according to treatment without PPI (n = 500) or with PPI (n = 500). Primary endpoint was the composite of all-cause death or myocardial infarction. No significant difference was observed in the primary endpoint between the group without PPI and the group with PPI (4.6% vs. 4.6%, P = 0.77). In contrast, a significant difference was found between the group without PPI and with PPI in regard to the incidence of gastrointestinal bleeding at the end of the follow-up period and the specific PPI prescribed (2.4% vs. 0.8%, adjusted HR = 0.30, 95% Confidence interval 0.08-0.87, P = 0.026) after propensity score matching. No significant association between PPI use and primary endpoint was observed in the Japanese population, whereas PPI use resulted in a significant reduction in the rate of gastrointestinal bleeding.


Surfactant-sensitized malachite green method for trace determination of orthophosphate in aqueous solution.
A surfactant-sensitized spectrophotometric method for determination of trace orthophosphate has been developed using anion surfactant (Ultrawet 60 L) with molybdate and malachite green in low acidic medium (pH(T) 1.0). The method detection limit (3 x standard deviation of blank, n=10) was 8 nM and the calibration curve was linear over a range of 10-400 nM (r2=0.997). The molar absorptivity was 1.26 x 10(5) L mol(-1) cm(-1) at 600 nm with the background correction at 530 nm. The precision of method was 3.4% at 50 nM and 2.4% at 100 nM orthophosphate (n=10). The hydrolysis of eight organic phosphorus and polyphosphate compounds was less than 2% of the total phosphorus present (5-10 microM). This method showed less arsenate interference than previous methods, with only 3% even in the presence of orthophosphate in the samples. No interference of silicate up to 40 microM was observed. Background anions (in an order of SO4(2-)>NO3->Cl-) have greater effects than cations (Ca2+>Mg2+>Na+) on the reagent blank and the molar absorptivity of the color product.


Atherosclerosis and ischemic cardiomyopathy in a captive, adult red-tailed hawk (Buteo jamaicensis).
An adult, male, captive red-tailed hawk (Buteo jamaicensis) of at least 19 years of age presented in dorsal recumbency. The hawk was nonresponsive, and despite initial supportive care, died shortly after presentation. Gross postmortem revealed no abnormal findings. Histologic examination demonstrated atherosclerosis and ischemic cardiomyopathy. This is the first reported case of atherosclerosis in a red-tailed hawk.


Exposure to methamphetamine exacerbates motor activities and alters circular RNA profile of cerebellum.
Methamphetamine (METH) is a psychostimulant drug that acts on monoaminergic systems in the brain. There are several lines of evidence indicating the devastating effects of addictive drugs on the cerebellum. Moreover, it was shown that circular RNAs (circRNAs) have an important role in neurodegenerative disorders. Herein, we explored the effects of METH on neuronal degeneration, motor coordination and muscle activity. We also inspected METH-mediated changes in circRNA expression profiling in the cerebellum. Accordingly, exposure to METH triggered destructive effects on the coordination of movement of rats along with disturbed muscle activity. The fluorescent staining exhibited a significant increase in neurodegeneration in the cerebellum under the influence of METH. Besides, the number of calbindin positive Purkinje cells noticeably declined in METH-treated group compared with the control. In this regard, we identified and characterized differentially expressed (DE) circRNAs in the cerebellum under METH treatment, mainly located in dendritic spines. Moreover, based on feature and function analyzes of host genes of DE circRNAs, a large number of these genes were essentially involved in cell growth, death, inflammation and oxidative metabolism. Taken together, this data might imply the potential involvement of circRNAs in METH neurotoxicity as well as motor activity deficits.


Myxovirescin A biosynthesis is directed by hybrid polyketide synthases/nonribosomal peptide synthetase, 3-hydroxy-3-methylglutaryl-CoA synthases, and trans-acting acyltransferases.
Myxococcus xanthus DK1622 is shown to be a producer of myxovirescin (antibiotic TA) antibiotics. The myxovirescin biosynthetic gene cluster spans at least 21 open reading frames (ORFs) and covers a chromosomal region of approximately 83 kb. In silico analysis of myxovirescin ORFs in conjunction with genetic studies suggests the involvement of four type I polyketide synthases (PKSs; TaI, TaL, TaO, and TaP), one major hybrid PKS/NRPS (Ta-1), and a number of monofunctional enzymes similar to the ones involved in type II fatty-acid biosynthesis (FAB). Whereas deletion of either taI or taL causes a dramatic drop in myxovirescin production, deletion of both genes (DeltataIL) leads to the complete loss of myxovirescin production. These results suggest that both TaI and TaL PKSs might act in conjunction with a methyltransferase, reductases, and a monooxygenase to produce the 2-hydroxyvaleryl-S-ACP starter that is proposed to act as the biosynthetic primer in the initial condensation reaction with glycine. Polymerization of the remaining 11 acetates required for lactone formation is directed by 12 modules of Ta-1, TaO, and TaP megasynthetases. All modules, except for the first module of TaL, lack cognate acyltransferase (AT) domains. Furthermore, deletion of a discrete tandem AT-encoded by taV-blocks myxovirescin production; this suggests an "in trans" mode of action. To embellish the macrocycle with methyl and ethyl moieties, assembly of the myxovirescin scaffold is proposed to switch twice from PKS to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)-like biochemistry during biosynthesis. Disruption of the S-adenosylmethionine (SAM)-dependent methyltransferase, TaQ, shifts production toward two novel myxovirescin analogues, designated myxovirescin Q(a) and myxovirescin Q(c). NMR analysis of purified myxovirescin Q(a) revealed the loss of the methoxy carbon atom. This novel analogue lacks bioactivity against E. coli.


Astrocytosis in the molecular layer of the dentate gyrus: a study in Alzheimer's disease and schizophrenia.
Recently, several authors have claimed prominent abnormalities in the entorhinal cortex of both patients with Alzheimer's disease (AD) and schizophrenia. The entorhinal cortex is the origin of the perforant pathway, a major input to granule cells of the dentate gyrus of the hippocampus. The present study explored the possibility of a lesion in the entorhinal cortex of both AD and schizophrenic patients by quantitating astrocytic markers within the terminal fields of the perforant pathway. An increase in fibrillary astrocytes was found in half (3/6) of the AD patients while none of the schizophrenic (n = 6) or control (n = 7) brains exhibited gliosis. Since the redistribution and hyperplasia of astrocytes within the molecular layer of the partially deafferented dentate gyrus depend on the chronicity of the entorhinal lesion, the abnormalities observed in AD patients are consistent with the progressive course of the illness. Furthermore, the presence of gliosis in the subiculum of three out of six AD patients suggested pathology secondary to projections from the entorhinal region, amygdala, or prepyriform cortex. The absence of similar changes in schizophrenic patients does not disprove previous claims of entorhinal pathology but suggests that the lesion, if it exists, is either static in nature or occurred long before death.


Statintherapy in the primary and the secondary prevention of ischaemic cerebrovascular diseases.
Stroke is a major public health problem. It is the third leading cause of death worldwide and results in hospital admissions, morbidity, and long-term disability. Despite the inconsistent or weak association between cholesterol and stroke, statins can reduce the incidence of stroke in high-risk populations and in patients with a stroke or transient ischaemic attack. The aim of our study was to review the efficacy of statin therapy in both primary and secondary stroke prevention. We also reviewed the effectiveness and cost-effectiveness among different statins and we also reviewed the possible effect of treatment added to statin monotherapy. There is evidence that statin therapy in both primary and secondary prevention significantly reduces subsequent major coronary events but only marginally reduces the risk of stroke recurrence. There is no clear evidence of beneficial effect from statins in those with previous haemorrhagic stroke and it is unclear whether statins should be started immediately post stroke or later. There is a pressing need for direct evidence, from head-to-head trials, to determine whether individual statins provide differing protection from clinically important events in stroke prevention. It is possible that combinations of lipid-lowering agents did not improve clinical outcomes more than high-dose statin monotherapy, although clinical trials are still ongoing.


Corrigendum to: "Race and genetics vs. 'race' in genetics: A systematic review of the use of African ancestry in genetic studies".
[This corrects the article DOI: 10.1093/emph/eoab018.].


