Riboswitch control of aminoglycoside antibiotic resistance.
The majority of riboswitches are regulatory RNAs that regulate gene expression by binding small-molecule metabolites. Here we report the discovery of an aminoglycoside-binding riboswitch that is widely distributed among antibiotic-resistant bacterial pathogens. This riboswitch is present in the leader RNA of the resistance genes that encode the aminoglycoside acetyl transferase (AAC) and aminoglycoside adenyl transferase (AAD) enzymes that confer resistance to aminoglycoside antibiotics through modification of the drugs. We show that expression of the AAC and AAD resistance genes is regulated by aminoglycoside binding to a secondary structure in their 5' leader RNA. Reporter gene expression, direct measurements of drug RNA binding, chemical probing, and UV crosslinking combined with mutational analysis demonstrate that the leader RNA functions as an aminoglycoside-sensing riboswitch in which drug binding to the leader RNA leads to the induction of aminoglycosides antibiotic resistance.


Social Support, Postpartum Depression, and Professional Assistance: A Survey of Mothers in the Midwestern United States.
Transition into motherhood is generally a joyful life event; for some women, however, it is marked by emotional turmoil. Lack of support can be associated with postpartum depression and can compromise both the mother and infant. A descriptive, cross-sectional study (N = 61) was conducted to explore the relationship between social support and postpartum depression and to determine whether mothers overwhelmed with childcare, or overwhelmed with life in general since becoming a mother, sought professional help. The results revealed that screening for depression alone may not be sufficient, that mothers are willing to contact a professional for help in the postpartum period, and that assessments after birth should include a broader assessment of life's difficulties rather than focusing on childcare responsibilities alone.


The heterogeneity of Covid-19 learning loss across Italian primary and middle schools.
This paper investigates the heterogeneous impact of school closures during Covid-19 pandemic in Italy on academic performance across different schools, grades, subjects and groups of students. Our analysis utilises an innovative dataset that combines administrative data on standardised tests in grades 5 and 8 with a specifically-designed survey that collects information about teachers' practices between February and June 2020. Firstly, by employing a multilevel (mixed-effects) model, we estimate the extent of learning loss and examine its variability across schools, for students in primary and middle levels during the school year 2020/21. The findings confirm that learning loss has been considerable (between 0.05 and 0.27 SD) although heterogeneity across disciplines and grades exists - higher in English in grade 5, and in mathematics and reading in grade 8. Secondly, as a main contribution of the paper, we explore the mechanisms behind the substantial differences observed across schools, which can be explained by the ability of teachers in using digital tools and evaluating their students, as well as by the leadership role exerted by school principals.


The oxidation and decarboxylation of retinoic acid by horseradish peroxidase.
The decarboxylation of retinoic acid by horseradish peroxidase was investigated. A marked increase in the yield of products was obtained. However, the data indicated the reaction was a nonenzymatic, heme catalyzed peroxidation. Previously reported requirements for phosphate, oxygen and ferrous ion were eliminated when hydrogen peroxide was provided. Peroxide also eliminated the EDTA and cyanide induced inhibition of the phosphate dependent system. In the presence of hydrogen peroxide, horseradish peroxidase was not essential to the reaction; heme equivalent amounts of hemoglobin decarboxylated retinoic acid with equal facility. However, hemoglobin was ineffective in the absence of hydrogen peroxide. Attainment of 50--60% decarboxylation represented complete utilization of the available retinoic acid. Thus the products of the reaction can be divided into two groups, products of retinoic acid oxidation and products of an oxidative decarboxylation of retinoic acid.


Genetic and Environmental Contributions to Autism Spectrum Disorder Through Mechanistic Target of Rapamycin.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual's reciprocal social interaction and communication ability. Numerous genetic and environmental conditions are associated with ASD, including tuberous sclerosis complex, phosphatase and tensin homolog hamartoma tumor syndrome, fragile X syndrome, and neurofibromatosis 1. The pathogenic molecular mechanisms of these diseases are integrated into the hyperactivation of mTORC1 (mechanistic target of rapamycin complex 1). Rodent models of these diseases have shown high mTORC1 activity in the brain and ASD-related behavioral deficits, which were reversed by the mTORC1 inhibitor rapamycin. Environmental stress can also affect this signaling pathway. In utero exposure to valproate caused ASD in offspring and enhanced mTORC1 activity in the brain, which was sensitive to mTORC1 inhibition. mTORC1 is a signaling hub for diverse cellular functions, including protein synthesis, through the phosphorylation of its targets, such as ribosomal protein S6 kinases. Metabotropic glutamate receptor 5-mediated synaptic function is also affected by the dysregulation of mTORC1 activity, such as in fragile X syndrome and tuberous sclerosis complex. Reversing these downstream changes that are associated with mTORC1 activation normalizes behavioral defects in rodents. Despite abundant preclinical evidence, few clinical studies have investigated the treatment of ASD and cognitive deficits. Therapeutics other than mTORC1 inhibitors failed to show efficacy in fragile X syndrome and neurofibromatosis 1. mTORC1 inhibitors have been tested mainly in tuberous sclerosis complex, and their effects on ASD and neuropsychological deficits are promising. mTORC1 is a promising target for the pharmacological treatment of ASD associated with mTORC1 activation.


Neoadjuvant clinical trials for the treatment of primary breast cancer: the experience of the German study groups.
The advantages of neoadjuvant chemotherapy are the ability to 1) increase the rate of breast conservation and improve operability, 2) to reduce mortality by recognizing resistance mechanisms early, and 3) to investigate the activity of new agents by assessing the pathological complete response rate as a surrogate marker for clinical efficacy. The German Breast Group (GBG) is a cooperative study group which focuses on neoadjuvant therapy for breast cancer. This group cooperates closely with the German Gynecological Oncology Working Group-Breast (AGO-B). Additionally, these two German study groups maintain close ties with other national and international study groups, such as the Breast International Group (BIG), Austrian Breast and Colorectal Cancer Study Group (ABCSG), Central European Cooperative Oncology Group (CECOG), International Cooperative Cancer Group (ICCG) and National Surgical Adjuvant Breast Project (NSABP). A series of clinical trials evaluating the role of neoadjuvant therapy in women with primary breast cancer have been designed, performed and published over the last 10 years. This article summarizes the results of the neoadjuvant trials that have been conducted by the German study groups, outlines ongoing clinical research projects, and discusses concepts for future clinical trials.


Autophagic cell death in viral infection: Do TAM receptors play a role?
Containment and clearance of invading pathogens, such as viruses, by suppression of viral replication through antiviral mechanisms (e.g. CRISPR, interferon response or programmed cell death) provide examples of evolutionary developed responses by hosts to limit the establishment of infection. Degradation of the cytoplasm en masse provides an ideal cellular response against intruding pathogens. Degradation of such scale is achieved by a process called (macro)autophagy, where double membrane vacuoles, autophagosomes, engulf cytoplasm and organelles for lysosomal degradation. However, chronic and unrestrained autophagy poses catastrophic consequences to a cell especially when vital organelles (e.g. mitochondria or nucleus) are engulfed and destroyed. Recent findings in the field of autophagy and cell death regulation describe mechanisms that distinguish whether autophagy takes a moderate or excess route. This review aims to present new perspectives and re-examines current assumptions related to cell death regulation by autophagy. The emerging role of TAM receptors in the modulation of autophagy (i.e. both homeostatic and lethal) in the context of virus infections is also discussed in addition to chemical strategies for studying autophagy.


C-phycocyanin Mitigates Cognitive Impairment in Doxorubicin-Induced Chemobrain: Impact on Neuroinflammation, Oxidative Stress, and Brain Mitochondrial and Synaptic Alterations.
Chemotherapy-induced cognitive impairment (CICI) is a common detrimental effect of cancer treatment, occurring in up to 75% of cancer patients. The widely utilized chemotherapeutic agent doxorubicin (DOX) has been implicated in cognitive decline, mostly via cytokine-induced neuroinflammatory and oxidative and mitochondrial damage to brain tissues. C-phycocyanin (CP) has previously been shown to have potent anti-inflammatory, antioxidant, and mitochondrial protective properties. Therefore, this present study was aimed to investigate the neuroprotective effects of CP against DOX-elicited cognitive impairment and explore the underlying mechanisms. CP treatment (50 mg/kg) significantly improved behavioral deficits in DOX-treated mice. Furthermore, CP suppressed DOX-induced neuroinflammation and oxidative stress, mitigated mitochondrial abnormalities, rescued dendritic spine loss, and increased synaptic density in the hippocampus of DOX-treated mice. Our results suggested that CP improves established DOX-induced cognitive deficits, which could be explained at least partly by inhibition of neuroinflammatory and oxidant stress and attenuation of mitochondrial and synaptic dysfunction.


In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions.
The importance of recognizing early melanoma is generally accepted. Because not all pigmented skin lesions can be diagnosed correctly by their clinical appearance, additional criteria are required for the clinical diagnosis of such lesions. In vivo epiluminescence microscopy provides for a more detailed inspection of the surface of pigmented skin lesions, and, by using the oil immersion technic, which renders the epidermis translucent, opens a new dimension of skin morphology by including the dermoepidermal junction into the macroscopic evaluation of a lesion. In an epiluminescence microscopy study of more than 3000 pigmented skin lesions we have defined morphologic criteria that are not readily apparent to the naked eye but that are detected easily by epiluminescence microscopy and represent relatively reliable markers of benign and malignant pigmented skin lesions. These features include specific patterns, colors, and intensities of pigmentation, as well as the configuration, regularity, and other characteristics of both the margin and the surface of pigmented skin lesions. Pattern analysis of these features permits a distinction between different types of pigmented skin lesions and, in particular, between benign and malignant growth patterns. Epiluminescence microscopy is thus a valuable addition to the diagnostic armamentarium of pigmented skin lesions at a clinical level.


