Cinnamic acids derived compounds with antileishmanial activity target Leishmania amazonensis arginase.
This study describes the activity of five natural hydroxycinnamic acids and derived compound: caffeic (1), rosmarinic (2), chlorogenic (3), and cryptochlorogenic (4), acids and isoverbascoside (5). All compounds inhibited Leishmania amazonensis arginase with IC50 -in range of 1.5-11 μM. Compounds 2 and 5 also showed activity against promastigotes of L. amazonensis with IC50 = 61 (28-133) μM and IC50 = 14 (9-24) μM, respectively. Further computational studies applying molecular docking simulations were performed on the competitive inhibitors to gain insight into the molecular basis for arginase inhibition and could be exploited to the development of new antileishmanials drug targeting parasite arginase.


Temporal changes in PCB and DDE levels among a cohort of frequent and infrequent consumers of Great Lakes sportfish.
A variety of environmentally persistent contaminants of the Great Lakes Basin are able to bioaccumulate in the aquatic food chain and pose a threat to the health and reproductive success of people and wildlife that depend on locally caught fish as a source of dietary protein. Exposure to polychlorinated biphenyls (PCBs) and 1,1-bis(4-chlorophenyl)-2,2-dichloroethene (DDE) has been linked to higher rates of cancer, reproductive problems, and endocrine disorders. To investigate the effects of exposure to persistent contaminants of the Great Lakes Basin, the health departments of five Great Lakes states formed a health-assessment consortium. Between 1988 and 1994, the consortium collected demographic and fish consumption information from 2548 licensed charter boat captains, 182 anglers, and 1667 referents. Between 1994 and 1995, a subset of 619 participants in this study provided additional fish consumption information and donated blood samples that were analyzed for PCBs and DDE. Follow-up studies conducted between 2001 and 2005 re-assessed fish consumption rates and blood levels of PCBs and DDE in 293 of these individuals. While there was a trend for increasing overall fish consumption among most participant groups, sportfish and Great Lakes sportfish consumption decreased significantly in the captains over the study period. Serum DDE concentrations, which were highest in men in the captain and angler groups, declined in 90% of study participants. Mean DDE levels fell from 5.6 to 3.2 microg/L. Total PCB levels declined in 80% of participants with the mean concentration falling from 4.2 to 2.8 microg/L. Annual declines in serum DDE and PCB concentrations averaged 4.6% and 3.5%, respectively.


Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes.
The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED50=1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential.


Study of nitrogen removal efficiency of the filled bed reactors using alkali-treated corncobs-sulfur (mixotrophic) for treating the effluent from simulated urban wastewater plants.
China's urban wastewater treatment plants' nitrogen discharge standards have become more stringent in recent years. In this experiment, the filled bed denitrification system with corncob-sulfur as fillers were constructed for the secondary effluent of the wastewater. The optimum operating conditions of the denitrification reactor with different fillers as electron donors were investigated by varying the operating parameters. According to the experiment, the alkali pretreated corncobs could maintain long-term denitrification effect. The optimum HRT for the mixotrophic denitrification reactor with alkali-treated corncob-sulfur as filler was 1.5 h, with a minimum effluent NO3--N concentration of 0.31 mg/L and a removal rate of 98.62%, and effluent nitrite nitrogen, NH4+-N, and sulfate accumulation of 0.03 mg/L, 0.71 mg/L and 72.4 mg/L. The reactor with mixed nutrient type had the most abundant species community structure by high-throughput sequencing analysis.


Resolution of quantifier scope ambiguities.
Various processing principles have been suggested to be governing the resolution of quantifier scope ambiguities in sentences such as Every kid climbed a tree. This paper investigates structural principles, that is, those which refer to the syntactic or semantic positions of the quantified phrases. To test these principles, the preferred interpretations for three grammatical constructions were determined in a task in which participants made speeded judgments of whether a sentence following a doubly quantified sentence was a reasonable discourse continuation of the quantified sentence. The observed preferences cannot be explained by any single structural principle, but point instead to the interaction of several principles. Contrary to many proposals, there is little or no effect of a principle that assigns scope according to the linear order of the phrases. The interaction of principles suggests that alternative interpretations of the ambiguity may be initially considered in parallel, followed by selection of the single interpretation that best satisfies the principles. These results are discussed in relation to theories of ambiguity resolution at other levels of linguistic representation.


DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins.
It is now known that proteins associated with neurodegenerative disease can spread throughout the brain in a prionlike manner. However, the mechanisms regulating the trans-synaptic spread propagation, including the neuronal release of these proteins, remain unknown. The interaction of neurodegenerative disease-associated proteins with the molecular chaperone Hsc70 is well known, and we hypothesized that much like disaggregation, refolding, degradation, and even normal function, Hsc70 may dictate the extracellular fate of these proteins. Here, we show that several proteins, including TDP-43, α-synuclein, and the microtubule-associated protein tau, can be driven out of the cell by an Hsc70 co-chaperone, DnaJC5. In fact, DnaJC5 overexpression induced tau release in cells, neurons, and brain tissue, but only when activity of the chaperone Hsc70 was intact and when tau was able to associate with this chaperone. Moreover, release of tau from neurons was reduced in mice lacking the DnaJC5 gene and when the complement of DnaJs in the cell was altered. These results demonstrate that the dynamics of DnaJ/Hsc70 complexes are critically involved in the release of neurodegenerative disease proteins.


Epigenetics of Epstein Barr virus - A review.
Epstein Barr is the first-in-human oncogenic virus, closely related to numerous lymphoproliferative and malignant diseases, including HL, BL, NPC, and GC. EBV establishes life-long persistence infection portraying a biphasic viral life cycle: latent period and lytic replication. B-cells serve as critical regions for EBV latent genes, wherein viral gene expression is suppressed, promoting viral genome maintenance and immune recognition evasion. Upon its lytic reactivation, viral gene expression induces its replication, progeny production, and transmission. Dysregulations of epigenetic regulation in expressions of TSGs lead to carcinogenesis. Several studies reveal that EBV is associated with aberrant viral DNA and host genome methylation patterns, promoting immune monitoring, recognition evasiveness and host cell persistence. Among other epigenetic modifications, DNA methylation suppresses the majority of viral latent gene promoters, sparing a few, and acts as a prerequisite for activating EBV's lytic cycle, giving rise to viral progeny. It affects the host's epigenome via reprogramming cells to oncogenic, long-lasting phenotypes, as evident in several malignancies. At each phase of its life cycle, EBV exploits cellular mechanisms of epigenetic regulation, implying its unique host-pathogen relationship. This review summarized the DNA methylation's regulatory roles on several EBV-related promoter regions, along with the host genome in pathological conditions, highlights viral genes involved in a latent, lytic and latent-lytic phase of EBV infection. Moreover, it provides diagrammatic insights into methylation-based pathways in EBV.


VLDL receptor deficiency enhances intimal thickening after vascular injury but does not affect atherosclerotic lesion area.
The very low density lipoprotein receptor (VLDLR) has been shown to modulate cell migration and foam cell formation in vitro. This suggests a role for the VLDLR in vascular pathology associated with intimal thickening and atherogenesis. In the present paper both intimal thickening and atherosclerosis were studied using VLDLR knockout and transgenic mouse models. The role of the VLDLR in intimal thickening was established in an in vivo model for vascular injury. A non-restrictive cuff was placed around the femoral artery of VLDLR deficient (VLDLR-/-), heterozygous deficient (VLDLR+/-) and wild type (WT) mice. Intimal thickening was assessed after 3 weeks by determining the intima to media (I/M) volume ratio. Both VLDLR-/- (I/M ratio 42%) and VLDLR+/- (I/M ratio 40%) mice showed a significant increase as compared with WT littermates (I/M ratio 25%). The effect of VLDLR deficiency on atherosclerosis was examined in VLDLR-/- mice on an LDLR deficient (LDLR-/-) background. In addition, we assessed whether increased endothelial VLDLR expression levels affect atherosclerotic lesion formation. Therefore, atherosclerosis was studied in LDLR deficient mice that over express the VLDLR in endothelial cells (PVL, LDLR-/-). Both VLDLR deficiency and endothelial VLDLR over expression did not affect the atherosclerotic lesion size. Interestingly, VLDLR-/-, LDLR-/- mice showed a high incidence of necrosis in both fatty streaks and atherosclerotic plaques as compared with LDLR-/- mice (75 vs. 0% and 76 vs. 45%, respectively). In conclusion, deficiency for the VLDLR profoundly increased intimal thickening after vascular injury.


DESE: estimating driver tissues by selective expression of genes associated with complex diseases or traits.
The driver tissues or cell types in which susceptibility genes initiate diseases remain elusive. We develop a unified framework to detect the causal tissues of complex diseases or traits according to selective expression of disease-associated genes in genome-wide association studies (GWASs). This framework consists of three components which run iteratively to produce a converged prioritization list of driver tissues. Additionally, this framework also outputs a list of prioritized genes as a byproduct. We apply the framework to six representative complex diseases or traits with GWAS summary statistics, which leads to the estimation of the lung as an associated tissue of rheumatoid arthritis.


Working memory in capuchin monkeys (Cebus apella).
It has been suggested that delayed (non-) matching to sample (DNMTS/DMTS) tasks using trial-unique stimuli and short, as well as longer delay intervals, can provide important insights into animal cognition. Therefore, this research examined the capability of the New World capuchin monkey (Cebus apella) in perform trial-unique DMTS and DNMTS tasks across delay intervals ranging between 8 s and 10 min. Subjects were tested using a version of the Wisconsin General Test Apparatus mounted in front of the animal's home cage. They were first trained on a basic DMTS/DNMTS task with an 8 s interval until they reached a learning criterion of nine correct responses in ten consecutive trials. All subjects reached the learning criterion in both DMTS/DNMTS tasks, and the number of trials to criterion did not differ between tasks. After reaching the criterion, subject's memory performance was successively assessed at delay intervals of 15 s, 60 s, 120 s and 10 min. For both DMTS/DNMTS tasks, the mean percentage of correct responses across delays was above chance and, interestingly, performance did not significantly decrease as function of delay increments. Comparisons based on each group's scores, averaged across the four delays, showed no difference between DMTS and DNMTS memory performance. These results indicate that capuchin monkeys are able to learn DMTS/DNMTS tasks in which they are required to respond to new pairs of stimuli on every trial. This demonstrates the capability of 'concept' learning in this species. Moreover, above chance performance on the memory tests indicates a working memory ability similar to that reported for the genus Macaca. Taken together, these data indicates that capuchin monkeys can be a valuable alternative model for investigations of the neuropsychological basis of memory.