Functional Morphology and Symmetry in the Odontocete Ear Complex.
Odontocete ear complexes or tympanoperiotic complexes (TPCs) were compared for asymmetry. Left and right TPCs were collected from one long-beaked common dolphin (Delphinus capensis) and one Amazon River dolphin (Inia geoffrensis). Asymmetry was assessed by volumetric comparisons of left and right TPCs and by visual comparison of superimposed models of the right TPC to a reflected mirror image of the left TPC. Kolmogorov-Smirnov tests were performed to compare the resonant frequencies of the TPCs as calculated by vibrational analysis. All analyses found slight differences between TPCs from the same specimen in contrast to the directional asymmetry in the nasal region of odontocete skulls.


In vivo production of plasma angiotensin I: is plasma renin sufficient?
Production and metabolism of angiotensin I (Ang I) were studied during a constant intravenous infusion of mono-iodinated 125I-Ang I in seven patients with essential hypertension taking 50 mg captopril twice a day. The elimination of arterially delivered 125I-Ang I reached 80% in the kidneys, 45% in the forearm, 58% in the leg and 95% in the hepatomesenteric vascular bed. Despite the high level of elimination of Ang I, plasma levels of Ang I in the leg, forearm and renal vein were not different from that of arterial plasma. In the hepatic vein the plasma level of Ang I was 50% lower than in the aorta. Thus, 50-90% of endogenous Ang I in the veins is derived from new regional production. The blood transit time through the kidneys, limbs and hepatomesenteric region is too short for plasma renin activity to account for the measured new Ang I production. Our results indicate that a high percentage of plasma Ang I may be produced locally in the tissues, and not in circulating plasma.


PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers.
Recently, OlympiAD and EMBRACA trials demonstrated the favorable efficacy/toxicity ratio of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. PARPi have been largely adopted in triple-negative metastatic breast cancer, but their place has been less clearly defined in endocrine-receptor positive, HER2 negative (ER+/ HER2-) mBC. The present narrative review aims at addressing this question by identifying the patients that are more likely benefit from PARPi. Frequencies of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients have been underestimated, and many experts assume than 50% of all BRCA1/2 mutated breast cancers are of ER+/HER2- subtype. Patients with ER+/HER2- BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and PARPi are effective especially when prescribed before exposure to chemotherapy. The OLYMPIA trial also highlighted the utility of PARPi in patients with early breast cancers at high risk of relapse and carrying PV of BRCA. PARPi might also be effective in patients with HRD diseases, representing up to 20% of ER+/HER2- breast cancers. Consequently, the future implementation of early genotyping strategies for identifying the patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.


Retrorectal endometrial cyst.
An unusual case of retrorectal endometriosis is presented. This presented as an asymptomatic pelvic mass at the level of the pelvic floor not contiguous with the pelvis or peritoneal cavity. It was successfully excised via an abdominal approach.


Proteolytic processing of foamy virus Gag and Pol proteins.
The foamy viral proteases (FV PRs) are set apart from other retroviral processing enzymes by unique features. The first remarkable property is that FV PRs are enzymatically active as high-molecular-mass Pro-Pol proteins. Hence there exist multiple forms of active FV PRs that likely contribute to cleavage site specificity. A FV PR of low molecular size is not detectable in purified virions, in contrast to PRs of other retroviruses that are found in virus particles. Because the major part of Pol remains attached to the amino-terminal enzymatically active PR protein region, the FV-specific way of expressing Pro-Pol polyproteins from a pol-specific transcript provides for the incorporation of Pro-Pol and IN into virus particles. Proteolytic processing of Gag and Pol proteins is incomplete and delayed. Another novel feature is that the catalytic center of the active dimers of cat FV PR consists of D-S/T-Q instead of D-S/T-G, an unprecedented feature of this enzyme. The temporal and spatial control and the factors that regulate FV PRs remain to be elucidated.


The TYMV tRNA-like structure.
The genomic RNA from turnip yellow mosaic virus presents a 3'-end functionally and structurally related to tRNAs. This report summarizes our knowledge about the peculiar structure of the tRNA-like domain and its interaction with tRNA specific proteins, like RNAse P, tRNA nucleotidyl-transferase, aminoacyl-tRNA synthetases, and elongation factors. It discusses also the biological role of this structure in the viral life cycle. A brief survey of our knowledge of other tRNA mimicries in biological systems, as well as their relevance for understanding canonical tRNA, will also be presented.


Liver damage and sickle cell disease: genotype relationship.
Sickle hepatopathy is a severe and not rare complication of sickle cell disease (SCD), showing mainly a cholestatic pattern. So far, no effective approaches to prevent or treat this condition have been recognized. We conducted a single-center observational study in 68 adult sickle cell patients, encompassing 17 with sickle cell anemia (SCA), 38 with sickle cell thalassemia (HbS/β-Thal), and 13 with HbSC disease. The aim of our study was to assess liver damage in the three main forms of SCD, through the evaluation of clinical, laboratory, and imaging findings. In our population, the role of hepatotropic viruses, high BMI, and alcohol consumption in liver damage was ruled out. SCA and HbS/β-Thal patients with lower Hb (p < 0.001), higher HbS (p < 0.001), and frequent vaso-occlusive crises showed functional (GGT values: SCA and HbS/β-Thal vs HbSC p = 0.047 and p = 0.009, respectively) and structural liver abnormalities, defined by abdominal ultrasound and vibration-controlled transient elastography (liver stiffness values: SCA and HbS/β-Thal vs HbSC p 0.022 and p 0.19, respectively), more severe than HbSC patients. Through univariate and multivariate analyses, male sex, SCA genotype, lower HbF, frequent transfusions, increased GGT values, and abnormal liver ultrasound and stiffness were identified as potentially early markers of sickle hepatopathy.


Functionalized cellulose nanocrystals as the performance regulators of poly(β-hydroxybutyrate-co-valerate) biocomposites.
To investigate the relationship between functional groups on cellulose nanocrystals (CNC) and the performance of poly(β-hydroxybutyrate-co-valerate) (PHBV), the surface of CNC was modified by surface graft modification and PHBV/CNC biocomposites were prepared by melt blending. To demonstrate the interfacial adhesion difference between hydrophobic PHBV and hydrophilic CNC, palmitoyl chloride and ε-caprolactone had been used to tailor the oleophilic property of CNC. Results showed that CNC had heterogeneous nucleation effect on the crystallization process of PHBV, while the entanglement of molecular chains weakened the promoting functions of CNC-g-C16 (CNC grafted with palmitoyl chloride) and CNC-g-CL (CNC grafted with ε-caprolactone). Furthermore, CNC-g-CL exhibited better interfacial adhesion with PHBV when compared with CNC-g-C16. And 1 wt% CNC-g-CL improved the tensile strength of PHBV biocomposite to 38.09 MPa, which is 26.25% higher than PHBV.


Trends and issues in clinical research on satisfaction and quality of life after mastectomy and breast reconstruction: a 5-year scoping review.
Breast reconstruction (BR) aims to improve the satisfaction and quality of life (QOL) of breast cancer survivors. Clinical studies using patient-reported outcomes (PROs) can therefore provide relevant information to the patients and support decision-making. This scoping review was conducted to analyze recent trends in world regions, methods used, and factors investigated. The literature search was conducted in August 2022. Databases of PubMed, MEDLINE, and CINAHL were searched for relevant English-language studies published from 2017 to 2022. Studies involving women with breast cancer who underwent BR after mastectomy and investigated PROs after BR using BR-specific scales were included. Data on the country, publication year, study design, PRO measures (PROMs) used, time points of surveys, and research themes were collected. In total, 147 articles met the inclusion criteria. BREAST-Q was the most widely used, contributing to the increase in the number and diversification of studies in this area. Such research has been conducted mainly in North America and Europe and is still developing in Asia and other regions. The research themes involved a wide range of clinical and patient factors in addition to surgery, which could be influenced by research methods, time since surgery, and even cultural differences. Recent BR-specific PROMs have led to a worldwide development of research on factors that affect satisfaction and QOL after BR. PRO after BR may be influenced by local cultural and social features, and it would be necessary to accumulate data in each region to draw clinically useful conclusion.


