Biogenic amine-stimulated adenylate cyclase and spiroperidol-binding sites in rabbit brain: evidence for selective loss of receptors with aging.
Evidence for selective decreases in biogenic amine receptor function with age in the rabbit has been obtained. Dopamine-stimulated adenylate cyclase activity in the striatum (caudate-putamen) of rabbit brain declined by about 50 percent as rabbits aged from less than 1 to 4 to 5 years of age. Similar decreases in transmitter-stimulated adenylate cyclase activity were found for histamine as well as for dopamine and norepinephrine in hypothalamus, frontal cortex and anterior limbic cortex. Isoproterenol-stimulated activity was also decreased with age in frontal cortex. These changes appeared to represent decreases in maximal response and not alteration in affinity for amine. In contrast, dopamine-stimulated adenylate cyclase of retina and transmitter-independent (basal or Gpp(NH)p-stimulated) activity in each of the regions studied were not altered with age. Dopamine receptors in striatum directly assessed by measurement of [3H]-spiroperidol binding revealed a comparable decrease in the number of binding sites without change in ligand affinity. Preliminary data also indicated decreased spiroperidol binding sites in the cortical regions of older animals. These changes in striatum and cortex were evident in the absence of decreases in either dopamine content or choline acetylase activity, an activity presumed to be present in neurons containing dopamine receptors. It is proposed that selective age-dependent decreases in postsynaptic biogenic amine receptor content occur in the absence of, or independent from, neuronal cell loss, possibly by a mechanism involving receptor desensitization. These changes occur in the animal model in those brain regions which in man are thought to be of importance in the loss of cerebral function that is found with senscence.


Orthognathic Surgery for Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA) involves obstruction or reduction of an individual's airway during sleep and is associated with several comorbidities. Patient evaluation includes detailed history, clinical and radiographic examination, endoscopy, and polysomnography. Management may be nonsurgical or surgical, and Phase II of the Stanford Protocol of surgical management involves maxillomandibular advancement (MMA). Surgical considerations (eg, degree of movement, timing of surgery) and potential complications specific to MMA are discussed in this review. With adequate planning and communication with the patient, MMA is effective in treating OSA, as measured with objective and subjective measures.


The Quality of Life for Children with Autism Spectrum Disorder Scale: Factor Analysis, MIMIC Modeling, and Cut-Off Score Analysis.
Our purpose in this study was to further examine the psychometric properties of the Quality of Life for Children with Autism Spectrum Disorder (QOLASD-C) scale. We first investigated the factor structure and the internal consistency of the scale. The bifactor model showed good fit and strong reliability. Second, we used multiple-indicators multiple-causes (MIMIC) modeling to examine the associations between demographic variables and the QOLASD-C dimensions. Results showed differences on overall QOL based on age, race/ethnicity, and autism spectrum disorder severity, but no relationships with gender. All demographic variables were associated with one or all three subscales (i.e., interpersonal relationships, self-determination, emotional well-being) of the QOLASD-C. Third, an optimal cut-off score of 37 was identified. Implications for research and practice are discussed.


Thermal properties of human IgG.
Dynamic light scattering experiments have been performed to study the aggregation kinetics of human immunoglobulin G (IgG). Aggregation and irreversible cluster growth results when IgG solutions (2-15 mg/ml) are heated above 50 degrees C. The measured scattering intensity I and effective hydrodynamic radius (R) can be described consistently by a Smoluchowski aggregation process. The number of clusters ni(t) containing i monomers at time t are computed. The radius of an i cluster is assumed to be Ri = R0 i beta, where beta is the cluster exponent. This kinetic process results in the following characteristic power law behavior: (R)/R0 = (1 + gamma R (T, C, c)t) alpha R and (I)/I0 = (1 + gamma 1 (T, C, c)t) alpha I. Here R0 = 5.51 nm, is the monomer hydrodynamic radius, and I0 the scattered intensity from the monomer solution at temperature T and concn C. A fraction, c approximately 0.48 of the IgG monomers are heat stable up to 63 degrees C and do not participate in the aggregation process. The power-law behavior of mean value of R/R0 and mean value of I/I0 indicates scaling, and indeed a very satisfactory data collapse results from our data. The best non-linear fit of the power-law forms gives alpha R = 0.48 +/- 0.05, alpha I = 1.00 +/- 0.01 and beta = 0.39 +/- 0.04. We also find that the heat aggregation of IgG is an activated process. Fits of the experimental data Gibbs free energy for the activated complex delta G* = 13.8 +/- 0.1 kcal/mole at 56 degrees C. The temp dependence of the growth rates exhibits an Arrhenius behavior with an enthalpy of activation delta H* = 120 +/- 5 kcal/mole.


Inside-out: normalising practice-based IPE.
Practice-based interprofessional education (IPE), a key feature in developing a collaboration-ready workforce, is poorly integrated in healthcare curriculums. This study aimed to synthesise educator perspectives on implementing practice-based IPE and develop recommendations to inform sustainable practice-based IPE. An ethnographic case study was carried out at a school of allied health. Data collection involved six observations, 11 interviews and a review of eight documents. Reflexive thematic analysis, informed by Normalisation Process Theory, established two key themes. First, we found that strategic planning is needed, with a coherent implementation agenda and planned reflection on activities. Second, building partnerships with placement partners was identified as essential. This can be achieved by supporting and championing practice-based IPE activities developed by placement sites and establishing how university and clinical educators can work collaboratively to deliver sustainable practice-based IPE. These conditions create a favourable environment for normalising practice-based IPE in healthcare curriculums, benefitting students, patients, and the overall healthcare service.


Multicoding in neural information transfer suggested by mathematical analysis of the frequency-dependent synaptic plasticity in vivo.
Two elements of neural information processing have primarily been proposed: firing rate and spike timing of neurons. In the case of synaptic plasticity, although spike-timing-dependent plasticity (STDP) depending on presynaptic and postsynaptic spike times had been considered the most common rule, recent studies have shown the inhibitory nature of the brain in vivo for precise spike timing, which is key to the STDP. Thus, the importance of the firing frequency in synaptic plasticity in vivo has been recognized again. However, little is understood about how the frequency-dependent synaptic plasticity (FDP) is regulated in vivo. Here, we focused on the presynaptic input pattern, the intracellular calcium decay time constants, and the background synaptic activity, which vary depending on neuron types and the anatomical and physiological environment in the brain. By analyzing a calcium-based model, we found that the synaptic weight differs depending on these factors characteristic in vivo, even if neurons receive the same input rate. This finding suggests the involvement of multifaceted factors other than input frequency in FDP and even neural coding in vivo.


A neuroanatomical model of prefrontal inhibitory modulation of memory retrieval.
Memory of past experience is essential for guiding goal-related behavior. Being able to control accessibility of memory through modulation of retrieval enables humans to flexibly adapt to their environment. Understanding the specific neural pathways of how this control is achieved has largely eluded cognitive neuroscience. Accordingly, in the current paper I review literature that examines the overt control over retrieval in order to reduce accessibility. I first introduce three hypotheses of inhibition of retrieval. These hypotheses involve: (i) attending to other stimuli as a form of diversionary attention, (ii) inhibiting the specific individual neural representation of the memory, and (iii) inhibiting the hippocampus and retrieval process more generally to prevent reactivation of the representation. I then analyze literature taken from the White Bear Suppression, Directed Forgetting and Think/No-Think tasks to provide evidence for these hypotheses. Finally, a neuroanatomical model is developed to indicate three pathways from PFC to the hippocampal complex that support inhibition of memory retrieval. Describing these neural pathways increases our understanding of control over memory in general.


Homozygous LOXL2 variant in individuals affected by non-syndromic occipital encephalocele.
Occipital encephaloceles is a rare congenital defect in which meninges and the brain protrude out as a sac-like structure through opening in the skull. The condition can result in neurologic complications as well as structural abnormalities of the skull. To the best of our knowledge, no genetic variant has been identified as an underlying cause of non-syndromic occipital encephaloceles. In this study, I report a family with 2 individuals having large occipital encephalocele. Clinical and radiological examination did not reveal any other neurological or skeletal manifestations in both affected individuals. Exome sequencing detected the previously unreported homozygous single nucleotide duplication (NM_002318.3:c.64dupC) in LOXL2 gene. This is a nonsense variant (NP_002309.1:p.Leu22Profs*7) leading to a premature truncation and loss-of-function of the lysyl oxidase-like 2 protein. The variant is segregating in an autosomal recessive manner in a family. Both parents are heterozygous carriers for the variant while unaffected sibs have wild type sequence. We hypothesize that LOXL2 is a potential candidate gene for occipital encephalocele due to the established role of LOXL3, a close paralog of LOXL2, in craniofacial development. This case illustrates the power of exome sequencing to establish genetic diagnosis and expands the spectrum of genetic defects in occipital encephalocele and related disorders.


Spectral plasmonic effect in the nano-cavity of dye-doped nanosphere-based photonic crystals.
We demonstrated three-dimensional PMMA-based photonic crystal (3D-PC) nanostructures attached to Au nanoparticles (AuNPs), which undergo self-organization into super lattice planes and enhance the fluorescence properties. This new structure exhibited interesting tunable spectral, peak broadening plasmonic behavior because of strong plasmonic interaction at high laser powers. The presented work provides an important tool to improve the efficiency of dye laser applications.