Histological types of lung cancer attributable to fine particulate, smoking, and genetic susceptibility.
Fine particulate matter (PM2.5), smoking, and genetic factors are associated with lung cancer. However, the relationship between PM2.5, smoking and subtypes of lung cancer remains unclear. Moreover, it is unclear whether genetic risk modifies the impact of PM2.5 and smoking on incident lung cancer. A total of 298,069 participants from the UK Biobank study without lung cancer at baseline were included in this study. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated using multivariable Cox proportional models for the association of lung cancer and its subtypes with PM2.5, smoking, and genetic risk. Potential gene-smoking or gene-PM2.5 interactions were also estimated. We further estimated population attributable fractions for incident lung cancer. During 10.4 years of follow-up, 1683 incident lung cancer cases were identified. Our analysis found that genetic variants, smoking, and PM2.5 were significantly associated with incident lung cancer. For different histological types of lung cancer, the HRs for squamous cell lung carcinoma associated with PM2.5 (per 5 μg/m3 increment) and current smoking were 2.76 (95 % CI: 1.72, 4.42, p < 0.001) and 48.64 (95 % CI: 27.96, 84.61, p < 0.001), while the HRs for lung adenocarcinoma were 1.59 (95 % CI: 1.13, 2.23, p < 0.001) and 9.89 (95 % CI: 7.91, 12.36, p < 0.001), respectively. We further found that participants with high levels of PM2.5 pollution and high genetic risk had the highest risk of incident lung cancer (HR = 1.81, 95 % CI: 1.39, 2.35, p < 0.001), while the interaction between PM2.5 and genetic risk was not statistically significant. We observed that the population attributable fractions of lung cancer attributable to current smoking and high PM2.5 exposure were estimated to be 67.45 % and 17.59 %. Genetic susceptibility, smoking, and PM2.5 are important risk factors for lung cancer. Both smoking and PM2.5 are more closely associated with an elevated risk of squamous cell lung cancer.


Paraganglioma of the nasal cavity: a case report.
We describe the case of a 72-year-old woman presenting with a 1-year history of recurrent epistaxis and unilateral progressive nasal obstruction with associated rhinolalia resulting from the presence of a tumor mass occupying two-thirds of the right nasal cavity. Histopathologically, neoplastic cells or "chief cells" were arranged in well-defined nests, which had the classic alveolar or so-called "zellballen" pattern. Immunohistochemical studies highlighted the presence of S-100 protein-positive sustentacular cells located at the periphery of the clusters of chief cells. The chief cells showed a diffuse and intense positivity for neuron-specific enolase and synaptophysin. A diagnosis of paraganglioma was made. The lesion was excised completely and the patient did not develop recurrences or distant metastases after 8 months of follow-up. Paragangliomas arising in the nasal cavity and paranasal sinuses are extremely rare tumors. We report on the clinical, histopathological and immunohistochemical findings of our case and review the cases previously described in the literature.


The interaction of placental micro-EVs with immune cells in vivo and in vitro.
Considerable evidence suggests that placental extracellular vesicles (EVs) interact with most types of leukocytes in vitro but in vivo biodistribution studies question whether these interactions are reflective of the situation in vivo. CellTracker Red CMTPX stained human placental micro-EVs were isolated from first trimester placental explant cultures. Equivalent amounts of micro-EVs were cultured with murine leukocytes in vitro or injected into pregnant or non-pregnant mice. After intravenous injection, on day 12.5 of gestation, major organs and blood samples were harvested 30 min or 24 h post injection. We screened cryosections of the organs and confirmed that human placental EVs were specifically localised to the spleen, liver and the lungs 30 min or 24 h after injection. Immunohistochemistry showed that most of the EVs interacted with macrophages in those three organs and some of them also associated with T and B lymphocytes in the spleen or endothelial cells in the lungs and liver. Flow cytometry demonstrated that there was very little interaction between circulating leukocytes and EVs in vivo. While minimal, significantly more EVs interacted with leukocytes in pregnant than nonpregnant mice. The major interaction between human placental micro-EVs and maternal leukocytes appear to be with macrophages predominantly in the splenic marginal zone, liver and lungs with little interaction between EVs and circulating leukocytes. Since marginal zone macrophages induce tolerance after phagocytosing apoptotic bodies it is likely that phagocytosis of placental EVs by marginal zone macrophages may also contribute to maternal immune tolerance.


Online sex-seeking among Chinese heterosexual men who seek care in sexually transmitted infections clinics: a cross-sectional study.
The Internet has become an important virtual venue for men who have sex with men to seek sexual partners, with a high potential threat to spread sexually transmitted infections (STIs). However, the online sex-seeking use and its risk causing STIs spread remain unclear among heterosexual men. We conducted a cross-sectional study to investigate the use of online sex-seeking venues and the related risky sex activities (e.g. condomless sex, quick sex) in STIs clinics in Guangdong, China. These STIs clinics were involved in the Guangdong governmental sentinel network and we recruited heterosexual men (age > = 18) between March and August 2018. Multivariable logistic regression models were used to identify the factors associated with online sex-seeking use and risky sex activities with online sex partners. 191 of 2,154 participants (8.9%) ever sought sex online. Among users,16.8% met their partners in-person within 24 h, 31.4% engaged in condomless sex with their last online partner. Online sex-seeking was positively associated with a) Ever been diagnosed with STIs (aOR = 3.0, 95%CI:2.0-4.6), and b) Had casual sex in the last three months (aOR = 3.3, 95%CI 2.4-4.6). Condomless sex with the last online partner was negatively associated with the correct answer of "Having only one partner can reduce the risk to infect HIV" (aOR = 0.3, 95%CI:0.1-0.8). In China, online sex-seeking and its related risky sexual activities are not rare among heterosexual men. Future prevention strategies to reduce STIs incidence should especially target heterosexual men engaging in online sex-seeking.


GAP-43 gene expression during development: persistence in a distinctive set of neurons in the mature central nervous system.
GAP-43 is a rapidly transported axonal protein most prominently expressed in regenerating and developing nerves. However, the low level persistence of GAP-43 in the adult CNS where growth and regenerative capacity are minimal may additionally indicate a role for this molecule in neuronal remodeling. Previous studies have revealed GAP-43 immunoreactivity in neurites throughout many regions of the CNS. To identify the CNS neurons that express GAP-43 at different stages of development, we utilized in situ hybridization and immunocytochemistry; the latter was performed with an antibody that recognizes GAP-43 immunoreactivity in both perikarya and neurites. In the perinatal period GAP-43 is expressed in all neurons. Subsequently its expression becomes progressively restricted such that by maturity most neurons no longer express detectable levels, although GAP-43 expression is still moderately high in the adult entorhinal cortex, and strikingly high in the adult hippocampus and olfactory bulb. In light of current notions about the function of GAP-43, it is tempting to speculate that this anatomy denotes neurons engaged in structural remodeling and functional plasticity.


The cessation of breathing in the chicken embryo during cold-hypometabolism.
The avian embryo toward end-incubation combines gas exchange through the chorioallantoic membrane (CAM) and pulmonary ventilation (V˙E). The main experiments examined breathing activity during cold-hypometabolism. Chicken embryos close to hatching were prepared for simultaneous measurements of oxygen consumption ( [Formula: see text] ) and carbon dioxide production ( [Formula: see text] ; open-flow methodology) and breathing frequency (f; barometric technique). As ambient (Ta) and egg temperature (Tegg) dropped, breathing eventually ceased at ∼18°C, when [Formula: see text] and [Formula: see text] were 22-28% of the normothermic values. With the eggshell experimentally covered to reduce CAM gas exchange breathing ceased at slightly lower [Formula: see text] and [Formula: see text] (17-18% of normothermia). Once breathing had stopped, egg exposure to hypoxia (10% or 5% O2) or hypercapnia (3% or 8% CO2) did not resume breathing, which recovered with re-warming. In normothermia, 10% O2 caused hypometabolism and tachypnea; differently, in 5% O2 [Formula: see text] dropped as much as with hypothermia and breathing stopped, to recover upon return in air. Correlation analysis among Ta, Tegg, [Formula: see text] , [Formula: see text] and f during cooling and re-warming indicated that f followed more closely the changes in [Formula: see text] and, especially, in [Formula: see text] than the changes in Ta or Tegg. Some considerations suggest that in this experimental model the cessation of breathing in hypothermia or severe hypoxia may be due to hypometabolism, while the lack of chemo-responses may have a different mechanistic basis.


Orthotopic Heart Transplantation in an Adult Patient with Heterotaxy Syndrome: Surgical Implications.
Modified techniques for orthotopic heart transplantation are mandatory when complex congenital anomalies are associated in adult patients. An unusual case of a heterotaxy syndrome and dilated cardiomyopathy following mitral ring annuloplasty is presented in a 62-year-old male. Orthotopic cardiac transplantation was performed by using a modified operative strategy: selective peripheral and central venous cannulation according to the thoraco-abdominal venous challenges, biatrial technique, and preservation of venous drainage via the native coronary sinus. We discuss the anatomical features of heterotaxy in adult patients and surgical approaches when heart transplantation is needed.