Monocyte Fc receptor function in rheumatoid arthritis. Enhanced cell-binding of IgG induced by rheumatoid factors.
Monocytes from 11 patients with rheumatoid arthritis and 10 control subjects were purified by countercurrent elutriation. Rheumatoid arthritis monocytes had more cell-associated IgG (P less than 0.001) and bound more 125I-labeled heat-aggregated IgG in vitro (P less than 0.02) than did monocytes from control subjects. Interaction of rheumatoid factor (RF) with monocytes was then investigated. Purified 125I-labeled IgM-RF and IgG-RF bound directly to monocytes from normal individuals. Furthermore, preincubation of normal monocytes with RF augmented subsequent binding of aggregated IgG to the cells. We conclude that monocyte-associated RF can enhance binding of IgG-containing immune complexes to the cells and can exaggerate the measured number of Fc receptors. Such cell-bound RF may affect clearance of immune complexes by the reticuloendothelial system in vivo.


ABCA12 homozygous mutation in harlequin ichthyosis: Survival without systemic retinoids.
Harlequin ichthyosis (HI) is associated with high mortality. Early systemic retinoids are widely used, although their use remains debatable. We reported two neonates with homozygous mutations in ABCA12 consistent with harlequin ichthyosis who survived to discharge home with intensive care and without use of systemic retinoids.


Relationship between circulating cytokine levels and physical or psychological functioning in patients with advanced cancer.
To investigate the relation between functional impairments of cancer patients and circulating cytokines using a multiplex technique. 50 patients with cancer were assessed using the quality of life (QOL) questionnaire. 27 plasma cytokine levels were determined by using the Bio-Plex array system. The relation to QOL scores was assessed using Chi-square test for categorical variables and univariate linear regression analysis for cytokine levels. Multivariate analysis showed that interleukin-6 (IL-6) level is a significant independent determinant of physical (β=-0.238, P=0.0126) and cognitive functioning (β=-0.462, P=0.0006) and that vascular endothelial growth factor (VEGF) level is a significant independent determinant of emotional functioning (β=-0.414, P=0.039). This study, in which 27 cytokines are simultaneously tested with cutting edge technology, demonstrates that plasma IL-6 and VEGF are significant independent determinants of functional impairments in patients with cancer.


Effects of growth hormone treatment on left ventricular dimensions in children with Noonan's syndrome.
To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan's syndrome (NS). Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart. At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment. Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS.


Climate modelling and structural stability.
Climate modelling plays a crucial role for understanding and addressing the climate challenge, in terms of both mitigation and adaptation. It is therefore of central importance to understand to what extent climate models are adequate for relevant purposes, such as providing certain kinds of climate change projections in view of decision-making. In this perspective, the issue of the stability of climate models under small relevant perturbations in their structure (or small relevant 'structural model errors' with respect to the target system) seems particularly important. Within this framework, a debate has emerged in the philosophy of science literature about the relevance for climate modelling of the mathematical notion of structural stability. This paper adresses several important foundational and epistemological questions that arise in this context, in particular about the the role of abstract mathematical considerations of a qualitative nature (in some precise, topological sense) for concrete modelling projects with mainly quantitative purposes.


Recent and innovative methods for detection of bacteremia and fungemia.
Advances continue to be made in methods for more reliable or more rapid means of detecting bacteremia and fungemia. The importance of blood sample volume and broth dilution has been established in controlled studies. New technology includes the use of resins that remove antimicrobials from blood samples, detection of radioactivity from organisms given radiolabeled substrate, use of dyes that stain microbial DNA and RNA, use of slides coated with growth media, and lysis-centrifugation for trapping microorganisms. Technology now being considered includes counterimmunoelectrophoresis, head-space gas chromatography, electrical impedance, microcalorimetry, and the use of lasers to detect pH changes and turbidity.


Numerical analysis of alpha spectra using two different codes.
This work presents an intercomparison between commercial software for alpha-particle spectrometry, Genie 2000, and the new free available software, Winalpha, developed by International Atomic Energy Agency (IAEA). In order to compare both codes, different environmental spectra containing plutonium, uranium, thorium and polonium have been analyzed, together with IAEA test alpha spectra. A statistical study was performed in order to evaluate the precision and accuracy in the analyses, and to enhance the confidence in using the software on alpha spectrometric studies.


Follow-up of spontaneous intracerebral haemorrhage by computed tomography.
The follow-up of 89 patients with spontaneous intracerebral haematomas was studied by computed tomography (CT). The aetiology of the haemorrhage was found to be hypertension in 52 cases, vascular malformation in 14 cases, and two haematomas were due to anticoagulant therapy. The lesion visible on CT consisted of an area of increased density surrounded by a rim of low attenuation. Most cases showed a progressive decrease in size of the total lesion. Exceptions to this pattern were observed, which may lead to the misdiagnosis of a tumour. The central area of increased density decreased in size much more quickly than the total lesion. Signs of a mass effect were observed up to the ninth week in the larger lesions. The resorption of blood, measured by the decrease in diameter of the central high attenuation area, was not dependent on the site or original size of the haematoma, but was slower in hypertensive haemorrhage than in haemorrhage due to vascular malformation. Contrast enhancement was observed up to the ninth week and was ring-like in most cases. Our data confirm the well-known finding that the bleeding cannot be demonstrated by examination of the CSF if the blood has not reached the ventricular system or the subarachnoid space.


Effects of various basic compounds on the degradation of formaldehyde-treated 125I-labeled bovine serum albumin in mouse liver lysosomes.
The effect of various basic compounds on degradation of formaldehyde-treated 125I-bovine serum albumin (denatured 125I-BSA) in livers of mice was studied in detail. Five basic compounds (BTTB, chloroquine, methylamine, ammonium chloride, and vinblastine) were tested. All the basic compounds inhibited the degradation of exogenous protein in lysosomes. When p-biphenylmethyl-(dl-tropyl-alpha-tropinium)bromide (BTTB) was used, the most effective inhibition was obtained at the concentration of 3.2 mM. Also, vinblastine, a well-known inhibitor of microtubular function, inhibited the degradation of an exogenous protein to the similar extent as that of chloroquine. The inhibition of protein degradation caused by BTTB closely related to the uptake of BTTB into lysosomes. It is supposed that BTTB accumulates in lysosomes and that it inhibits the hydrolytic enzyme by neutralizing intralysosomal pH. Furthermore, it is supposed that BTTB, a quaternary ammonium compound, becomes a useful tool in the study of protein degradation in lysosomes as well as the typically lysosomotropic compounds (chloroquine, ammonium chloride, and methylamine).


Localized necrotizing arteritis of the central nervous system.
We describe a case of necrotizing arteritis of the brain in a 26-year-old man who presented as organic brain syndrome. The lesion has been confused clinically with acute encephalitis. At necropsy, no other abnormalities suggestive of systemic arteritis were found. Such CNS-restricted necrotizing arteritis of medium and small arteries in the absence of granuloma is extremely uncommon.


[Structure of the Surveillance and management of infectious diseases in the European Union. The EU surveillance networks and the European Centre for Disease Prevention und Control (ECDC)].
In 1998, the European Parliament and Council published the Decision on setting up a network for the epidemiological surveillance of communicable diseases in the Community. As a first step, the Network Committee (representatives of the Member States) and the Commission determined the diseases for European surveillance. Subsequently, case definitions were developed for these diseases. For rapid information exchange among Member States on serious diseases, outbreaks and the control measures taken, a web-based, password protected early warning system was established. In parallel disease-specific networks were developed for enhanced surveillance of important diseases. A training programme (EPIET) and a European bulletin (Eurosurveillance) complete the network. The directive on the monitoring of zoonoses constitutes the basis for the joint analysis and evaluation of data on human illnesses, animals and foods. Starting in May 2005, the coordination and further development of the Community Network will be carried out by the European Centre for Disease Prevention and Control (ECDC).