Modular Endo-Bentall Procedure Using a "Rendez-Vous Access".
The concept of a single endovascular valve-carrying conduit device was designated endo-Bentall, but published experience is limited to a single case. This technical note describes an alternative modular endo-Bentall technique and a novel access technique to implant it. A 82-year-old woman with chest pain referred for a 10 cm symptomatic aneurysm of the distal arch and descending aorta. An ascending aortic aneurysm of 5.5 cm prevented endovascular aortic arch repair due to lack of a proximal landing zone. The technique is a modular approach combining a physician-modified endograft (PMEG) with 3 large fenestrations for coronary artery perfusion and a transcatheter aortic valve implantation (TAVI). A "rendez-vous access" with a transapical and transfemoral through-and-through wire offered rapid sequential deployment in a modular fashion of both components. The PMEG was deployed first, landing 5 mm deep in the left ventricular outflow tract (LVOT) and the transcatheter aortic valve was implanted few millimeters below. The endo-Bentall procedure was combined with endovascular aortic arch repair. A modular endo-Bentall procedure combining a PMEG and TAVI is feasible and adaptable to emergent setting using the "rendez-vous access."


Cerebrovascular complications in children with sickle cell disease.
Cerebrovascular accidents were until recently responsible for much mortality and morbidity in children with sickle cell disease; the likelihood of a child with HbSS having a stroke was 11% before age 20 years, with a peak incidence of ischemic stroke between 2 and 5 years of age, and of hemorrhagic strokes between 20 and 29 years of age. Vessels occlusion is likely initiated by intimal proliferation and amplified by inflammation, excessive adhesion of cells to activated endothelium, hypercoagulable state, and vascular tone dysregulation. Silent infarcts may occur and are associated with decreased cognitive functions. Transcranial Doppler ultrasonography (TCD) was more recently demonstrated able to achieve early detection of the children at high risk for clinical strokes. A randomized study demonstrated that a first stroke may be prevented by monthly transfusion in children with abnormal TCD, leading to a recommendation for annual TCD screening of children aged between 2 and 16 years and monthly transfusion for those with abnormal results. In children who have had a first stroke, the risk of recurrence is more than 50% and is greatly reduced by chronic transfusion, although not completely abolished. Hematopoietic stem cell transplant is indicated in children with cerebral vasculopathy who have an HLA-identical sibling.


Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus.
Body weight is related to fat mass, which is associated with obesity. Our study explored the effect of fat-1 gene on body weight in fat-1 transgenic mice. In present study, we observed that the weight/length ratio of fat-1 transgenic mice was lower than that of wild-type mice. The serum levels of triglycerides (TG), cholesterol (CT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and blood glucose (BG) in fat-1 transgenic mice were all decreased. The weights of peri-bowels fat, perirenal fat and peri-testicular fat in fat-1 transgenic mice were reduced. We hypothesized that increase of n-3 PUFAs might alter the expression of hypothalamic neuropeptide genes and lead to loss of body weight in fat-1 transgenic mice. Therefore, we measured mRNA levels of appetite neuropeptides, Neuropeptide Y (NPY), Agouti-related peptides (AgRP), Proopiomelanocortin (POMC), Cocaine and amphetamine regulated transcript (CART), ghrelin and nesfatin-1 in hypothalamus by real-time PCR. Compared with wild-type mice, the mRNA levels of CART, POMC and ghrelin were higher, while the mRNA levels of NPY, AgRP and nesfatin-1 were lower in fat-1 transgenic mice. The results indicate that fat-1 gene or n-3 PUFAs participates in regulation of body weight, and the mechanism of this phenomenon involves the expression of appetite neuropeptides and lipoproteins in fat-1 transgenic mice.


Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.
It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.


Mitochondrial DNA abnormalities in ophthalmological disease.
Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by lack of cellular energy due to genetic defects of oxidative phosphorylation (OXPHOS). Ocular involvement is a prominent clinical feature of mitochondrial disease. This can manifest as optic nerve dysfunction specifically involving retinal ganglion cells as typified by Leber hereditary optic neuropathy (LHON), or progressive external ophthalmoplegia (PEO) and ptosis involving the extraocular muscles which is commonly associated with either primary mitochondrial DNA (mtDNA) mutations or acquired mtDNA defects secondary to a nuclear genetic disorder of mtDNA maintenance. In this short review, we will outline the unique characteristics of mitochondrial genetic disease and its investigation with reference to the clinical features and molecular genetic abnormalities underlying mitochondrial ophthalmological disease.


Cooperative Microbial Tolerance Behaviors in Host-Microbiota Mutualism.
Animal defense strategies against microbes are most often thought of as a function of the immune system, the primary function of which is to sense and kill microbes through the execution of resistance mechanisms. However, this antagonistic view creates complications for our understanding of beneficial host-microbe interactions. Pathogenic microbes are described as employing a few common behaviors that promote their fitness at the expense of host health and fitness. Here, a complementary framework is proposed to suggest that, in addition to pathogens, beneficial microbes have evolved behaviors to manipulate host processes in order to promote their own fitness and do so through the promotion of host health and fitness. In this Perspective, I explore the idea that patterns or behaviors traditionally ascribed to pathogenic microbes are also employed by beneficial microbes to promote host tolerance defense strategies. Such strategies would promote host health without having a negative impact on microbial fitness and would thereby yield cooperative evolutionary dynamics that are likely required to drive mutualistic co-evolution of hosts and microbes.


The sympathetic nervous system and new nonpharmacologic approaches to treating hypertension: a focus on renal denervation.
The sympathetic nervous system is activated in a variety of cardiovascular and metabolic diseases. This is particularly the case for essential hypertension, in which various indices of adrenergic activity, such as plasma norepinephrine, norepinephrine spillover, and sympathetic nerve firing rate, are all well above the reference range of values, thereby documenting sympathetic overdrive. Evidence is available that sympathetic neural factors participate in disease progression, as well as in the development of cardiac and renal organ damage. These findings represent the rationale for therapeutic interventions that counteract the adrenergic overdrive in the hypertensive state. This paper, after reviewing the key findings of the neuroadrenergic abnormalities occurring in hypertension, examines the rationale and the technical details, as well as the results achieved so far, with the use of a new technique that allows the elimination of afferent and efferent innervation of the kidney in resistant hypertension, ie, the ablation of renal nerves. Strengths and potential limitations of the renal denervation approach are briefly addressed.


Defects in cell-mediated immunity during growth of a syngeneic simian virus-induced tumor.
Four assays of tumor-specific cell-mediated immunity were compared during growth of a syngeneic Simian-virus-40-induced tumor, mKSA. Major differences were found in immunity detected by the tumor neutralization test (the Winn test), direct tumor challenge, the microcytotoxicity assay and the -51chromium-release lymphocytotoxicity assay. Progressive growth of the neoplasm followed by loss of immunity (the eclipse phenomenon) was documented with the Winn test. It was established that this eclipse phenomenon represented a lesion in the T-cell system of tumor-bearing hosts. This lesion was found to be specific and unrelated to anatomic tumor location. The ability to produce graft-versus-host reactions, and the ability to respond to mitogens, were found to be generally intact in tumor-bearing animals. Cells capable of recognizing mKSA tumor antigens and reconstituting an immune response following surgical removal of tumor or upon transfer to normal mice were found in the spleens of mice bearing advanced tumors. No suppressor cells that might account for the eclipse phenomenon could be demonstrated. Tumor-bearer serum did not block neutralizing activity of immune spleen cells in the Winn test, and immune cells were capable of neutralizing tumor even in tumor-bearing hosts. The possibility that the lesion is intrinsic to T-cell precursors of effector cells is discussed.


Pharmacological studies on zymosan inflammation in rats and mice. 1: Zymosan-induced paw oedema in rats and mice.
Injections of zymosan in mouse and rat paws provoke inflammatory reactions, the kinetics of which are different. In both models, inflammation occurs at an early stage but oedema is maximal at 30 min in rat paw and 6 h in mouse paw. In this study the two reactions have been studied up to 6 h. The reduction of oedema by anti-H1 compounds, as well as by disodium cromoglycate, proves the active role played by histamine in rat paw oedema. In mouse its role appears to be minor or non-existent. Serotonin seems to be clearly implicated in the early stages of the oedema in mouse, somewhat less in rat. In the two species, non-steroidal anti-inflammatory compounds only reduce the 4-6 h phase. BW755C and phenidone reduce the early and late phase of paw oedema in both species, with the exception of phenidone which is inactive on the 4-6 h phase in the mouse. We can hypothesize that in the two species some leukotrienes seem to be implicated principally in the early phases, while derivatives of cyclooxygenase play a more important role in the late phases. Theophylline reduces inflammation in the two models, hydrocortisone acetate, however, is only active on the late phases. These results indicate that there are important differences in the participation of the various mediators studied in the two models.


Role of astrocytes in depolarization-coupled release of glutamate in cerebellar cultures.
Release of preloaded D-[3H]aspartate in response to depolarization induced by high potassium, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or the endogenous agonist glutamate was studied using cultured glutamatergic cerebellar granule neurons, cerebellar astrocytes, and corresponding cocultures. Release from the vesicular and the cytoplasmic glutamate pools, respectively, was distinguished employing the competitive, non-transportable glutamate transport inhibitor DL-threo-beta-benzyloxyaspartate (DL-TBOA). The results indicate that the release in response to AMPA (30 microM) in the presence of cyclothiazide (50 microM) to block desensitization, was of a vesicular origin. Pulses of 55 mM K+ caused a DL-TBOA resistant efflux of preloaded D-[3H]aspartate from astrocytes, indicating that this release was not mediated by glutamate transporters. The results furthermore support the notion of an important function of the astrocytes in the uptake of released glutamate, because DL-TBOA caused a large, apparent increase in the depolarization-coupled release of preloaded D-[3H]aspartate in the cocultures, compared to neuronal monocultures.