[THE GENETIC BASIS OF CHRONIC KIDNEY DISEASE IN CHILDREN AND YOUNG ADULTS].
Chronic kidney disease (CKD) in children arises from heterogeneous disease etiologies. A large portion is caused by monogenic diseases, which are also known as single-gene disorders or Mendelian diseases. Understanding the genetic underpinnings of childhood and young adulthood, CKD has increased significantly over the last decade due to increased availability of genetic testing as well as clinician's awareness. This led to the discovery of numerous genes that, if mutated, may lead to early onset CKD. So far, hundreds of CKD-causing genes have been reported, explaining ~30% of cases among children and ~10% in adults. Nonetheless, the genetic diagnostic yield varies markedly across different study cohorts, depending on clinical presentation, geographic region and ethnicity. In clinical practice, the diagnosis of genetic kidney diseases may be challenging due to variable expressivity, incomplete penetrance, low index of suspicion, lack of overt symptoms at early disease stages and insufficient availability of next generation sequencing methods. Detection of monogenic causes of CKD provides definitive diagnosis that might end a long distressing odyssey. It enables personalized surveillance and treatments, spares unnecessary diagnostic procedures such as kidney biopsies, prevents the use of inappropriate therapies, and might also prevent incompatible transplantation from an affected relative. Additionally, it allows family genetic consulting and early diagnosis of asymptomatic family members. The notable progress in the field of genetics in addition to the diagnostic challenges of genetic kidney disease led to the emergence of nephrogenetics - a rapidly evolving subspecialty of nephrology and genetics. Preferably, the management of patients with genetic kidney disease should be multi-disciplinary and include collaboration between nephrologists, geneticists and additional consultants as needed. We anticipate that a routine use of genetic testing for CKD patients, as well as additional advancements in genetic discoveries, will further lead to understanding of genetic CKD patho-mechanisms and to the development of novel gene-based therapies. In this review, we will discuss the genetic basis of CKD in children and young adults. We will also discuss the clinical approach to patients with suspected genetic kidney disease.


Densitometric quantification for the validation of decolorization of Disperse Orange ERL by lichen Parmelia sp.
Densitometric high performance thin layer chromatography (HPTLC) quantification method was developed to validate the decolorization/biotransformation of Disperse Orange ERL and dye mixture by lichen Parmelia sp. which release several colored compounds during decolorization process, hence unable to use colorimetric estimation. Percent decolorization of Disperse Orange ERL and dye mixture by lichen Parmelia sp. was observed when estimated using developed HPTLC method. Limit of detection and limit of quantification for both dyes in mixture were obtained as 0.3 and 1 μg/μl, respectively. Area of peak of control Disperse Orange ERL was reduced by 43% after 12 h, 71% after 48 h and upto 82% after 72 h of incubation. Precision and repeatability of data elucidated the % relative standard deviation less than 3 for all the values thus indicating statistically acceptable. Biodegradation of dye and mixture was confirmed with Fourier transform infrared spectroscopy analysis, i.e., altered fingerprinting spectral pattern.


Working conditions, serotonin transporter gene polymorphism (5-HTTLPR) and anxiety disorders: a prospective cohort study.
The etiology and pathology of anxiety disorders involve both genetic and environmental influences. Adverse working conditions may contribute to the development of anxiety. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in stress sensitivity. Therefore, we investigated the potential interplay between 5-HTTLPR and job-related risk factors in the prediction of the occurrence of anxiety. We conducted a prospective study using the first two waves of a Swedish population-based cohort. At Wave I, 1585 individuals without anxiety, depression or dysthymia who were active in the labor market during both waves were included. Information on job demands, skill discretion, decision authority and social climate was collected at Wave I. After a three year interval, the presence of anxiety disorders was determined at Wave II. All 1585 participants were genotyped for 5-HTTLPR. Both additive and multiplicative models were considered in examining the potential interaction between 5-HTTLPR and adverse working conditions on the development of anxiety. Anxiety was associated with high job demands but not with 5-HTTLPR. An interaction was observed between 5-HTTLPR and high job demands among females. Individuals with 5-HTTLPR high expression genotype (LL) developed anxiety disorders more frequently when exposed to high job demands compared to 'LS/SS' carriers. A limited number of participants developed anxiety. High job demands predict the development of anxiety. The 5-HTT polymorphism has a moderating effect on the relationship between high job demands and anxiety among females.


[Phototherapeutic keratectomy (o-PTK) with 193 nm excimer laser for superficial corneal scars. Prospective long-term results of 31 consecutive operations].
To investigate the functional and morphological long-term outcome of phototherapeutic keratectomy (PTK) for superficial corneal scars of varying origin. Between 1989 and 11/2002, 317 PTKs were performed in Erlangen, of which 31 consecutive procedures were assessed in this prospective study. The intended laser ablation depth after epithelial debridement and pannectomy varied from 12 to 150 microm. We used the slit-scanning-mode (Carl Zeiss Meditec AG) with a repetition rate of 20/s or 25/s, a pulse energy of 14.5 mJ (median) and a pulse rate of 2565+/-2036 (222-6962). In most cases a 6.0 mm metal mask was used to protect peripheral Bowman's layer. After a mean follow-up of 2.0+/-1.9 (maximum 6.9) years, best-corrected visual acuity increased from preoperatively 0.3+/-0.2 to 0.5+/-0.3 (increase 87%, no change 10%, decrease 3%). Corneal surface topography regularized significantly (p=0.02). The spherical equivalent increased only slightly from -0.4+/-2.5 D preoperatively to 0.2+/-2.9 D postoperatively. Likewise, mean keratometric central power did not change significantly. In 10 eyes the maximum postoperative haze was mild, in 4 eyes moderate, and there was only one recurrent scar after delayed epithelial healing following epidemic keratoconjunctivitis. In superficial corneal scars of varying origin an o-PTK using the 193 nm excimer laser can moderately increase visual acuity in most cases. Therefore, a lamellar or penetrating keratoplasty might be avoided.


Identification of a nuclear protein in Trypanosoma brucei with homology to RNA-binding proteins from cis-splicing systems.
Gene expression in trypanosomes is controlled at the level of pre-mRNA maturation via trans-splicing and polyadenylation and through changes in mRNA stability. To identify the trans- acting factors involved in this regulation, we have used a degenerate PCR approach to clone genes encoding the RNA recognition motif (RRM) consensus. We have identified a single-copy gene encoding a protein (designated RRM1) which contains three consensus RRM motifs, two tandem copies of a retroviral gag-like CCHC 'zinc finger' and an arginine-serine (RS) rich region. Western blotting indicates that RRM1 is expressed in both procyclic and bloodstream-form trypanosomes and has an apparent mobility on SDS-PAGE of ca. 70 Kd. RRM1 is localized in the trypanosome nucleus in substructures which may be functionally analogous to the 'speckles' associated with cis-splicing in higher eukaryotic cells. The structure of RRM1, its pattern of expression and its intracellular location suggest that it may play a role in trans-splicing.


Telomeres and telomerase in hematologic neoplasia.
Normal hematopoietic cells express telomerase activity, however the presence of telomerase does not necessarily imply stable and thus unchanging telomere length. Gradual telomere loss with aging and rapid cycling of hematopoietic stem cells might contribute to immunosenescence, exhausted hematopoiesis, and increased likelihood of malignant transformation. In leukemias and lymphomas, telomere length may reflect the cellular proliferative history, prior to immortalization. The level of telomerase activity is generally influenced by the fraction of cells in the proliferative pool. Shortened telomeres and high telomerase activity almost always correlates with disease severity in hematologic neoplasias such as relapsed leukemia and high-grade lymphomas, indicating that measurement of telomere length and telomerase activity might be useful to monitor disease condition. Since the mode of action of telomerase inhibitors may require telomeric shortening before induction of apoptosis, anti-telomerase therapy might be helpful for adjuvant therapy following conventional chemotherapy, in vitro purging of neoplastic cells in stem cell transplantation, and treating minimal residual disease. Some promising areas of tissue engineering include rejuvenation of hematopoietic stem cells for improving stem cell transplants or enhancing general immunity for older patients.


The AAA+ superfamily of functionally diverse proteins.
The AAA+ superfamily is a large and functionally diverse superfamily of NTPases that are characterized by a conserved nucleotide-binding and catalytic module, the AAA+ module. Members are involved in an astonishing range of different cellular processes, attaining this functional diversity through additions of structural motifs and modifications to the core AAA+ module.


Progressive dilated cardiomyopathy in a patient with longstanding and complete prednisone-induced hematological remission of idiopathic hypereosinophilic syndrome.
A female patient is described in whom the diagnosis of idiopathic hypereosinophilic syndrome (HES) with heart disease and peripheral neuropathy was made at the age of 32 years. Although prednisone induced a prompt and longstanding complete hematological remission, progressive and eventually intractable heart failure developed, and the patient died 6 years later. Endomyocardial biopsy at diagnosis showed infiltration with intact and disintegrated eosinophils and Charcot-Leyden crystals. Echocardiographic follow-up (including Doppler-Echocardiography) revealed mitral regurgitation with thickening and impaired motility of the posterior mitral leaflet, as well as progressive dilated cardiomyopathy. At autopsy, a diffuse interstitial fibrosis with patchy prominence in an eccentric hypertrophic and highly dilated heart was found. There were no significant endocardial thickening and no mural thrombi. In contrast to the findings of the initial endomyocardial biopsy, autopsy revealed no eosinophilic infiltrate. In this case, eosinophil-induced heart disease manifested as dilated cardiomyopathy, without endocardial fibrosis as originally described by Löffler. We speculate, that eosinophils have been deposited predominantly in the myocard at an early stage of disease, and - activated locally - secreted their granule proteins producing an initial damage to capillary endothelial cells and myocytes. After prednisone-induced clearance of eosinophils from blood and tissues, progressive, self-perpetuating interstitial fibrosis of the myocard and loss of myocytes eventually resulted in end-stage dilated cardiomyopathy.


The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.
Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.


Ischaemic colitis in systemic lupus erythematosus--report of a case and review of the literature.
We report a case of perforation of the colon from systemic lupus erythematosus (SLE) presenting initially with diarrhoea and later with acute abdominal symptoms. She was found to have widespread arteriolitis involving the colon resulting in necrosis, ulceration and perforation with peritonitis and ultimately, death from septicaemia. Although intra-abdominal symptoms are not uncommon in cases of SLE, actual involvement of the gastrointestinal tract of a degree severe enough to warrant surgical intervention is a relatively uncommon phenomenon.