A transformed murine myocardial vascular endothelial cell clone: characterization of cells in vitro and of tumours derived from clone in situ.
In the course of maintaining a cloned murine myocardium-derived endothelial cell line (mouse heart endothelial cell clone 5; MHEC5) a spontaneously transformed variant has been identified (clone MHEC5-T). On injection into histocompatible mice, clone MHEC5-T uniformly generated epithelioid haemangioendotheliomas. Clone MHEC5-T underwent significant additional alterations in addition to the acquisition of tumour-forming potential in vivo along with the diagnostic correlate of loss of cellular contact inhibition in vitro. Whereas the transformed cells maintained lectin-binding properties characteristic of endothelial cells, they lost the cell surface receptor(s) for acetylated low density lipoprotein and no longer bound antibodies to either angiotensin converting enzyme or von Willebrand factor-associated antigen. Vascular cell adhesion molecule-1 (VCAM-1), expressed constitutively on the parent clone, was down-regulated in the transformed cell line. The transformed cells acquired immunoreactivity to antibodies directed against cytokeratin, and they showed a markedly increased response to migration-inducing factors in vitro. The cell line described in this report demonstrates that the in vitro transformation of myocardium-derived endothelial cells can lead through transitional stages of differentiation to a new stable phenotype characterized by endothelial--to--epithelioid transition. The study of MHEC5-T cells, in addition to providing insight into the biology of cardiac neoplasms, may help to elucidate regulatory mechanisms involved in endothelial cell activation, transition and transformation.


Studies on the preparation and properties of ribonucleoprotein particles from rat liver nuclei.
Ribonucleoprotein particles of 38 S were extracted from rat liver nuclei with isotonic salt buffer under concomitant sonication. The fate of the endogeneous nuclear RNAases assayed with poly(A), high molecular weight yeast RNA and rapidly labeled hnRNA was followed during the preparation of 38-S nuclear ribonucleoprotein (nRNP) particles. Essentially all the RNAase activity could be removed from the particle preparation. The effect of synthetic RNAase inhibitors on the nRNP particles was studied. Upon extraction of nuclei with 0.14 M NaCl, approximately 38% of the total nuclear radioactivity was found in the 38-S nRNP particles. By two successive extractions of the remaining chromatin with either isotonic or 0.22 and 0.3 M NaCl, an additional 25 and 9% of rapidly labeled hnRNA of 38 S particle were dissociated from chromatin, respectively. The chromatin components, DNA, nonhistone proteins, histones and RNA were determined after successive salt extractions. Particularly alterations in the nonhistone proteins and RNA were found. The protein patterns upon SDS-acrylamide gel electrophoresis of the salt-extracted chromatin preparations were compared with those of the 38-S nRNP particles. Particularly proteins in the molecular weight range of 32 000-43 000 were dissociated from chromatin after treatment with 0.22 or 0.3 M NaCl.


Age-dependent changes in the activities of ATPase and some pyridine nucleotide-linked enzymes in the chick testis.
The ontogeny of some of the enzymes connected with carbohydrate metabolism in the testis were studied in the White-Rock chicks. In the first place testicular growth in these chicks relate to their overall growth as measured by their body weights. ATPase and NAD+-dependent succinic dehydrogenase activities decreased both with advancing age and increasing testicular weight. However, these enzymes showed maximum activities at 17 and 28 weeks respectively. NAD+-linked isocitric dehydrogenase activity continually increased with increasing testicular weight and age. It is suggested that during spermatogenesis the activities of these enzymes are controlled by different developmental mechanisms.


Surgical treatment of otitis media with effusion in Maori children.
This study aimed to compare the incidence and outcomes of Maori and non-Maori children with otitis media with effusion who underwent myringotomy plus ventilation tube insertion (MVTI). De-identified extraction of Auckland District Health Board (ADHB) morbidity records belonging to all children who underwent an MVTI procedure between January 1996 and June 2016 at Starship Children's Hospital was performed. Demographic, procedural and outcome data were analysed. A total of 11 941 children aged less than 10 years underwent at least one MVTI procedure in the Auckland region from January 1996 to June 2016. Of those, 2387 (20%) were Maori and 9554 (80%) were non-Maori. There was no difference in gender, age, length of stay, 30-day readmissions or complications between Maori and non-Maori at index or subsequent surgeries. Maori were not more likely than non-Maori to require subsequent MVTI (P = 0.13). There was no difference between Maori and non-Maori rates of having MVTI alone (P = 0.11) or MVTI with adenoidectomy ± tonsillectomy (P = 0.61). Some epidemiological evidence suggests that Maori have a higher incidence of middle ear disease in the community. However, this study indicates that there is no difference in the post-operative course between Maori and non-Maori children.


Protective effect of resveratrol against chronic intermittent hypoxia-induced spatial memory deficits, hippocampal oxidative DNA damage and increased p47Phox NADPH oxidase expression in young rats.
Long-term intermittent hypoxia (IH) is a characteristic hallmark of obstructive sleep apnea (OSA) and causes most of the neurological aspects of OSA, such as spatial memory and learning deficits. These deficits are accompanied by an increase in oxidative stress and inflammation in brain areas involved in cognition, such as the hippocampus, particularly in children. Resveratrol is a natural polyphenolic compound with potent antioxidant, anti-inflammatory and neuroprotective properties. The aim of this work is to study the possible protective effect of resveratrol against IH-induced neurobehavioral deficits and to investigate the possible mechanism of this protective effect in the young rat model of OSA. The effect of resveratrol (5 and 10mg/kg, orally) on anxiety, spatial memory and learning deficits in young rats exposed to IH for 6 weeks and the corresponding biochemical changes were studied. Resveratrol attenuated IH-induced anxiety and spatial memory deficits, as indicated by the elevated plus maze and Morris water maze tests, respectively, in a dose-dependent manner. In addition, resveratrol antagonized IH-induced increases in hippocampal glutamate, TBARS and 8-OHdG levels and p47Phox expression and decreases in GSH levels and GSH-Px activity in the hippocampus of IH-exposed young rats. Resveratrol ameliorates IH-induced anxiety and spatial learning deficits through multiple beneficial effects on hippocampal oxidative pathways that involve decreased expression of the p47Phox subunit of NADPH oxidase. Hence, the potential therapeutic role of resveratrol in OSA may be utilized in the near future and deserves further exploration.


Complete sequence and genetic characterization of a novel insect-specific reovirus discovered from Laodelphax striatellus.
The small brown planthopper, Laodelphax striatellus (Hemiptera: Delphacidae), is an efficient vector of several economically important plant viruses. In this study, a novel reovirus-like virus was identified in L. striatellus, named Laodelphax striatellus reovirus (LSRV). The complete genome of LSRV was 28,207 nt, comprising of ten segments encoded 11 deduced proteins. All genome segments were conserved with AGUAA at the 5'-terminal and GUUGUC at 3'-terminal and segment-specific inverted terminal repeats. In addition, genomic characteristics and phylogenetic analysis suggested that LSRV was a new member of genus Fijivirus. Importantly, LSRV was widely distributed in various tissues and highest expressed in adult heads. However, LSRV was unable to horizontal replication in rice plants. Moreover, typical profiles of LSRV-derived small interfering RNAs indicated host antiviral RNA interference pathway was involved in LSRV infection. In conclusion, LSRV may be considered as a new species of the genus Fijivirus in the order Reovirales.


[Patient safety in nursing homes. The experience of the Autonomous Community of the Region of Murcia].
The pandemic has exposed the vulnerability of residential centers and the fragility of the population that lives there. In the Region of Murcia, care for this population group became a priority and a regional plan was drawn up to attend the needs of residents from the ethical framework of procedural justice. The immediacy imposed by the health crisis has meant that all this intervention is not without risks. Based on the Reason model, we have carried out a root cause analysis of the contributing factors that led the nursing homes to suffer a devastating impact, categorizing the security failures at three levels: infection control, social health environment and health-clinical environment. The pandemic has shown the urgency of strengthening the care model that we offer to our elders. A model that guarantees the coverage of the needs of extremely fragile patients that go beyond health and biomedical care and that considers their preferences and values.