Factors predisposing to wound infection in cardiac surgery. A prospective study of 517 patients.
Postoperative wound infection can greatly prolong hospital stay after cardiac surgery, so the identification of predisposing factors may help in prevention or early institution of treatment. Transfer of organisms from the leg to the sternum during coronary artery surgery has been proposed as a major additional cause of sepsis. The definition of wound infection is not standardised and therefore makes comparison between centres difficult. In a prospective study of 517 patients, a wound scoring method (ASEPSIS) has been used to register all abnormal wounds to maximise the chances of identifying factors predisposing to infection. Abnormal healing was noted in 99 (19%) sternal wounds and 29 (8%) leg wounds. Obesity was the principal risk factor (P less than 0.005). Diabetes, reoperation, length of preoperative hospital stay, age, sex, or previous cardiac surgery had little effect on wound healing. The range of bacteria isolated from chest wounds after coronary artery surgery was similar to that after valvular surgery, but the rate of isolation was significantly greater. With careful attention to technique, leg wound infection rarely presented a clinical problem and did not appear to be a source of bacteria infecting the chest wound.


Colostral immunity in piglets from sows vaccinated with inactivated Aujeszky disease virus vaccine.
Neutralizing antibodies against ADV were transmitted from sows, vaccinated with inactivated ADV adjuvanted with DEAE dextran, to their offspring via colostrum. The suckling piglets were protected by colostral immunity against contact infection with ADV at week 1 p.p., however, they were not protected against i.n. infection (10(8) TCD50). At 2 and 3 weeks p.p. all the piglets were protected against both contact infection and i.n. infection. At 4 weeks p.p. 50 per cent of the litter were protected against i.n. infection, in spite of very low antibody titres (1:2--1:4). The colostral antibodies did not interfere with active antibody response when the piglets were vaccinated with the inactivated vaccine from 2 weeks p.p. onward. Lymphocytes from suckling piglets of a vaccinated sow showed in vitro reactivity (enhanced 3H-thymidine incorporation) against ADV and BHK antigen, both contained in the vaccine used for the immunization of the sow.


Integrated protein function prediction by mining function associations, sequences, and protein-protein and gene-gene interaction networks.
Protein function prediction is an important and challenging problem in bioinformatics and computational biology. Functionally relevant biological information such as protein sequences, gene expression, and protein-protein interactions has been used mostly separately for protein function prediction. One of the major challenges is how to effectively integrate multiple sources of both traditional and new information such as spatial gene-gene interaction networks generated from chromosomal conformation data together to improve protein function prediction. In this work, we developed three different probabilistic scores (MIS, SEQ, and NET score) to combine protein sequence, function associations, and protein-protein interaction and spatial gene-gene interaction networks for protein function prediction. The MIS score is mainly generated from homologous proteins found by PSI-BLAST search, and also association rules between Gene Ontology terms, which are learned by mining the Swiss-Prot database. The SEQ score is generated from protein sequences. The NET score is generated from protein-protein interaction and spatial gene-gene interaction networks. These three scores were combined in a new Statistical Multiple Integrative Scoring System (SMISS) to predict protein function. We tested SMISS on the data set of 2011 Critical Assessment of Function Annotation (CAFA). The method performed substantially better than three base-line methods and an advanced method based on protein profile-sequence comparison, profile-profile comparison, and domain co-occurrence networks according to the maximum F-measure.


Restless legs syndrome and akathisia as manifestations of acute pontine infarction.
Although restless legs syndrome (RLS) and akathisia have similar clinical manifestations and seem to share a common pathophysiology, they are regarded as distinct clinical syndromes. We present three patients with acute pontine infarction and RLS or akathisia as clinical manifestations. They presented with abrupt onset of restlessness of various body parts, as well as other neurological signs including dysarthria or weakness of the legs. Brain MRI of all three patients showed acute pontine infarction. The clinical syndrome in two of the patients was compatible with RLS and one with akathisia. Their symptoms improved after a brief period. Our finding of secondary RLS and akathisia as manifestations of acute pontine infarction provides information that assists in understanding the common anatomical and pathophysiological basis of RLS and akathisia.


[Leprosy in Brazil].
Leprosy or Hansen's disease is a chronic infectious disease caused by the Mycobacterium leprae. The skin and nervous manifestations of the disease present a singular clinical picture that is easily recognized. After India, Brazil still is the second country with the greatest number of cases in the world. Around 94% of the known cases and 94% of the new cases reported in America, come from Brazil. The disease presents itself in two well-defined stable and opposite poles (lepromatous and tuberculoid) and two unstable groups (indeterminate and dimorphic). The spectrum of presentation of the disease may also be classified as: tuberculoid tuberculoid (TT), borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL) and lepromatous lepromatous (LL). The finding of acid fast bacillus in tissue is the most useful method of diagnosis. The effective treatment of leprosy includes the use of specific therapy, suppression of lepra reactions, prevention of physical incapacity, and physical and psychosocial rehabilitation. Chemotherapy with rifampin, dapsone and clofazimine have produced very good results and the control of the disease in Brazil in the foreseeable future is likely.


Efficient Many-Body Non-Markovian Dynamics of Organic Polaritons.
We show how to simulate a model of many molecules with both strong coupling to many vibrational modes and collective coupling to a single photon mode. We do this by combining process tensor matrix product operator methods with a mean-field approximation which reduces the dimension of the problem. We analyze the steady state of the model under incoherent pumping to determine the dependence of the polariton lasing threshold on cavity detuning, light-matter coupling strength, and environmental temperature. Moreover, by measuring two-time correlations, we study quadratic fluctuations about the mean field to calculate the photoluminescence spectrum. Our method enables one to simulate many-body systems with strong coupling to multiple environments, and to extract both static and dynamical properties.


Group a streptococcal puerperal sepsis: historical review and 1990s resurgence.
There appears to be a resurgence of puerperal sepsis due to a historically important pathogen, group A beta-hemolytic streptococcus.


LncRNAs and PTEN/PI3K signaling: A symphony of regulation in cancer biology.
The Emergence of Long Non-coding RNAs (lncRNAs) as Key Regulators in Diverse Biological Processes: A Paradigm Shift in Understanding Gene Expression and its Impact on Cancer. The PTEN/PI3K pathway, a pivotal signaling cascade involved in cancer progression, orchestrates critical cellular functions such as survival, proliferation, and growth. In light of these advances, our investigation delves into the intricate and multifaceted interplay between lncRNAs and the PTEN/PI3K signaling pathway, unearthing previously undisclosed mechanisms that underpin cancer growth and advancement. These elusive lncRNAs exert their influence through direct targeting of the PTEN/PI3K pathway or by skillfully regulating the expression and activity of specific lncRNAs. This comprehensive review underscores the paramount significance of the interaction between lncRNAs and the PTEN/PI3K signaling pathway in cancer biology, unveiling an auspicious avenue for novel diagnostic tools and targeted therapeutic interventions. In this review, we navigate through the functional roles of specific lncRNAs in modulating PTEN/PI3K expression and activity. Additionally, we scrutinize their consequential effects on downstream components of the PTEN/PI3K pathway, unraveling the intricacies of their mutual regulation. By advancing our understanding of this complex regulatory network, this study holds the potential to revolutionize the landscape of cancer research, paving the way for tailored and efficacious treatments to combat this devastating disease.


Rapid screening of urine for significant bacteriuria by Gram stain, acridine orange stain, and the Autobac MTS system.
Urine specimens submitted for microbiologic examination were screened for evidence of bacteriuria by three rapid methods: Gram staining, acridine orange staining, and the Autobac MTS system. The screening results were compared with those obtained by semiquantitative colony counts on agar plates. In this comparative study 1055 urine specimens were examined, of which 146 (13.8%) had colony counts of greater than or equal to 1 X 10(5)/ml. All three urine screening methods detected this level of bacteriuria at a sensitivity of 98% and a specificity of 55.2% (acridine orange), 66.0% (Gram stain), and 83.2% (Autobac), respectively. Of the 1055 urine specimens examined, 185 (17.5%) had colony counts of greater than or equal to 1 X 10(4)/ml, at which level the sensitivity of the three methods was 93% and the specificity was 56.7% (acridine orange), 68.0% (Gram stain), and 86.0% (Autobac), respectively. For any level of sensitivity, the Autobac urine screen was shown to be more specific than either the Gram stain or the acridine orange method. The acridine orange stain was the least specific urine screen, especially at the upper limits of sensitivity.


Effect of methyl jasmonate application to grapevine leaves on grape amino acid content.
Over the last few years, considerable attention has been paid to the application of elicitors to vineyard. However, research about the effect of elicitors on grape amino acid content is scarce. Therefore, the aim of this study was to evaluate the influence of foliar application of methyl jasmonate on must amino acid content. Results revealed that total amino acid content was not modified by the application of methyl jasmonate. However, the individual content of certain amino acids was increased as consequence of methyl jasmonate foliar application, i.e., histidine, serine, tryptophan, phenylalanine, tyrosine, asparagine, methionine, and lysine. Among them, phenylalanine content was considerably increased; this amino acid is precursor of phenolic and aromatic compounds. In conclusion, foliar application of methyl jasmonate improved must nitrogen composition. This finding suggests that methyl jasmonate treatment might be conducive to obtain wines of higher quality since must amino acid composition could affect the wine volatile composition and the fermentation kinetics.


Blunted activation of NF-kappaB and NF-kappaB-dependent gene expression by geranylgeranylacetone: involvement of unfolded protein response.
Geranylgeranylacetone (GGA), an anti-ulcer agent, has anti-inflammatory potential against experimental colitis and ischemia-induced renal inflammation. However, molecular mechanisms involved in its anti-inflammatory effects are largely unknown. We found that, in glomerular mesangial cells, GGA blocked activation of nuclear factor-kappaB and consequent induction of monocyte chemoattractant protein 1 (MCP-1) by inflammatory cytokines. It was inversely correlated with induction of unfolded protein response (UPR) evidenced by expression of 78kDa glucose-regulated protein (GRP78) and suppression of endoplasmic reticulum stress-responsive alkaline phosphatase. Various inducers of UPR including tunicamycin, thapsigargin, A23187, 2-deoxyglucose, dithiothreitol, and AB(5) subtilase cytotoxin reproduced the suppressive effects of GGA. Furthermore, attenuation of UPR by stable transfection with GRP78 diminished the anti-inflammatory effects of GGA. These results disclosed a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of GGA.


