Interleukin-1beta expression in human gastric carcinoma with Epstein-Barr virus infection.
The KT tumor is a transplantable strain of a human Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), established in severe combined immunodeficiency (SCID) mice, with which the cytokine expression of EBVaGC can be investigated without interference from the infiltrating lymphocytes. As a part of a high-density oligonucleotide array (GeneChip) analysis of EBVaGC, the interleukin-1beta (IL-1beta) gene was the only cytokine gene that showed markedly higher expression in the KT tumor cells than in two tumor strains of EBV-negative GC. The results were confirmed by Northern blotting, Western blotting, and enzyme-linked immunosorbent assay. Furthermore, we demonstrated a positive signal for IL-1beta mRNA in the carcinoma cells of a surgically resected EBVaGC, but not in EBV-negative GC, by in situ hybridization. In vitro, IL-1beta increased the cell growth of a GC cell line, TMK1. Thus, IL-1beta may act as an autocrine growth factor in EBVaGC.


Balloon valvuloplasty for mild mitral stenosis.
Of a total number of 288 patients with mitral stenosis treated by percutaneous balloon valvuloplasty, 21 patients had a basal mitral area equal to or greater than 1.5 cm2, as measured hemodynamically. The immediate hemodynamic results of this particular group of patients with mild mitral stenosis are described, as well as the clinical and echo doppler findings at follow-up (22 +/- 12 mo). Patients with mild mitral stenosis (group I) had more pliable valves (p less than 0.01), as assessed by echo, and higher incidence of sinus rhythm (p less than 0.02) than that observed in the remaining 267 patients (group II). After valvuloplasty the valve area increased in group I from 1.7 +/- 0.2 to 3.1 +/- 0.7 cm2 (p less than 0.0001). This mean final area was significantly different (p less than 0.0001) than that observed in group II (1.98 +/- 0.6 cm2). No patients with mild mitral stenosis developed progression of mitral regurgitation, and none had any other major complications. Most of them reached a grade I final functional status. At echo doppler follow-up studies we did not observe significant changes in the mean mitral gradient as compared with the immediate hemodynamic results. These findings suggest that early mitral balloon valvuloplasty could be an alternative in trying to favorably influence the natural course of the rheumatic mitral disease in selected patients.


Phosphorylation of the D1 photosystem II reaction center protein is controlled by an endogenous circadian rhythm.
The light dependence of D1 phosphorylation is unique to higher plants, being constitutive in cyanobacteria and algae. In a photoautotrophic higher plant, Spirodela oligorrhiza, grown in greenhouse conditions under natural diurnal cycles of solar irradiation, the ratio of phosphorylated versus total D1 protein (D1-P index: [D1-P]/[D1] + [D1-P]) of photosystem II is shown to undergo reproducible diurnal oscillation. These oscillations were clearly out of phase with the period of maximum in light intensity. The timing of the D1-P index maximum was not affected by changes in temperature, the amount of D1 kinase activity present in the thylakoid membranes, the rate of D1 protein synthesis, or photoinhibition. However, when the dark period in a normal diurnal cycle was cut short artificially by transferring plants to continuous light conditions, the D1-P index timing shifted and reached a maximum within 4 to 5 h of light illumination. The resultant diurnal oscillation persisted for at least two cycles in continuous light, suggesting that the rhythm is endogenous (circadian) and is entrained by an external signal.


[Cerebrospinal fluid rhinorrhea and Streptococcus equisimilis-related meningitis 16 years after a head injury].
A case of meningitis caused by Streptococcus Equisimilis and cerebrospinal fluid rhinorrhea, in which the head trauma occurred 16 years before, is presented. To the best of the author's knowledge this is the first case reported with such characteristics. Several precipitating factors could be responsible for the unusually late reopening of the fistula Streptococci equisimilis is an uncommon cause of the bacteremia. An appropriate antimicrobrial therapy against S. Equisimilis followed by surgical dural repair were performed.


Study of fluid dynamics at the boundary wall of a microchannel by Bloch surface waves.
Understanding how a fluid flows at the boundaries when it is confined at the microscale/nanoscale is crucial for a broad range of engineering and biology applications. We propose an experimental technique based on Bloch surface waves sustained by a one-dimensional photonic crystal to evaluate the speed of the contact line, i.e., the triple junction separating three phases, in the low Reynold's number regime, and with a nanometric resolution. Here, we report on the experimental characterization of the translatory motion of the contact line that separates two water solutions with a relatively high refractive index mismatch (7.35×10-3) and its slipping over a solid surface. The advantages are the relative simplicity and economy of the experimental configuration.


Learning Lessons from COVID-19 Requires Recognizing Moral Failures.
The most powerful lesson learned from the 2013-2016 outbreak of Ebola in West Africa was that we do not learn our lessons. A common sentiment at the time was that Ebola served as a "wake-up call"-an alarm which signalled that an outbreak of that magnitude should never have occurred and that we are ill-prepared globally to prevent and respond to them when they do. Pledges were made that we must learn from the outbreak before we were faced with another. Nearly five years later the world is in the grips of a pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). It is therefore of no surprise that we are now yet again hearing that the COVID-19 pandemic serves as the "wake-up call" we need and that there are many lessons to be learned to better prepare us for future outbreaks. Will anything be different this time around? We argue that nothing will fundamentally change unless we truly understand and appreciate the nature of the lessons we should learn from these outbreaks. Our past failures must be understood as moral failures that offer moral lessons. Unless we appreciate that we have a defect in our collective moral attitude toward remediating the conditions that precipitate the emergence of outbreaks, we will never truly learn.


The Griffith area palliative care service: a pilot project.
In September 2000 the Commonwealth released, as part of its National Palliative Care Strategy under the Australian Health Care Agreements, a National Framework for Palliative Care Service Development. The new National Framework stressed an important set of values to guide models of palliative care delivery. It notes that the challenge is to secure the place of palliative care as an integral part of health care across Australia, routinely available within local communities to those people who need it. Care and support for people who are dying and their families need to be built not only into health care services, but also into the fabric of communities and their support networks. While few would disagree with this, little is known about how best to achieve it in rural Australia. The Griffith Area Palliative Care Service (GAPS) is a two-year pilot project delivering a palliative care service through a truly integrated approach to care for patients, their carers and families within the Griffith Local Government Area and Carrathool Shire areas. This paper describes how GAPS is successfully meeting the challenges of service provision to rural and remote areas.