A physiological view of in vivo calcium dynamics: the regulation of a nonlinear self-organized system.
Our aim is neither to re-evaluate the term homeostasis, nor to summarize the conventional concepts in the field of calcium metabolism and its regulation, nor even to comment on their advantages and their limitations (excellent recent reviews have been published). This paper is rather a position article and references to the current literature will be made only if they contribute to a better understanding of our proposals; in contrast, emphasis will be placed on a literature which has, until now, remained unfamiliar to the field of calcium metabolism. The text is organized around three related features which are largely dictated by the characteristics of our recently published compartmental self-oscillatory model for rat calcium metabolism: (a) The circadian behavior associated with calcium dynamics in vivo may be viewed as a "key" temporal behavior for investigating the spatiotemporal organization of calcium metabolism in the normal rat. Within the bone, a large part of this circadian behavior should stem from the physico-chemical properties of the transformations of calcium-phosphate associations at the extracellular fluid (ECF)/mature bone interface; (b) an important part of the maintenance of a nearly constant plasma calcium concentration (homeostasis) results from interaction between nonlinear oscillators belonging to both calcium metabolism and calcium-regulating hormones. This implies that: firstly, calcium metabolism, like any biological system, is a complex dynamic system which has evolved over a long period and whose metabolic components--gut, kidney, bone--are organized as dynamic entities, adapted to periodic relationships with the external environment. The intrinsic nature of the circadian behavior of bone calcium efflux proposed here is a sufficient demonstration of this. Secondly, the existence of rhythmic variations in the main calcium regulating hormones, parathyroid hormone (PTH), calcitonin (CT) and vitamin D (VitD), are in agreement with this argument. As developed below, fascinating properties emerge from interaction between oscillators (hormones and target organs) which provide a new perspective on calcium regulation; and (c) one of the striking properties of the kind of nonlinear dynamic system required for this representation of calcium metabolism is that periodicity is only one of many temporal expressions. Thus, qualitative diversity in the temporal expression of calcium metabolism can be expected with varying experimental situations and different modes of temporal regulation of calcium metabolism might be physiologically effective, depending on the species studied.(ABSTRACT TRUNCATED AT 400 WORDS)


Renal resistive index as a marker of vascular damage in cardiovascular diseases.
The article presents changeability of renal resistive index (RRI) in various cardiovascular diseases and considers the usefulness of the marker and interpretational difficulties of the index. The values of RRI are not specific to an individual disease, but in a selected group of patients, it seems to be a perfect marker of cardiovasculorenal changes and a predictor of rapid loss of a renal function. The RRI usually does not reflect the vascular resistance, but is dependent on total and local vascular bed compliance changing with age, in the course of consecutive diseases and the influence of drugs. Under specific conditions, RRI appears to be a good marker of vascular damage. This review summarizes current concepts in RRI interpretation against the cardiovascular pathologies, focusing on the vascular damage association with regard to the complex nature of RRI value variability.


Exploring the role of moral injury outcomes in intimate relationship functioning among U.S. combat veterans.
Moral injury entails psychological, social, and possible spiritual issues that might interfere with veterans' functioning in romantic or intimate relationships. To date, research has not examined the contribution of moral injury outcomes in this core functional domain in many veterans' lives. In total, 65 combat veterans who were engaging in a peer-led intervention for moral injury in a Veteran Service Organization completed the Expressions of Moral Injury Scale, posttraumatic stress disorder (PTSD) checklist for DSM-5, and the romantic relationship subscale of the Inventory of Psychosocial Functioning Scale. Bivariate analyses revealed that moral injury and PTSD symptoms were each associated with worse relationship functioning among the veterans. When including moral injury and PTSD symptoms as predictors in a multivariate analysis, only moral injury was uniquely linked with poorer relationship functioning. Overall, these findings suggest that moral injury could play a pernicious role in many veterans' issues in relationship problems with their spouses or partners. Future research needs to examine the potential utility of addressing moral injury among veterans who are struggling to meet demands for intimacy and connection in their intimate or romantic relationships. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


The ECS1 gene of Arabidopsis encodes a plant cell wall-associated protein and is potentially linked to a locus influencing resistance to Xanthomonas campestris.
The interaction between Arabidopsis and Xanthomonas campestris pv. campestris (Xcc) provides a useful model system to identify components that are involved in incompatible interactions of this phytopathogen and cruciferous plants. We have previously described a new gene from Arabidopsis thaliana, ECS1 (formerly CXC750), which showed an ecotype-specific expression pattern, although homologous sequences are present in the genomes of all ecotypes tested. Interestingly, ECS1 mRNA transcripts were only detected in ecotypes which showed the resistant phenotype against Xcc race 750. Subsequent genetic studies with F3 progeny of a cross between a Xcc750 resistant ecotype (Col-0) and a Xcc750 sensitive ecotype (Oy-0) revealed segregation of the ECS1RNA-phenotype away from the Xcc750 susceptible phenotype in one out of 16 F3 families. In addition, transformation of Xcc750 sensitive plants that did not express ECS1, with a constitutively transcribed ECS1 gene, did not lead to the resistant phenotype in the transgenic plants. From these results we conclude that ECS1 is not a Xcc750 resistance gene, but the genetic data indicate that ECS1 is linked to a locus influencing resistance to Xcc750. ECS1 was localized to YACs 3H12 and 12F3 of the CIC library, which map to chromosome 1. Subcellular localization of the gene product indicated that the ECS1 protein is associated with the plant cell wall. Further molecular investigation of 10 ecotypes revealed the utility of ECS1 as a new marker for chromosome 1, which is detectable by RFLP, PCR or expression analysis.


Transdermal hormone replacement therapy improves vertebral bone density in primary biliary cirrhosis: results of a 1-year controlled trial.
Retrospective studies have suggested that hormone replacement therapy may reduce the rate of bone loss in primary biliary cirrhosis, but no controlled data are available. Forty-two post-menopausal women with primary biliary cirrhosis were treated with calcium and vitamin D, either alone (n = 21) or together with transdermal hormone replacement therapy (n = 21). Bone densitometry was performed at baseline and at 1 year, and serum and urinary markers of bone turnover were measured at three-monthly intervals. At entry, 17 patients (40%) had spinal or femoral osteopenia (T score - 1 to - 2.5) and nine (21%) had osteoporosis (T < - 2.5). In those given hormone replacement therapy, there was a significant decrease in the mean urinary deoxypyridinoline :creatinine ratios at 3 months (7.8 vs. 6.1 nm/mm creatinine for no hormone replacement therapy vs. hormone replacement therapy; P = 0.04) and a 48% reduction in urinary calcium excretion at 1 year (0.66 vs. 0.32 mm/mm creatinine; P = 0.01). Repeat bone densitometry at 1 year revealed a 2.25% increase in the hormone replacement therapy group (P = 0.02), compared with a non-significant 0.87% decrease in L2-L4 bone mineral density in those not given hormone replacement therapy. Both treatment regimens were well tolerated, with no increase in cholestasis. Compared with calcium and vitamin D alone, supplemental treatment with transdermal hormone replacement therapy for 1 year improved the vertebral bone density and urinary markers of bone turnover in post-menopausal women with primary biliary cirrhosis.


Differential Effects of Rapamycin and Metformin in Combination With Rapamycin on Mechanisms of Proteostasis in Cultured Skeletal Myotubes.
mTOR inhibition extends life span in multiple organisms. In mice, when metformin treatment (Met) is added to the mTOR inhibitor rapamycin (Rap), median and maximal life span is extended to a greater degree than with Rap or Met alone. Treatments that extend life span often maintain proteostasis. However, it is less clear how individual tissues, such as skeletal muscle, maintain proteostasis with life span-extending treatments. In C2C12 myotubes, we used deuterium oxide (D2O) to directly measure two primary determinants of proteostasis, protein synthesis, and degradation rates, with Rap or Met+Rap treatments. We accounted for the independent effects of cell growth and loss, and isolated the contribution of autophagy and mitochondrial fission to obtain a comprehensive assessment of protein turnover. Compared with control, both Rap and Met+Rap treatments lowered mitochondrial protein synthesis rates (p < .001) and slowed cellular proliferation (p < .01). These changes resulted in greater activation of mechanisms promoting proteostasis for Rap, but not Met+Rap. Compared with control, both Rap and Met+Rap slowed protein breakdown. Autophagy and mitochondrial fission differentially influenced the proteostatic effects of Rap and Met+Rap in C2C12 myotubes. In conclusion, we demonstrate that Met+Rap did not increase protein turnover and that these treatments do not seem to promote proteostasis through increased autophagy.


Imaging of colon and rectal cancer.
Colon and rectal cancer imaging has traditionally been performed to assess for distant disease (typically lung and liver metastases) and to assess the resectability of the primary tumor. With technological and scientific advances in imaging and the evolution of treatment options, the role of imaging has expanded. Radiologists are now expected to provide a precise description of primary tumor invasion extent, including adjacent organ invasion, involvement of the surgical resection plane, extramural vascular invasion, lymphadenopathy, and response to neoadjuvant treatment, and to monitor for recurrence after clinical complete response.


Aqueous chamber taps in toxoplasmic chorioretinitis.
The clinical value of the determination of toxoplasma antibodies in anterior chamber taps was evaluated in 12 posterior uveitis patients suspected of a toxoplasmic retinochoroiditis, in four patients with Fuchs's heterochromia and in 31 cataract patients. The posterior uveitis patients all had marked inflammation of the vitreous obstructing the examination of the fundus of the time of aqueous humour aspiration. The clinical diagnosis toxoplasmic uveitis (n = 9) was made after the inflammation of the vitreous had subsided and fundus examination became possible again. Paired serum and aqueous samples were tested for total immunoglobulin levels and toxoplasma antibodies. Eight of the nine clinical toxoplasmic uveitis patients had detectable toxoplasma antibodies in their aqueous, whereas none of the other seven uveitis patients were positive. All of these eight toxoplasmic uveitis patients had a coefficient above 1.5. Of the 31 control patients only one had a positive antibody titer at a dilution of 1/2 with a corresponding coefficient of 1.1. This study shows that aqueous humour examination for toxoplasma antibodies is a valuable diagnostic tool in a selected group of posterior uveitis patients.


The bradykinin/soluble guanylate cyclase signaling pathway is impaired in androgen-independent prostate cancer cells.
The activation of soluble guanylate cyclase by bradykinin and sodium nitroprusside (SNP), a direct activator of soluble guanylate cyclase, was evaluated in androgen-sensitive LNCaP and androgen-independent PC3 and DU145 prostate cancer cells. Bradykinin and SNP activated soluble guanylate cyclase in LNCaP cells, but not in PC3 and DU145 cells. Western blot analysis revealed that the bradykinin B2 receptor, Gqalpha, phospholipase Cgamma and endothelial nitric oxide synthase were expressed in LNCaP, PC3 and DU145 cells. However, both Western blotting and reverse transcriptase--polymerase chain reaction indicated that soluble guanylate cyclase was only expressed in LNCaP cells. These results demonstrate that the impaired bradykinin-soluble guanylate cyclase pathway in PC3 and DU145 cells is likely due to lack of expression of soluble guanylate cyclase.