Vasodilator effect of urotensin II, one of the most potent vasoconstricting factors, on rat coronary arteries.
The effects of human urotensin II on coronary flow were studied in the perfused rat heart. Urotensin II transiently decreased coronary flow, then induced sustained vasodilatation. In the presence of a cyclooxygenase inhibitor, diclofenac, coronary vasodilatation was significantly inhibited. A nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NNA), attenuated the urotensin-induced vasodilatation. These data suggest that urotensin II modulates coronary flow through factors such as cyclooxygenase products and nitric oxide to elicit coronary vasodilatation.


Laser flow measurements of scattering and fluorescence from cell nuclei in the presence of increasing Mg++ concentrations.
The effects of Mg++ on the spatial organization of nuclei from rat hepatocytes are analyzed in the range 0-60 mM, in the presence of suitable concentrations of KCl to reproduce physiological conditions. It is shown that the scatter-signal distribution measured by means of a flow microfluorimeter is greatly affected by this range of Mg concentrations. By coupling this result to phase-contrast-automated image analysis, it is possible to identify a shrinking process induced by Mg++ in the range 0-2.5 mM, which reaches a plateau in the range 5-20 mM and is followed by a swelling process in the range 30-60 mM. The same Mg ranges are shown to affect the intercalation of the fluorochrome acridine orange into chromatin, suggesting that the shrinking-swelling phenomenon has also a molecular correspondence at the genome level. Possible implications in terms of the influence of Mg++ on the organization of chromatin inside intact cells are briefly discussed.


Merkel cell carcinoma in a black human immunodeficiency virus-infected patient.
Merkel cell carcinoma (MCC) is a rare malignant tumour that develops in sun-exposed areas in immunocompromised patients (chronic lymphocytic leukaemia, transplant recipients) older than 50 years. We report MCC in a young black woman with human immunodeficiency virus (HIV) infection. A 2-cm binodular violaceous lesion developed on her left ear lobe. Extensive work-up, including computed tomographic scans of the neck, chest, abdomen and pelvis, octreotide scan and sentinel node biopsy, did not demonstrate any metastasis. A wide excision was performed and the patient remained free of disease after 9 months. This case is the fourth observation of MCC in an HIV-infected patient.


An audit of cavity and crown preparations and two direct restorations carried out by foundation dentists in the Oxford and Wessex Deaneries.
It is likely that many foundation dentists (FDs) will have completed only minimal amounts of restorative dentistry for a number of months immediately prior to commencing work as FDs. Thus this audit aimed to assess the performance of the FDs when they carried out a number of simulated clinical exercises: amalgam cavities and restoration; Class IV resin composite restorations; and full crown preparations for metal-ceramic restorations. A total of 67 FDs completed the assessments and some results did indicate a high level of concern and need for further evaluation of restorative practice.


Screening tests for N sorption allow to select and engineer biochars for N mitigation during biomass processing.
Biochar amendment during biomass processing can improve those processes and products, and reduce the emissions of greenhouse gases and NH3, resulting in ecologic and economic benefits. The potential positive effects of biochar are related to NH4+-N and NH3 sorption, which in turn are depending on different biochar characteristics. By knowing the relationship between biochar characteristics and NH4+-N and NH3 sorption, biochar production can be steered towards a higher N sorption or existing biochars can be selected for targeted applications for high N sorption. Therefore, this study aims to develop fast screening tests to estimate the potential for both NH4+-N and NH3 sorption of biochar, before application in biomass processing. Further, the effects of feedstock, pyrolysis temperature, biochar characteristics and biochar treatments on N sorption are studied. The results show that NH4+-N sorption varied between 0 and 1.54 mg NH4+-N/g fresh biochar and was highest for manure-based biochars with a high nutrient content and cation exchange capacity, produced at lower temperatures (300-450 °C). For some biochars, the feedstock itself had a higher NH4+-N sorption than the biochar. Grinding and washing increased the NH4+-N sorption. In addition, a general linear model was proposed to predict the NH4+-N sorption based on three chemical characteristics· NH3 sorption varied between 0 and 100 % of the negative control and showed a linear positive relationship with the NH4+-N sorption, moisture retention factor and cation exchange capacity. Pyrolysis temperature and feedstock type did not significantly affect NH3 sorption. NH4+-N and NH3 desorption varied amongst biochar type.


Rectal dose-volume differences using proton radiotherapy and a rectal balloon or water alone for the treatment of prostate cancer.
To describe dose-volume values with the use of water alone vs. a rectal balloon (RB) for the treatment of prostate cancer with proton therapy. We analyzed 30 proton plans for 15 patients who underwent CT and MRI scans with an RB or water alone. Simulation was performed with a modified MRI endorectal coil and an RB with 100 mL of water or water alone. Doses of 78-82 gray equivalents were prescribed to the planning target volume. The two groups were compared for three structures: rectum, rectal wall (RW), and rectal wall 7 cm (RW7) at the level of the planning target volume. Rectum and RW volumes radiated to low, intermediate, and high doses were small: rectum V10, 33.7%; V50, 17.3%; and V70, 10.2%; RW V10, 32.4%; V50, 20.4%; and V70, 14.6%. The RB effectively increased the rectal volume for all cases (139.8 +/- 44.9 mL vs. 217.7 +/- 32.2 mL (p < 0.001). The RB also decreased the volume of the rectum radiated to doses V10-V65 (p < or = 0.05); RW for V10-V50; and RW7 for V10-V35. An absolute rectum V50 improvement >5% was seen for the RB in 5 of 15 cases, for a benefit of 9.2% +/- 2.3% compared with 2.4% +/- 1.3% for the remaining 10 cases (p < 0.001). Similar benefit was seen for the rectal wall. No benefit was seen for doses > or =70 gray equivalents for the rectum, RW, or RW7. No benefit of < or =1% was seen with an RB in 46% for the rectum V70 and in 40% for the rectal wall V70. Rectum and rectal wall doses with proton radiation were low whether using water or an RB. Selected patients will have a small but significant advantage with an RB; however, water alone was well tolerated and will be an alternative for most patients.


Probability of obsessive and compulsive symptoms in Huntington's disease.
The purpose of this study was to examine the probability of obsessive and compulsive (OC) symptoms across stages of Huntington's disease (HD) with both cross sectional and longitudinal data. We present the largest sample to date of individuals at risk for HD (N = 3964). Obsessive and compulsive symptoms were assessed with the Unified Huntington's Disease Rating Scale OC items. The probability of meeting the threshold for obsessions and compulsions increased with greater disease severity. Those with no motor abnormalities ("at risk") had a 7% probability of obsessions and a 3.5% probability of compulsions; the peak probability for obsessions (24%) and compulsions (12%) occurred in patients with advanced disease with significant functional disability. The probability of OC symptoms is more than three times greater by stages 3 and 4 (clearly manifest disease) than in our at-risk group with no apparent motor abnormalities.


Score reliability and construct validity of the Flinn Performance Screening Tool for adults with symptoms of carpal tunnel syndrome.
We investigated the psychometric properties of the Flinn Performance Screening Tool (FPST) for people referred with symptoms of carpal tunnel syndrome (CTS). An occupational therapist collected data from 46 participants who completed the Functional Status Scale (FSS) and FPST after the participants' nerve conduction velocity study to test convergent and contrasted-group validity. Seventy-four percent of the participants had abnormal nerve conduction studies. Cronbach's α coefficients for subscale and total scores of the FPST ranged from .96 to .98. Intrarater reliability for six shared items of the FSS and the FPST was supported by high agreement (71%) and a fair κ statistic (.36). Strong to moderate positive relationships were found between the FSS and FPST scores. Functional status differed significantly among severe, mild, and negative CTS severity groups. The FPST shows adequate psychometric properties as a client-centered screening tool for occupational performance of people referred for symptoms of CTS.


Synergistic effect of biological and advanced oxidation process treatment in the biodegradation of Remazol yellow RR dye.
The current study investigated the efficiency of synergistic biological and Advanced Oxidation Process (AOPs) treatment (B-AOPs) using Aeromonas hydrophila SK16 and AOPs-H2O2 in the removal of Remazol Yellow RR dye. Singly, A. hydrophila and AOPs showed 90 and 63.07% decolourization of Remazol Yellow RR dye (100 mg L-1) at pH 6 and ambient temperature within 9 h respectively. However, the synergistic B-AOPs treatments showed maximum decolorization of Remazol Yellow RR dye within 4 h. Furthermore, the synergistic treatment significantly reduced BOD and COD of the textile wastewater by 84.88 and 82.76% respectively. Increased levels in laccase, tyrosinase, veratryl alcohol oxidase, lignin peroxidase and azo reductase activities further affirmed the role played by enzymes during degradation of the dye. UV-Visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), high-performance liquid chromatography (HPLC) and gas chromatography-mass spectroscopy (GC-MS) confirmed the biotransformation of dye. A metabolic pathway was proposed based on enzyme activities and metabolites obtained after GC-MS analysis. Therefore, this study affirmed the efficiency of combined biological and AOPs in the treatment of dyes and textile wastewaters in comparison with other methods.


The EyeIRR-IS assay: Development and evaluation of an in vitro assay to measure the eye irritation sub-categorization of liquid chemicals.
Several alternative methods have been developed and regulatory adopted by OECD as in vitro alternatives to the Draize eye irritation assay either to detect chemicals not requiring classification (No Category) or inducing serious damage to the eye (Category 1) but none are sensitive enough to identify chemicals inducing reversible eye effects (category 2) which are categorised by default. Therefore, the discriminatory power of a genomic approach applied to the SkinEthic™ Human Corneal Epithelium (HCE) model was investigated to allow subcategorization capacity according to UN GHS classification. An algorithm based on gene expression modulation on a training (62) and a test (31 liquids) chemical set, tested neat and at 30%was evaluated in an assay called EyeIRR-IS. Its accuracy prediction to distinguish Cat1/Cat2 from No Cat was 95% with a specificity of 89% and a sensitivity of 98%. For subcategorization into the 3 GHS classes the accuracy reached 84% with 94% Cat1, 67% Cat2 and 89% No Cat correctly predicted. No Cat.1 chemicals were underestimated as negative with a majority of misclassified Cat2 over predicted as Cat 1. In conclusion, the performance of the assay suggests its added value in a defined approach for liquids to replace the Draize assay.