Comparison of methods for generation of absolute reflectance-factor values for bidirectional reflectance-distribution function studies.
Currently, spectrophotometric standard reference materials are calibrated only by using the illumination and viewing geometries recommended by the Commission Internationale de l'Eclairage, and for some geometries the spectral range is limited to the visible wavelengths. A need exists for procedures that calibrate standards at many other geometries and for a broader spectral range. Two methods for calibrating the spectral bidirectional reflectance factor are described. The absolute bidirectional reflectance factor of a sintered polytetrafluoroethylene (PTFE) sample is determined for nearly all the possible illumination and viewing geometries from 400 nm to 2500 nm. The references are a 45/0 reflectance standard calibrated by the National Institute of Standards and Technology and a sintered PTFE sample with a directional, hemispherical reflectance factor traceable to the Institute. The results of the two methods agree to within 0.01 in reflectance factor values. With this PTFE sample as a transfer standard, the instrument described can also be used to measure the absolute bidirectional reflectance factor at nearly all the illumination and viewing geometries from 400 nm to 2500 nm.


Alopecia Neoplastica due to Gastric Adenocarcinoma Metastasis to the Scalp, Presenting as Alopecia: A Case Report and Literature Review.
Alopecia neoplastica is defined as hair loss secondary to a visceral malignancy that has metastasized to the scalp. The scalp is a relatively common site of cutaneous metastasis, usually presenting as a single or multiple firm scalp nodules. Alopecia neoplastica is a well-recognized but rare presentation, and its pathogenesis is incompletely understood. Atrophy of the hair follicles due to tumor invasion of the scalp plays a role in the development of alopecia. Herein, we describe a 33-year-old woman with gastric adenocarcinoma who developed alopecia neoplastica while receiving cancer chemotherapy. Scalp biopsy revealed metastatic adenocarcinoma cells interspersed between collagen bundles and around hair follicles. Immunohistochemical analysis indicated that the tumor cells originated from the primary gastric adenocarcinoma. Therefore, she was diagnosed with alopecia neoplastica due to gastric adenocarcinoma. The findings from this report may be helpful for understanding the mechanism of alopecia neoplastica.


Hsp70 May Be a Molecular Regulator of Schistosome Host Invasion.
Schistosomiasis is a debilitating disease that affects over 240 million people worldwide and is considered the most important neglected tropical disease following malaria. Free-swimming freshwater cercariae, one of the six morphologically distinct schistosome life stages, infect humans by directly penetrating through the skin. Cercariae identify and seek the host by sensing chemicals released from human skin. When they reach the host, they burrow into the skin with the help of proteases and other contents released from their acetabular glands and transform into schistosomula, the subsequent larval worm stage upon skin infection. Relative to host invasion, studies have primarily focused on the nature of the acetabular gland secretions, immune response of the host upon exposure to cercariae, and cercaria-schistosomulum transformation methods. However, the molecular signaling pathways involved from host-seeking through the decision to penetrate skin are not well understood. We recently observed that heat shock factor 1 (Hsf1) is localized to the acetabular glands of infectious schistosome cercariae, prompting us to investigate a potential role for heat shock proteins (HSPs) in cercarial invasion. In this study, we report that cercarial invasion behavior, similar to the behavior of cercariae exposed to human skin lipid, is regulated through an Hsp70-dependent process, which we show by using chemical agents that target Hsp70. The observation that biologically active protein activity modulators can elicit a direct and clear behavioral change in parasitic schistosome larvae is itself interesting and has not been previously observed. This finding suggests a novel role for Hsp70 to act as a switch in the cercaria-schistosomulum transformation, and it allows us to begin elucidating the pathways associated with cercarial host invasion. In addition, because the Hsp70 protein and its structure/function is highly conserved, the model that Hsp70 acts as a behavior transitional switch could be relevant to other parasites that also undergo an invasion process and can apply more broadly to other organisms during morphological transitions. Finally, it points to a new function for HSPs in parasite/host interactions.


Hepatoid carcinoma of the ovary: a case report.
A case of a right ovarian tumor in a 64-year-old patient showing high blood levels of alpha-fetoprotein (AFP) is reported. Histologically, the tumor resembled hepatocellular carcinoma with hyaline globules. Localization of AFP was detected by the immunoperoxidase method. Electron microscopically, the rough-surfaced endoplasmic reticulum had developed into a meshwork, and the mitochondria were present within this meshwork. Because a transition from adenocarcinoma to a region resembling hepatocellular carcinoma was observed, this tumor was considered to originate as a common epithelial carcinoma. In the blood, 67% of the AFP was bound with concanavalin A (Con A), and the fraction pattern obtained by lentil agglutinin affinity chromatography (LCA) was of the germ cell type. From these results, the current case may be labeled clinicopathologically a hepatoid carcinoma of the ovary as described by Ishikura and Scully.


The ethnic composition of migration in the former Soviet Union.
"This paper examines the impact of the disintegration of the Soviet Union on migration patterns within the newly independent states. Data on migration between Russia and the other 14 former Soviet republics are analyzed to reveal the magnitude and ethnic composition of migration after independence and to examine the assumption that Russians will tend to return to Russia, whereas members of other titular groups will emigrate to their respective newly independent states. The data suggest that nationalization not only pushes non-titular groups to emigrate from the former Soviet republics, but also pulls titular groups to immigrate to the newly independent states from Russia."