Electrical stimulation on biodegradation of phenol and responses of microbial communities in conductive carriers supported biofilms of the bioelectrochemical reactor.
Conductive carbon felts (Cf) were used as biofilm carriers in bioelectrochemical reactors to enhance the electrical stimulation on treatment of phenol-containing synthetic wastewater. In batch test, phenol biodegradation was accelerated under an optimum direct current (DC), which was 2mA for Cf biofilm carriers, lower than that for non-conductive white foam carriers. The stimulation effect was consistent with Adenosine Triphosphate contents in biofilms. The long-term operation further demonstrated that a high and stable phenol removal efficiency could be achieved with applied DC of 2mA, and intermittent DC application was better than continuous one, with phenol removal efficiency of over 97%. Although the quantities of whole microbial communities kept at a high level under all conditions, special microorganisms related with genera of Zoogloea and Desulfovibrio were distinctively enriched under intermittent applied DC pattern. This study shows that the electrical stimulation is potentially effective for biofilm reactors treating phenol-containing wastewater.


Attachment-inducing capacities of fish skin epithelial extracts on oncomiracidia of Benedenia seriolae (Monogenea: Capsalidae).
Attachment-inducing capacities of skin epithelial extracts of yellowtail, Japanese flounder and red sea bream on oncomiracidia of the monogenean Benedenia seriolae were examined. Clear differences were not detected in the capacity among the fish species, although B. seriolae infects only yellowtail and its congeners in Seriola. This suggests that either the capacity is not host specific or host-specific attachment-inducing capacity cannot be detected by the assay method. Further, the attachment-inducing capacities were suppressed by wheat-germ lectin and concanavalin A in skin epithelial extracts of Japanese flounder and yellowtail, respectively. This suggests that some sugar-related chemical substances existing in fish epithelia induce the attachment of B. seriolae oncomiracidia.


[The Working Group of Enforcement Officers (WGEO) : The European Network of Drug Regulatory Authorities to Combat Pharmaceutical Crime].
Ten years ago the Heads of Medicines Agencies (HMA) officially founded the Working Group of Enforcement Officers (WGEO), a European working group to reduce falsifications of human and veterinarian medicinal products in the legal and illegal supply chain. Police, customs and other international organisations are also represented in the WGEO. Partner organisations are for example the Directorate General for Health and Food Safety of the European Commission, the European Medicines Agency (EMA), the European Police Office (Europol), the International Criminal Police Organization (Interpol), the European Directorate for the Quality of Medicines and Healthcare (EDQM) and the World Health Organization (WHO). The main goal of the group is the protection of public health from harmful medicines for both humans and animals. The WGEO has created a network of its members and a rapid alert system to exchange confidential information on falsified or stolen medicinal products. There are face-to-face meetings twice a year including training using case studies.


Detection of West Nile Virus Envelope Protein in Brain Tissue with an Immunohistochemical Assay.
Immunohistochemistry is a valuable tool for probing not only scientific questions but also clinical diagnoses. It provides power from localization of a protein within the milieu of a tissue section that may reflect positioning within or beyond the boundaries of a cell that is representative of the tissue at a discrete moment in time. The method can be applied broadly, including to tissues under normal, developmental, chemically, or genetically altered conditions and disease states.Disease manifesting from West Nile virus infection ranges from acute, systemic febrile symptoms to compromise of central nervous system function. Immunohistochemistry has been used to assess WNV infection in the nervous system in postmortem and experimental conditions, despite the lack of understanding of the precise route of viral entry. In addition to imprecise knowledge of initial viral entry into cells and whether entry is even the same between cell types, the fact that spontaneous viral mutations and environmental pressures from climate change may alter the prevalence of the disease state across geographical and climatological boundaries highlights the need for continued assessment of infection. Immunohistochemistry is a useful way to assess these aspects of WNV infection with the aim being to better understand the organs and cell types that are compromised by WNV infection. This chapter outlines how this can be carried out on brain tissue, but the procedures discussed can also be applied more broadly on tissue outside of the central nervous system.


Cantharidin analogue alleviates dextran sulfate sodium-induced colitis in mice by inhibiting the activation of NF-κB signaling.
Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα, and NF-κB p65, and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.


Dynamic Modeling of a 100-Million-Atom Organelle at the Source of Life.
In this issue of Cell, Singharoy et al. present a rate kinetic model for the chromatophore of photosynthetic purple bacteria generated from molecular dynamics simulations. It shows that the chromatophore's architecture is optimized for producing bioenergy under low light typical of the natural bacterial habitat while minimizing photodamage under stress conditions.


The protective effects of sophocarpine on sepsis-induced cardiomyopathy.
This investigation elucidates the impact of sophocarpine treatment on lipopolysaccharide (LPS) stimulated sepsis-induced cardiomyopathy (SIC) via in vivo and in vitro experiments. Echocardiography, ELISA, TUNEL, Western blotting experiments, and Hematoxylin/Eosin, Dihydroethidium, and Immunohistochemistry staining assays, were carried out to identify associated indicators. The echocardiography revealed that sophocarpine treatment alleviated LPS-induced cardiac dysfunction as indicated by fractional shortening shortened and improved ejection fraction. Heart injury biomarkers, such as creatine kinase, lactate dehydrogenase, and creatine kinase-MB, were assessed, and indicated that sophocarpine treatment could alleviate LPS-induced upregulation of these indices. Furthermore, different experimental protocols revealed that sophocarpine treatment inhibits LPS-induced pathological alterations and decreases LPS-stimulated inflammatory cytokines, IL-1β, monocyte chemoattractant protein-1, IL-6, NOD-like receptor protein-3, and TNF-α, increase. Apoptotic proteins such as cytochrome-c, Bax, and cleaved-caspase-3 were increased, and Bcl-2 was alleviated after LPS stimulation; however, these effects were inhibited by sophocarpine treatment. Decreased antioxidant proteins [superoxide dismutase-1 (SOD-1) and SOD-2] induced by LPS stimulation were upregulated by sophocarpine treatment. LPS upregulated autophagic proteins such as Beclin-1 and the ratio of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II/LC3-I and downregulated sequestosome 1 (SQSTM1, or P62), sophocarpine therapy reversed these effects. Moreover, it was indicated that sophocarpine treatment inhibited the Toll-like receptor-4 (TLR-4)/nuclear transcription factor-kappa B (NF-κB) signaling pathway and activated nuclear factor erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In conclusion, sophocarpine treatment could alleviate LPS-trigger SIC by repressing oxidative stress, autophagy, inflammation, and apoptosis via TLR-4/NF-κB inhibition and Nrf2/HO-1 signaling pathway activation, implicating the potential of sophocarpine as a new therapeutic approach against SIC.


Biomimetic fibronectin/mineral and osteogenic growth peptide/mineral composites synthesized on calcium phosphate thin films.
Composites of fibronectin/mineral and osteogenic growth peptide/mineral were synthesized on calcium phosphate coated substrates immersed in Dulbecco's phosphate-buffered saline solution containing biomolecules. The kinetics of coprecipitation for two biomolecules was similar, and the biomolecules participated in the formation of the crystal latticework and influenced the mineral structure and composition.


Efficacy of a short-term residential smoking cessation therapy versus standard outpatient group therapy ('START-Study'): study protocol of a randomized controlled trial.
In Germany, evidence-based outpatient smoking cessation therapies are widely available. Long-term abstinence rates, however, are limited. Studies suggest that short-term residential therapy enables a higher level of environmental control, more intense contact and greater support among patients and from therapists, which could result in higher abstinence rates. The aim of the current START-study is to investigate the long-term efficacy of a short-term residential therapy exclusively for smoking cessation, conducted by a mobile team of expert therapists. A randomized controlled trial (RCT) is conducted to examine the efficacy of residential behavior therapeutic smoking cessation therapy compared to standard outpatient behavior therapeutic smoking cessation group therapy. Adult smokers consuming 10 or more cigarettes per day, who are willing to stop smoking, are randomized in a ratio of 1:1 between therapy groups. The primary endpoint is sustained abstinence for 6-month and 12-month periods. Secondary endpoints include smoking status after therapy, 7-day point abstinence after the 6-month and 12-month follow-ups, level of physical dependence, cost-effectiveness, use of nicotine replacement products, health-related quality of life, self-efficacy expectation for tobacco abstinence, motivational and volitional determinants of behavior change, self-reported depressive symptom severity, adverse events and possible side effects. Assessments will take place at baseline, post-therapy, and at 6-month and 12-month intervals after smoking cessation. There is a high demand for long-term effective smoking cessation therapies. This study represents the first prospective RCT to examine the long-term efficacy of a residential smoking cessation therapy program compared to standard outpatient group therapy as an active control condition. The residential therapeutic concept may serve as a new model to substantially enhance future cessation therapies and improve the understanding of therapeutic impact factors on tobacco abstinence. Utilizing a mobile team, the model could be applied efficiently to medical centers that do not have permanent and trained personnel for smoking cessation at their disposal. German Register for Clinical Trials (Deutsches Register für Klinische Studien), DRKS00013466. Retrospectively registered on 1 April 2019. https://www.drks.de/drks_web/navigate.do?navigationId=start.