Homeobox genes in normal hematopoiesis and leukemogenesis.
Homeobox genes are broadly classified into two subclasses: HOX and non-HOX homeobox genes. A number of genes in both classes are expressed in a variety of hematopoietic cells. Two major categories of evidence implying the involvement of these genes in normal hematopoiesis have been demonstrated. First, the expression pattern of the homeobox genes in hematopoietic cells is lineage- and differentiation-stage specific. Second, enforced and suppressed expression of various homeobox genes cause defects in the hematopoietic cells of specific lineages. The reduction in myeloid, erythroid and B cell progenitors is found in mice with a disrupted HOXA9 gene. The thymuses of HOXB3-overexpressed marrow recipients contain a markedly decreased number of CD4/CD8 double-positive T cells. These examples suggest that the proper level of expression and timely down-regulation of some homeobox genes are necessary for normal hematopoiesis. Homeobox genes are also implicated in human and mouse leukemias. In human leukemias, a HOX gene (HOXA9) and two non-HOX homeobox genes (PBX1 and HOX11) are involved in chromosomal translocations. In mouse leukemias, provirus integrations cause aberrant expression of several HOX and non-HOX genes. Currently available information will be discussed separately on HOX and non-HOX genes, in normal and leukemic hematopoiesis, respectively.


Long-term followup after exstrophy closure: late improvement and good quality of life.
Now that we have observed the growth and development of 17 of our anatomically reconstructed exstrophy patients through 20 or more years of followup, we are convinced that reconstruction should be the preferred primary treatment. Most of these patients are healthy, attractive, well educated adults and have achieved emotional maturity and stability, despite their many problems. Anatomical reconstruction also has considerable advantages over other current treatments for exstrophy that were not apparent initially.


Conversion of Escherichia coli cell-produced metabolic energy into electric form.
The formation of membrane potential in energized E. coli cells has been investigated by means of ionic penetrants. The fluxes of anions and cations in opposite directions have been observed: anions moved out and cations moved into the cells. The energy-linked uptake of cations was stoichiometrically coupled with the outflow of H+ ions from the cells. The value of a membrane potential in the energized cells calculated from a distribution of permanent cations was in the range of -140 mV (inside minus). The uptake of penetrating cations by deenergized cells has been observed following the non-enzymatic generation of a membrane potential. The influx of synthetic and natural (lactose) penetrants collapsed the non-enzymatic membrane potential. The effect of lactose was sensitive to N-ethyl maleimide. These results are in favour of the conception that in the energized E. coli cells an energy-linked H+-pump generates a membrane potential which is a driving force for the transport of synthetic and some natural penetrants.


Asian females without diabetes are protected from obesity-related dysregulation of glucose metabolism compared with males.
The impact of obesity on the risk for type 2 diabetes differs between males and females; however, the underlying reasons are unclear. This study aimed to investigate the effect of sex on obesity-driven changes in the mechanisms regulating glucose metabolism (insulin sensitivity and secretion) among Asian individuals without diabetes in Singapore. The study assessed glucose tolerance using oral glucose tolerance test, insulin-mediated glucose uptake using hyperinsulinemic-euglycemic clamp, acute insulin response using an intravenous glucose challenge, and insulin secretion rates in the fasting state and in response to glucose ingestion using mathematical modeling in 727 males and 952 females who had normal body weight (n = 602, BMI < 23 kg/m2 ), overweight (n = 662, 23 ≤ BMI < 27.5), or obesity (n = 415, BMI ≥ 27.5). There were no sex differences among lean individuals. Obesity gradually worsened metabolic function, and the progressive adverse effects of obesity on insulin action and secretion were more pronounced in males than females, such that among participants with obesity, females had greater insulin sensitivity, lower insulin secretion, and lower fasting insulin concentration than males. The increase in waist to hip ratio with increasing BMI was more pronounced in males than females. The female sex exerts a protective effect on obesity-driven dysregulation of glucose metabolism in Asian individuals without diabetes.


Magnetic resonance imaging pontine signal abnormality in neurological Wilson disease: A case report.
WD is diagnosed with the help of a brain MRI, which frequently reveals hyperintensities in the lentiform nucleus. But occasionally, high signals can be seen in the pons, thalamus, and midbrain. Wilson disease is a rare inherited disorder due to impaired copper excretion. The brain MRI mainly shows hyperintensities in the lentiform nucleus. We report the case of an 18 years old female diagnosed with neurological Wilson disease, presenting with uncommon brain MRI hyperintensities, predominantly in the pons, thalamus, and midbrain.


Use of muscular flaps for the treatment of hip prosthetic joint infection: a systematic review.
Deep periprosthetic infection after total hip arthroplasty (THA) is a serious and challenging complication for the orthopedic surgeon. Muscular flaps may represent a valid management option for the treatment of this condition. We present a systematic literature review about the use of muscular flaps for the treatment of hip prosthetic joint infection. The review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventy-seven articles, out of 279 titles, were considered eligible for the full-text analysis. Finally 15 studies that met inclusion criteria were included in this review. Overall, 210 patients (49% males, 48.6% females and 2.4% not reported) suffering from THA infection treated with muscular flaps were collected. The mean age was 69.6 years. Mean follow-up, reported in all studies, was 3.3 years. The results presented by the different authors, highlight the effectiveness of muscular flaps for the treatment of periprosthetic infection, in terms of function, limb salvage, prevention of the recurrences, cost-effectiveness, and quality of life postoperatively. Muscle flaps provide an excellent management option for patients with persistent infection after total hip arthroplasty.


Maxillary tooth splinting in periodontally compromised patients using fiber-reinforced composite: the Targis-Vectris method.
To show the Targis-Vectris retention technique, illustrating its features and clinical applications in periodontally compromised patients. The Targis-Vectris technique is constituted by an esthetic external layer (Targis) combined with and supported by a metal-free structure (Vectris). An adult female with a full Class II malocclusion and compromised periodontal condition with significant bone loss on the maxillary central incisor was treated. Before debonding, a fiber-reinforced splint was placed on the palatal surface of the maxillary anterior teeth, using the Targis-Vectris method, to permit long-term stability. The final result remained stable at 5 years posttreatment. The correction of the Class II malocclusion took 24 months. The Targis-Vectris method ensured maintenance of tooth position and periodontal condition. The Targis-Vectris technique represents a useful procedure for splinting maxillary teeth in selected periodontally compromised patients. The 5-year posttreatment follow-up visit showed no relapse. Correct occlusal relationships are necessary to reduce the risk of breakage.


Atropodiastereoselectivity in solid state BINOL synthesis: leads from the estradiol platform.
A novel functionalized steroidal BINOL scaffold is produced via a remarkable sequence of dehydrogenation, chlorination and atroposelective phenolic coupling steps. Its formation is straightforwardly obtained in a one-step synthesis under solid state conditions and in the absence of chiral additives.


[Cardiac contractility modulation].
Cardiac contractility modulation (CCM) is a device-based electrical therapy for the additive treatment of chronic drug-refractory heart insufficiency. High-amplitude signals are applied during the absolute refractory period and have been shown to enhance the strength of left ventricular (LV) contraction and improve exercise tolerance and quality of life. The mechanisms of action appear to involve effects on myocardial gene expression and on normalization of key myocardial proteins. So far, more than 3500 CCM devices have been implanted worldwide. For patients with therapy refractory heart insufficiency and narrow QRS complex, CCM is together with baroreceptor activation the only additive electrical therapy which had been approved in Germany. For the first time CCM has been referenced in the current guidelines on cardiac insufficiency. Prognostic data with respect to mortality have been evaluated in case series. Ongoing randomized trials and registries will address these specific endpoints and have to a significant extent already been recently published. A Food and Drug Administration (FDA) approval is expected within the next few months.


A case of nodular fasciitis arising in the auricle.
Nudular fasciitis is an uncommon benign proliferative lesion in the head and neck, and is extremely rare in the auricle. A case of nodular fasciitis arising in the auricle of 53-year-old man is reported by immunohistochemical and electron microscopical studies. Initially, he had noticed a small painless nodule on the posterior side of right auricle, and it grew up rapidly in size over 2 months. A biopsy revealed nodular fasciitis. This lesion was resected totally with the auricular cartilage. Histological examination revealed proliferation of spindle-shaped cells and immunohistochemical-positive staining was observed with actin, and focally positive staining was seen with vimentin. Electron microscopically some tumor cells contained dilated rough endoplasmic reticulum and myofilament-like bundles in cytoplasm.


Genotype of alcohol dehydrogenase and aldehyde dehydrogenase loci in Japanese alcohol flushers and nonflushers.
A much higher incidence of alcohol flushing among Orientals in comparison to Caucasians, i.e., greater than 50% vs 5%-10%, has been attributed to racial differences in alcohol-metabolizing enzymes. A large majority of Orientals are "atypical" in alcohol dehydrogenase-2 locus (ADH2), and their livers exhibit significantly higher ADH activity than the livers of most Caucasians. Approximately 50% of Orientals lack the mitochondrial aldehyde dehydrogenase (ALDH2) activity, and elimination of acetaldehyde might be disturbed. We determined by means of hybridization of genomic DNA samples with allele specific oligonucleotide probes, genotypes of the ADH2 and ALDH2 loci in Japanese alcohol flushers and nonflushers. We found that all individuals with homozygous atypical ALDH2(2)/ALDH2(2) and most of those with heterozygous atypical ALDH1(2)/ALDH2(2) were alcohol flushers, while all subjects with homozygous usual ALDH1(2)/ALDH1(2) were nonflushers. Frequency of the atypical ADH2(2) was found to be higher in alcohol flushers than in nonflushers, but the statistical significance was not established in the sample size examined.


Predictive factors for liver volume and function recovery after resection using three-dimensional analysis.
Clinical and biological factors that predict liver volume recovery rate (LVRR) after liver resection of different resected volume (RV) have not been studied extensively. Moreover, it remains uncertain whether remnant liver volume influences the liver function recovery rate (LFRR). This study examined the predictive factors for LVRR after liver resections of different RV and investigated LFRR by focusing on LVRR improvements after hepatectomy. Patients who underwent hepatectomy between January 2013 and August 2015 were reviewed retrospectively. LVRR and LFRR were assessed at postoperative months (POMs) 3, 6, and 12. LVRR was evaluated on the basis of RV (0%-15%, 15%-30%, 30%-45%, and >45%). LFRR was evaluated using total bilirubin, prothrombin time, and platelet count. LVRR was lower with more extensive liver resections. Significant independent predictors of LVRR were type IV collagen 7s domain levels and resection magnitude. Platelet count correlated positively with LVRR at all POMs. Resected livers regenerated after surgery but did not reach preoperative volumes. Preserving the liver as much as possible during resection can result in greater LFRR after hepatectomy. Therefore, decisions regarding liver resection volume should be made very carefully, particularly in patients with higher type IV collagen 7s domain levels.