Changes in psychological well-being in female patients with clinically diagnosed depression: an exploratory approach in a therapeutic setting.
The objective of this exploratory one-group pretest-posttest study was to evaluate the nature of psychological change in inward depressed psychiatric patients attending multi-disciplinary treatment, including physical activity, designed to improve mental well-being. Female depressed psychiatric patients (n = 51) were examined before and after this programme over a period of 3 months. The following psychological parameters were assessed: depression, anxiety, global self-esteem, and physical self-perceptions. Depressed patients demonstrated statistically significant improvements in depression, anxiety, global self-esteem and physical self-worth (t(50) ranging from -3.76 to 4.65, all p < 0.007; ES ranging from 0.53 to -0.65). Changes in depression and anxiety displayed a strong negative correlation with changes in global self-esteem, and those changes are independent of the initial severity of the depressive symptoms ( F(2,48) ranging from 0.03 to 0.70, n.s.). Patients with greater improvement in physical self-perceptions reported greater improvement anxious symptoms then patients who did not improve. Consequently, within the limitations of the research design it can be concluded that the programme appeared successful in improving psychological well-being in female depressed patients. Results also provide preliminary insight into the potential role of the physical self in recovery.


Bcl-XL protects cancer cells from p53-mediated apoptosis.
Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53.


Polymorphism of cyclic 3',5'-adenosine monophosphate stimulation in rat erythrocytes.
Significant differences were found in the cyclic 3',5'-adenosine monophosphate (cAMP) levels in (-)-isoproterenol-stimulated rat erythrocytes. The BN strain had the highest level (13.1 +/- 1.29 pmol cAMP/10 mg Hb) and the LEW strain had the lowest cAMP level (3.29 +/- 1.76 pmol cAMP/10 mg Hb) in the erythrocytes. The high levels were inherited in three intercrosses in a dominant fashion. The results of the backcross breeding suggested diallelic inheritance. However, the polygenic effect was not ruled out.


Adaptive NN Tracking Control for Uncertain MIMO Nonlinear System With Time-Varying State Constraints and Disturbances.
In this article, an adaptive neural network (NN) tracking control scheme is proposed for uncertain multi-input-multi-output (MIMO) nonlinear system in strict-feedback form subject to system uncertainties, time-varying state constraints, and bounded disturbances. The radial basis function NNs (RBFNNs) are adopted to approximate the system uncertainties. By constructing the intermediate variables, the external disturbances that cannot be directly measured are approximated by the disturbance observers. The time-varying barrier Lyapunov function (TVBLF) is constructed to guarantee the boundedness of the errors lie in the sets. To overcome the potential singularity problem that the denominator of the barrier function term approaches zero in controller design, the adaptive NN tracking control scheme with time-varying state constraints is proposed. Based on the TVBLF, the controller will be designed to guarantee tracking performance without violating the appropriate error constraints. The analysis of TVBLF shows that all closed-loop signals remain semiglobally uniformly ultimately bounded (SGUUB). The simulation results are performed to validate the validity of the proposed scheme.


Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides.
Antisense oligodeoxynucleotides specific for sequences in mRNAs from the B-cell lymphoma/leukemia-2 (BCL2) gene were used to inhibit the growth in culture of a human leukemia cell line, 697. Normal phosphodiester (PO) and nuclease-resistant phosphorothioate (PS) oligodeoxynucleotides were compared with regard to specificity, potency, and kinetics. Both PO and PS antisense BCL2 oligodeoxynucleotides were specific inhibitors of cellular proliferation, since sense versions of these synthetic DNAs were inactive at similar concentrations. Specificity was further confirmed by quantitative immunofluorescence studies, showing that PO and PS antisense BCL2 oligodeoxynucleotides (when used at appropriate concentrations) reduced levels of BCL2 protein without influencing expression of HLA-DR and other control antigens. The onset of inhibition by PO oligodeoxynucleotides was faster, with reductions in cell numbers occurring within 1 day of addition to cultures, in contrast to phosphorothioates, which were ineffective until 3-4 days. Phosphorothioates were more potent that phosphodiesters, however, with half-maximal inhibition of leukemic cell growth occurring at concentrations 5-10 times lower. As expected from previous studies demonstrating the importance of BCL2 for regulating lymphoid cell survival, BCL2 antisense oligodeoxynucleotides also led to 697 leukemic cell death through sequence-specific mechanisms, with reductions in cellular viability generally lagging the inhibitory effects on cellular growth by about 2 days. Taken together, these data indicate that PO and PS oligodeoxynucleotides targeted against the human BCL2 protooncogene can be sequence-specific inhibitors of leukemic cell growth and survival.


Composition-Dependent Reaction Pathways and Hydrogen Storage Properties of LiBH₄/Mg(AlH₄)₂ Composites.
Herein, an initial attempt to understand the relationships between hydrogen storage properties, reaction pathways, and material compositions in LiBH4-x Mg(AlH4)2 composites is demonstrated. The hydrogen storage properties and the reaction pathways for hydrogen release from LiBH4-x Mg(AlH4)2 composites with x=1/6, 1/4, and 1/2 were systematically investigated. All of the composites exhibit a four-step dehydrogenation event upon heating, but the pathways for hydrogen desorption/absorption are varied with decreasing LiBH4/Mg(AlH4)2 molar ratios. Thermodynamic and kinetic investigations reveal that different x values lead to different enthalpy changes for the third and fourth dehydrogenation steps and varied apparent activation energies for the first, second, and third dehydrogenation steps. Thermodynamic and kinetic destabilization caused by the presence of Mg(AlH4)2 is likely to be responsible for the different hydrogen desorption/absorption performances of the LiBH4-x Mg(AlH4)2 composites.


Histological approach to Bacillus subtilis colony-biofilm: evolving internal architecture and sporulation dynamics.
Bacillus subtilis has been used as a classic model to study biofilm formation and sporulation process. Colonies of wild-type strains usually have a complex external morphology, but the details of their internal architecture are still undisclosed. Since bacterial biofilms fulfill the criteria to be considered tissues, the aim of this work was to analyse B. subtilis colony-biofilm internal architecture evolution and sporulation dynamics using histological techniques. Transversal sections of colony-biofilms incubated from 24 hours up to 20 days were stained using histochemical techniques to analyse the internal structure by light and electron microscopy. A morphometric study of the different structural biofilm components was performed by image analysis, and an application to quantify spores was developed. Internal biofilm architecture was characterised by a stratified pattern, which evolved from 3 strata at 24 hours, up to 5 strata at 20 days. At 48 hours, strata at the central area of the biofilm was folded, resulting in elevated structures (vein-like structures) that could reach up to 465 μm in height. Sporulation started at 48 hours, at the top of the vein-like structures, at the interface between the two uppermost strata. At 20 days spores formed a continuous central layer, representing 7.5% of the total biofilm. In summary, our results demonstrate that B. subtilis colony-biofilm has a complex and organized internal architecture, evolving over time, and taking place in different cell subpopulations with different functionalities. Furthermore, in situ spore quantification described in this work could be a good alternative to the classical chamber counting.