Evidence that 3-hydroxy-3-methylglutaric and 3-methylglutaric acids induce DNA damage in rat striatum.
3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive disorderaffecting the final step of leucine degradation and ketogenesis and biochemically characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in biological fluids and tissues of affected patients. Considering that previous studies reported that HMG and MGA have pro oxidant properties, the present study evaluated the ex vivo and in vitro effects of HMG and MGA on frequency and index of DNA damage in cerebral cortex and striatum of young rats. The ex vivo effects of both organic acids on 8-hydroxy-2'-deoxyguanosine (OHdG) levels and their in vitro effects on 2',7'-dichlorofluorescin (DCFH) oxidation and glutathione (GSH) concentrations in rat striatum were also determined. We also investigated the ex vivo effects of both organic acids on 8-hydroxy-2'-deoxyguanosine (OHdG) levels in rat striatum. In the ex vivo experiments, DNA damage was determined in striatum homogenates prepared 30 min after a single intrastriatal administration of HMG or MGA. On the other hand, the in vitro evaluation was performed after an incubation of rat cerebral cortex or striatum homogenates or slices in the presence of HMG or MGA during 1 h at 37 °C. We observed that the intrastriatal administration of HMG and MGA increased the frequency and the index of DNA damage, as well as OHdG staining in rat striatum. We also verified that MGA, but not HMG, increased DNA damage frequency and index in vitro in striatum of rats. In contrast, no alterations were verified in vitro in cerebral cortex. Finally, we found that HMG and MGA increased DCFH oxidation and decreased GSH concentrations in rat striatum. Therefore, it may be presumed that DNA damage provoked by HMG and MGA possibly via reactive species generation is involved, at least in part, in the pathophysiology of brain injury, particularly in the striatum of HL-deficient patients.


Hydroxyapatite-calcium sulfate-hyaluronic acid composite encapsulated with collagenase as bone substitute for alveolar bone regeneration.
Periodontitis is a very severe inflammatory condition of the periodontium that progressively damages the soft tissue and destroys the alveolar bone that supports the teeth. The bone loss is naturally irreversible because of limited reparability of the teeth. Advancement in tissue engineering provides an effective regeneration of osseous defects with suitable dental implants or tissue-engineered constructs. This study reports a hydroxyapatite, calcium sulfate hemihydrate and hyaluronic acid laden collagenase (HAP/CS/HA-Col) as a bone substitute for the alveolar bone regeneration. The composite material was mechanically tested and the biocompatibility was evaluated by WST-1 assay. The in vivo bone formation was assessed in rat with alveolar bone defects and the bone augmentation by the HAP/CS/HA-Col composite was confirmed by micro-CT images and histological examination. The mechanical strength of 6.69 MPa with excellent biocompatibility was obtained for the HAP/CS/HA-Col composite. The collagenase release profile had facilitated the acceleration of bone remodeling process and it was confirmed by the findings of micro-CT and H&E staining. The bone defects implanted with HAP/CS/HA composite containing 2 mg/mL type I collagenase have shown improved new bone formation with matured bone morphology in comparison with the HAP/CS/HA composite that lacks the collagenase and the porous hydroxyapatite (p-HAP) granules. The said findings demonstrated that the collagenase inclusion in HAP/CS/HA composite is a feasible approach for the alveolar bone regeneration and the same design can also be applied to other defective tissues.


NaCl stress-induced transcriptomics analysis of Salix linearistipularis (syn. Salix mongolica).
Salix linearistipularis (syn. S. mongolica) is a woody halophyte, which is distributed naturally in saline-alkali soil of Songnen plain, Heilongjiang, China. It plays an important role in maintaining ecological balance and in improving saline soil. Furthermore, S. linearistipularis is also a genetic resource; however, there is no available information of genomic background for salt tolerance mechanism. We conducted the transcriptome analysis of S. linearistipularis to understand the mechanisms of salt tolerance by using RNA-seq technology. The transcription profiles of both the salt stress (SLH-treated) and the control (SLH-control) sample for S. linearistipularis were obtained by using RNA-seq in this study. By comparative analysis, only 3034 of 53,362 all-unigenes between two samples were expressed differently at more than 1.5-fold ([Formula: see text], FDR ≤ 0.05), including 1397 up-regulated genes and 1637 down-regulated genes. In total, 2199 genes were classified into 50 Gene Ontology (GO) terms and 1103 genes were involved in 116 biological pathways. To find salt stress related genes, all-unigenes of S. linearistipularis were classified into three categories according to their degree of the differentially expressed genes (DEGs) at 0-1.5-fold (non differently expressed genes, N-DEGs), at 1.5-4.0-fold and more than 4.0-fold. The pathways of three categorized genes were compared with the DEGs of Arabidopsis thaliana, showing that 22, 10 and 1 pathway of S. linearistipularis were overlapped with A. thaliana. Degree of the overlapping was categorized as 0-1.5-fold, 1.5-4.0-fold and more than 4.0-folds. Our study revealed that the N-DEGs of 22 pathways in S. linearistipularis were overlapped with the DEGs of A. thaliana. This result suggests that those overlapped genes that contrasted with the up- or down-regulated genes in A. thaliana were possibility evolved into housekeeping genes in S. linearistipularis under salt stress.


Pericentrin expression in Down's syndrome.
Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.


Locomotion and brain gene expression exhibit sex-specific non-monotonic dose-response to HFPO-DA during Drosophila melanogaster lifespan.
Legacy per- and polyfluoroalkyl substances (PFAS), known for their environmental persistence and bio-accumulative properties, have been phased out in the U.S. due to public health concerns. A newer polymerization aid used in the manufacture of some fluoropolymers, hexafluoropropylene oxide-dimer acid (HFPO-DA), has lower reported bioaccumulation and toxicity, but is a potential neurotoxicant implicated in dopaminergic neurodegeneration. We investigated HFPO-DA's bio-accumulative potential and sex-specific effects on lifespan, locomotion, and brain gene expression in fruit flies. We quantified bioaccumulation of HFPO-DA in fruit flies exposed to 8.7 × 104 µg/L of HFPO-DA in the fly media for 14 days via UHPLC-MS. Long-term effect on lifespan was determined by exposing both sexes to 8.7 × 102 - 8.7 × 105 µg/L of HFPO-DA in media. Locomotion was measured following 3, 7, and 14 days of exposures at 8.7 × 101 - 8.7 × 105 µg/L of HFPO-DA in media, and high-throughput 3'-end RNA-sequencing was used to quantify gene expression in fly brains across the same time points. Bioaccumulation of HFPO-DA in fruit flies was not detected. HFPO-DA-induced effects on lifespan, locomotion, and brain gene expression, and lowest adverse effect level (LOAEL) showed sexually dimorphic patterns. Locomotion scores significantly decreased in at least one dose at all time points for females and only at 3-day exposure for males, while brain gene expression exhibited non-monotonic dose-response. Differentially expressed genes correlated to locomotion scores revealed sex-specific numbers of positively and negatively correlated genes per functional category. Although HFPO-DA effects on locomotion and survival were significant at doses higher than the US EPA reference dose, the brain transcriptomic profiling reveals sex-specific changes and neurological molecular targets; gene enrichments highlight disproportionately affected categories, including immune response: female-specific co-upregulation suggests potential neuroinflammation. Consistent sex-specific exposure effects necessitate blocking for sex in experimental design during HFPO-DA risk assessment.


Principles of immunotherapy.
Gliomas are the most common primary brain tumors of the central nervous system, and carry a grim prognosis. Novel approaches utilizing the immune system as adjuvant therapy are quickly emerging as viable and effective options. Immunotherapeutic strategies being investigated to treat glioblastoma include: vaccination therapy targeted against either specific tumor antigens or whole tumor lysate, adoptive cellular therapy with cytotoxic T lymphocytes, chimeric antigen receptors and bi-specific T-cell engaging antibodies allowing circumvention of major histocompatibility complex restriction, aptamer therapy with aims for more efficient target delivery, and checkpoint blockade in order to release the tumor-mediated inhibition of the immune system. Given the heterogeneity of glioblastoma and its ability to gain mutations throughout the disease course, multifaceted treatment strategies utilizing multiple forms of immunotherapy in combination with conventional therapy will be most likely to succeed moving forward.


Riyadh Mother and Baby Multicenter Cohort Study: The Cohort Profile.
To assess the effects of non-communicable diseases, such as diabetes, hypertension and obesity, on the mother and the infant. A multicentre cohort study was conducted in three hospitals in the city of Riyadh in Saudi Arabia. All Saudi women and their babies who delivered in participating hospitals were eligible for recruitment. Data on socio-demographic characteristics in addition to the maternal and neonatal outcomes of pregnancy were collected. The cohort demographic profile was recorded and the prevalence of maternal conditions including gestational diabetes, pre-gestational diabetes, hypertensive disorders in pregnancy and obesity were estimated. The total number of women who delivered in participating hospitals during the study period was 16,012 of which 14,568 women participated in the study. The mean age of the participants was 29 ± 5.9 years and over 40% were university graduates. Most of the participants were housewives, 70% were high or middle income and 22% were exposed to secondhand smoke. Of the total cohort, 24% were married to a first cousin. More than 68% of the participants were either overweight or obese. The preterm delivery rate was 9%, while 1.5% of the deliveries were postdate. The stillbirth rate was 13/1000 live birth. The prevalence of gestational diabetes was 24% and that of pre-gestational diabetes was 4.3%. The preeclampsia prevalence was 1.1%. The labour induction rate was 15.5% and the cesarean section rate was 25%. Pregnant women in Saudi Arabia have a unique demographic profile. The prevalence of obesity and diabetes in pregnancy are among the highest in the world.


A comparative study of the Coulter Counter Model S, for the enumeration of peripheral leukocyte counts below 3.0 x 10(9)/l using whole blood and prediluted blood.
In this study low leukocyte counts were carried out using several methods. The results obtained by the visual method, the Coulter Model "S" using "whole blood", and the Coulter DN, show close correlation, but discrepancies exist when the Coulter S uses "prediluted blood". This is explained by excessive bubbles. This does not allow the Coulter Model S to be used with confidence for low leukocyte counts if "whole blood" is not available.


Molecule-Induced Radical Formation (MIRF) Reactions-A Reappraisal.
Radical chain reactions are commonly initiated through the thermal or photochemical activation of purpose-built initiators, through photochemical activation of substrates, or through well-designed redox processes. Where radicals come from in the absence of these initiation strategies is much less obvious and are often assumed to derive from unknown impurities. In this situation, molecule-induced radical formation (MIRF) reactions should be considered as well-defined alternative initiation modes. In the most general definition of MIRF reactions, two closed-shell molecules react to give a radical pair or biradical. The exact nature of this transformation depends on the σ- or π-bonds involved in the MIRF process, and this Minireview specifically focuses on reactions that transform two σ-bonds into two radicals and a closed-shell product molecule.