An evolutionary perspective on stress responses, damage and repair.
Variation in stress responses has been investigated in relation to environmental factors, species ecology, life history and fitness. Moreover, mechanistic studies have unravelled molecular mechanisms of how acute and chronic stress responses cause physiological impacts ('damage'), and how this damage can be repaired. However, it is not yet understood how the fitness effects of damage and repair influence stress response evolution. Here we study the evolution of hormone levels as a function of stressor occurrence, damage and the efficiency of repair. We hypothesise that the evolution of stress responses depends on the fitness consequences of damage and the ability to repair that damage. To obtain some general insights, we model a simplified scenario in which an organism repeatedly encounters a stressor with a certain frequency and predictability (temporal autocorrelation). The organism can defend itself by mounting a stress response (elevated hormone level), but this causes damage that takes time to repair. We identify optimal strategies in this scenario and then investigate how those strategies respond to acute and chronic exposures to the stressor. We find that for higher repair rates, baseline and peak hormone levels are higher. This typically means that the organism experiences higher levels of damage, which it can afford because that damage is repaired more quickly, but for very high repair rates the damage does not build up. With increasing predictability of the stressor, stress responses are sustained for longer, because the animal expects the stressor to persist, and thus damage builds up. This can result in very high (and potentially fatal) levels of damage when organisms are exposed to chronic stressors to which they are not evolutionarily adapted. Overall, our results highlight that at least three factors need to be considered jointly to advance our understanding of how stress physiology has evolved: (i) temporal dynamics of stressor occurrence; (ii) relative mortality risk imposed by the stressor itself versus damage caused by the stress response; and (iii) the efficiency of repair mechanisms.


Therapeutic benefit of pentostatin in severe IL-10-/- colitis.
Pentostatin, an adenosine deaminase (ADA) inhibitor, is a purine antimetabolite used for the treatment of leukemias. ADA inhibition blunts expansion of proliferating lymphocytes and increases adenosine release, a potent anti-inflammatory molecule. Human inflammatory bowel disease (IBD) is driven by expansion of effector T cells (T(eff)) that overwhelm reulatory T cells (T(reg)) and propagate innate immune reponses. Here we study the therapeutic benefits of ADA inhibition to impair T(eff) cell expansion and reduce inflammatory cytokine release in IL-10-deficient (IL-10-/-) mice. Colitis was induced in IL-10-/- mice by administering piroxicam for two weeks. Mice were treated with daily pentostatin or phosphate-buffered saline for 1 week and effects on tissue inflammation, lymphocyte numbers and cytokine production examined. Pentostatin reduced inflammation by >50% and nearly normalized serum amyloid A levels. Lymphocyte expansions in the colon and mesenteric lymph node (MLN) (3.5-fold and >5-fold respectively) dropped by >50-90%. Pro-inflammatory factors in the colon and MLN (IL-1beta, IFN-gamma, IL-6, CXCL10, TNF) dropped whereas FoxP3 and TGF-beta were unchanged. Reductions in cytokine production from equivalent numbers of T cells from pentostatin-treated mice after in vitro (36h) or in vivo (3h) activation suggested anti-inflammatory effects of pentostatin independent of lymphodepletion contributed to its therapeutic benefit. Analysis of mucosal lymphocyte subsets suggested pentostatin reduced numbers of effector CD4+ CD69+ T cells, while sparing CD4+ CD62L+ T cells. Pentostatin dosages that avoid severe lymphocyte depletion effectively treat colitis by impairing T(eff) cell expansion and reducing pro-inflammatory cytokine production while preserving regulatory T(reg) populations and function.


Treatment with maresin 1, a docosahexaenoic acid-derived pro-resolution lipid, protects skin from inflammation and oxidative stress caused by UVB irradiation.
Acute exposure to UVB irradiation causes skin inflammation and oxidative stress, and long-term exposure to UVB irradiation may lead to carcinogenesis. Our organism has endogenous mechanisms to actively limit inflammation. Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid) is a pro-resolution lipid mediator derived from the docosahexaenoic acid, which presents anti-inflammatory and pro-resolution effects. However, it remains to be determined if treatment with MaR1 can inhibit inflammatory and oxidative alterations in the skin triggered by UVB. The treatment with MaR1 (0.1-10 ng/mice at -10 min relative to the UVB irradiation protocol) reduced UVB-induced skin edema, neutrophil recruitment (MPO; myeloperoxidase activity, and migration of LysM-eGFP+ cells), cytokine production, matrix metalloproteinase-9 activity, keratinocyte apoptosis, epidermal thickening, mast cells counts and degradation of skin collagen in hairless mice. UVB irradiation caused a decrease of GSH (reduced glutathione) levels, activity of the enzyme catalase, ferric reducing ability (FRAP), and ABTS radical scavenging capacity as well as induced lipid hydroperoxide, superoxide anion production, and gp91phox mRNA expression. These parameters that indicate oxidative stress were inhibited by MaR1 treatment. Therefore, these data suggest MaR1 as a promising pharmacological tool in controlling the deleterious effects related to UVB irradiation.


A methodological constraint influencing measurement of food intake rates in sucking predators.
In a number of studies which provide food extraction curves for sucking predators, data were obtained by separating the predator from the prey (i.e. by artificially interrupting feeding) at predetermined intervals within the total feeding time. The amount of food the predator had extracted at these time intervals was then determined by measuring either the mass gain in the predator or the mass loss in the prey. An implicit assumption of this method is that at the time feeding is interrupted, the food extracted by the predator is contained within its own digestive system and no part of the food has been released back into the prey. I found this was not the case with the crab spider Diaea sp. indet. feeding on the fruit fly Drosophila immigrans. The food Diaea extracts from prey is retained in its own digestive system only at times when the spider changes feeding sites on the prey and when it discards the prey when finished feeding. At other times it cycles the extracted food between itself and the prey (i.e. a sucking phase is alternated with a relaxing phase during which the extracted food is released back into the prey). Unless feeding is interrupted as close as possible to the end of the sucking phase, the mass change measured in the spider will be an underestimate of the actual amount of food extracted at this time. My results suggest that understanding how a sucking predator's feeding mechanism affects the transfer of food is necessary, not only in identifying constraints affecting feeding efficiency, but also in identifying how these constraints relate to the design of empirical tests. The precision of these tests will, in part, reflect the degree to which these mechanisms are incorporated into the test design.


Emotional prosody recognition is impaired in Alzheimer's disease.
The ability to understand emotions is often disturbed in patients with cognitive impairments. Right temporal lobe structures play a crucial role in emotional processing, especially the amygdala, temporal pole (TP), superior temporal sulcus (STS), and anterior cingulate (AC). Those regions are affected in early stages of Alzheimer´s disease (AD). The aim of our study was to evaluate emotional prosody recognition (EPR) in participants with amnestic mild cognitive impairment (aMCI) due to AD, AD dementia patients, and cognitively healthy controls and to measure volumes or thickness of the brain structures involved in this process. In addition, we correlated EPR score to cognitive impairment as measured by MMSE. The receiver operating characteristic (ROC) analysis was used to assess the ability of EPR tests to differentiate the control group from the aMCI and dementia groups. Eighty-nine participants from the Czech Brain Aging Study: 43 aMCI due to AD, 36 AD dementia, and 23 controls, underwent Prosody Emotional Recognition Test. This experimental test included the playback of 25 sentences with neutral meaning each recorded with different emotional prosody (happiness, sadness, fear, disgust, anger). Volume of the amygdala and thickness of the TP, STS, and rostral and caudal parts of AC (RAC and CAC) were measured using FreeSurfer algorithm software. ANCOVA was used to evaluate EPR score differences. ROC analysis was used to assess the ability of EPR test to differentiate the control group from the aMCI and dementia groups. The Pearson's correlation coefficients were calculated to explore relationships between EPR scores, structural brain measures, and MMSE. EPR was lower in the dementia and aMCI groups compared with controls. EPR total score had high sensitivity in distinguishing between not only controls and patients, but also controls and aMCI, controls and dementia, and aMCI and dementia. EPR decreased with disease severity as it correlated with MMSE. There was a significant positive correlation of EPR and thickness of the right TP, STS, and bilateral RAC. EPR is impaired in AD dementia and aMCI due to AD. These data suggest that the broad range of AD symptoms may include specific deficits in the emotional sphere which further complicate the patient's quality of life.


Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis.
This study's aim was to assess the role of interleukin (IL)-5 in modulating the levels of antibodies binding to oxidized low-density lipoprotein (OxLDL) in human atherosclerosis. Various pro- and anti-inflammatory cytokines have been implicated in atherogenesis, and recent findings in mice indicate that the cytokine IL-5 plays a protective role in atherosclerosis in part via the induction of antibodies binding to OxLDL. Plasma IL-5 levels and antibody titers to 2 most commonly used models of OxLDL (copper OxLDL and malondialdehyde-modified LDL) were measured in 1,011 Finnish middle-aged subjects with chemiluminescent enzyme-linked immunosorbent assay. Intima-media thickness (IMT) was assessed ultrasonographically from the internal carotid artery, the bifurcation, and the common carotid artery. There was a significant positive association between plasma IL-5 levels and antibody titers to copper OxLDL (p = 0.010 and p = 0.044, immunoglobin [Ig] M and G, respectively) and IgM to malondialdehyde-modified LDL (p < 0.001) in the association analysis performed between different IL-5 quartiles. Furthermore, plasma IL-5 levels were found to be inversely associated with bifurcational IMT, and even after adjustments for traditional risk factors of atherosclerosis (age, gender, smoking, systolic blood pressure, LDL, and body mass index), IL-5 remained an independent determinant of the mean bifurcational IMT (p = 0.010). Our data demonstrate that plasma IL-5 levels are related to the plasma levels of antibodies binding to OxLDL and to decreased subclinical atherosclerosis in humans. These results are in line with earlier findings in murine atherosclerosis and indicate for the first time that IL-5 may play a role in human atherosclerosis.