CCN2 (Cellular Communication Network Factor 2) Deletion Alters Vascular Integrity and Function Predisposing to Aneurysm Formation.
CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood. Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible Ccn2-deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta. Ang II infusion in CCN2-silenced mice lead to 60% mortality within 10 days due to rapid development and rupture of aortic aneurysms, as evidenced by magnetic resonance imaging, echography, and histological examination. Ccn2 deletion decreased systolic blood pressure and caused aortic structural and functional changes, including elastin layer disruption, smooth muscle cell alterations, augmented distensibility, and increased metalloproteinase activity, which were aggravated by Ang II administration. Gene ontology analysis of RNA sequencing data identified aldosterone biosynthesis as one of the most enriched terms in CCN2-deficient aortas. Consistently, treatment with the mineralocorticoid receptor antagonist spironolactone before and during Ang II infusion reduced aneurysm formation and mortality, underscoring the importance of the aldosterone pathway in Ang II-induced aorta pathology. CCN2 is critically involved in the functional and structural homeostasis of the aorta and in maintenance of its integrity under Ang II-induced stress, at least, in part, by disruption of the aldosterone pathway. Thus, this study opens new avenues to future studies in disorders associated to vascular pathologies.


Dairy herd reproductive management programs with or without synchronization of estrus.
Reproductive efficiencies were compared among herds with (treated, n = 25) or without (visited control, n = 25) routine synchronization of estrus and herds without investigator visits (unvisited control, n = 22). Treatment groups were subdivided based on participation in veterinary herd health programs. Reproductive tracts were palpated rectally at 21-d intervals for 6 mo in two sets of treated and visited control herds. Data were collected during the visitation period and from the 6-mo period before visits. In treated herds, cows more than 40 d postpartum with a corpus luteum received prostaglandin F2 alpha. In visited control herds, cows received prostaglandin F2 alpha after 82 d postpartum if they were not observed in estrus. Routine synchronization of estrus did not enhance herd reproductive efficiency compared with no synchronization of estrus in visited herds. Small changes in reproductive efficiency occurred during visits in herds with an established reproductive health program. However, herds not using a health program had 15.2 fewer d from calving to insemination, and the pregnancy rate at 120 d postpartum was 13.0 percentage units higher than before herd visits. Consequently, reproductive performance of those herds during visits was similar to that of contemporaries under a herd health program.


Inherited metastasis susceptibility and the implications for clinical prognosis.
Extract: Metastasis, the spread of cancer throughout the body, remains the leading cause of cancer-related death despite decades of investigation and the efforts of thousands of doctors and scientists. Over the past thirty to forty years tremendous strides have been made in understanding the origins of cancer. Advances in new therapeutic agents and strategies have resulted in improved survival and cure rates in many cancers, particularly pediatric cancers. However, the presentation of a cancer patient with symptomatic metastatic disease continues to be a harbinger of poor outcome, given that secondary tumors are frequently both surgically untreatable and are frequently resistant to currently available anti-tumor drugs. To better battle this proximal cause of cancer mortality, a clearer understanding of the origins and mechanisms of the metastatic process are critical for the design of new clinical interventions. Metastasis is an extraordinarily complex process, and to successfully colonize a secondary site a cancer cell must complete a sequential series of steps before it becomes a clinically detectable tumor. These steps include separation from the primary tumor, invasion through surrounding tissues, entry into and survival in blood or lymph vessels, arresting in a distant site, usually followed by penetration into the surrounding tissue, survival in the distant organ site, proliferation, and creation of new blood vessels, all the while evading the immune response and intrinsic apoptosis mechanisms.


Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets.
The heterogeneous nature of human hepatocellular carcinoma (HCC) has hampered both treatment and prognostic predictions. Gene expression profiles of human HCC were analyzed to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. By applying global gene expression analyses, including unsupervised and supervised methods, 2 distinctive subclasses of HCC that were highly homogeneous for both the underlying biology and the clinical outcome were discovered. Tumors from the low survival subclass had strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and sumoylation, suggesting an etiologic involvement of these processes in accelerating the progression of HCC. Genes most strongly associated with survival were identified by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provided new molecular insights into the pathogenesis of HCC. Future studies will evaluate potential diagnostic markers and therapeutic targets identified during the global gene expression studies. Furthermore, cross-species similarity of gene expression patterns will also allow prioritization of a long list of genes obtained from human gene expression profiling studies and focus on genes whose expression is altered during tumorigenesis in both species.


Sequence analysis of cytoplasmic mRNA-binding proteins of Xenopus oocytes identifies a family of RNA-binding proteins.
Storage of maternal mRNAs as nontranslated ribonucleoprotein (RNP) complexes is an adaptive strategy in various vertebrate and invertebrate oocytes, for rapid translational recruitment during embryonic development. Previously, we showed that Xenopus laevis oocytes have a soluble cytoplasmic pool of mRNA-binding proteins and particles competent for messenger RNP assembly in vitro. Here we report the isolation of cDNAs for the most abundant messenger RNPs, the 54- and 56-kDa polypeptide (p54/p56) components of the approximately 6S mRNA-binding particle, from an ovarian expression library. The nucleotide sequence of p56 cDNA is almost identical to that recently reported for the putative Xenopus transcription factor FRG Y2. p54 and p56 are highly homologous and are smaller than expected by SDS/PAGE (36 kDa and 37 kDa) due to anomalous electrophoretic mobility. They lack the "RNP consensus motif" but contain four arginine-rich "basic/aromatic islands" that are similar to the RNA-binding domain of bacteriophage mRNA antiterminator proteins and of tat protein of human immunodeficiency virus. The basic/aromatic regions and a second conspicuous 100-amino acid "domain C" of p54 and p56 are conserved in the following DNA-binding proteins: human proteins dpbA, dpbB, and YB-1, rat protein EFIA, and Xenopus protein FRG Y1, all reported to bind to DNA; domain C is homologous to the major Escherichia coli cold-stress-response protein reportedly involved in translational control. Antibodies raised against a peptide of domain C have identified similar proteins in Xenopus somatic cells and in some mammalian cells and tissues. We conclude that p54 and p56 define a family of RNA-binding proteins, at least some of which may be involved in translational regulation.