Effect of nitration on protein tyrosine phosphatase and protein phosphatase activity in neuronal cell membranes of newborn piglets.
Protein tyrosine phosphatase predominantly determines the status of protein tyrosine kinase-dependent phosphorylation of specific proteins and controls the survival and death of neurons. Previous studies have shown that protein tyrosine phosphatase activity is decreased during hypoxia in cortical membranes of the newborn piglet. We have also shown that nitric oxide (NO) free radicals are generated during hypoxia, and may result in modification of protein tyrosine phosphatase via peroxynitrite-mediated modification. The present study tests the hypothesis that the hypoxia-induced decrease in protein tyrosine phosphatase activity is NO-mediated. To test this hypothesis, in vitro experiments were conducted by measuring protein tyrosine phosphatase activity in the presence of an NO donor, sodium nitroprusside (SNP), or peroxynitrite. Since 3-nitrotyrosine is produced as a consequence of peroxynitrite reactions, we have also examined the effect of 3-nitrotyrosine on protein phophatase activity. Cerebral cortical P(2) membranes were prepared from seven normoxic newborn piglets and each sample was divided into three aliquots: a control group, a SNP group (exposed to 200 microM SNP), and a peroxynitrite group (exposed to 100 microM peroxynitrite). Protein tyrosine phosphatase activity was determined spectrophotometrically in the presence or absence of 2 microM bpV(phen), a highly selective inhibitor of protein tyrosine phosphatase. The protein tyrosine phosphatase activity was 198+/-25 nmol/mg protein/h in the normoxic group, 177+/-30 nmol/mg protein/h in the SNP group (p=NS versus normoxic) and 77+/-20 nmol/mg protein/h in the peroxynitrite group (p<0.001 versus normoxic). The results show that peroxynitrite but not SNP exposure results in decreased protein tyrosine phosphatase activity in vitro. Furthermore 3-nitrotyrosine (100 microm), a product of peroxynitrite, decreased the enzyme activity from 926+/-102 to 200+/-77 (p<0.001). We conclude that protein tyrosine phosphatase regulation is mediated by peroxynitrite. We propose that hypoxia-induced NO production leading to peroxynitrite formation is a potential mechanism of protein tyrosine phosphatase inactivation in vivo. The NO-induced decrease in protein tyrosine phosphatase and protein phosphatase activity, leading to Bcl-2 protein phosphorylation and loss of its antiapoptotic activity may be a NO-mediated mechanism of programmed cell death in the hypoxic brain.


Genome-wide association analysis reveals loci and candidate genes involved in fiber quality traits in sea island cotton (Gossypium barbadense).
Sea island cotton (Gossypium barbadense) has markedly superior high quality fibers, which plays an important role in the textile industry and acts as a donor for upland cotton (G. hirsutum) fiber quality improvement. The genetic characteristics analysis and the identification of key genes will be helpful to understand the mechanism of fiber development and breeding utilization in sea island cotton. In this study, 279 sea island cotton accessions were collected from different origins for genotyping and phenotyping fiber quality traits. A set of 6303 high quality single nucleotide polymorphisms (SNPs) were obtained by high-density CottonSNP80K array. The population characteristics showed that the sea island cotton accessions had wide genetic diversity and were clustered into three groups, with Group1 closely related to Menoufi, an original sea island cotton landrace, and Group2 and Group3 related to widely introduced accessions from Egypt, USA and Former Soviet Union. Further, we used 249 accessions and evaluated five fiber quality traits under normal and salt environments over 2 years. Except for fiber uniformity (FU), fiber length (FL) and fiber elongation (FE) were significantly decreased in salt conditions, while fiber strength (FS) and fiber micronaire (MIC) were increased. Based on 6303 SNPs and genome-wide association study (GWAS) analysis, a total of 34 stable quantitative trait loci (QTLs) were identified for the five fiber quality traits with 25 detected simultaneously under normal and salt environments. Gene Ontology (GO) analysis indicated that candidate genes in the 25 overlapped QTLs were enriched mostly in "cellular and biological process". In addition, "xylem development" and "response to hormone" pathways were also found. Haplotype analyses found that GB_A03G0335 encoding an E3 ubiquitin-protein ligase in QTL TM6004 had SNP variation (A/C) in gene region, was significantly correlated with FL, FS, FU, and FE, implying a crucial role in fiber quality. The present study provides a foundation for genetic diversity of sea island cotton accessions and will contribute to fiber quality improvement in breeding practice.


The structure and reactions of the microcirculation in a subcutaneous air pouch in the rat.
Studies by a combination of vascular perfusion, histological and electron microscopic techniques show that subcutaneous injection of air into rats excites no acute inflammatory response, but leads to the formation of a pouch lined by avascular fibrous tissue. Existing subcutaneous blood vessels are displaced by the pouch but no new blood vessels are formed. By contrast injection of carrageenan with the air or into a preformed air pouch leads to a severe inflammatory reaction and the rapid development of a thick layer of granulation tissue. Either type of pouch is a useful system in which to study inflammation. However because the distribution and ultrastructure of small blood vessels in the pouch wall is quite different from the known characteristics of the microcirculation of synovial membrane, the air pouch is an unsuitable model for the study of injury to joints or experimental arthritis.


Genetic influence on ERP slow wave measures of working memory.
Individual differences in the variance of event-related potential (ERP) slow wave (SW) measures were examined. SW was recorded at prefrontal and parietal sites during memory and sensory trials of a delayed-response task in 391 adolescent twin pairs. Familial resemblance was identified and there was a strong suggestion of genetic influence. A common genetic factor influencing memory and sensory SW was identified at the prefrontal site (accounting for an estimated 35%-37% of the reliable variance) and at the parietal site (51%-52% of the reliable variance). Remaining reliable variance was influenced by unique environmental factors. Measurement error accounted for 24% to 30% of the total variance of each variable. The results show genetic independence for recording site, but not trial type, and suggest that the genetic factors identified relate more directly to brain structures, as defined by the cognitive functions they support, than to the cognitive networks that link them.


Novel cyclic thiourea derivatives of aminoalcohols at the presence of AlCl3 catalyst as potent α-glycosidase and α-amylase inhibitors: Synthesis, characterization, bioactivity investigation and molecular docking studies.
The article is devoted to the targeted synthesis and study of cyclic thiourea and their various new derivatives as new organic compounds containing polyfunctional group in the molecule. First time the reaction of the corresponding synthesized pyrimidinethione with 1,2-epoxy-3-chlorpropane at the presence of AlCl3 catalyst in 75-80% yield alkyl-1-(3-chloro-2-hydroxypropyl)-4-alkyl-6-phenyl-2-thioxo-1,2,5,6- tetrahydropyrimidine-5-carboxylates. In the next stage, new cyclic thiourea derivatives of aminoalcohols were synthesised from the reaction of chlorinated derivatives of pyrimidinethiones with single amines and their structures were investigated by spectroscopic methods. In this study, a series of novel compounds were tested towards some metabolic enzymes including α-glycosidase (α-Gly) and α-amylase (α-Amy) enzymes. Novel compounds showed Kis in ranging of 10.43 ± 0.94-111.37 ± 13.25 µM on α-glycosidase and IC50 values in ranging of 14.38-106.51 µM on α-amylase. The novel cyclic thiourea derivatives of aminoalcohols had effective inhibition profiles against all tested metabolic enzymes. Binding affinity and inhibition mechanism of the most active compounds were detected with in silico studies and have shown that 2-Hydroxypropyl and butan-1-aminium moieties play a key role for inhibition of the enzymes.


National prevalence of frailty in the older Japanese population: Findings from a nationally representative survey.
Japan has the largest aging population in the world, thus, a focus on frailty is important in clinical geriatric practice. Using a nationally representative sample, this study provided national estimates of the prevalence of frailty among community-dwelling older Japanese people. We also examined variations in the prevalence by sociodemographic characteristics, health conditions, and geographical regions. Data came from the National Survey of the Japanese Elderly in 2012. The data were collected using a home visit and face-to-face interviews with trained interviewers. The sample consisted of 2206 adults aged ≥65 years. We used the widely accepted definition of physical frailty phenotype and calculated weighted estimates of the prevalence of frailty. Overall estimated prevalence was 8.7 % (7.5 %-9.9 %) for frail, 40.8 % (38.7 %-42.9 %) for prefrail, and 50.5 % (48.4 %-52.6 %) for robust. Frailty was more prevalent in older groups, women, and those with lower socioeconomic status, which was measured by education and household income. Frail people tended to have worse health. We also observed a regional variation: frailty prevalence tended to be higher in eastern than western Japan. This study provides important evidence on the prevalence of frailty in older Japanese people and found substantial disparities by sociodemographic characteristics, health conditions, and geographical regions.


Incremental Contribution of the Minnesota Multiphasic Personality Inventory - 3 to Predicting One-Year Postoperative Spinal Cord Surgery/Spinal Cord Stimulation Outcomes.
Pre-surgical psychological assessments are becoming common in the United States and are recommended or required prior to surgical/spinal cord stimulator intervention for chronic back pain. Psychological testing is often recommended for these evaluations and the various versions of the Minnesota Multiphasic Personality Inventory (MMPI) have demonstrated utility for predicting outcomes in this setting. This investigation sought to extend that literature with the newest version of the MMPI, the MMPI-3. The sample comprised of 909 patients (50.5% men, 49.5% women) who consented to participating in an outcome study and took the MMPI-3 along with other self-report measures of pain, functional disability, and emotional functioning prior to surgery as part of their pre-surgical psychological assessment. Self-report measures of pain, functional disability, and emotional functioning were administered again one-year following the intervention. MMPI-3 scale scores accounted for up to 9% of additional variance in the outcomes after controlling for pre-surgical measures. Measures of emotional/internalizing dysfunction, somatic dysfunction, and, to a lesser extent, behavioral/externalizing dysfunction contributed the most to the prediction of poorer outcomes.