Heat shock protein--peptide complexes as immunotherapy for human cancer.
Heat shock proteins (Hsps), ubiquitous in nature, act as chaperones for peptides and other proteins. They have been implicated in loading immunogenic peptides onto major histocompatibility complex molecules for presentation to T cells. When isolated from tumor cells, Hsps are complexed with a wide array of peptides, some of which serve as tumor-specific antigens. Animal studies have demonstrated that heat shock protein--peptide complexes (HSPPCs) from tumor cells can act as vaccines to prevent or treat tumors. Potent and specific tumor antigens have long been the holy grail in cancer immunotherapy; HSPPCs from tumor cells could become a safe and reliable source of tumor-specific antigens for clinical application.


Influence of water quality on in vitro fertilization and embryo development for the mouse.
Mouse in vitro fertilization and embryo culture were performed in media prepared with five different water preparations. The results of the experiments improved with the frequency of distillation. Each water preparation was analyzed by the measurement of the electrical conductivities and inorganic ion concentrations and by high-performance liquid chromatography to examine the mutual relation between water quality and the method of water purification. The best results were obtained with Milli-Q water, which had the lowest concentration of inorganic ions and organic compounds. On the contrary, unexpected contamination by organic compounds and zinc ions occurred after multiple distillation, possibly leached from the glassware and silicon tube. The hatching rate seemed to be an appropriate indicator to assess the biological qualities of media for the development of embryos cultured in vitro.


Infertility considerations in klinefelter syndrome: From origin to management.
Klinefelter syndrome (KS) is defined as the presence of one or more extra "X" chromosome in a male patient. It affects approximately 1 in 600 newborn males and the most common chromosomal abnormality, leading to male hypogonadism and infertility. There is a lack of data supporting best practices for KS patients' care. In this paper we review controversial issues in KS research ranging from mechanisms of variation in KS phenotype to abnormalities resulting in reduced sperm production to successful sperm retrieval disparities after testicular sperm extraction (TESE). Translation to live birth and offspring health is also examined. Finally, medical therapies used to optimize the hormonal status and chances of fertility in KS patients are reviewed. We will also discuss the experimental spermatogonial stem cell (SSC) treatments, which are considered the future for TESE negative patients.


Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles.
First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not standardized. We report here the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups. Patient's staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported. 25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group. Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup.


Lateral cephalometric analysis of the pharyngeal airway space affected by head posture.
To clarify the relationship between head posture and pharyngeal airway space (PAS), the cephalometric parameters at different head postures were examined. Twelve normal Japanese adults (6 males and 6 females) were examined. Lateral cephalometric radiographs were taken at five different head postures in each person. All radiographs were traced, and the measurements were analyzed statistically. PAS was significantly increased by forward inclination of the cervical spine. The most significant correlation was found between the change in CVT/NSL (cranio-cervical inclination in the second and fourth vertebrae) and the change in PAS-TP (the minimal pharyngeal airway space) (r(2)=0.79 in males, r(2)=0.67 in females). The mean CVT/NSL when the head was in the natural (neutral) position was 100.9 degrees in males and 103.5 degrees in females. Linear regression analysis revealed DeltaPAS (mm)=0.37DeltaCVT/NSL (degree) (r(2)=0.79, p<0.0001) in males, and DeltaPAS (mm)=0.33DeltaCVT/NSL (degree) (r(2)=0.51, p<0.0001) in females. The correlation equations were obtained as follows: the corrected PAS (mm)=the actual PAS (mm)+0.37[100.9-the actual NSL/CVT (degree)] in males, and the corrected PAS (mm)=the actual PAS (mm)+0.33[103.5-the actual NSL/CVT (degree)] in females. These results will contribute to obtaining an accurate assessment of the PAS that should be corrected by the cranio-cervical inclination.


Investigation of superconducting gap structure in HfIrSi using muon spin relaxation/rotation.
We have investigated the superconducting state of HfIrSi using magnetization, specific heat, muon spin rotation and relaxation ([Formula: see text]SR) measurements. Superconductivity was observed at [Formula: see text] K in both specific heat and magnetization measurements. From an analysis of the transverse-field [Formula: see text]SR data, it is clear that the temperature variation of superfluid density is well fitted by an isotropic Bardeen-Cooper-Schrieffer (BCS) type s-wave gap structure. The superconducting carrier density [Formula: see text] m-3, the magnetic penetration depth, [Formula: see text] nm, and the effective mass, [Formula: see text], were calculated from the TF-[Formula: see text]SR data. Zero-field [Formula: see text]SR data for HfIrSi reveal the absence of any spontaneous magnetic moments below [Formula: see text], indicating that time-reversal symmetry (TRS) is preserved in the superconducting state of HfIrSi. Theoretical investigations suggest that the Hf and Ir atoms hybridize strongly along the c-axis, and that this is responsible for the strong three-dimensionality of this system which screens the Coulomb interaction. As a result, despite the presence of d-electrons in HfIrSi, these correlation effects are weakened, making the electron-phonon coupling more important.


Serum thrombomodulin levels in patients with typhoid fever.
Elevated plasma or serum levels of thrombomodulin (TM) have been reported in some diseases. However, to our knowledge, plasma and serum levels of TM have not been investigated in febrile patients with typhoid fever. Serum TM and creatinine levels were determined in 7 male Japanese febrile patients with typhoid fever and 6 male Japanese healthy controls. The serum TM values of the patients and controls, in arbitrary units/mL, were 5.04 (SD = 1.69) and 2.93 (SD = 0.74), respectively (P < 0.025). The serum creatinine levels of the patients and controls were 0.93 (SD = 0.16) mg/dL and 0.77 (SD = 0.10) mg/dL, respectively, and the lack of any significant difference between them suggests that delayed clearance from the kidneys was not the predominant explanation for the elevated serum TM levels. Although the numbers of patients and controls were small and more studies are needed, we conclude that elevated serum TM levels during the course of a febrile infection with Salmonella serovar typhi may reflect the disease activity.


Association Between Opioid Prescribing Patterns and Abuse in Ophthalmology.
Drug overdoses have become the number 1 cause of mortality in American adults 50 years and younger. Prescription opioid abuse is a growing concern that has garnered widespread attention among policymakers and the general public. To determine the opioid prescribing patterns among ophthalmologists and elucidate their role in the prescription opioid abuse epidemic. In this observational cohort study, beneficiaries and their physicians were analyzed using 2013 to 2015 Medicare Part D Prescriber Data. The Centers for Medicare and Medicaid Services Medicare Part D Prescriber Public Use Files for 2013, 2014, and 2015 were accessed. Analysis began in June 2017. Data were collected and analyzed regarding the prescribing patterns for opioid drugs (eg, number of prescriptions written including refills, number of days' supply, and prescriber rates) for all participating ophthalmologists. The mean number of opioid prescriptions written annually by ophthalmologists; prescriber rates compared with all prescriptions written; and geographic distribution of opioid prescriptions written per ophthalmologist. In 2013, 4167 of 19 615 ophthalmologists were women (21.2%). Consistently, most ophthalmologists (88%-89%) wrote 10 opioid prescriptions or fewer annually. Approximately 1% (0.94%-1.03%) of ophthalmologists wrote more than 100 prescriptions per year. On average, ophthalmologists wrote 7 opioid prescriptions per year (134 290 written annually by 19 638 physicians, on average) with a mean supply of 5 days. The 6 states with the highest volume of opioid prescriptions written annually per ophthalmologist were located in the southern United States. In general, ophthalmologists show discretion in their opioid prescribing patterns. The present opioid abuse epidemic should prompt physicians to consider revisiting their prescribing protocols given the high risk for dependency.


Synergistic photocatalysis of Cr(VI) reduction and 4-Chlorophenol degradation over hydroxylated α-Fe2O3 under visible light irradiation.
A series of Fe2O3 materials with hydroxyl are synthesized in different monohydric alcohol (C2-C5) solvents by solvothermal method and characterized by XRD, BET, XPS, TG and EA. The amount of hydroxyl is demonstrated to be emerged on the surface of the as-synthesized Fe2O3 particles and their contents are determined to be from 7.99 to 3.74 wt%. The Cr(VI) reduction experiments show that the hydroxyl content of Fe2O3 samples exacts great influence on the photocatalytic activity under visible light irradiation (λ>400 nm) and that the Fe2O3 sample synthesized in n-butyl alcohol exhibits the optimal photocatalytic activity. The synergistic photocatalysis for 4-Chlorophenol (4-CP) degradation and Cr(VI) reduction over above Fe2O3 sample is further investigated. The photocatalytic ratio of Cr(VI) reduction are enhanced from 24.8% to 70.2% while that of 4-CP oxidation are increased from 13.5% to 47.8% after 1 h visible light irradiation. The Fe2O3 sample keeps good degradation rates of mixed pollutants after 9 runs. The active oxygen intermediates O2(-)˙, ˙OH and H2O2 formed in the photoreaction process are discovered by ESR measurement and UV-vis test. The photocatalytic degradation mechanism is proposed accordingly.