Gamma Loop Dysfunction as a Possible Neurophysiological Mechanism of Arthrogenic Muscle Inhibition: A Narrative Review of the Literature.
Quadriceps activation failure has been observed following various pathological conditions in a knee joint such as knee surgery, pain, effusion in knee, and osteoarthritis also could be aging matter. Those patients are unable to attain maximal quadriceps strength for a long period of time although their quadriceps itself is not damaged. This impairment is termed arthrogenic muscle inhibition (AMI). AMI has been of concern to clinicians because this weakness hinders the rehabilitation process considerably and delays recovery because strengthening protocols for the AMI could be largely ineffective. Clinically, it is important to understand neurophysiological mechanisms of the AMI to treat patients with the impairment. This is a narrative review of the literature. The purpose of this review is to understand the following: (1) Why investigations of only peripheral spinal reflexive pathways are not enough for elucidation of the mechanisms of the AMI? (2) What we know about the role of the gamma spindle system in AMI so far? (3) Could a dysfunctional gamma spindle system contribute to AMI lead neural changes in upper central nervous system? and (4) Concerns that a clinician should take into consideration when deciding whether to apply therapeutic interventions for AMI. The databases PubMed, MEDLINE, SPORTDiscus, and CINAHL were searched with the terms arthrogenic muscle inhibition (AMI), reflex inhibition, joint mechanoreceptor, gamma loop, corticospinal pathway, spinal reflex, effusion, and joint injury. The remaining citations were collected from references of similar papers. AMI is a limiting factor in the rehabilitation of joint injury. Motor unit recruitment could be hindered in patients with AMI as a result of a dysfunctional gamma spindle system. Clinicians should understand the mechanism of AMI well in order to establish effective rehabilitation programs for AMI. Indeed, AMI is not caused by a single factor, but rather, multiple neural factors can change over time following the appearance of AMI. Therefore, multiple interventions targeting different neural pathways should be combined to achieve the ideal therapeutic goal for the treatment of AMI.


[Pompe's disease--acid alpha-glucosidase deficiency--a review].
The importance of the role of acid alpha-glucosidase in the lysosomal degradation of glycogen has been emphasized because the deficiency of this enzyme in glycogenosis type II causes glycogen accumulation in lysosomes. Three clinical variants are distinguished. The infantile type has its onset shortly after birth and is known as generalized glycogen storage disease. The adult variant manifests itself mostly after the second decade of life and is characterized by progressive skeletal muscle weakness. The other is childhood type which is usually fatal by the second decade of life. Many biochemical reports of acid alpha-glucosidase have been published. Martiniuk et al reported the cDNA and amino acid sequence of human acid alpha-glucosidase. In prior studies, they reported that the lysosomal acid alpha-glucosidase was polymorphic with three alleles. The rarer allele GAA2 allozyme had a lower affinity for glycogen and starch. We also reported the enzyme heterogeneity in its affinity to Sephacryl S-200 gel. Whereby the enzyme separated into two fractions, S1 and S2. Each fraction contained 76 kDa and 67 kDa components on SDS/PAGE. The spleen enzyme consisted mainly of S1 fraction, containing only a 76 kDa component. In previous extensive studies, different mutations of Pompe's disease have been inferred from alterations in biochemical parameters. More recently Martiniuk et al, Hoefsloot et al and Van der Ploeg et al reported the analysis of cDNA and mRNA. These studies have revealed an absence or abnormal size of mRNA in large numbers of patients and altered restriction endonuclease fragments in a few patients.(ABSTRACT TRUNCATED AT 250 WORDS)


[Theoretical and conceptual contribution to evaluative research in health surveillance context].
Initially this article revises some of the conceptual and operational elements on evaluative research by gathering knowledge and action fields on public health practices. Such concepts are taken according to a wider conception of quality. Then, the article intends to arrange a theoretical model design considering the proposition for implementation of health surveillance actionsAn image-objective definition of organization and integration of health polices and practices based on hierarchic and local logic also take place. Finally, becomings and challenges around the theory in the health evaluation field turn to be the aim of our reflection in order to enable the production of knowledge and approaches to construct logic models which reveals the complexity of interventionist objects as well as its transforming nature of social practices.


Case report: Directional infusion of peripheral blood stem cells into the necrotic zone in femoral heads through the medial circumflex femoral artery: A tracing study.
This study aimed to explore whether peripheral blood stem cells (PBSCs) infused through the medial circumflex femoral artery to treat osteonecrosis of the femoral head (ONFH) could migrate into the necrotic area of femoral head. We collected PBSCs from a patient who had bilateral ONFH by apheresis technique using COBE spectra apheresis system (COBE BCT Inc, Lakewood, CO, USA) after subcutaneous injections of granulocyte-colony stimulating factor (G-CSF) at a dosage of 10 μg/kg for 4 days to mobilize PBSCs. After that, 100 MBq 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) was used to label PBSCs. 18F-FDG labeled PBSCs were infused into the left femoral head via the medial circumflex femoral artery to treat ONFH. Then the patient was underwent three-dimensional positron emission tomography (3D-PET) examination 60 min after cell infusion to monitor the biological distribution of 18F-FDG-labeled PBSCs, and to observe whether the transplanted PBSCs could migrate into the necrotic area of femoral head. The total number of monouclear cells in the peripheral blood stem cell suspension was 1.95 × 108 which contained 2.20 × 106 CD34+ cells. The activity of 18F-FDG in the labeled cells was 1.8Bq/103 monouclear cells. 3D-PET imaging showed that 18F-FDG radioactivity was detected in the necrotic area of femoral head, acetabulum and femoral bone marrow cavity after transplantation of 18F-FDG-labeled PBSCs via the medial circumflex femoral artery. It is worth noting that although PBSCs labeled with 18F-FDG were widely distributed around the hip, such as femoral bone marrow cavity, femoral head and acetabulum, PBSCs were generally located in the necrotic area of femoral head. PBSCs could enter into the femoral head and migrate into the necrotic field of femoral head participating in the repair of osteonecrosis after infusion through the medial circumflex femoral artery.