[Anatomy of recurrent laryngeal nerve during thyroid surgery: 198 cases report].
To observe the surgical anatomy of the recurrent laryngeal nerve during thyroid surgery and provide theory basis for surgical experience. The surgical anatomy of recurrent laryngeal nerve of 201 sides of 198 cases were observed during thyroid lobectomy or total thyroidectomy. The anatomical relationship of recurrent laryngeal nerve and inferior thyroid artery were recorded and classified as risk and safe types according to the recurrent laryngeal nerve easy to be injured or not. The safe type and risk type of 117 right sides were 84.6% and 15.4%, and that of 82 left sides were 92.7% and 7.3% respectively. That indicated the incidence of risk type of the right side was higher than that of the left side. The incidence of risk type of the right side was higher than that of the left side and more attention should be paid during thyroid lobectomy of the right sides.


Triazole-bearing calixpyrroles: strong halide binding affinities through multiple N-H and C-H hydrogen bonds.
Triazole-bearing calixpyrroles (TCPs) were synthesized as artificial anion binding receptors. The additional C-HX hydrogen bonding interaction induced strong binding affinity towards halide ions. Using this strong binding affinity, Cl- was successfully extracted from the aqueous to organic phase.


Adverse effects of iron-based nanoparticles on freshwater phytoplankton Scenedesmus armatus and Microcystis aeruginosa strains.
Zero-valent nano-iron particles (nZVI) are increasingly present in freshwater aquatic environments due to their numerous applications in environmental remediation. However, despite the broad benefits associated with the use and development of nZVI nanoparticles, the potential risks of introducing them into the aquatic environment need to be considered. Special attention should be focused on primary producer organisms, the basal trophic level, whose impact affects the rest of the food web. Although there are numerous acute studies on the acute effects of these nanoparticles on photosynthetic primary producers, few studies focus on long-term exposures. The present study aimed at assessing the effects of nZVI on growth rate, photosynthesis activity, and reactive oxygen activity (ROS) on the freshwater green algae Scenedesmus armatus and the cyanobacteria Microcystis aeruginosa. Moreover, microcystin production was also evaluated. These parameters were assessed on both organisms singly exposed to 72 h-effective nZVI concentration for 10% maximal response for 28 days. The results showed that the cell growth rate of S. armatus was initially significantly altered and progressively reached control-like values at 28 days post-exposure, while M. aeruginosa did not show any significant difference concerning control values at any time. In both strains dark respiration (R) increased, unlike net photosynthesis (Pn), while gross photosynthesis (Pg) only slightly increased at 7 days of exposure and then became equal to control values at 28 days of exposure. The nZVI nanoparticles generated ROS progressively during the 28 days of exposure in both strains, although their formation was significantly higher on green algae than on cyanobacteria. These data can provide additional information to further investigate the potential risks of nZVI and ultimately help decision-makers make better informed decisions regarding the use of nZVI for environmental remediation.


Graft-versus-tumor effect after reduced-intensity allogeneic hematopoietic stem cell transplantation in a patient with advanced colon cancer.
A 27-year-old man with advanced colon cancer that was resistant to conventional chemoradiotherapies was treated with reduced-intensity allogeneic peripheral blood stem cell transplantation (PBSCT). After obtaining complete donor-type chimerism, there was an apparent graft-versus-tumor effect accompanied by severe hepatic graft-versus-host disease (GVHD) showing hyperbilirubinemia, resulting in a stable disease condition that lasted for 18 months, which had not been seen previously in his previous disease history. The antitumor effect observed in this patient was insufficient for the patient to achieve complete remission, because the disease was at an already widespread and treatment-resistant stage. He finally died of hepatic failure due to extensive liver GVHD 65 months after the diagnosis of the advanced colon cancer and 29 months after the allogeneic PBSCT. Prospective studies are necessary to achieve better clinical results in patients with advanced colon cancer.


The story of a largely unknown evolution - Germ theory hoax.
The Piltdown Man debacle provides us with the most infamous forgery in science. However, another equally intriguing story exists concerning a document by a Bostonian called George Sleeper, which purported to be a pre-Darwin-Wallace anticipation of evolution and an equally convincing account of the germ theory published before Louis Pasteur's famous studies on this subject. The story involves two giants in the world of evolutionary theory, Alfred Russel Wallace and E.B. Poulton. While Wallace was convinced that the Sleeper document was genuine, Poulton's detailed investigations showed that it was a fake and a hoax. Despite this conclusion, doubts still exist about the authenticity of the Sleeper document.


Correlation between Bacterial Cell Density and Abundance of Antibiotic Resistance on Milking Machine Surfaces Assessed by Cultivation and Direct qPCR Methods.
The relative abundance of antibiotic-resistant bacteria and antibiotic-resistance genes was surveyed for different parts of a milking machine. A cultivation approach based on swab samples showed a highly diverse microbiota, harboring resistances against cloxacillin, ampicillin, penicillin, and tetracycline. This approach demonstrated a substantial cloxacillin resistance of numerous taxa within milking machine microbiota coming along with regular use of cloxacillin for dry-off therapy of dairy cows. For the less abundant tetracycline-resistant bacteria we found a positive correlation between microbial cell density and relative abundance of tetracycline-resistant microorganisms (R2 = 0.73). This indicated an accelerated dispersion of resistant cells for sampling locations with high cell density. However, the direct quantification of the tetM gene from the swap samples by qPCR showed the reverse relation to bacterial density if normalized against the abundance of 16S rRNA genes (R2 = 0.88). The abundance of 16S rRNA genes was analyzed by qPCR combined with a propidium monoazide treatment, which eliminates 16S rRNA gene signals in negative controls.


The present roles and future perspectives of Interleukin-6 in biliary tract cancer.
Biliary tract cancer (BTC) is a highly malignant tumor that originates from bile duct epithelium and is categorized into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA) and gallbladder cancer (GBC) according to the anatomic location. Inflammatory cytokines generated by chronic infection led to an inflammatory microenvironment which influences the carcinogenesis of BTC. Interleukin-6 (IL-6), a multifunctional cytokine secreted by kupffer cells, tumor-associated macrophages, cancer-associated fibroblasts (CAFs) and cancer cells, plays a central role in tumorigenesis, angiogenesis, proliferation, and metastasis in BTC. Besides, IL-6 serves as a clinical biomarker for diagnosis, prognosis, and monitoring for BTC. Moreover, preclinical evidence indicates that IL-6 antibodies could sensitize tumor immune checkpoint inhibitors (ICIs) by altering the number of infiltrating immune cells and regulating the expression of immune checkpoints in the tumor microenvironment (TME). Recently, IL-6 has been shown to induce programmed death ligand 1 (PD-L1) expression through the mTOR pathway in iCCA. However, the evidence is insufficient to conclude that IL-6 antibodies could boost the immune responses and potentially overcome the resistance to ICIs for BTC. Here, we systematically review the central role of IL-6 in BTC and summarize the potential mechanisms underlying the improved efficacy of treatments combining IL-6 antibodies with ICIs in tumors. Given this, a future direction is proposed for BTC to increase ICIs sensitivity by blocking IL-6 pathways.


Nonadditivity of nanoparticle interactions.
Understanding interactions between inorganic nanoparticles (NPs) is central to comprehension of self-organization processes and a wide spectrum of physical, chemical, and biological phenomena. However, quantitative description of the interparticle forces is complicated by many obstacles that are not present, or not as severe, for microsize particles (μPs). Here we analyze the sources of these difficulties and chart a course for future research. Such difficulties can be traced to the increased importance of discreteness and fluctuations around NPs (relative to μPs) and to multiscale collective effects. Although these problems can be partially overcome by modifying classical theories for colloidal interactions, such an approach fails to manage the nonadditivity of electrostatic, van der Waals, hydrophobic, and other interactions at the nanoscale. Several heuristic rules identified here can be helpful for discriminating between additive and nonadditive nanoscale systems. Further work on NP interactions would benefit from embracing NPs as strongly correlated reconfigurable systems with diverse physical elements and multiscale coupling processes, which will require new experimental and theoretical tools. Meanwhile, the similarity between the size of medium constituents and NPs makes atomic simulations of their interactions increasingly practical. Evolving experimental tools can stimulate improvement of existing force fields. New scientific opportunities for a better understanding of the electronic origin of classical interactions are converging at the scale of NPs.


Phase I clinical study of 9-hydroxy-2N-methyl-ellipticinium acetate (NSC-264137) administered on a 5-day i.v. schedule.
Twenty-three patients with advanced solid tumors received 9-hydroxy-2N-methyl-ellipticinium acetate at a single daily i.v. dose of 15-80 mg/m2 for 5 consecutive days, repeated every 3 weeks. One partial and one minor response were achieved in two patients with breast cancer. Dryness of the mouth was dose-related and dose-limiting. Local phlebitis was also dose-related and frequently severe at the highest dose levels. Other non-hematologic toxic effects were essentially mild to moderate and included nausea, vomiting, diarrhea, stomatitis, fever, weakness, transient renal and hepatic impairment, alopecia and chest pain. Minimal myelosuppression was encountered. It appears that 60 mg/m2/day is the maximum tolerated dose with a five-day schedule. According to our findings, this schedule does not seem to offer any advantage over the previously tested weekly administrations.


Human beta-glucuronidase. I. Recognition and uptake by animal fibroblasts suggests animal models for enzyme replacement studies.
As part of an effort to develop an animal model for studies of uptake of human beta-glucuronidase, fibroblasts were established from primary explants of connective tissue from nine different animal species, and examined for their ability to take up human platelet beta-glucuronidase. Endogenous fibroblast beta-glucuronidase was inactivated by heating extracts to 65 degrees for 30 min. Human beta-glucuronidase was stable to this treatment. Uptake of human beta-glucuronidase by animal fibroblasts was measured as heat-stable beta-glucuronidase present in fibroblasts after exposure to partially purified human platelet beta-glucuronidase for 48 hr. Althought all animal fibroblasts examined exhibited some uptake capacity for human beta-glucuronidase, the uptake capacity of different animal fibroblasts varied over a 10-fold range. The uptake capacity of bovine fibroblasts was at least 80% that of human fibroblasts. Rat and hamster fibroblasts showed about half the uptake capacity of human fibroblasts. The rat fibroblasts resembled the human fibroblasts in the kinetics of uptake of hihg uptake (platelet) enzyme, poor uptake of human placental enzyme, and lack of appreciable turnover of enzyme taken up over 4 days. Heating extracts of rat organs containing added human beta-glucuronidase at 65 degrees selectively inactivated rat enzyme.