Prevalence of biofilm forming Salmonella in different seafood contact surfaces of fishing boats, fish landing centres, fish markets and seafood processing plants.
The prevalence of biofilm forming Salmonella on different seafood contact surfaces was investigated. Out of 384 swab samples, 16.14 % and 1 % were confirmed biochemically and molecularly as Salmonella respectively. One out of four isolates was from the boat deck, and three were from the seafood processing plant. Salmonella was more prevalent in January, June, and September months. Different assays investigated the biofilm forming ability of isolates. Two out of four isolates have shown strong biofilms, and the others were moderate biofilm formers by microtitre plate assay. In the CRA assay, three isolates showed 'rdar' morphotype, and one showed 'bdar' morphotype. All isolates were positive for gcpA gene (~1700 bp), a critical gene found in Salmonella biofilms. The microbial load of Salmonella biofilms on different contact surfaces were determined, stainless steel and HDPE were found prone to biofilms. With this, a suitable mechanism shall be formulated to control the biofilms of Salmonella.


Purification of platelet-derived endothelial cell growth inhibitor and its characterization as transforming growth factor-beta type 1.
In 1986, Brown and Clemmons (Proc. natl Acad. Sci. USA 83 (1986) 3321) showed that platelets contain a substance, platelet-derived growth inhibitor (PDGI), that inhibits in vitro endothelial cell replication. Although platelets are rich in transforming growth factor beta (TGF-beta), PDGI was considered not to be related to TGF-beta, on the basis of its reported properties (extraction from platelets at neutral pH, binding to heparin-Sepharose). However, we purified PDGI to near homogeneity and showed that on the basis of HPLC retention behavior, in vitro growth inhibitory activities with several cell types, receptor binding, and immunoneutralization of growth inhibitory activity with specific anti-TGF-beta type 1 antibodies, PDGI is most probably identical with TGF-beta type 1.


Changes in ultrasonic attenuation and backscatter of muscle with state of contraction.
We have previously demonstrated that backscatter (uncompensated for attenuation) of canine myocardium varies systematically throughout the cardiac cycle and in relation to regional contractile performance. To elucidate these phenomena under conditions independent of blood flow and complex myofibrillar architecture, we measured attenuation with a phase-insensitive receiver and backscatter over a wide range of frequencies in an intermittently tetanized (10 stimulations), isolated frog gastrocnemius preparation (n = 12 muscles). Muscle contraction, as compared with relaxation, was associated with increased values of slope of attenuation (0.78 +/- 0.04 vs 0.58 +/- 0.03 dB/(cm MHz); p less than 0.001) and increased values of integrated backscatter (-29.5 +/- 0.9 vs -35.5 +/- 0.8 dB; p less than 0.005). Differences in attenuation and backscatter diminished with the number of muscle stimulations (as the muscle fatigued). Thus, quantitative ultrasonic indices of skeletal muscle vary systematically with the contractile performance of the tissue. Extrapolation of these results to cardiac muscle suggests that the sensitivity of these indices to contractile function of muscle may provide an approach for noninvasive assessment of intrinsic properties of myocardium that determines its performance.


Personalizing medicine for autoimmune and inflammatory diseases.
Therapies that target molecular pathways do not provide uniform benefits for all patients at present. New transformative therapies for autoimmune and inflammatory diseases require greater molecular understanding of patient subsets and the ability to personalize targeted therapies for each subset.


Widespread short-latency stretch reflexes and their modulation during stumbling over obstacles.
The present study investigated whether short-latency stretch reflexes are present during human stumbling reactions. While subjects walked on a treadmill, the forward sway of the foot was unexpectedly obstructed with an obstacle. All subjects showed reflex responses with average latencies of 34-42 ms in both the upper and the lower leg flexors and extensors of the obstructed leg. The amplitudes of these responses depended on the phase in the step cycle and were not strictly related to either the background activity of the corresponding muscles or variations in the perturbation. Hence, mechanisms at a premotoneuronal level might play a role in the active phase-dependent control of these responses. The coactivation of antagonists as well as the lack of obvious kinesiologic consequences following the responses suggest that the short-latency responses may generate joint stiffness. This may be a first line of defense in preparing for the functional reaction, which is generated by longer latency responses, in order to take appropriate action concerning the obstacle.


The effects of calcitonin on bone resorption in hyperthyroidism: a placebo-controlled clinical study.
The effects of intranasal calcitonin on bone metabolism were investigated in patients with hyperthyroidism. Urinary deoxypyridinoline (uDPD) levels were measured as a bone turnover marker and lumbar spine (L2) bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA) in 7 patients who were given only antithyroid drug (group 1), in 10 patients who were given antithyroid drug plus intranasal calcitonin (group 2), and in 10 healthy subjects who were given placebo (group 3) at the beginning and at the end of the study. The study continued until the patients with hyperthyroidism became euthyroidic according to the laboratory values. This period was approximately 3 months in groups 1 and 2. At the beginning of the study, uDPD was 21.5 +/- 2.6 nM DPD/mM creatinine in group 1, 23.3 +/- 3.6 nM DPD/mM creatinine in group 2, and 4.3 +/- 1.2 nM DPD/mM creatinine in group 3. uDPD levels measured in groups 1 and 2 were significantly higher than those in group 3 ( P << 0.001). Area BMD Z scores of the patients in groups 1 and 2 were significantly lower than the healthy controls ( P << 0.01, for both). At the end of the study, uDPD was 11.5 +/- 1.6 nM DPD/mM creatinine in group 1, 5.3 +/- 0.6 nM DPD/mM creatinine in group 2, and 4.4 +/- 1.3 nM DPD/mM creatinine in group 3. The levels of uDPD obtained in group 1 were significantly higher than those obtained in groups 2 and 3 ( P << 0.05, for both). The difference between groups 2 and 3 was not significant. Area BMD Z scores measured at the end of the study were found to be increased in groups 1 and 2 compared to early values, but the values were slightly lower than the normal values. In comparison of early and late uDPD values, the decrease in late period was statistically significant in groups 1 ( P << 0.05) and 2 ( P << 0.001). We concluded that bone turnover is high in hyperthyroidism. The treatment of hyperthyroidism decreases the rate of bone turnover, but it is not sufficient to prevent the degradation of bone in hyperthyroidism. The addition of intranasal calcitonin to the treatment of hyperthyroidism prevents the degradation of bone.


Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets.
The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort for the past few decades. However, despite significant progress on elucidating the function of key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information on the genes expressed in reproductive tissues, and no contraceptive targets have so far reached clinical trials. To advance product development, further identification of novel reproductive tract-specific genes leading to potentially druggable protein targets is imperative. In this study, we expand on previous single tissue, single species studies by integrating analysis of publicly available human and mouse RNA-seq datasets whose initial published purpose was not focused on identifying male reproductive tract-specific targets. We also incorporate analysis of additional newly acquired human and mouse testis and epididymis samples to increase the number of targets identified. We detected a combined total of 1178 genes for which no previous evidence of male reproductive tract-specific expression was annotated, many of which are potentially druggable targets. Through RT-PCR, we confirmed the reproductive tract-specific expression of 51 novel orthologous human and mouse genes without a reported mouse model. Of these, we ablated four epididymis-specific genes (Spint3, Spint4, Spint5, and Ces5a) and two testis-specific genes (Pp2d1 and Saxo1) in individual or double knockout mice generated through the CRISPR/Cas9 system. Our results validate a functional requirement for Spint4/5 and Ces5a in male mouse fertility, while demonstrating that Spint3, Pp2d1, and Saxo1 are each individually dispensable for male mouse fertility. Our work provides a plethora of novel testis- and epididymis-specific genes and elucidates the functional requirement of several of these genes, which is essential towards understanding the etiology of male infertility and the development of male contraceptives.


Adeno-associated-virus-mediated transduction of the mammary gland enables sustained production of recombinant proteins in milk.
Biopharming for the production of recombinant pharmaceutical proteins in the mammary gland of transgenic animals is an attractive but laborious alternative compared to mammalian cell fermentation. The disadvantage of the lengthy process of genetically modifying an entire animal could be circumvented with somatic transduction of only the mammary epithelium with recombinant, replication-defective viruses. While other viral vectors offer very limited scope for this approach, vectors based on adeno-associated virus (AAV) appear to be ideal candidates because AAV is helper-dependent, does not induce a strong immune response and has no association with disease. Here, we sought to test the suitability of recombinant AAV (rAAV) for biopharming. Using reporter genes, we showed that injected rAAV efficiently transduced mouse mammary cells. When rAAV encoding human myelin basic protein (hMBP) was injected into the mammary glands of mice and rabbits, this resulted in the expression of readily detectable protein levels of up to 0.5 g/L in the milk. Furthermore we demonstrated that production of hMBP persisted over extended periods and that protein expression could be renewed in a subsequent lactation by re-injection of rAAV into a previously injected mouse gland.


A New Standard in Graft-versus-Host Disease Prophylaxis? An Introduction to Blood and Marrow Transplant Clinical Trials Network 1703.
Effective immunosuppressive regimens to prevent the development of graft-versus-host disease (GVHD) are essential to the success of allogeneic hematopoietic cell transplantation (HCT). After revolutionizing haploidentical transplantation, post-transplantation cyclophosphamide (PTCy) is now being evaluated for HCT performed from related and unrelated donors. In this setting, 2 recent randomized studies have demonstrated lower rates of GVHD and superior GVHD-free, relapse-free survival with PTCy compared with conventional GVHD prophylaxis. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is currently conducting a large, randomized phase III, multicenter trial (BMT CTN 1703) comparing PTCy/tacrolimus/mycophenolate mofetil to tacrolimus/methotrexate as GVHD prophylaxis regimens in reduced-intensity allogeneic HCT. Here we review the ongoing study, highlight its importance to the field, and explore the possible implications of its results on clinical practice.