Influenza A(H1N1)pdm09 antibodies after pandemic and trivalent seasonal influenza vaccination as well as natural infection in November 2010 in Hamburg, Germany.
The 2009 influenza pandemic has introduced the new re-assorted influenza A(H1N1)pdm09 virus which recirculated during the 2010/11 influenza season. Before that season, it was possible to acquire protective immunity either by pandemic or seasonal influenza vaccination against influenza A(H1N1)pdm09 or by natural infection. To obtain data on vaccination coverage and antibody levels in a reference population and to calculate whether or not the herd immunity threshold (HIT, calculated as 33% given an R0 of 1.5) was reached at the beginning of the 2010/11 season we performed a seroprevalence study in November 2010 in Hamburg, Germany. Antibody titres were assessed applying a haemagglutination inhibition test. Vaccination coverage was very low: 14% for pandemic and 11% for seasonal 2010/11 vaccinations. Even in those with underlying risk factors, vaccination coverage was not much higher: 17% for both vaccines. Serological analysis revealed antibody titres of ≥1:10 in 135 of 352 (38%) and of ≥1:40 in 61 of 352 study participants (17%). Specific antibodies were measurable in 26% of those without history of vaccination or natural infection, indicating a high proportion of subclinical and mild influenza disease. Nevertheless, the HIT was not reached, leaving the majority of the population susceptible to influenza A(H1N1)pdm09 and its potential complications.


Historical Antecedents and Challenges of Racialized Immigrant Women in Access to Healthcare Services in Canada: an Exploratory Review of the Literature.
Examining the historical antecedents of racialized immigrant women are important precursors to understanding the challenges they face in access to quality and timely healthcare in Canada. Changes to immigration policies, structural and systemic racial discrimination perpetuate the feminization of migration in Canada, create structural barriers in labour market integration, increase social exclusion and ultimately create unequal access to healthcare services. Despite their high levels of education, racialized immigrant women in Canada are over-represented in low-paid, low-skill precarious jobs. They also face powerful structural barriers to decent professional employment due to the lack of acceptance of foreign educational and licencing credentials. Ultimately, these challenges negatively impact how they interact with healthcare services. Utilizing an intersectional and socio-ecology framework, this review aims to highlight the historical antecedents of racialized immigrant women in access to healthcare services in Canada and examine the challenges racialized immigrant women face in access to healthcare services in Canada. Findings from this review can be used to open dialogues on possible changes to immigration and social policies in Canada, including changes to labour market practices, and initiatives to address structural and systemic barriers, to enable racialized immigrant women overcome the challenges they face in accessing quality healthcare services in a timely manner.


Comparison of contact radiographed and stained histological sections for osseointegration analysis of dental implants: an in vivo study.
Histology is still regarded as the gold-standard to determine bone implant contact (BIC) as a parameter representing implant stability. As the further processing of cut slices for contact radiography (CR) to stained and polished histological sections is time consuming and error prone, our aim was to assess agreement between CR and Giemsa-eosin (GE) stained sections with regard to dental implants. Threaded dental titanium implants (n = 54) from the maxillae of Goettingen minipigs were evaluated. After 28 and 56 days, BIC and the ratio of bone volume to total volume (BV/TV; 1000 μm) were determined on the same sections by using CR and GE staining, and the results were compared. Moderate differences for BIC (0.6%; P = .53) and BV/TV (1.3%; P = .01) between the methods were determined, in which CR overestimated BIC and BV/TV. A strong correlation was seen between the modalities concerning BIC (28 days: r = 0.84; 56 days: r = 0.85; total: r = 0.85) and BV/TV (r = 0.96; r = 0.94; r = 0.96; all: P < .0001). CR enabled determination of the bone-to-implant interface in comparison with GE-stained sections. BIC and BV/TV were slightly overestimated but correlated strongly between the methods. Therefore, if BIC and BV/TV are sufficient endpoints, CR is adequate and no further preparation and staining are necessary.


Occupational fatalities involving forklifts.
Forklift rollovers account for approximately 18% of all fatalities involving forklifts and many of the more serious injuries in the workplace. Proportionate mortality ratios were calculated by using Occupational Safety and Health Administration fatality inspection records for forklift rollovers that resulted in a fatality by industry. An analysis of variance procedure was performed on the average ages of the victims by industry. The retail trades industry had a significantly higher (p < 0.05) than expected proportion of fatalities attributable to forklift rollovers. The analysis of variance identified significant differences in the average ages of the victims; however, post hoc comparisons did not yield significant differences. The majority of the fatalities in the retail trades industry occurred in the building materials, garden supply, and hardware retail trades. Engineering and administrative prevention measures are discussed.


Derivation of novel human ground state naive pluripotent stem cells.
Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3β signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre-inactivation X chromosome state, and global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters. Upon withdrawal of 2i/LIF, naive mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include predominant use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalent domain acquisition on lineage regulatory genes. The feasibility of establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in mouse ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation of cross-species chimaeric mouse embryos that underwent organogenesis following microinjection of human naive iPS cells into mouse morulas. Collectively, our findings establish new avenues for regenerative medicine, patient-specific iPS cell disease modelling and the study of early human development in vitro and in vivo.