Association between Acrylamide Metabolites and Cardiovascular Risk in Children With Early Stages of Chronic Kidney Disease.
Cardiovascular disease (CVD) begins early in children with chronic kidney disease (CKD). Reduced nitric oxide (NO) bioavailability has been associated with increased CVD in CKD patients. Children tend to have more exposure to acrylamide, one of the most common toxins in food. We aimed to determine whether urinary levels of acrylamide metabolites N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-cysteine (GAMA) are associated with CV risk markers in children with CKD. Data on 112 children and adolescents ages three to 18 years old with CKD stage G1-G4 are reported. We observed that 24 h ambulatory blood pressure monitoring (ABPM) abnormalities were greater, and left ventricular (LV) mass and ambulatory arterial stiffness index (AASI) were higher in children with CKD stage G2-G4 versus G1. Patients with CKD stage G2-G4 had a lower urinary acrylamide level, but a higher AAMA-to-GAMA ratio than those with CKD stage G1. Urinary acrylamide level was negatively associated with high systolic blood pressure (SBP) and diastolic BP (DBP) load on 24 h ABPM. Lower urinary levels of acrylamide, AAMA, and GAMA were correlated with LV mass. Additionally, GAMA are superior to AAMA related to NO-related parameters, namely citrulline and symmetric dimethylarginine (SDMA). This study suggests that determinations of urinary acrylamide level and its metabolites in the early stages of pediatric CKD may identify patients at risk of CVD. Further studies should clarify mechanisms underlying acrylamide exposure to define the treatment for protection against CVD.


Stability and movement of a one-link neuromusculoskeletal sagittal arm.
This paper's focus is the stability, point-to-point, and rhythmic movements of a one-link sagittal arm. The system is highly nonlinear in all its physical and physiological attributes. The major physiological characteristics of this system are simultaneous activation of a pair of nonlinear muscle-like actuators for control purposes, existence of nonlinear spindle-like sensors, and actions of gravity and loading. Transmission delays are included in the afferent and efferent neural paths to account for a more accurate representation of the reflex loops. An algorithm for computation of the actuator forces and the feedback signals in the system is provided. It automatically renders positive forces and positive neural signals. The positiveness of the forces represents the unidirectional character of muscular forces, i.e., natural muscles can only pull in the direction of shortening. The positiveness of the neural signals implies these signals can correspond to firing rates. The stability of the system is analyzed. The role of the nonlinearities in the dynamics, actuators, and feedback signals, and the delays in the feedback loops in destabilizing the system, and the consequently undesirable oscillations are studied by simulation. The system is designed to perform stable point-to-point movement. The effects of the presetting of the input signals, gain of the feedback loops, and the duration of delays in generating undesirable tremor-like oscillations at the end of the movement are studied and demonstrated by digital computer simulations.


HIF-1α and Caspase-3 expression in aggressive papillary thyroid carcinoma.
Tumor cells adapt to hypoxia by regulating transcription factors that involved in regulation of metabolism, angiogenesis, cell proliferation, and apoptosis. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1α and HIF-1β subunits, acts as a key transcription factor mediating the adaptive cellular responses. Caspase-3 is a key apoptosis-related protease that plays a role in tumor growth and development. Studies have shown that caspase-3 could be regulated by HIF-1α under pathological conditions. Therefore, HIF-1α and caspase-3 expression may be related to the poor prognosis of tumors. In this study, we analyzed the possible relationships between these two signaling factors in correlation with the clinical behavior of PTC. We detected the expression levels of HIF-1α and caspase-3 in 70 samples of PTC and para-cancerous tissues (control group) by immunohistochemistry (IHC). Furthermore, various clinicopathological parameters were assessed to determine their correlations with HIF-1α and caspase-3 expressions. First, HIF-1α and caspase-3 expressions (60% and 37.1%, respectively) increased significantly in the PTC samples as compared to normal tissues (2.9% for both HIF-1α and caspase-3) (p < 0.05) as determined by IHC. Second, although there was no significant difference between the expression of HIF-1α and caspase-3 in regard to gender, age distribution, tumor size, lymph node metastasis, and BRAFV600E mutation (all p > 0.05), HIF-1α and caspase-3 expressions were associated with capsule invasion and cell subtypes of PTC (p < 0.05). The percent positivity of caspase-3 expression in tall-cell variant (TCV) was the highest (63.6%). Third, HIF-1α expression was positively correlated with that of caspase-3 (rs = 0.326; p < 0.05). Overexpression of HIF-1α and caspase-3 is associated with carcinogenesis. These factors might serve as promising predictors of aggressive PTC. These findings also suggest their potential as therapeutic targets.


Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer.
Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.


Natural killer cell therapy in children with relapsed leukemia.
Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population. Twenty-nine children who had relapsed or refractory leukemia were treated with chemotherapy followed by the infusion of haploidentical NK cells. Cohort 1 included 14 children who had not undergone prior allogeneic hematopoietic cell transplantation (HCT), whereas Cohort 2 included 15 children with leukemia that had relapsed after HCT. Twenty-six (90%) NK donors were KIR mismatched (14 with one KIR and 12 with 2 KIRs). The peak NK chimerism levels were >10% donor in 87% of the evaluable recipients. In Cohort 1, 10 had responsive disease and 12 proceeded to HCT thereafter. Currently, 5 (36%) are alive without leukemia. In Cohort 2, 10 had responsive disease after NK therapy and successfully proceeded to second HCT. At present, 4 (27%) are alive and leukemia-free. The NK cell infusions and the IL-2 injections were well-tolerated. NK cell therapy is safe, feasible, and should be further investigated in patients with chemotherapy-resistant leukemia.


[Determination of SARS-CoV by simplified nested fluorescent RT-PCR].
To establish a simple rapid and sensitive nested RT-PCR method for detection of SARS coronavirus RNA by designing the specific primers for SARS and optimizing the parameters for PCR. Primers and fluorescent probes were designed according to the sequences of SARS coronavirus genes available from GenBank. The optimization of the parameters for PCR was performed in PE 7700 thermal cycle. The 36 serum samples and 40 mouthwash of SARS patients and 80 samples of healthy people were tested. The positive rate of patient serum and mouthwash was 33.6%, (12/36) and 67.5%, (27/40), respectively, while the positive rate of healthy people was zero (0/160). The simple nested RT-PCR method was a rapid, efficient and sensitive one for SARS early diagnosis.


N-nitrosodimethylamine, N-nitrosodiethylamine, and N-nitrosomorpholine fail to generate 8-hydroxy-2'-deoxyguanosine in liver DNA of male F344 rats.
The possible oxidative effects of the hepatocarcinogens 2-nitropropane (2-NP), N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosomorpholine (NMOR) on nuclear DNA were studied in vivo in male F344 rats. 2-NP and the N-nitrosamines were administered intraperitoneally. In addition, NDEA was given by gavage. DNA was isolated from rat liver and hydrolysed enzymatically. Oxidative DNA damage was determined by measuring 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in a mixture of 2'-deoxyribonucleosides by electrochemical detection. This method allows a detection limit of about 0.1 residue 8-OH-dG per 10(5) 2'-deoxyguanosine (dG). 2-NP drastically increased the content of 8-OH-dG in rat liver by a factor of ca. 12. No elevation above control values could be proved after having dosed the rats with N-nitrosamines.


Prevalence of growth hormone deficiency in children with cleft lip or palate.
Two hundred children 7 to 14 years of age with isolated cleft defects of the lip, palate, or both were surveyed for stature. Twelve percent were less than the third percentile in height and were designated "short." All of the short children received an endocrine evaluation. Endogenous growth hormone was examined after two days' pretreatment with stilbesteral. Four of the 25 short children with CLP had total, and four had partial, GH deficiency. Three of the GH-deficient patients were also deficient in ACTH or TSH. In contrast, in a series of 75 short (less than third percentile) children 7 to 14 years of age without cleft defect or other apparent congenital abnormality, only two had total and two had partial GH deficiency. The data suggest that children with isolated CLP have short stature about four times more often, and GH-deficiency about 40 times more often, than children without CLP. The increased prevalence of GH-deficiency may stem from the embryologic relation of adenohypophysis and oral ectoderm.


Green Ambient-Dried Aerogels with a Facile pH-Tunable Surface Charge for Adsorption of Cationic and Anionic Contaminants with High Selectivity.
The fabrication of reusable, sustainable adsorbents from low-cost, renewable resources via energy efficient methods is challenging. This paper presents wet-stable, carboxymethylated cellulose nanofibril (CNF) and amyloid nanofibril (ANF) based aerogel-like adsorbents prepared through efficient and green processes for the removal of metal ions and dyes from water. The aerogels exhibit tunable densities (18-28 kg m-3), wet resilience, and an interconnected porous structure (99% porosity), with a pH controllable surface charge for adsorption of both cationic (methylene blue and Pb(II)) and anionic (brilliant blue, congo red, and Cr(VI)) model contaminants. The Langmuir saturation adsorption capacity of the aerogel was calculated to be 68, 79, and 42 mg g-1 for brilliant blue, Pb(II), and Cr(VI), respectively. Adsorption kinetic studies for the adsorption of brilliant blue as a model contaminant demonstrated that a pseudo-second-order model best fitted the experimental data and that an intraparticle diffusion model suggests that there are three adsorption stages in the adsorption of brilliant blue on the aerogel. Following three cycles of adsorption and regeneration, the aerogels maintained nearly 97 and 96% of their adsorption capacity for methylene blue and Pb(II) as cationic contaminants and 89 and 80% for brilliant blue and Cr(VI) as anionic contaminants. Moreover, the aerogels showed remarkable selectivity for Pb(II) in the presence of calcium and magnesium as background ions, with a selectivity coefficient more than 2 orders of magnitude higher than calcium and magnesium. Overall, the energy-efficient and sustainable fabrication procedure, along with good structural stability, reusability, and selectivity, makes these aerogels very promising for water purification applications.