Improvement of Subthalamic Nucleus Deep Brain Stimulation in Sleeping Symptoms in Parkinson's Disease: A Meta-Analysis.
The aim of this meta-analysis was to evaluate the effects of STN DBS on sleep quality and restless leg symptoms in individuals with PD. We searched the PubMed, Web of Science, EMBASE, CNKI, and WANFANG databases published between 1990 and 2019. The articles included were those that contained both pre- and postsurgery data acquired using International RLS Study Group criteria and the Pittsburgh sleep quality index (PSQI) questionnaire with patients' follow-up of at least three months. All studies that met the quality requirements were included in a meta-analysis performed using STATA 12.0 software. Of 73 articles identified, 7 studies comprising 82 patients were qualified for the current meta-analysis. After adjusting for heterogeneity in study effect sizes, the random effects meta-analysis indicated that STN DBS improved sleep quality and restless leg symptoms significantly (SMD = -1.111, 95% CI: -1.918∼-0.304, P=0.007). Subgroup analysis showed that different sleep scoring criteria had different effects on the condition of sleeping after surgery. STN DBS is a powerful method in the management of sleep quality and restless leg symptoms in PD patients, but its long-term effects with larger populations must be thoroughly assessed.


Reliability of pubertal self-assessment in Hong Kong Chinese children.
To validate a Tanner stages self-assessment questionnaire using gender-specific line drawings and brief explanatory text in Chinese. A cross sectional study design. One primary and two secondary schools. 172 boys and 182 girls aged between 8 and 18 years. Students' self-assessments of pubertal maturation were compared with assessments made by a same gender rater using visual depiction physical examination. Raters' physical examinations were performed after the children had answered the self-assessment questionnaire individually and in private. Raters were blinded to the self-assessment results. Accuracy rates and weighted kappa statistic were used to evaluate the degree of agreement between children and raters. Substantial to almost perfect agreement was found between self- and rater's assessments of breast development and pubic hair growth in girls [weighted kappa 0.72 (P < 0.0001, 95% CI 0.66, 0.79) and 0.83 (P < 0.0001, 95% CI 0.78, 0.87) respectively]. Moderate to substantial agreement was found between self- and rater's assessments of male genital development and pubic hair growth [weighted kappa 0.58 (P < 0.0001, 95% CI 0.48, 0.68) and 0.80 (P < 0.0001, 95% CI 0.74, 0.86) respectively]. Most agreements between self- and rater's assessments differed by only one Tanner stage. Agreement was higher for girls than boys. Girls tended to overestimate their breast stages and boys tended to underestimate their genitalia development. This study confirms that a Tanner pubertal self-assessment questionnaire with line drawings and explanatory Chinese text can reliably estimate sexual maturation status in Hong Kong Chinese children.


Common emergent pediatric neurologic problems.
Although there are a variety of neurologic disease processes that the emergency physician should be aware of the most common of these include seizures, closed head injury, headache, and syncope. When one is evaluating a patient who has had a seizure, differentiating between febrile seizures, afebrile seizures, and SE helps to determine the extent of the work-up. Febrile seizures are typically benign, although a diagnosis of meningitis must not be missed. Educating parents regarding the likelihood of future seizures, and precautions to be taken should a subsequent seizure be witnessed, is important. The etiology of a first-time afebrile seizure varies with the patient's age at presentation, and this age-specific differential drives the diagnostic work-up. A follow-up EEG is often indicated, and imaging studies can appropriate on a nonurgent basis. Appropriate management of SE requires a paradigm of escalating pharmacologic therapy, and early consideration of transport for pediatric intensive care services if the seizure cannot be controlled with conventional three-tiered therapy. Closed head injury frequently is seen in the pediatric emergency care setting. The absence of specific clinical criteria to guide the need for imaging makes management of these children more difficult. A thorough history and physical examination is important to uncover risk factors that prompt emergent imaging. Headaches are best approached by assessing the temporal course, associated symptoms, and the presence of persistent neurologic signs. Most patients ultimately are diagnosed with either a tension or migraine headache; however, in those patients with a chronic progressive headache course, an intracranial process must be addressed and pursued with appropriate imaging. Syncope has multiple causes but can generally be categorized as autonomic, cardiac, or noncardiac. Although vasovagal syncope is the most common cause of syncope, vigilance is required to identify those patients with a potentially fatal arrhythmia or with heart disease that predisposes to hypoperfusion. As such, all patients who present with syncope should have an ECG. Additional work-up studies are guided by the results of individual history and physical examination.


[External biliary fistulae following surgery of the bile ducts].
Twenty-nine patients with external biliary fistulae were under observation. In 22 cases the formation and functioning of the fistula was caused by obstruction of the flow of bile into the intestine. The abdominal cavity was drained in the acute stage, and then, after the formation of the fistula was concluded and the general condition normalized, its source was removed. In addition to liquidation of the fistula for removal of the cause of biliary hypertension, choledochoenteroanastomosis was established in 4 patients and various manipulations on the papilla were performed in 16 patients.


Synthesis of lauryl grafted sodium alginate and optimization of the reaction conditions.
Lauryl grafted sodium alginate (SA-C(12)) was prepared by the reaction between sodium alginate and dodecanol with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) as a coupling agent. The structure of SA-C(12) was confirmed by FT-IR, (1)H NMR, and thermoanalysis. Meantime, the degree of substitution (DS) of SA-C(12) was determined by GC. The reaction conditions were studied systematically, which included reaction time and temperature, the molar ratio of hexuronic acid in alginate to dodecanol (N(hexuronic)/N(dodecanol)) and N(hexuronic)/N(EDC), the mass of toluenesulfonic acid. By investigating the relationship between these conditions and DS, the optimal conditions with the maximum DS were obtained.


Bio-assisted potentiometric multisensor system for purity evaluation of recombinant protein A.
Recombinant proteins became essential components of drug manufacturing. Quality control of such proteins is routine task, which usually requires a lot of time, expensive reagents, specialized equipment and highly educated personnel. In this study we propose a new concept for protein purity evaluation that is based on application of bio-assisted potentiometric multisensor system. The model object for analysis was recombinant protein A from Staphylococcus aureus (SpA), which is commonly used for monoclonal antibody purification. SpA solutions with different amount of host cell related impurities (Escherichia coli, bacterial lysate) were analyzed. Two different bio-transducers were employed: proteinase K from Tritirachium album and baker's yeast Saccharomyces cerevisiae. It was shown that both bio-transducers are able to induce changes in pure and lysate-contaminated SpA samples. Different products of yeast digestion and proteolysis with proteinase of pure SpA and lysate were detected with size exclusion high-performance liquid chromatography (SE-HPLC). The induced changes of chemical composition are detectible with potentiometric multisensor system and can be related to SpA purity through projection on latent structures (PLS) regression technique. The proposed method allows for estimation of the impurity content with 12% accuracy using proteinase K and 16% accuracy using baker's yeast. The suggested approach could be useful for early contamination warning at initial protein purification steps. The analysis requires no expensive materials and equipment, no bio-material immobilization, and its duration time is comparable with other commonly used methods like chromatography or electrophoresis though the main part of this time is related to the sample preparation.


Functional MRI responses to naturalistic stimuli are increasingly typical across early childhood.
While findings show that throughout development, there are child- and age-specific patterns of brain functioning, there is also evidence for significantly greater inter-individual response variability in young children relative to adults. It is currently unclear whether this increase in functional "typicality" (i.e., inter-individual similarity) is a developmental process that occurs across early childhood, and what changes in BOLD response may be driving changes in typicality. We collected fMRI data from 81 typically developing 4-8-year-old children during passive viewing of age-appropriate television clips and asked whether there is increasing typicality of brain response across this age range. We found that the "increasing typicality" hypothesis was supported across many regions engaged by passive viewing. Post hoc analyses showed that in a priori ROIs related to language and face processing, the strength of the group-average shared component of activity increased with age, with no concomitant decline in residual signal or change in spatial extent or variability. Together, this suggests that increasing inter-individual similarity of functional responses to audiovisual stimuli is an important feature of early childhood functional brain development.


Prolonged suppression of hirsutism with combination therapy in an adolescent with insulin resistance and acanthosis nigricans.
Spironolactone and oral contraceptives have been used separately with some success in the treatment of hirsutism. Hirsutism associated with the Kahn type-A syndrome of insulin resistance, acanthosis nigricans, and polycystic ovaries may be severe and refractory to conventional treatment. In view of their different sites and mechanisms of action, spironolactone and an oral contraceptive were used in combination to treat severe hirsutism in a 13-year-old girl with features of this syndrome. The two therapeutic agents, apparently acting together, resulted in a marked reduction in facial hair and serum androgen concentrations, which persisted during 18 months of treatment. Testosterone and androstenedione levels fell from 100 ng/dl and 628 ng/dl, respectively, to 47 ng/dl and 230 ng/dl by six months and to 35 ng/dl and 156 ng/dl by 18 months. This result suggests that combination therapy may be an effective treatment for severe hirsutism.


The effect of cyclosporine A on the phosphorylation of the AMPK pathway in the rat hippocampus.
Cyclosporine A (CsA), an immunosuppressant and calcineurin inhibitor, induces hyperlipidemia in humans and animals. AMP-activated protein kinase (AMPK) is involved in metabolic homeostasis and lipid metabolism through modulating downstream molecules acetyl CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR). AMPK activity is regulated by the phosphorylation at the Thr-172 residue by its upstream liver kinase B 1 (LKB1), Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) or transforming growth-factor-β-activated kinase 1 (TAK1). AMPK can be deactivated through dephosphorylation by protein phosphatase 2Cα (PP2Cα). In this study, we demonstrated that phosphorylation at Thr-172-AMPK increased with a concurrent increase in the phosphorylation of Ser-431-LKB1 and Thr-184/187-TAK1 in the rat hippocampus at 5 h after an intraperitoneal CsA (50 mg/kg) injection. CsA did not affect the phosphorylation of Thr-196-Ca(2+)/calmodulin-dependent protein kinase 4 (CaMK4) and the amount of PP2Cα. An increased phosphorylation of Ser-79-ACC and Ser-872-HMG-CoAR was also observed. In conclusion, our data indicate that CsA activates the AMPK pathway in the rat hippocampus, which suggests that CsA affects the regulatory signaling pathway of lipid metabolism in the rat brain.