Self-Reported Symptoms and Pesticide Use among Farm Workers in Arusha, Northern Tanzania: A Cross Sectional Study.
The objective of the study was to describe self-reported health symptoms, the use of personal protective gear and clothing and poor safety procedures when applying pesticides among farm workers. A total of 128 adult farm workers were interviewed using a structured questionnaire during the farming season. The commonly used pesticides included profenofos, mancozeb, chlorpyrifos, cypermethrin, deltamethrin, permethrin, lambda-cyhalothrin, endosulfan and carbosulfan. The majority (>90%) of farm workers used no personal protective clothing while handling pesticides. More than one-third of farm workers ate and drank without washing their hands following pesticide handling, while a smaller number smoked or chewed gum. Wearing special boots during pesticide application was found to reduce the risk of skin rash (OR = 0.2, 95% CI: 0.06-0.66), whereas smoking when applying pesticides increased the risk of chest pain occurrence (OR = 4.0, 95% CI: 1.14-15.43), as well as forgetfulness (OR = 4.0, 95% CI: 1.30-14.02). Chewing gum and eating when applying pesticides was associated with diarrhoea (OR = 11.0, 95% CI: 1.80-6.84 and OR = 7.0, 95% CI: 1.27-3.67 respectively). The increased self-reported prevalence of post-exposure adverse health effects among farm workers was associated with poor use of personal protective clothing and poor safety practices during pesticide use and handling. These data indicate the need for improved availability and use of protective equipment, and training in crop and pest management practices to prevent risky behavioursand for safer and sustainable vegetable production.


The Effect of Curcumin on Iron Overload in Patients with Beta-Thalassemia Intermedia.
β-thalassemia is an inherited disorder that stems from a defect in beta-globin chain synthesis. Iron overload toxicity is one of the major clinical complications in β-thalassemia that may be due to a reduction in the hepcidin level. As a result, intestinal iron absorption increases and finally iron overload occurs. The current study aimed to investigate the effect of curcumin on serum iron status, ferritin, and transferrin in patients with β-thalas-semia intermedia. This study was a randomized, controlled, double-blind clinical trial. Before and after the intervention period with curcumin, 5 ml blood was taken for the measurement of the entire index related to iron status. Our results demonstrated the levels of serum iron (p-value < 0.001), ferritin (p-value = 0.002), and transferrin saturation (p-value < 0.001) significantly decreased in the curcumin group compared to placebo. The data presented in this article show that curcumin supplementation would be effective in alleviating iron overload in patients with β-thalassemia intermedia.


Modified arterial switch operation by sharing the common wall between the great arteries.
Suprapulmonary stenosis and coronary arterial obstruction still remain as problems after an arterial switch operation (ASO). We used a modified ASO applying the common wall and in situ transfer techniques to improve the current procedure. From October 1996 to December 1997, 11 babies aged 6 days to 3 months with transposition of the great arteries underwent a modified ASO which included sharing the common wall between the great arteries until above the anterior neoaortic suture-line for coronary and pulmonary artery reconstruction. Coronary arteries were of usual type in three cases, juxtacommissural origin in five, and a high takeoff in one; all were redirected almost in situ. There was no early death (< 30 d), coronary or bleeding problems. One late death occurred after a repeat surgery for suprapulmonary stenosis. This was caused by upward stretching of the left pulmonary artery, which was placed above the high left-sided neoaortic anastomosis for in situ transfer of the high takeoff coronary arteries. Intraluminal growth of the adventitia also contributed to suprapulmonary stenosis, which decreased significantly when the common wall adventitia was cleaned in the last two cases we operated on. Ten patients were doing well at follow-up (30.9 +/- 5.2 mo). This modified ASO by common wall and in situ transfer might avoid coronary kinking and lessen the chance of postoperative bleeding. To avoid suprapulmonary stenosis, common wall adventitia inside the pulmonary pathway should be cleaned, and the left and right pulmonary arteries should also be kept in situ as possible as in coronary redirection.


RFRP-3 synchronized with photoperiods regulates the seasonal reproduction of striped hamsters.
The purpose of this study was to investigate the effect of RFRP-3 synchronized with photoperiods on regulating the seasonal reproduction of striped hamsters. The striped hamsters were raised separately under long-day (LD; 16 h light/8 h dark), medium-day (MD; 12 h light/12 h dark) or short-day (SD; 8 h light/16 h dark) conditions for 8 weeks. RFRP-3 and gonadotropin-releasing hormone (GnRH) mRNA levels in the hypothalamus, testis or ovaries in three groups were detected using reverse transcription polymerase chain reaction (RT-PCR). Melatonin (MLT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations in serum were detected using enzyme-linked immunosorbent assay (ELISA). The correlation between RFRP-3 and GnRH mRNA and FSH and LH concentrations was also analyzed. MLT negatively regulated the expression of RFRP-3. Significant differences for RFRP-3 mRNA existed in the three groups, which positively correlated with the GnRH and the FSH and LH concentrations. RFRP-3 mRNA levels in the hypothalamus were significantly higher than those in ovaries or testis. RFRP-3 levels in the hypothalamus were significantly lower in female than in male under SD conditions, while those in ovaries were significantly higher than those in testes under LD conditions. MLT decreased RFRP neuron activity, and RFRP-3 regulated the reproduction of striped hamsters.


Part Two: The role of constitutional factors, diet, and infectious disease in the etiology of porotic hyperostosis and periosteal reactions in prehistoric infants and children.
Abstract A model of analysis incorporating methodological improvements and epidemiological refinements has been employed to investigate the etiology of porotic hyperostosis and periosteal reactions in infants and children from the Libben Site, a Late Woodland ossuary and occupation site from Ottawa County, Ohio. Results of the age-specific intrapopulational analysis of porotic hyperostosis demonstrate that the skeletal lesion strongly fits the age-specific distribution of hypochromic microcytic iron-deficiency anemia in infants and children. The data indicate that the lesion is a response to nutritional stress. Similarly, our findings show that the age-specific distribution of periosteal reactions strongly coincides with, and appears to be a response to, infectious disease as it occurs in infants and children. More importantly, survivorship and growth data indicate that porotic hyperostosis and periosteal reactions are strongly associated with patterns of infant and child morbidity and mortality, and therefore appear to play an important role in selection and fitness at Libben. Based upon the age-specific patterns and associations observed for porotic hyperostosis and periosteal reactions in the Libben infants and children, it is suggested that: 1. the current methodological procedure of partitioning skeletal populations into broad age categories can significantly distort important age-specific pathophysiological relationships; 2. skeletal lesions should be classified according to their physical quality (i.e., remodeled and unremodeled) to provide an estimate of both the morbidity and mortality associated with the age-specific distribution of a particular skeletal lesion; 3. porotic hyperostosis may be a valuable indicator of nutritional stress which can be employed to evaluate the nutritional status of prehistoric human populations; 4. the pathogenesis of porotic hyperostosis can best be understood in terms of the synergistic interactions between constitutional factors, diet, and infectious disease.