Male genital trauma.
We have attempted to discuss genital trauma in relatively broad terms. In most cases, patients present with relatively minimal trauma. However, because of the complexity of the structures involved, minimal trauma can lead to significant disability later on. The process of erection requires correct functioning of the arterial, neurologic, and venous systems coupled with intact erectile bodies. The penis is composed of structures that are compliant and distensible to the limits of their compliance. These structures therefore tumesce in equal proportion to each other, allowing for straight erection. Relatively minimal trauma can upset this balance of elasticity, leading to disabling chordee. Likewise, relatively minimal injuries to the vascular erectile structures can lead to significantly disabling spongiofibrosis. The urethra is a conduit of paramount importance. Whereas the development of stricture is generally related to the nature of the trauma, the extent of stricture and of attendant complications is clearly a function of the immediate management. Overzealous debridement can greatly complicate subsequent reconstruction. A delicate balance between aggressive initial management and maximal preservation of viable structures must be achieved.


EIciRNA-mediated gene expression: tunability and bimodality.
Biological experiments have verified that EIciRNAs (a class of circRNA) produced from pre-mRNA can regulate gene expression, but the effect of regulation remains unexplored. Here, we refine a mechanistic gene model from experimental facts, in which we assume pre-mRNA synthesizes EIciRNAs and mRNAs in a probabilistic manner, with the probability called the pathway strength, and the resulting EIciRNAs positively regulate the pre-mRNA synthesis. We show that there is a critical pathway strength such that the mRNA mean and the mRNA noise reach the highest and lowest levels, respectively. The EIciRNA can induce the unimodal and bimodal mRNA expressions, as well as the transition between them. Our investigation hints that EIciRNA is a non-negligible factor affecting cell-to-cell variability in gene expression.


Advanced surface characterization of silver nanocluster segregation in Ag-TiCN bioactive coatings by RBS, GDOES, and ARXPS.
Surface modification by means of wear protective and antibacterial coatings represents, nowadays, a crucial challenge in the biomaterials field in order to enhance the lifetime of bio-devices. It is possible to tailor the properties of the material by using an appropriate combination of high wear resistance (e.g., nitride or carbide coatings) and biocide agents (e.g., noble metals as silver) to fulfill its final application. This behavior is controlled at last by the outmost surface of the coating. Therefore, the analytical characterization of these new materials requires high-resolution analytical techniques able to provide information about surface and depth composition down to the nanometric level. Among these techniques are Rutherford backscattering spectrometry (RBS), glow discharge optical emission spectroscopy (GDOES), and angle resolved X-ray photoelectron spectroscopy (ARXPS). In this work, we present a comparative RBS-GDOES-ARXPS study of the surface characterization of Ag-TiCN coatings with Ag/Ti atomic ratios varying from 0 to 1.49, deposited at room temperature and 200 °C. RBS analysis allowed a precise quantification of the silver content along the coating with a non-uniform Ag depth distribution for the samples with higher Ag content. GDOES surface profiling revealed that the samples with higher Ag content as well as the samples deposited at 200 °C showed an ultrathin (1-10 nm) Ag-rich layer on the coating surface followed by a silver depletion zone (20-30 nm), being the thickness of both layers enhanced with Ag content and deposition temperature. ARXPS analysis confirmed these observations after applying general algorithm involving regularization in addition to singular value decomposition techniques to obtain the concentration depth profiles. Finally, ARXPS measurements were used to provide further information on the surface morphology of the samples obtaining an excellent agreement with SEM observations when a growth model of silver islands with a height d = 1.5 nm and coverage θ = 0.20 was applied to the sample with Ag/Ti = 1.49 and deposited at room temperature.


Preparation of quantum information encoded on three-photon decoherence-free states via cross-Kerr nonlinearities.
We present a scheme to encode quantum information (single logical qubit information) into three-photon decoherence-free states, which can conserve quantum information from collective decoherence, via nonlinearly optical gates (using cross-Kerr nonlinearities: XKNLs) and linearly optical devices. For the preparation of the decoherence-free state, the nonlinearly optical gates (multi-photon gates) consist of weak XKNLs, quantum bus (qubus) beams, and photon-number-resolving (PNR) measurement. Then, by using a linearly optical device, quantum information can be encoded on three-photon decoherence-free state prepared. Subsequently, by our analysis, we show that the nonlinearly optical gates using XKNLs, qubus beams, and PNR measurement are robust against the decoherence effect (photon loss and dephasing) in optical fibers. Consequently, our scheme can be experimentally implemented to efficiently generate three-photon decoherence-free state encoded quantum information, in practice.


Association analysis of methionine synthase gene 2756 A>G polymorphism and Alzheimer disease in a Chinese population.
Homocysteine has been identified to be associated with Alzheimer disease (AD) and methionine synthase (MS) is one of the enzymes involved in homocysteine metabolism. Confused data were reported on the association between the MS 2756 A>G polymorphism and AD. To determine if this polymorphism could affect the occurrence of AD, we investigated the association between the MS 2756 A>G polymorphism and AD risk in 353 sporadic AD patients and 346 controls in a Chinese Han population. No significant differences of allele and genotype distributions between the AD cases and the controls were observed in the total samples, neither when the samples were stratified by age/age at onset and gender. When the samples were stratified by APOE epsilon4 status, a trend of A allele and AA genotype over-representation in the AD patients in comparison with the controls was observed, but it was not statistically significant (for the alleles, A versus G OR=1.549, 95% CI 0.920-2.609, p=0.098; for the genotypes, AA versus AG+GG OR=1.485, 95% CI 0.861-2.560, p=0.153). Similar trend was observed in the APOE epsilon4 non-carrier samples of the >or=65 year subgroups and it was not statistically significant too (for the alleles, A versus G OR=1.682, 95% CI 0.901-3.140, p=0.099, for the genotypes, AA versus AG+GG OR=1.690, 95% CI 0.884-3.232, p=0.110). Our data did not reveal significant association between the MS 2756 A>G polymorphism and AD development. However, a weak effect of the A allele on developing AD could not be completely excluded.


A new antitumor compound from the plant Oryctanthus sp. as a VEGF receptor binding inhibitor.
The 70% aqueous methanolic extract of the Peruvian plant Oryctanthus sp. was found to contain a novel saccharide of a diene alpha,omega-diacid. Compound 1 was identified as an inhibitor of the VEGF receptor. The structure of this compound was established based on NMR studies. Compound 1 inhibited ligand binding to the VEGF receptor with an IC50 of 5.0 microM.


Effects of nutrition supplementation and physical exercise on muscle mass, muscle strength and fat mass among sarcopenic elderly: a randomized controlled trial.
This study aimed to determine the impact of nutrition supplementation (whey protein, fish oil, vitamin D) and physical exercise (resistance and aerobic exercise) on muscle mass, muscle strength and fat mass among sarcopenic elderly. Participants (N = 241) with sarcopenia (aged ≥ 60 y) enrolled from 2 centers were randomized into groups undergoing nutrition supplementation (Nutr), physical exercise (Ex), nutrition combined with exercise (Nutr+Ex), or routine consultation for 12 weeks. Muscle-related indicators, grip strength as well as fat-related indicators were compared pre- and post-intervention. The per-protocol analysis showed that all indicators were significantly different between groups (P < 0.001). Further pairwise comparisons showed that compared with controls, appendicular muscle mass and grip strength were significantly higher in Nutr (P < 0.001, 95% CI: 0.578, 1.475; P < 0.001, 95% CI: 3.614∼9.118), Ex (P = 0.010, 95% CI: 0.157, 1.153; P < 0.001, 95% CI: 2.904, 8.732), and Nutr+Ex (P < 0.001, 95% CI: 0.564, 1.471; P < 0.001, 95% CI: 3.441, 8.907) groups, while fat mass was significantly lower in the Nutr (P < 0.001, 95% CI: -4.676, -2.358) and Nutr+Ex (P < 0.001, 95% CI: -4.717,-1.790) groups. When compared with Ex, fat mass decreased significantly in the Nutr (P = 0.001, 95% CI: -4.856,-1.359) and Nutr+Ex (P = 0.005, 95% CI: -4.810, -0.878) groups. The findings indicate that nutrition supplementation and physical exercise could improve muscle mass, strength and fat mass among sarcopenic elderly. Nutrition supplementation might be better at decreasing fat mass in this population. ClinicalTrials.gov registration no.: NCT02873676. Novelty: Nutrition supplementation improved muscle mass, strength and fat mass among sarcopenic elderly. Aerobic and resistance exercise improved muscle mass and strength in sarcopenic elderly. Combined nutrition supplementation and physical exercise improved muscle mass, strength and fat mass among sarcopenic elderly.


Reporting of Ethical Considerations Associated with Clinical Trials Published in Iranian Dental Journals between 2001 and 2011.
Ethical consideration is a basic requirement for design of randomized clinical trials. The purpose of this study was to assess whether reports of Iranian dental clinical trials complied with the requirements of the ethical principles of human research. In this retrospective observational study electronic search was performed to identify all dental clinical trials published between 2001 and 2011. Each trial report was assessed for inclusion of a statement that 17 items about research ethics. Totally 242 papers were identified, of which 15.3%, stated that ethical approval had been obtained and 50.4% of the trial reports indicated that informed consent had been obtained. The mean ethical score for the mentioned studies was 7/68 out of 17. Most Iranian dental clinical trial reports failed to consider important ethical principles. The reporting of the ethical issues associated with these trials could be improved further not only by the instructions to authors, but also by Journal editors refusing to publish trials that do not comply.