A bimetallic metal-organic framework with high enzyme-mimicking activity for an integrated electrochemical immunoassay of carcinoembryonic antigen.
Metal-organic frameworks (MOFs) show excellent catalytic activity and have been widely applied in diagnosis of diseases and tumors. However, current assay methods usually involve cumbersome configurations and complicated procedures, which inhibit their practical applications. Hence, a Cu-Ni MOF/carbon printed electrode (CPE)-based integrated electrochemical immunosensor was constructed for highly sensitive and efficient determination of carcinoembryonic antigen (CEA). First, highly conductive carbon ink was screen-printed onto a polyethylene terephthalate substrate to manufacture a CPE. Afterward, an aminated Cu-Ni MOF was prepared by a typical solvothermal strategy and modified on the CPE. Owing to its excellent peroxidase activity, the Cu-Ni MOF can catalytically oxidize hydroquinone using hydrogen peroxide, which greatly amplifies the peak current signal. Then the formation of an immune complex inhibited the catalytic activity of the MOF, thus enabling the quantitative determination of CEA content with a wide linear range of 0.5 pg mL-1-500 ng mL-1 and a low detection limit of 0.16 pg mL-1. Furthermore, the Cu-Ni MOF/CPE-based integrated portable electrochemical immunosensor also showed satisfactory performance in the detection of CEA in clinical serum samples with excellent accuracy, showing great potential for application in point-of-care disease diagnosis.


Risk Factors for Glaucoma Drainage Device Revision or Removal Using the IRIS Registry.
To elucidate risk factors for revision or removal of glaucoma drainage devices (GDD) in glaucoma patients in the United States. Retrospective cohort study. IRIS Registry (Intelligent Research in Sight) patients who underwent GDD insertion between January 1, 2013 and December 31, 2018 were included. Various demographic and clinical factors were collected. Kaplan-Meier survival plots, Cox proportional-hazard models utilizing Firth's Penalized Likelihood, and multivariate linear regression models were used. The main outcome measures were hazard ratios (HR) and beta coefficient (β) estimates. A total of 44,330 distinct patients underwent at least 1 GDD implantation, and 3354 of these underwent subsequent GDD revision or removal surgery. With failure defined as GDD revision/removal, factors significantly associated with decreased failure included unknown race (HR = 0.83; P = .004) and unknown ethnicity (HR = 0.68; P < .001). Factors associated with increased risk of GDD revision/removal surgery included presence of chronic angle-closure glaucoma (HR = 1.32; P < .001) and dry eye disease (HR = 1.30; P = .007). Additionally, factors associated with a decreased average time (in days) to GDD revision/removal included male sex (β = -25.96; P = .044), unknown race (β = -55.28; P = .013), and right-eye laterality (β = -38.67; P = .026). Factors associated with an increased average time to GDD revision/removal included having a history of a past eye procedure (β = 104.83; P < .001) and being an active smoker (β = 38.15; P = .024). The size and scope of the IRIS Registry allows for detection of subtle associations between risk factors and GDD revision or removal surgery. The aforementioned demographic and clinical factors may all have an impact on GDD longevity and can inform the treatment options available for glaucoma patients.


Expression of chimeric cDNAs in cell culture defines a region of UDP glucuronosyltransferase involved in substrate selection.
The cDNAs encoding two forms of UDP glucuronosyltransferase have been expressed in cultured cells to demonstrate that one form, UDPGTr-3, glucuronidates testosterone, whereas the second form, UDPGTr-4, is mainly active toward etiocholanolone (Mackenzie, P. I. (1986) J. Biol. Chem. 261, 14112-14117; Mackenzie, P. I. (1987) J. Biol. Chem. 262, 9744-9749). In order to localize areas of the polypeptide chain involved in substrate selection, the 5' regions of UDPGTr-3 and -4 cDNAs were exchanged to form two chimeric cDNAs. A 53-kDa protein was synthesized in COS cells transfected with the chimeric UDPGTr-3.4 cDNA, which encodes the amino-terminal 298 residues of UDPGTr-3 and the carboxyl-terminal 232 residues of UDPGTr-4. This protein glucuronidated testosterone rather than etiocholanolone and had a faster electrophoretic mobility when transfected COS cells were cultured in the presence of tunicamycin, an inhibitor of N-linked glycosylation. The unglycosylated variant produced by this treatment also glucuronidated testosterone. In contrast, a 50-kDa protein that was more active toward etiocholanolone as substrate was synthesized in COS cells transfected with UDPGTr-4.3, a chimeric cDNA that encodes the amino-terminal region of UDPGTr-4 joined to the carboxyl-terminal region of UDPGTr-3. The electrophoretic mobility of this chimeric protein was unaffected by tunicamycin treatment. These results demonstrate that amino acid sequences that specify substrate specificity are localized in the amino-terminal half of the UDP glucuronosyltransferase polypeptide chain and that the presence of N-linked oligosaccharide chains on the protein does not affect the choice of substrate.


Cervical intraepithelial neoplasia in lymphoma patients: a cytological and colposcopic study.
Twenty-seven patients with Hodgkin's (n = 19) and non-Hodgkin's (n = 8) lymphomas underwent cytological and colposcopic screening of the uterine cervix. Colposcopically directed cervical punch biopsies were taken from all patients in whom a colposcopic abnormality was detected. Lymphoma patients were compared with 79 controls with normal cervical cytology and no known haematological abnormality. Colposcopically directed punch biopsies were taken from the cervical transformation zone of all controls. Significantly more lymphoma patients (19%) than controls (3%) had CIN II or III (P less than 0.01) and cervical human papillomavirus infection, as judged by the presence of koilocytes (52% of lymphoma patients; 27% of controls; P less than 0.02). All six lymphoma patients with CIN had Hodgkin's disease (HD), and five had received combination chemotherapy. Half of the cases of CIN in lymphoma patients and all the cases of CIN in control patients were not detected by cervical cytology. This study suggests that female patients with HD are at increased risk of CIN, and that cervical cytology alone may be an inadequate form of screening for these patients.


Diagnosis and follow-up of ultrasonographical sinus changes in children.
Retained secretion within the maxillary sinus was diagnosed by ultrasonography in 86 (19%) of 452 children (4-10 years) who entered Turku University ENT-clinic for adenoidectomy or adenotonsillectomy. Occipitomental radiographs showed signs of sinusitis in 168 (37%) of the children. All 86 children with secretion in one or both maxillary sinuses were operated on and treated with amoxicillin and a nasal decongestant. Fifty children (72 sinuses) were treated with antral lavage and 36 children (49 sinuses) were treated conservatively. After 10 days ultrasonography revealed no secretion in 86% of the irrigated sinuses and in 74% of the sinuses treated without irrigation. After 30 days all the irrigated sinuses were healed but in 5 (10%) of the sinuses treated without irrigation ultrasonography still revealed retained secretion. The difference was statistically significant. The disappearance of the radiographic sinus changes was considerably slower. As a non-ionizing method ultrasonography was found to be especially practical in the follow-up of treatment results. It seems that the disappearance of ultrasonic signs of sinusitis correlates better with the clinical resolving of sinusitis in childhood than the disappearance of radiographic signs of sinusitis.


Developing a model to explain users' ethical perceptions regarding the use of care robots in home care: A cross-sectional study in Ireland, Finland, and Japan.
To date, research on ethical issues regarding care robots for older adults, family caregivers, and care workers has not progressed sufficiently. This study aimed to build a model that universally explains the relationship between the use of care robots and ethical awareness, such as regarding personal information and privacy protection in home care. We examined data obtained from cross-sectional surveys conducted in Japan (n=528), Ireland (n=296), and Finland (n=180). We performed a confirmatory factor analysis by using responses to 11 items related to the ethical use of care robots. We evaluated the model based on the chi-square to degrees of freedom ratio, the comparative fit index, and the root mean square error of approximation. Subsequently, we compared the model with the Akaike's information criterion. Ten items were adopted in the final model. There were 4 factors in the model: 'acquisition of personal information', 'use of personal information for medical and long-term care', 'secondary use of personal information', and 'participation in research and development'. All factor loadings of the final model ranged between 0.63 and 0.92, which were greater than 0.6, showing that the factors had a high influence on the model. The final model was applied to each country; the fit was relatively good in Finland and poor in Ireland. Although the three countries have different geographies, cultures, demographics, and systems, this study showed that the impact of ethical issues regarding the use of care robots in home care can be universally explained by the same model.


Application of sand particles modified with NH2-MIL-101(Fe) as an efficient visible-light photocatalyst for Cr(VI) reduction.
This study presented chemical immobilization of an iron(III)-based metal-organic framework [NH2-MIL-101(Fe)] on the surface of sand particles and its application for Cr(VI) photocatalytic reduction using visible light. The surface of sand particles was functionalized with (3-chloropropyl)trimethoxy silane to provide the active sites for bond formation with MOF particles. Using a heat treatment step, MOF particles were bonded on the surface of sand particles, thereby providing a photocatalyst more applicable in real environments. The presence of amino-functional groups in MOF was influential in bond formation. Furthermore, they are effective in the activation of the photocatalyst under visible-light irradiation. The photocatalyst properties were investigated by FESEM, FTIR, XPS, EDS, and DRS analysis. The impact of various parameters, such as light power, irradiation and contact time, TDS impact, and pH, was examined. The composite produced by immobilization of NH2-101(Fe) on the surface of sand-Cl showed the high Cr(VI) removal efficiency (80% at 20 mg L-1) as a result of the strong chemical bond formation through the suitable functional groups incorporated in materials. Under the optimum conditions, the reduction rate reached more than 99% using irradiation by 1000 W visible light for 30 min.