Uterine choriocarcinoma coexistence with endometroid adenocacinoma: a case report and literature review.
Choriocarcinoma coexisting with endometrial carcinoma is rare. To the best of our knowledge, only one case of choriocarcinoma coexisting with endometrial carcinoma has been reported. Here, we present this case and provide a literature review. A 38-year-old unmarried nulliparous woman presented to the clinic with a menstrual disorder for more than 3 months. She then underwent a hysteroscopic procedure. The pathological findings were malignant, two types of carcinoma, and no transitional lesions were observed; about 85% of them were choriocarcinoma with smooth muscle infiltration and intravascular investigation of the thrombus; about 15% were highly differentiated endometrioid adenocarcinoma; Immunohistochemistry (endometrioid/choriocarcinoma): Vim (+ + / + + +), P40 (+ ±), CK5/6 multifocal ( ±), CK7 ( ±), EMA (+ ±), P16 multifocal ( ±), P53 (+ / + +), WT-1 (-/ + +), hCG (-/ + + +), CD138 (-/ + + +), Gly-3 (-/-), ER ( ±), PR (+ ±), Sall-4 (-/-), P21 (-/ +), P27 (-/ + + +), CyclinE (-/ + +), Ki67 positivity rate (10%/95%). We performed a laparoscopic hysterectomy, bilateral adnexectomy, and pelvic and para-abdominal lymph node dissection after five cycles of chemotherapy. She was diagnosed with choriocarcinoma with endometrial cancer, stage IVb choriocarcinoma and stage IA endometrial cancer. Postoperative radiochemotherapy was administered. The patient was disease-free 40 months after the treatment ended. We report a case of choriocarcinoma coexisting with endometrial carcinoma and provide a literature review that may help inspire additional studies in the future.


Inhibition of mitochondrial calcium uniporter protects neurocytes from ischemia/reperfusion injury via the inhibition of excessive mitophagy.
Mitophagy plays an important role in mitochondrial quality control and cell survival during the process of ischemia/reperfusion (I/R) injury. Mitochondrial calcium uniporter (MCU) is the most important channel responsible for Ca(2+) influx into mitochondria and Ca(2+) signal plays a potential role in modulating mitophagy. However, the effect of MCU on mitophagy during the process of I/R injury remains unknown. This study constructed an in vitro I/R model by subjecting oxygen and glucose deprivation/reperfusion (OGD/RP) model to SH-SY5Y cells to mimic the cerebral I/R injury and aimed to explore the exact effect of MCU on I/R induced mitophagy. The results showed that OGD/RP induced autophagy and mitophagy in SH-SY5Y cells. Ru360, the inhibitor of MCU, improved mitochondrial morphology and fuctional stability as well as cell viability, significantly reduced OGD/RP induced mitophagy as evidenced by the decrease in Beclin-1 and the increase in Tom20 and P62 expression. Whereas spermine, the agonist of MCU, had no significant impact on the expression of those mitophagy related proteins compared with OGD/RP group. This study indicates that inhibition of MCU can inhibit excessive mitophagy and protect the neurocytes from I/R injury.


The effects of temporal modulation on the oblique effect in humans.
Contrast thresholds were measured for vertical and oblique grating patterns. As shown previously, at higher spatial frequencies sensitivity for vertical is much greater than that for oblique. Present results show that this difference is sensitivity is found only with low rates of temporal modulation; with higher temporal frequencies this orientation difference disappears. Moreover, when contrast thresholds are based on the perception of flicker, vertical and oblique sensitivities are essentially identical even at low flicker rates. These results indicate that the so-called "oblique effect' is confined to mechanisms with poor temporal resulving power, probably the sustained channels which have been studied psychophysically and neurophysiologically by others.


Prediction of incident atherosclerotic cardiovascular disease with polygenic risk of metabolic disease: Analysis of 3 prospective cohort studies in Korea.
Studies have demonstrated that the risk of atherosclerotic cardiovascular disease (ASCVD) can be assessed by polygenic risk score (PRS) using common genetic variants. Because metabolic syndrome is a well-known, robust risk factor of ASCVD, we established PRS of metabolic disease and analyzed whether this PRS could predict incident ASCVD. We constructed PRSs for eight quantifiable metabolic phenotypes-systolic/diastolic blood pressure, body mass index (BMI), four blood lipid components, and fasting blood glucose-by genome-wide association studies of two prospective Korean cohorts (n = 37,285). We conducted a grid search of combinations of metabolic PRSs to identify the most optimal weighted score for incident ASCVD (PRSMetS-ASCVD). The utility of PRSMetS-ASCVD was validated in an independent prospective cohort (n = 4333). The individuals in the highest PRS quintile demonstrated a 1.4-2.0-fold increased risk of incident hypertension, obesity, hyperlipidemia, and diabetes. Using the PRSMetS-ASCVD, we identified 6.7% of the population as a high risk group demonstrating a 3.3-fold (95% confidence interval 1.7-6.1, p < 0.001) higher risk for incident ASCVD. The model combining the PRSMetS-ASCVD demonstrated a better performance for predicting ASCVD than that consisting of only conventional risk factors, such as age, sex, BMI, smoking, hypertension, diabetes and hyperlipidemia. The population with high PRSMetS-ASCVD minimally overlapped with that of high Framingham risk score, thus suggesting the additive independent benefits beyond the Framingham risk score, especially in younger individuals. The polygenic risk of metabolic disease independently predicts those at an increased risk of ASCVD, identifying those at a genetically high risk of incident ASCVD.


Pre-existing frontal lobe dysfunction signs as predictors of subsequent neurotoxicity in CAR T cell therapy: insights from a case series.
Chimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell-associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity. In our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction. Based on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy.


Behavioral medicine in the general hospital.
The application of behavioral procedures to the treatment of medical disorder has greatly expanded the techniques available to the psychiatrist practicing in the general hospital. While there are diverse behavioral strategies that have proven quite useful, the bases for these are limited and readily implemented in the hospital setting. In this paper, the behavioral methods of assessment and various strategies of treatment of medical, psychophysiological, and "psychosomatic" disorders are overviewed.


Reconstruction of the middle third of mandible.
The radial forearm flap is established as a suitable method of providing bone with soft tissue lining or skin cover in reconstruction of the mandible. A simple and effective method of modelling the radius to provide the appropriate contour to the anterior arch of the mandible is described.


Neuropeptides in the thyroid gland: distribution of substance P and gastrin/cholecystokinin and their effects on the secretion of iodothyronine and calcitonin.
Previously, vasoactive intestinal polypeptide was localized to intrathyroidal nerve fibers. It stimulates iodothyronine secretion in mice. In the present study two populations of nerve fibers containing substance P and gastrin/cholecystokinin (CCK)-like immunoreactivity, respectively, were demonstrated in the thyroid gland of several mammals. The substance P fibers occurred around blood vessels and follicles, whereas the gastrin/CCK fibers occurred mainly around follicles. In the chicken thyroid and ultimobranchial glands only substance P-containing fibers could be demonstrated. Such fibers were particularly numerous in the ultimobranchial gland. CCK-4, CCK-8, and substance P did not increase thyronine secretion measured as release of radioiodine into the circulation of mice pretreated with Na125I and T4. The TSH-induced release of radioiodine was also unaffected. Calcitonin secretion in rats was stimulated by CCK-4, CCK-8, substance P, and vasoactive intestinal polypeptide.


Corrigendum: Improving Hand Function of Severely Impaired Chronic Hemiparetic Stroke Individuals Using Task-Specific Training With the ReIn-Hand System: A Case Series.
[This corrects the article DOI: 10.3389/fneur.2018.00923.].