Prophylactic feeding tube placement for squamous cell carcinoma of the head and neck.
Percutaneous endoscopic gastronomy (PEG) tubes are commonly used to administer enteral nutrition during head and neck cancer (HNC) treatment. However, the benefits of placing a prophylactic feeding tube (PFT; prior to radiotherapy [RT]) or reactive feeding tube (RFT, after RT initiation) are unclear. We sought to compare survival, body mass trends, and hospitalization rates between strategies. We conducted a retrospective cohort study of 11,473 Veterans with stages III-IVC HNC treated with chemoradiotherapy. Patients with PEG tube placement within 30 days prior to treatment initiation (PFT) were compared to all other patients (non-PFT) or patients with PEG tube placement within 3 months after treatment initiation placement (RFT). We compared survival, longitudinal body mass changes, and hospitalization rates for PFT versus non-PFT or RFT patients in propensity score (PS)-matched Cox regression models. 3,186 (28 %) patients received PFT and 8,287 (72 %) were non-PFT, of which 1,874 (23 %) received RFT. After PS-matching, there were no significant differences in overall survival (HR 0.97, 95 % CI 0.92-1.02), HNC-specific survival (HR 0.98, 95 % CI 0.92-1.09), change in BMI (p = 0.24), or hospitalization rates between PFT and non-PFT groups. Significant differences in hospitalization rates between PFT and RFT groups persisted after PS-matching (-0.11 hospitalizations/month), but no differences were found for other outcomes. Timing of PEG tube placement in Veterans with HNC was not associated with any significant survival or body mass advantage. However, patients who received PFT had a lower hospitalization rate than those who received RFT.


The μ-opioid receptor nonsynonymous variant 118A>G is associated with prolonged abstinence from heroin without agonist treatment.
This study assesses whether opioid-related gene variants contribute to reduced vulnerability to relapse to heroin in persons who are not treated with μ-opioid receptor agonist. Genotypes of 71 SNPs, in nine genes, were analyzed for association with long-term abstinence in former heroin-dependents of European/Middle Eastern ancestry, either without agonist treatment (n = 129) or in methadone maintenance treatment (n = 922). The functional OPRM1 nonsynonymous SNP rs1799971 (118A>G) showed significant association with long-term abstinence (Ppermutation = 0.03, dominant model, OR: 2.2; 95% CI: 1.5-3.3). Since the stress axis is regulated in part by β-endorphin, this functional OPRM1 SNP may blunt the endogenous stress response and contribute to reduced vulnerability for relapse.


Prevalence of biliary ascariasis and its relation to biliary lithiasis.
Hepatobiliary ultrasound was carried out on 2224 consecutive patients at the Center for Nuclear Medicine and Ultrasound and at one private diagnostic center in Mymensingh for ultrasound examination of different systems. The purpose of this study was to investigate the prevalence of biliary ascariasis and its association with other biliary diseases, specially biliary lithiasis. Data regarding the presence of stone, worm or other diseases were recorded accordingly in this prospective study. There were 952 male and 1272 female patients with an age range of 5-90 years. Biliary diseases were detected in 305 patients (13.71%), of whom 97 were male (10.19%) and 208 were female (16.35%). The most common biliary disease in both sexes was cholelithiasis (11.87%), which was found in 84 male patients (8.82%) and in 180 female patients (14.15%). Other diseases found were choledocholithiasis in 14 patients (3 males, 11 females), gall bladder mass in 9 patients (3 males, 6 females), common bile duct mass in 7 patients (4 male, 3 female) and biliary ascariasis in 10 patients (3 male, 7 female). Overall prevalence of biliary ascariasis was 0.45% (0.31% in male patients and 0.55% in female patients), and age range of patients with the condition was 6-50 years. No case of biliary ascariasis was associated with cholelithiasis or choledocholithiasis. Acute cholecystitis was associated with 8 cases (80%) of biliary ascariasis. Common sonographic findings in patients with biliary ascariasis were a single long, linear or curved echogenic structure within the bile duct, without acoustic shadowing. Other findings were gall bladder distention with sludge inside, an edematous wall and mildly dilated biliary tree. Prevalence of biliary ascariasis in the study was 0.45%, with incidence being higher in female subjects (0.55%). No correlation was found between biliary ascariasis and biliary lithiasis. Most of the cases of biliary ascariasis were associated with acute cholecystitis. We concluded that a careful search for biliary ascariasis should be considered for patients with acute acalculus cholecystitis, especially in areas in which ascariasis is endemic, such as Bangladesh.


Rehabilitation for the post-cleft nasolabial stigma.
The post-cleft central facial stigma is a psychologically crippling deformity that challenges the reconstructive surgeon's imagination. Rewarding improvements can be achieved through a combination of an "elephant trunk" open approach and restoration of existing structural elements with addition of a central cartilage or bony columellar strut capped by cartilage to provide nasal tip projection. The entire deformity must be considered and, if needed, maxillary or lip revisional surgery must be done to obtain optimal results.


Effects of thienorphine on release of dopamine and noradrenalin: an in vivo microdialysis study in rats.
Thenorphine is a new potent long-acting partial opioid agonist. In present study, the effect of thienorphine on noradrenalin (NA) in the locus coeruleus (LC) and dopamine (DA) and its metabolites in the nucleus acumbens (NAc) and the striatum were examined in freely moving rats during acute and chronic thienorphine treatment followed by naloxone-precipitated withdrawal using the in vivo microdialysis technique. Acute thienorphine (1.0mg/kg, s.c.) treatment had no effect on the level of NA in the LC and the level of DA in the NAc and the striatum. Chronic thienorphine (1.0mg/kg, s.c.) third per day for continued 5 days treatment followed by naloxone-precipitated (5.0mg/kg, i.p.) had not alter the extracellular NA level in the LC and the extracellular level of DA in the NAc and the striatum, but significantly increased the level of DOPAC in the striatum. These changes are thought to reflect a direct effect of thienorphine on release of NA and DA. Thus thienorphine deserves further study as a new treatment for opioid dependence.


Visual tuning and metrical perception of realistic point-light dance movements.
Humans move to music spontaneously, and this sensorimotor coupling underlies musical rhythm perception. The present research proposed that, based on common action representation, different metrical levels as in auditory rhythms could emerge visually when observing structured dance movements. Participants watched a point-light figure performing basic steps of Swing dance cyclically in different tempi, whereby the trunk bounced vertically at every beat and the limbs moved laterally at every second beat, yielding two possible metrical periodicities. In Experiment 1, participants freely identified a tempo of the movement and tapped along. While some observers only tuned to the bounce and some only to the limbs, the majority tuned to one level or the other depending on the movement tempo, which was also associated with individuals' preferred tempo. In Experiment 2, participants reproduced the tempo of leg movements by four regular taps, and showed a slower perceived leg tempo with than without the trunk bouncing simultaneously in the stimuli. This mirrors previous findings of an auditory 'subdivision effect', suggesting the leg movements were perceived as beat while the bounce as subdivisions. Together these results support visual metrical perception of dance movements, which may employ similar action-based mechanisms to those underpinning auditory rhythm perception.


Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice.
Epileptic seizures can occur as a result of mitochondrial dysfunction. Mitochondria have vital functions such as energy generation, control of cell death, neurotransmitter synthesis, and free radical production. Which of these critical mitochondrial functions contributes to epileptic seizures is unknown. We demonstrate here that a subset of mice with partial deficiency of the mitochondrial superoxide dismutase (Sod2(-/+)) show increased incidence of spontaneous and handling-induced seizures that correlates with chronic mitochondrial oxidative stress (increased aconitase inactivation and 8-hydroxy-2'-deoxyguanosine formation in mitochondria) and diminished mitochondrial oxygen utilization. Before the age at which spontaneous seizures appear in a subset of the mice, Sod2(-/+) mice demonstrated increased susceptibility to behavioral seizures, mitochondrial aconitase inactivation, and neurodegeneration induced by the administration of kainate. These data suggest that chronic mitochondrial oxidative stress initiated by superoxide (O(2)(.-)) radicals is sufficient to increase seizure susceptibility due to aging, environmental stimulation, or excitotoxin administration. Sod2(-/+) mice showed an age-related decrease in the expression of glial glutamate transporters (GLT-1 and GLAST), suggesting that oxidant-induced inhibition of glutamate transport may play a mechanistic role in rendering some Sod2(-/+) mice susceptible to seizures. In summary, mitochondrial oxidative stress and resultant dysfunction may be an important mechanism underlying certain seizure disorders.


Calcium Pyrophosphate Dihydrate Crystal Deposition in Gouty Tophi.
The coexistence of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate crystals in gouty tophi has rarely been reported. We undertook this study to investigate CPPD crystal deposits in a series of surgically removed gouty tophi and to identify factors associated with these deposits. Twenty-five tophi from 22 gout patients were analyzed using polarized light microscopy, field emission scanning electron microscopy (FESEM), and μ Fourier transform infrared (μFTIR) spectroscopy. Tophi consisted of multiple lobules separated by fibrous septa and surrounded by a foreign-body giant cell reaction. CPPD crystal aggregates were identified in 9 of 25 tophi from 6 patients. CPPD crystals were dispersed or highly compacted, localized at the edge or inside the tophus lobules, with some lobules completely filled with crystals. Both monoclinic and triclinic CPPD crystal phases were identified using FESEM and μFTIR. Compared to patients without CPPD, those with CPPD-containing tophi were older (mean 60.5 years versus 47.2 years; P = 0.009), and had longer-term gout duration (mean 17.0 years versus mean 9.0 years; P < 0.05) and tophi duration (mean 10.0 years versus mean 4.6 years; P < 0.01). None of the patients had radiographic chondrocalcinosis of the knee or wrist. CPPD crystal formation seems to be a late and frequent event of tophus maturation, occurring more frequently with aging, and could contribute to the speed of tophus dissolution and the apparent persistence of tophus sometimes observed even after effective, long-lasting urate-lowering therapy.