Melanotic neuroectodermal tumor of infancy with highly differentiated neural component. Light and electron microscopic study.
A pigmented tumor was removed from the maxillar alveolar process of a 5-month-old boy. It was examined by light and electron microscopy and a diagnosis of melanotic neuroectodermal tumor was made. In addition to connective tissue, three main cell types were identified: undifferentiated (stem) cells, melanocytes, and nerve cells with processes forming an abundant neuropil. Numerous axo-dendritic and occasional axo-somatic synapses were observed. The neural component demonstrated better differentiation in this example than in any reported so far.


Molecular polymorphism and expression analysis of MHC class II B gene from red sea bream (Chrysophrys major).
MHC class II (major histocompatibility complex class II) plays an important role in the immune response of vertebrates. Its function is to present antigenic peptides to the T-cell receptor. In order to study the function and molecular polymorphism of class II B gene in fish, we have isolated cDNAs encoding class II B from spleen cDNA library of red sea bream (Chrysophrys major) by using EST sequencing, and examined genomic organization, molecular polymorphism and expression of red sea bream class II B gene. As in other vertebrates, five exons and four introns were identified in red sea bream class II B gene. Seven class II B alleles were identified from seven individuals of red sea bream. The deduced amino acid sequence of red sea bream MHC class II B 1(Chma-DAB*0101) had 87.1, 85.1, 87.1, 90.4, 87.1, 90.8% identity with those of red sea bream class II B 2, 3, 4, 5, 6, 7(Chma-DAB*0201-Chma-DAB*0701), respectively, and had 75.2, 74.5, 55.9, 55.1, 34.3 and 30.4% identity with those of striped sea bass, cichlid, rainbow trout, Atlantic salmon, mouse and human, respectively. Four different class II B alleles were observed in a single individual and two different 3' untranslated region (3' UTR) sequences from this individual may infer the existence of two loci at least. Semi-quantitative RT-PCR demonstrated that high expression was detected in liver, head kidney, kidney, intestine, gill, stomach, hear and spleen, low expression in muscle and blood. Challenge of red sea bream with the pathogenic bacteria, Vibrio anguillarum, resulted in a significant decrease in the expression of MHC class II B mRNA from 5 to 72 h after infection in liver, spleen, head kidney and intestine, followed by a recovery to normal level after 96 h.


Risk of Incident Venous Thromboembolism Among Patients With Bullous Pemphigoid or Pemphigus Vulgaris: A Nationwide Cohort Study With Meta-Analysis.
Background Bullous pemphigoid (BP) and pemphigus vulgaris (PV) share similar pathophysiology with venous thromboembolism (VTE) involving platelet activation, immune dysregulation, and systemic inflammation. Nevertheless, their associations have not been well established. Methods and Results To examine the risk of incident VTE among patients with BP or PV, we performed a nationwide cohort study using Taiwan's National Health Insurance Research Database and enrolled 12 162 adults with BP or PV and 12 162 controls. A Cox regression model considering stabilized inverse probability weighting was used to calculate the hazard ratios (HRs) for incident VTE associated with BP or PV. To consolidate the findings, a meta-analysis that incorporated results from the present cohort study with previous literature was also conducted. Compared with controls, patients with BP or PV had an increased risk for incident VTE (HR, 1.87 [95% CI, 1.55-2.26]; P<0.001). The incidence of VTE was 6.47 and 2.20 per 1000 person-years in the BP and PV cohorts, respectively. The risk for incident VTE significantly increased among patients with BP (HR, 1.85 [95% CI, 1.52-2.24]; P<0.001) and PV (HR, 1.99 [95% CI, 1.02-3.91]; P=0.04). In the meta-analysis of 8 studies including ours, BP and PV were associated with an increased risk for incident VTE (pooled relative risk, 2.17 [95% CI, 1.82-2.62]; P<0.001). Conclusions BP and PV are associated with an increased risk for VTE. Preventive approaches and cardiovascular evaluation should be considered particularly for patients with BP or PV with concomitant risk factors such as hospitalization or immobilization.


Relative surface charge density mapping with the atomic force microscope.
An experimental approach for producing relative charge density maps of biological surfaces using the atomic force microscope is presented. This approach, called D minus D (D-D) mapping, uses isoforce surfaces collected at different salt concentrations to remove topography and isolate electrostatic contributions to the tip-sample interaction force. This approach is quantitative for surface potentials below 25 mV, and does not require prior knowledge of the cantilever spring constant, tip radius, or tip charge. In addition, D-D mapping does not require tip-sample contact. The performance of D-D mapping is demonstrated on surfaces of constant charge and varying topography (mechanically roughened mica and stacked bilayers of dipalmitolphosphatidylserine), a surface of varying charge and varying topography (patches of dipalmitolphosphatidylcholine on mica), and bacteriorhopsin membranes adsorbed to mica.


Course of localized adenocarcinoma of the prostate treated by radical prostatectomy.
Among 562 patients with histologic stage B-1, B-2, or C adenocarcinoma of the prostate treated by radical prostatectomy and pelvic lymphadenectomy, analysis revealed that increasing histologic stage, tumor size, degree of capsular invasion, seminal vesicle involvement, and histologic grade all were highly correlated with both local and systemic progression (log-rank two-sided P less than or equal to 0.0001). No variable correlated with survival--a result that may reflect appropriate adjuvant therapy given at the time of progression. The death rate from prostatic cancer did appear to rise progressively with increase of stage. Overall, the projected 10-year survival was 76%.


Human reproduction: a comparative background for medical hypotheses.
Successful reconstruction of any aspect of human evolution requires broad-based comparisons with other primates and other eutherian mammals. If quantitative data are involved, the scaling influence of body size must be taken into account, and bivariate allometric analysis is a very useful tool. Broad-based comparisons lead to recognition of general principles that can feed into hypotheses concerning human reproductive medicine. Here, this approach is applied to basic life-history parameters (age at sexual maturity, gestation period, litter size, lactation period, interbirth interval, maximum lifespan), testicular dimensions and male mating strategies, female ovarian processes and mating cycles, placentation and embryonic/fetal development, gestation periods and neonatal condition, and brain development in relation to reproduction. Comparisons reveal that some features claimed to be unique to human beings in fact occur more widely in primates, such as 'loss of oestrus', which probably evolved in the common ancestor of higher primates (monkeys, apes and humans). Although humans show an extreme condition, in most higher primates mating is not strictly confined to the periovulatory period. Because this condition introduces the danger of fertilization with ageing gametes, it must have been favoured by strong selection and accompanied by the evolution of compensatory mechanisms. Overall, it seems likely that the high incidence of pre-eclampsia in human pregnancies is attributable to a partial failure of compensatory mechanisms associated with highly invasive placentation.


Eccentric exercise 24 h prior to hypobaric decompression increases decompression strain.
Animal studies have shown that recent musculoskeletal injuries increase the risk of decompression sickness (DCS). However, to date no similar experimental study has been performed in humans. The aim was to investigate if exercise-induced muscle damage (EIMD)-as provoked by eccentric work and characterized by reduced strength and delayed-onset muscle soreness (DOMS)-leads to increased formation of venous gas emboli (VGE) during subsequent hypobaric exposure. Each subject (n = 13) was on two occasions exposed to a simulated altitude of 24,000 ft for 90 min, whilst breathing oxygen. Twenty-four hours prior to one of the altitude exposures, each subject performed 15 min of eccentric arm-crank exercise. Markers of EIMD were reduction in isometric m. biceps brachii strength and DOMS as assessed on the Borg CR10 pain scale. The presence of VGE was measured in the right cardiac ventricle using ultrasound, with measurements performed at rest and after three leg kicks and three arm flexions. The degree of VGE was evaluated using the six-graded Eftedal-Brubakk scale and the Kisman integrated severity score (KISS). Eccentric exercise induced DOMS (median 6.5), reduced the biceps brachii strength (from 230 ± 62 N to 151 ± 8.8 N) and increased the mean KISS at 24,000 ft, both at rest (from 1.2 ± 2.3 to 6.9 ± 9.2, p = 0.01) and after arm flexions (from 3.8 ± 6.2 to 15.5 ± 17.3, p = 0.029). EIMD, induced by eccentric work, provokes release of VGE in response to acute decompression.


[Central hemodynamic indices of patients with chronic kidney failure treated by hemodialysis].
Examination of the central hemodynamics in patients with chronic renal failure and of symptomatic arterial hypertension revealed two hemodynamic variants of hypertension, namely, that corrected by dialysis arterial hypertension is based on an increase of the cardiac output associated with decrease of the peripheral resistance in the course of treatment and that noncorrectable by dialysis hypertension characterized by a stably high resistance of the arteriolar bed associated with an increased minute blood volume. It was also established that working overloading by resistance and volume results in essential disorders of the intracardiac hemodynamics.


In Vitro and In Vivo Modeling of Spinal and Bulbar Muscular Atrophy.
Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease characterized by late-onset, progressive degeneration of lower motor neurons and skeletal muscle atrophy. SBMA is caused by expansions of a CAG trinucleotide repeat in the gene encoding the androgen receptor (AR). One striking feature of SBMA is sex specificity: SBMA fully manifests only in males, whereas females show subclinical or mild disease manifestations even when homozygous for the mutation. Since the identification of the mutation responsible for SBMA in 1991, several cell and animal models have been developed to recapitulate the main features of disease in vitro and in vivo. In this review, we describe the most widely used cellular and animal models of SBMA, highlighting advantages and disadvantages in the use of these models to gain mechanistic and therapeutic insights into SBMA.


[Semen analysis in involuntary childlessness. What information does it provide?].
Involuntary childlessness is a common problem. In about 50% of cases, inadequate semen quality plays a relevant role. A semen analysis provides information regarding exocrine function of the male reproductive organs of the testes, epidydimis, seminal vesicles, prostate gland, and vas deferens. These parameters can only be interpreted in conjunction with medical history and physical examination. Then they can be useful to identify relevant disorders or the causes of these disturbances. The fundamental principles for the interpretation of a semen analysis are easily learned and traditionally belong to the field of dermatology. This article explains the variables which are examined in a routine semen analysis as well as the reference values. Furthermore, common causes for deviations from the normal values are discussed to allow decision-making for further diagnostic workup. The interpretation of these values must always take into account the situation of the couple.