Expression strategy of densonucleosis virus from Mythimna loreyi.
The genome of Mythimna loreyi densovirus (MlDNV) was cloned into the pEMBL(19)+ vector. This clone was infectious upon transfection, both in LD cells and larvae. The genome possessed ITRs of 543 nucleotides of which the distal 126 nucleotides could form a hairpin. The nonstructural (NS) and structural (VP) genes were located on the 5'-halves of the complementary strands and their transcripts started 27 nts downstream of the ITRs. These transcripts had an overlap of 57 nucleotides in middle of the genome. The NS cassette consisted of three genes with NS1 and the overlapping NS2 downstream of NS3. The NS3 gene was spliced out from a fraction of the NS transcripts to allow leaky scanning translation of the downstream bicistronic NS1 and NS2 genes. The four VPs were similarly generated by leaky scanning translation of unspliced mRNA. The 5'-untranslated region of the VP transcript was only seven nucleotides long.


BKM120 inhibits malignant rhabdoid tumor of the kidney through induction of apoptosis and G0/G1 phase arrest.
Malignant rhabdoid tumor of the kidney (MRTK) has an inferior prognosis and is insensitive to radiotherapy and chemotherapy. Search for novel, potent medicinal agents is urgent. Herein, data on the gene expression and clinical characteristics of malignant rhabdoid tumors (MRT) were retrieved from the TARGET database. Prognosis-related genes were identified by differential analysis and one-way cox regression analysis, and prognosis-related signalling pathways were identified by enrichment analysis. The prognosis-related genes were imported into the Connectivity Map database for query, and BKM120 was predicted and screened as a potential therapeutic agent for MRTK. A combination of high-throughput RNA sequencing and Western blot verified that the PI3K/Akt signaling pathway is associated with MRTK prognosis and is overactivated in MRTK. Our results outlined that BKM120 inhibited the proliferation, migration, and invasion ability of G401 cells and induced apoptosis and cell cycle G0/G1 phase arrest. In vivo, BKM120 inhibited tumor growth and had no significant toxic side effects. Western blot and immunofluorescence results confirmed that BKM120 could reduce the expression of PI3K and p-AKT, critical proteins of the PI3K/Akt signaling pathway. BKM120 inhibits MRTK by inhibiting PI3K/Akt signalling pathway to induce apoptosis and cell cycle G0/G1 phase arrest, which is anticipated to give the clinical treatment of MRTK a new direction.


Diagnosis of dual accessory pathways by ajmaline test.
In a patient with the Wolff-Parkinson-White syndrome, the existence of dual accessory pathways, both right-sided, was suspected during ajmaline test and confirmed during electrophysiologic study. The first accessory pathway was manifest in sinus rhythm while the second was obscured and revealed during low right atrial pacing. Ajmaline abolished conduction over the first pathway which most probably had a long refractory period allowing manifestation of the second pathway which had a very short refractory period. A longer conduction time over the second accessory pathway was suggested to explain its concealment during sinus rhythm.


Structure of HAP1-18-DNA implicates direct allosteric effect of protein-DNA interactions on transcriptional activation.
HAP1 is a yeast transcriptional activator that binds with equal affinity to the dissimilar upstream activation sequences UAS1 and UAS(CYC7), but activates transcription differentially when bound to each site. HAP1-18 harbors an amino acid change in the DNA binding domain. While binding UAS1 poorly, HAP1-18 binds UAS(CYC7) with wild-type properties and activates transcription at elevated levels relative to HAP1. We have determined the structure of HAP1-18-UAS(CYC7) and have compared it to HAP1-UAS(CYC7). Unexpectedly, the single amino acid substitution in HAP1-18 nucleates a significantly altered hydrogen bond interface between the protein and DNA resulting in DNA conformational changes and an ordering of one N-terminal arm of the protein dimer along the DNA minor groove. These observations, together with a large subset of transcriptionally defective mutations in the HAP1 DNA-binding domain that map to the HAP1-DNA interface, suggest that protein-DNA interactions may have direct allosteric effects on transcriptional activation.


A touch screen based Stop Signal Response Task in rhesus monkeys for studying impulsivity associated with chronic cocaine self-administration.
Among a range of cognitive deficits, human cocaine addicts display increased impulsivity and decreased performance monitoring. In order to establish an animal model that can be used to study the underlying neurobiology of these deficits associated with addiction, we have developed a touch screen based Stop Signal Response Task for rhesus monkeys. This task is essentially identical to the clinically used Stop Signal Task employed for diagnostic and research purposes. In this task, impulsivity is reflected in the amount of time needed to inhibit a response after it has been initiated, the Stop Signal Response Time (SSRT). Performance monitoring is reflected by the slowing of response times following Stop trials (Post-Stop Slowing, PSS). Herein we report on the task structure, the staged methods for training animals to perform the task, and a comparison of performance values for control and cocaine experienced animals. Relative to controls, monkeys that had self-administered cocaine, followed by 18 months abstinence, displayed increased impulsivity (increased SSRT values), and decreased performance monitoring (decreased PSS values). Our results are consistent with human data, and thereby establish an ideal animal model for studying the etiology and underlying neurobiology of cocaine-induced impulse control and performance monitoring deficits.


Factors affecting outcomes of embryo transfer in dromedary camels: A retrospective study.
The present study aimed to use a comprehensive approach for evaluating 12 factors related to embryo quality (shape, size and transparency), donors (age, ET type, number of recovered embryos and day of uterine flushing), recipients (age), males (age and individual variations) and environment (season and year) which could affect the outcome of ET in terms of pregnancy (PR) and pregnancy losses in dromedary camels. During three breeding seasons, 116 donor females were mated repeatedly at 12- to 14-day intervals by fertile male camels (n = 33) without stimulation of the ovaries (WSPO). Superovulation (SPO ET) regimen was applied for each donor female twice or thrice per season. In the occasions of applying superovulation regimen, donor females having an ovulatory follicle were mated instead of GnRH administration and superovulation regimen was applied 4 days post-mating (MIX ET). The uteri of all donor females were flushed at Day 8 or 9 post-mating, and a total of 2,095 embryos were recovered and transferred individually to 924 recipient females. Pregnancy diagnoses were conducted at Day 10 after ET (Days 18-19 of gestation) by using progesterone assay and by transrectal ultrasonography (TRU) at Days 30 and 60 of gestation. By using logistic regression analysis, transparency of embryos and age of recipient females had significant effects on PR at Days 18-19 (p < .01), 30 (p < .01) and 60 (p < .01; p < .05, respectively) of gestation. The shape of embryos had significant effects on the PR at Days 30 (p < .05) and 60 (p < .01) of gestation. Type of ET and the breeding season (year) had significant (p < .05) effects on the PR at Day 30, while day of flushing had the same effect on PR at Day 60. Regarding the pregnancy losses, transparency and shape of the embryo, type of ET, breeding season had significant (p < .05) effect on the late embryonic mortalities (LEM) and shape and season of year had significant (p < .01 and p < .05, respectively) effect on LEM/early foetal mortalities (EFM). Regarding male individual factor, there was a tendency for a significant (p = .055) effect of male camels on the PR at Days 18-19 and rate of LEM. In conclusion, transferring a spherical, transparent or a large-sized embryo (>750 µm) into recipient females ageing between 8 and 11 y could greatly improve the PR from Days 18 to 60 of gestation. Also, embryo recovered from donor females with Mix ET type or embryos sired by certain male camel or at Day 8 post-mating of the donor could improve the 2-month PR. In addition, transferring a transparent or spherical-shaped embryo or embryos recovered from donor females with SPO or Mix ET could reduce the pregnancy losses during the first 2 months of pregnancy.


Low serum 25-hydroxyvitamin D levels are associated with liver injury markers in the US adult population.
To examine the associations between serum 25-hydroxyvitamin D (25(OH)D) levels and serum liver enzymes in a representative sample of US adults. The cross-sectional study sample consisted of 24 229 adults with data on serum 25(OH)D levels and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transaminase (GGT) concentrations, in addition to data on other potential confounders. Multivariate logistic regression and linear regression were applied to assess the associations between serum 25(OH)D levels and ALT, AST, ALP and GGT concentrations. The National Health and Nutrition Examination Survey, 2001-2006. The cross-sectional study sample consisted of 24 229 adults. We found a significant association between low serum 25(OH)D levels (<30 nmol/l) and ALP levels in all participants (OR 2·67; 95 % CI 1·98, 3·59; P < 0·001), a confirmed healthy population (OR 3·02; 95 % CI 2·25, 4·07; P < 0·001) and individuals with viral hepatitis (OR 2·87; 95 % CI 1·52, 5·44; P = 0·006) compared with those who had normal 25(OH)D levels (>50 nmol/l). Moreover, in both the logistic regression and linear regression, the associations between 25(OH)D levels and ALP levels were stronger in the subgroups with obesity. No association was present between ALT, AST or GGT levels and serum 25(OH)D levels in this population. The results of the present study provide epidemiological evidence that vitamin D deficiency is associated with liver ALP levels in humans. This finding suggests a potential adverse effect of low 25(OH)D levels on human liver function. However, the underlying mechanisms still need further investigation.