Differences in number and activity of peripheral natural killer cells in primary versus secondary recurrent miscarriage.
To compare peripheral natural-killer (NK) cell numbers and activity in women with primary recurrent miscarriage, secondary recurrent miscarriage and controls. Observational study. Academic medical center. Thirty-eight women with primary recurrent miscarriage, 29 women with secondary recurrent miscarriage, and 25 control women. None.[1] The proportion of NK cells in the total lymphocyte population, [2] the concentration of NK cells per microliter of blood, and [3] NK activity (NKA), using both standard and whole-blood assays. Primary aborters had the highest proportion and concentration of NK cells and had the highest activity using the standard assay. Secondary aborters had an intermediate level of these NK cell indices, whereas the control patients had the lowest levels. Using the whole-blood NKA assay, the differences between primary and secondary aborters were most apparent: primary aborters had significantly higher NKA than did either secondary aborters or control women (72, 40, and 35 lytic units, respectively). Approximately 50% of the variability in NKA could be attributed to differences in concentrations of NK cell per microliter of blood. The higher NKA evident in primary recurrent miscarriage and the reported higher efficacy of immunotherapy in primary aborters support the involvement of NK cells in the etiology of primary recurrent miscarriage.


Subject-specific calibration of neuromuscular parameters enables neuromusculoskeletal models to estimate physiologically plausible hip joint contact forces in healthy adults.
In-vivo hip joint contact forces (HJCF) can be estimated using computational neuromusculoskeletal (NMS) modelling. However, different neural solutions can result in different HJCF estimations. NMS model predictions are also influenced by the selection of neuromuscular parameters, which are either based on cadaveric data or calibrated to the individual. To date, the best combination of neural solution and parameter calibration to obtain plausible estimations of HJCF have not been identified. The aim of this study was to determine the effect of three electromyography (EMG)-informed neural solution modes (EMG-driven, EMG-hybrid, and EMG-assisted) and static optimisation, each using three different parameter calibrations (uncalibrated, minimise joint moments error, and minimise joint moments error and peak HJCF), on the estimation of HJCF in a healthy population (n = 23) during walking. When compared to existing in-vivo data, the EMG-assisted mode and static optimisation produced the most physiologically plausible HJCF when using a NMS model calibrated to minimise joint moments error and peak HJCF. EMG-assisted mode produced first and second peaks of 3.55 times body weight (BW) and 3.97 BW during walking; static optimisation produced 3.75 BW and 4.19 BW, respectively. However, compared to static optimisation, EMG-assisted mode generated muscle excitations closer to recorded EMG signals (average across hip muscles R2 = 0.60 ± 0.37 versus R2 = 0.12 ± 0.14). Findings suggest that the EMG-assisted mode combined with minimise joint moments error and peak HJCF calibration is preferable for the estimation of HJCF and generation of realistic load distribution across muscles.


Characteristics of optic disc melanocytomas presenting with visual dysfunction.
A retrospective review study was designed to describe five cases of optic disc melanocytomas with tumor-related visual impairment. Five patients with optic disc melanocytoma presented with visual complaints to a tertiary eye hospital in Saudi Arabia. Demographic and clinical data were analyzed, including the results of ocular examination, lesion laterality, best-corrected Snellen visual acuity, pupillary reflex, visual field testing, color fundus photography, fundus fluorescein angiography, and ophthalmic ultrasound. Visual dysfunction secondary to optic disc melanocytoma was identified. Case 1 had macular star edema with mild tumor enlargement, Case 2 had optic atrophy, Case 3 had juxtapapillary choroidal neovascular membrane with macular involvement, Case 4 had optic disc swelling with an enlarged blind spot, and Case 5 had a large altitudinal visual field defect. Although melanocytomas of the optic disc tend to have a benign behavior with slow evolution and stable vision, they may adversely affect visual function through a variety of mechanisms.


[Assessment of allergenicity of genetically modified food crops].
The placing on the European Union's market of genetically modified crops requires authorization by the European Commission which is based on the proof that the derived foods are as safe as their conventional counterparts. The assessment of potential allergenicity is part of the necessary investigations recommended in the updated Guidance Document of the Scientific Panel on Genetically Modified Organisms (GMO) of the European Food Safety Authority (EFSA), which is based on internationally agreed recommendations. All genetically modified crops which so far have been authorized in the European Union were evaluated by the EFSA GMO Panel which considered it unlikely that their overall allergenicity has been altered.


Netilmicin in human CSF after parenteral administration in patients with slightly and severely impaired blood CSF barrier.
After administration of 150 mg netilmicin samples of CSF and blood were obtained. In one group of nine patients with no or only slight impairment of the blood-CSF-barrier 29 samples of CSF were assayed for netilmicin concentrations. All samples, obtained after the first dose, failed to reveal detectable drug levels. Drug levels up to 0.18 mg/l were detected in samples of CSF of three patients after 3 to 22 doses. Only the lumbar CSF of one patient contained netilmicin concentrations higher than 1.0 mg/l. In comparison 19 samples of CSF, obtained from patients with meningitis after more than one dose of netilmicin, had levels of 0.27-5.0 mg/l. Three CSF samples from patients out of this group, collected after the first dose of netilmicin failed to show any drug activity.


The electrocardiogram in right ventricular myocardial infarction.
Right ventricular (RV) myocardial infarction most often occurs in the setting of inferior wall myocardial infarction. Right ventricular infarction complicates approximately 25% (range, 20%-60%) of inferior acute myocardial infarction; it is uncommon to quite rare in anterior and lateral wall acute myocardial infarction. With infarction of the RV, the RV will fail. As such, left ventricular filling pressures are entirely dependent upon the patient's preload; with significant reductions in the preload, hypotension likely results (this hypotension may be worsened by nitroglycerin and morphine). The clinical presentation, in the setting of an ST-elevation myocardial infarction (STEMI) of the inferior wall, involves hypotension, jugular venous distension, and the following electrocardiographic findings: ST-segment elevation of greatest magnitude in lead III (compared with leads II and aVF), ST-segment elevation in lead V1, and/or ST-segment elevation in right chest leads (RV1 through RV6). Therapy, in addition to appropriate management for STEMI, relies largely on enhancing the preload with intravenous fluid and judicious use of vasodilator medications. Patients with inferior wall STEMI with RV infarction have a markedly worse prognosis (both acute cardiovascular complications and death) compared with patients with isolated inferior wall STEMI.


Deletion of Lysophosphatidic Acid Receptor 3 (Lpar3) Disrupts Fine Local Balance of Progesterone and Estrogen Signaling in Mouse Uterus During Implantation.
Lpar3 encodes LPA3, the third G protein-coupled receptor for lysophosphatidic acid (LPA). Lpar3(-/-) female mice had delayed embryo implantation. Their serum progesterone and estrogen levels were comparable with control on Gestation Day 3.5 (D3.5) at 1100 h. There was reduced cell proliferation in D3.5 and D4.5 Lpar3(-/-) stroma. Progesterone receptor (PGR) disappeared from D4.5 Lpar3(+/+) uterine luminal epithelium (LE) but remained highly expressed in D4.5 Lpar3(-/-) LE. Pgr and PGR- target genes but not estrogen receptor alpha (ERalpha [Esr1]) or ESR target genes, were upregulated in D4.5 Lpar3(-/-) LE. It was hypothesized that suppression of PGR activity in LE could restore on-time uterine receptivity in Lpar3(-/-) mice. A low dose of RU486 (5 μg/mouse) given on D3.5 at 900 h rescued delayed implantation in all pregnant Lpar3(-/-) females and significantly increased number of implantation sites compared to vehicle-treated pregnant Lpar3(-/-) females detected on D4.5. E2 (25 ng/mouse) had a similar effect as 5 μg RU486 on embryo implantation in Lpar3(-/-) females. However, when the ovaries were removed on late D2.5 to create an experimentally induced delayed implantation model, 25 ng E2 activated implantation in Lpar3(+/+) but not Lpar3(-/-) females detected on D4.5. These results demonstrate that deletion of Lpar3 leads to an increased ratio of progesterone signaling/estrogen signaling that can be optimized by low doses of RU486 or E2 to restore on-time implantation in Lpar3(-/-) females.