Erythrocyte mean corpuscular volume as a surrogate marker for 6-thioguanine nucleotide concentration monitoring in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.
Mean corpuscular volume may correlate with erythrocyte 6-thioguanine nucleotide concentrations in patients treated with azathioprine and 6-mercaptourine. We conducted a study of 166 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentrations, disease activity as measured by the Inflammatory Bowel Disease Questionnaire (active disease <170, remission >170), and leukopenia. Blood was submitted for mean corpuscular volume, whole blood 6-thioguanine nucleotide concentration, and leukocyte count. The mean +/- SD mean corpuscular volume during treatment was 94.7 +/- 6.6 fL and the mean +/- SD change in mean corpuscular volume was 7.5 +/- 6.3 fL. There were significant correlations between mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentration (r(s) = 0.33, p < 0.001) and between change from baseline in mean corpuscular volume and erythrocyte 6-thioguanine nucleotide concentration (r(s) = 0.26, p = 0.001). There was no correlation between Inflammatory Bowel Disease Questionnaire scores and mean corpuscular volume values (r(s) = 0.01, p = 0.94). The mean corpuscular volume values in 55 patients with active disease and 111 patients in remission were similar (95.1 vs. 94.5 fL, p = 0.57). There was a weak negative correlation between the mean corpuscular volume and the leukocyte count, (r(s) = -0.18, p = 0.022). In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, mean corpuscular volume and change from baseline in mean corpuscular volume correlated with erythrocyte 6-thioguanine nucleotide concentrations and negatively with leukocyte counts, but did not correlate with disease activity as measured by the Inflammatory Bowel Disease Questionnaire. Measurement of mean corpuscular volume is a simple and inexpensive alternative to measurement of 6-thioguanine nucleotide concentrations in patients treated with azathioprine or 6-mercaptopurine.


Identification of sample-specific regulations using integrative network level analysis.
Histologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. We present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample-specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup. We applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS-OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set. We present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovarian cancer data showing our method is able to identify reliable and potentially important regulations with high reproducibility. R package is available at http://csbi.ltdk.helsinki.fi/pub/czliu/DERA/.


Manifestations of Inhalant Allergies Beyond the Nose.
The upper and lower airways are linked epidemiologically and pathophysiologically. The upper and lower airways are considered a single, functional unit characterized by shared immunologic mechanisms, often referred to as the unified airway. Upper and lower airway inflammatory disease frequently coexist in the same patient. Allergic rhinitis and rhinosinusitis are associated with asthma. Treatment of both diseases impacts asthma outcomes. The otolaryngologist may be the first physician to suspect and diagnose asthma in patients with upper airway complaints. A thorough understanding of the relationship between allergic rhinitis, rhinosinusitis, and asthma will facilitate early identification of asthma and improve patient outcomes.


CRISPR-Cas fluorescent cleavage assay coupled with recombinase polymerase amplification for sensitive and specific detection of Enterocytozoon hepatopenaei.
Enterocytozoon hepatopenaei (EHP) is a parasite that infects pacific whiteleg shrimp, Penaeus vannamei, causing growth retardation and uneven size distributions that lead to severe losses in shrimp productivity. Routine monitoring is crucial to timely prevention and management of EHP, but field-deployable diagnostic kits for EHP are still scarce. Here, we proposed the use of recombinase polymerase amplification (RPA) and CRISPR-Cas12a fluorescence assay, henceforth RPA-Cas12a, for detection of EHP. Targeting ptp2 gene, RPA-Cas12a could detect as few as 50 copies of DNA and showed no reactivity with closely related microsporidia. The entire procedure could be performed at a temperature close to 37 °C within 1 h. Naked eye visualization was possible with UV/blue-light excitation or lateral flow detection. Thus, RPA-Cas12a is a rapid, sensitive and specific detection platform that requires no sophisticated equipment and shows promise for on-site surveillance of EHP.


Interactions between the Intrinsically Disordered Regions of hnRNP-A2 and TDP-43 Accelerate TDP-43's Conformational Transition.
Most biological functions involve protein-protein interactions. Our understanding of these interactions is based mainly on those of structured proteins, because encounters between intrinsically disordered proteins (IDPs) or proteins with intrinsically disordered regions (IDRs) are much less studied, regardless of the fact that more than half eukaryotic proteins contain IDRs. RNA-binding proteins (RBPs) are a large family whose members almost all have IDRs in addition to RNA binding domains. These IDRs, having low sequence similarity, interact, but structural details on these interactions are still lacking. Here, using the IDRs of two RBPs (hnRNA-A2 and TDP-43) as a model, we demonstrate that the rate at which TDP-43's IDR undergoes the neurodegenerative disease related α-helix-to-β-sheet transition increases in relation to the amount of hnRNP-A2's IDR that is present. There are more than 1500 RBPs in human cells and most of them have IDRs. RBPs often join the same complexes to regulate genes. In addition to the structured RNA-recognition motifs, our study demonstrates a general mechanism through which RBPs may regulate each other's functions through their IDRs.


The effect of a single injection of hydroxyurea on cell population kinetics in the small bowel mucosa of the rat.
The effect of a single injection of hydroxyurea (HU) on cell population kinetics in the jejunal crypt of the rat was studied using autoradiography with tritiated thymidine and metaphase arrest with vincristine. HU appeared to act selectively on cells in the S phase producing inhibition of DNA synthesis and cell death. The deficit in proliferating cells was made good by a decrease in cell cycle time and an increase in growth fraction. Particular attention was paid to the basal, slowly cycling (and possibly clonogenic) crypt cells; early in the recovery sequence an increase in cell production rate was found in the base of the crypt. It is proposed that basal crypt cells, having survived cycle-specific insult because of long cell cycle times, proceed to repopulated the depleted proliferative compartment.


Coronary artery surgery: the end of the beginning.
In each of the first three decades of myocardial revascularization, conventional treatment has been revised completely. This lecture comments on three areas of discovery that have shaped the evolution of myocardial revascularization: science, technology development, and revascularization. The discoveries in all three areas are inexorably interrelated. The single greatest lesson learned so far is that conduit performance carries more prognostic weight than any other factor. We have observed that vein graft atherosclerosis is predictable, and that the first-generation lipid lowering drugs have a favorable effect in patients who achieve marked LDL reduction. Biologically better revascularization begins with use of the internal thoracic artery for grafting to the anterior descending coronary artery. As the results of internal thoracic artery grafting are widely reported, arterial bypass revascularization has expanded, notably by radial and gastroepiploic arteries. The results of bilateral internal thoracic artery grafting are discussed, including large-scale registry results of internal thoracic artery usage in the United States. The internal thoracic artery is significantly underutilized. Diabetes affects both endoluminal and surgical revascularization. The new pharmacology in cardiology interventions shows promise in diminishing restenosis and thrombosis even in diabetic patients. Conversely, extended internal thoracic artery grafting may also benefit diabetic patients. Now we are entering a new age of minimally invasive coronary surgery. We have passed through the early stages of mini-thoracotomy, and we are moving on to access through 1-cm ports, intrathoracic cannulation, antegrade and retrograde myocardial protection, and computer guided three-dimensional vision and instrumentation. The potential for robotic control adds greater precision, ease of use, and safety. This new technology will be integrated with diagnostic information, intraoperative monitoring, anesthesia and perfusion data, cost accounting, and surgical note transcription. The operating room of the future will package intraoperative information and is adaptable to all surgical specialties. The future of coronary artery surgery will depend on minimally invasive techniques, all-arterial grafting, and selective lipid modification to reduce progressive atherosclerosis. The conclusion of this decade marks the end of the beginning. The new generation of cardiothoracic surgeons will share in an array of technology and research unmatched in previous decades.


Innate immunity and the role of defensins in otitis media.
Otitis media is the most common pediatric disease in developed countries and a significant cause of morbidity and hearing loss in developing countries. The innate immune system is essential to protecting the middle ear from infection. Defensins, broad-spectrum cationic antimicrobial peptides, have been implicated in prevention of and the early response to acute otitis media; however, the mechanisms by which defensins and other antimicrobial molecules mediate this protection have not been completely elucidated. In both animal otitis media models and human middle ear epithelial cell culture models, β-defensins are highly induced and effectively kill the common pathogens associated with otitis media. We review the importance of innate immunity in protecting the middle ear and recent advances in understanding the roles of defensins and other antimicrobial molecules in the prevention and treatment of otitis media. The extremely high prevalence of otitis media, in spite of sophisticated innate and adaptive immune systems, is a vexing problem for clinicians and scientists. We therefore also review mechanisms by which bacteria evade innate immune defenses.


Biophysical properties of redness-prone skin in Korean women.
Facial skin redness can have a negative impact on the quality of life. In this study, we investigated the skin biophysical parameters associated with facial skin redness as a function of aging. Our aims were as follows: (1) to understand the impact of non-pathological facial skin redness on the quality of life of Korean women through a survey; and (2) compare skin biophysical properties between women with and without facial skin redness. Women aged between 20 and 39 years perceived their own facial skin redness at a higher rate than those aged ≥40 years. In addition, in redness-prone women, the intensity of skin redness and skin surface perfusion were higher, while skin hydration was lower regardless of age. In redness-prone women aged ≥40 years, the values for transepidermal water loss, elasticity, and skin thickness were lower, and the mean pore depth was greater. Facial redness intensity was higher, and the distribution was wider in redness-prone younger women, while only redness intensity increased in the older age group. Overall, redness-prone women aged ≥40 years had weaker skin properties. Our study indicated the age-related biophysical characteristics of non-pathological facial skin redness. We believe that our findings will help improve its negative effects.


Pre-COVID-19 Physician Awareness of Mental Health Resources During and After Natural and Human-Made Disasters.
Physician mental health is critical during the recovery of natural and human-made disasters (NHDs), yet the accessibility of mental health resources to physicians has not been characterized. This study examined emergency medicine and trauma physician knowledge of and access to mental health resources in NHD settings. The survey was electronically disseminated to the American College of Emergency Physicians and the American Association of the Surgery of Trauma between February 4, 2020, and March 9, 2020. The 17-question survey assessed physician awareness and access to emergency preparedness resources at their institutions. Of the responders, 86% (n = 229) were aware of written emergency response plans for their facility. While 31% were aware of the hospital's mental health policies and resources outside of the emergency response plan, only 25% knew how to access these resources during and after NHDs. Finally, 10% reported the incorporation of mental health resources during institutional practice drills. Physicians reported knowledge of emergency preparedness policies; however, significant gaps remain in physician knowledge and access to mental health resources NHD settings. As NHDs increase on a global scale, it is critical for health systems to ensure accessible infrastructure to support the mental well-being of health professionals.