An improved method for measuring aggregation of certain streptococcal bacteria found in dental plaque.
Various cells were incubated with either dextran or sucrose and the reaction was terminated by the addition of a 20 per cent solution of formaldehyde. A reaction mixture consisting of cells and aggregated cells was applied to a step-gradient glycerol column (0-60 per cent) and 0.5 ml fractions were collected from the bottom of the column. Non-aggregated cells remained in the top layer of the column. Aggregated cells settled in the 30 per cent glycerol layer as determined by either spectrophotometric or radioactive methods. The amount of aggregated cells demonstrated in this layer increased with either incubation time or concentration of sucrose, dextran or cells. Cells of Strep, mutans strains 6715, AHT, 10449, OMZ-176, OMZ-175 and two mutants of Strep. mutans strain 6715 (designated C4 and C307) aggregated strongly. Cells of Strep. mutans strain LM7 aggregated weakly, whereas cells of Strep. mutans 6715 mutant UAB165, a mutant defective in aggregation. Strep. mutans strain BHT, Strep. salivarius and Strep. sanguis did not aggregate in the presence of either sucrose or dextran. Experiments testing co-aggregation between two different types of cells were done by using 3H-labelled and 14C-labelled cells. Strep. mutans strain 6715 co-aggregated with Strep. sanguis in the presence of sucrose or dextran, whereas Strep. mutans strain 6715 did not aggregate with Strep. salivarius. The method separates aggregated from non-aggregated cells and enables quantitation of sucrose- or dextran-induced aggregation and co-aggregation.


Differentiating psychogenic nonepileptic seizures from epileptic seizures: An observational study of patients undergoing video-electroencephalography (VEEG) in Australia.
Video-electroencephalography (VEEG) is an invaluable tool for the differentiation of psychogenic nonepileptic seizures (PNES) from epileptic seizures (ES). This paper (i) evaluates the demographics of patients undergoing VEEGs at the Princess Alexandra Hospital from July 1 2017 to July 1 2019 and identifies those subsequently diagnosed with PNES, (ii) determines the delay in PNES diagnosis and proportion of PNES patients on antiepileptic drugs (AEDs) prior to a VEEG, and (iii) determines the proportion of PNES patients who subsequently ceased their AEDs. Of the 94 patients in the study group, 51 were female and 43 were male. In total, 22 (23%) of VEEGs were consistent with epilepsy (ES), 25 (26%), with PNES, 5 (5%) mixed (PNES and ES), 5 (5%) with other types of events, and 37 were nondiagnostic. Two patients with non-diagnostic VEEGs were subsequently treated as PNES at the treating clinician's discretion. Regarding AEDs, 62 of the patients were on at least one agent at the time of VEEG recording. The mean durations of AED therapy and diagnostic delay for patients subsequently diagnosed with PNES were six years and seven years, respectively. Of these, the majority had their AEDs subsequently weaned/ceased. This study highlights the value of VEEG in diagnostic differentiation of epileptic from nonepileptic events, thereby preventing unnecessary AED therapy for patients with PNES. The results are consistent with previous studies in the literature evaluating VEEG clinical outcomes.


Homology induction: the use of machine learning to improve sequence similarity searches.
The inference of homology between proteins is a key problem in molecular biology The current best approaches only identify approximately 50% of homologies (with a false positive rate set at 1/1000). We present Homology Induction (HI), a new approach to inferring homology. HI uses machine learning to bootstrap from standard sequence similarity search methods. First a standard method is run, then HI learns rules which are true for sequences of high similarity to the target (assumed homologues) and not true for general sequences, these rules are then used to discriminate sequences in the twilight zone. To learn the rules HI describes the sequences in a novel way based on a bioinformatic knowledge base, and the machine learning method of inductive logic programming. To evaluate HI we used the PDB40D benchmark which lists sequences of known homology but low sequence similarity. We compared the HI methodology with PSI-BLAST alone and found HI performed significantly better. In addition, Receiver Operating Characteristic (ROC) curve analysis showed that these improvements were robust for all reasonable error costs. The predictive homology rules learnt by HI by can be interpreted biologically to provide insight into conserved features of homologous protein families. HI is a new technique for the detection of remote protein homology--a central bioinformatic problem. HI with PSI-BLAST is shown to outperform PSI-BLAST for all error costs. It is expect that similar improvements would be obtained using HI with any sequence similarity method.


The short-term effect of ozone on pregnancy loss modified by temperature: Findings from a nationwide epidemiological study in the contiguous United States.
Pregnancy loss, a major health issue that affects human sustainability, has been linked to short-term exposure to ground-surface ozone (O3). However, the association is inconsistent, possibly because of the co-occurrence of O3 and heat episodes, as increased temperature is a risk factor for pregnancy loss. To explain this inconsistency, the effect of O3 on pregnancy loss needs to be examined jointly with that of high temperature. A total of 247,305 pregnancy losses during the warm season were extracted from fetal death certificates from the 386 counties in contiguous United States from 1989 to 2005. We assessed environmental exposure based on the daily maximum 8 h average of O3 from Air Quality System monitors and the 24 h average temperature from the North American Regional Reanalysis product. We conducted a bidirectional, time-stratified case-crossover study of the association between pregnancy loss and exposures to O3 and temperature and their multiplicative interaction. The main time window for the exposure assessment was the day of case occurrence and the preceding 3 days. To estimate the association, we used conditional logistic regression with adjustment for relative humidity, height of the planetary boundary layer, and holidays. Sensitivity analyses were performed on the lagged structure, nonlinearity, and between-subpopulation heterogeneity of the estimated joint effect. The joint effect was first estimated by the regression against categorical exposure by tertile. Compared to the low-low exposure group (O3 ≤ 78 μg/m3 and temperature ≤ 18 °C), the odds of pregnancy loss was significantly higher by 6.0 % (95 % confidence interval [CI] 2.4-9.7 %), 9.8 % (6.1-13.8 %), and 7.5 % (4.7-10.3 %) in the high-low (>104 μg/m3 and ≤18 °C), low-high (≤78 μg/m3 and >23 °C), and high-high (>104 μg/m3 and >23 °C) groups. The model of linear exposure and the multiplicative interaction yielded similar results. Each increment of 10 μg/m3 in O3 and 1 °C in temperature was associated with a 3.0 % (2.0 %-4.0 %) and 3.9 % (3.5 %-4.3 %), respectively, increase in the odds of pregnancy loss. A decrease in odds of 0.2 % (0.1 %-0.2 %) was associated with the temperature × O3 interaction. The finding of an antagonistic interaction between temperature and O3 was confirmed by models parametrizing the joint exposure as alternative nonlinear terms (i.e., a two-dimensional spline term or a varying-coefficient term) and was robust to a variety of exposure lags and stratifications. Therefore, the marginal effect of O3 was estimated to vary by climate zone. A significant association between O3 and pregnancy loss was observed in the northern, but not southern, United States. Joint exposure to O3 and high temperature can increase the risk for pregnancy loss. The adverse effect of O3 is potentially modified by ambient temperature. In high-latitude cities, controlling for O3 pollution could protect maternal health.


The regulatory function of the AAA4 ATPase domain of cytoplasmic dynein.
Cytoplasmic dynein is the primary motor for microtubule minus-end-directed transport and is indispensable to eukaryotic cells. Although each motor domain of dynein contains three active AAA+ ATPases (AAA1, 3, and 4), only the functions of AAA1 and 3 are known. Here, we use single-molecule fluorescence and optical tweezers studies to elucidate the role of AAA4 in dynein's mechanochemical cycle. We demonstrate that AAA4 controls the priming stroke of the motion-generating linker, which connects the dimerizing tail of the motor to the AAA+ ring. Before ATP binds to AAA4, dynein remains incapable of generating motion. However, when AAA4 is bound to ATP, the gating of AAA1 by AAA3 prevails and dynein motion can occur. Thus, AAA1, 3, and 4 work together to regulate dynein function. Our work elucidates an essential role for AAA4 in dynein's stepping cycle and underscores the complexity and crosstalk among the motor's multiple AAA+ domains.