Substantive Morphological Descriptions, Phylogenetic Analysis and Single Nucleotide Polymorphisms of Aspergillus Species From Foeniculum vulgare.
Ascomycetous fungi are found associated with a wide variety of substrates which range from fresh water to marine ecosystems, tropical to temperate forest soils and deserts, throughout the world over. These demystifying fungi exist as endophytes, pathogens and saprobes. They have been studied due to their ability to contaminate foods and feedstuffs, causing an elaboration of mycotoxins. The objectives of the study included extensive analyses of the morphological features of fungi, especially Aspergilli, which have been presented while studying them on specific mycological media. It is also an elaborate compilation of substantive macro- and micro-morphological characterization of different Aspergilli isolated from the spice Foeniculum vulgare used in India and other countries in the world. Further, a first of its kind attempt has been made to study their relative abundance and frequency of occurrence, molecular phylogeny and genetic relatedness to characterize the Aspergilli into specific sections, groups and clades. Single nucleotide polymorphism (SNP) analysis was carried out to evaluate the functional consequences of nucleotide variations, synonymous and non-synonymous mutations in the protein structure. The study resulted in a total of 3,506 Aspergillus isolates, which were obtained from seventy (70) fennel samples, representing 14 Aspergillus species. The two most frequently found species were A. niger and A. flavus with a relative abundance of 32.24 and 11.63%, respectively. The taxonomy and current placements have been reappraised with suggestions and prospects for future research from six sections namely Terrei, Flavi, Fumigati, Nidulantes, Nigri, and Versicolores. In addition, a total number of 27 isolates were studied and deposited at the National Centre for Biotechnology Information (NCBI) and five Aspergillus species have been identified and are being reported for the first time from the fennel seeds, based on partial sequence analysis of the official fungal barcode namely, Internal Transcribed Spacer (ITS) and a functional gene, beta tubulin gene locus, coupled with phenotypic characterization. SNPs for specific DNA regions have been used to identify variants in Aspergilli obtained from Indian fennel seeds for the first time. The need for a polyphasic approach of morphological identification and genetic characterization of Aspergilli from Foeniculum vulgare is addressed and presented here in adequate detail. Our current work makes extensive use of partial beta-tubulin gene sequences analyses to evaluate the association between SNPs in five Aspergillus species sections.


A semi-dominant mutation in the ribosomal protein L10 gene suppresses the dwarf phenotype of the acl5 mutant in Arabidopsis thaliana.
Disruption of the Arabidopsis thaliana ACAULIS5 (ACL5) gene, which has recently been shown to encode thermospermine synthase, results in a severe dwarf phenotype. A previous study showed that sac51-d, a dominant suppressor mutant of acl5-1, has a premature termination codon in an upstream open reading frame (ORF) of SAC51, which encodes a putative transcription factor, and suggested the involvement of upstream ORF-mediated translational control in ACL5-dependent stem elongation. Here we report the identification of a gene responsible for sac52-d, another semi-dominant suppressor mutant of acl5-1. SAC52 encodes ribosomal protein L10 (RPL10A), which is highly conserved among eukaryotes and implicated in translational regulation. Transformation of acl5-1 mutants with a genomic fragment containing the sac52-d allele rescued the dwarf phenotype of acl5-1. GUS reporter activity under the control of a SAC51 promoter with its upstream ORF was higher in acl5-1 sac52-d than in acl5-1, suggesting that suppression of the acl5-1 phenotype by sac52-d is attributable, in part, to enhanced translation of certain transcripts including SAC51. We also found that a T-DNA insertion allele of SAC52/RPL10A causes lethality in the female gametophyte.


Structure and function of E. coli promoter DNA.
The process of transcription initiation requires both the recognition of a promoter site by RNA polymerase and the melting of a short stretch of DNA. In this review I discuss the properties of promoters that are relevant to sequence recognition and to the ability of the polymerase to act as a melting protein. The regulation of promoter activity is thus dependent on both factors interacting with RNA polymerase and so altering its affinity for promoter sites and also modulations of DNA structure.


Tumor-promoting phorbol esters inhibit cardiac functions and induce redistribution of protein kinase C in perfused beating rat heart.
Activation of protein kinase C has been implicated in the regulation of a variety of cellular reactions. Although we, and others, have found protein kinase C and its substrate proteins to be present in both membrane and cytosolic fractions in the heart, the physiologic role of this kinase in the regulation of cardiac functions remains unknown. In the present study, we found that in isolated perfused rat heart, administration of phorbol esters 4 beta-phorbol 12,13-dibutyrate(PDBu) and 12-0-tetradecanoylphorbol 13-acetate(TPA), which are specific activators of protein kinase C, produced marked dose-dependent negative changes in inotropy and chronotropy. A dose-dependent decrease in coronary flow was also observed. The diacylglycerol analogues, 1,2-oleoylacetyl-glycerol and 1,2-dioctanoylglycerol, produced similar effects as the active phorbol esters on these isolated perfused hearts. An inactive analogue of phorbol ester, 4 alpha-phorbol, failed to produce any effect. Protein kinase C activity in both membrane and cytosolic fractions prepared from rat heart could be activated by TPA and PDBu at the same concentration range as used in the experiments with perfused hearts. Following perfusion of the hearts with PDBu, a rapid translocation of protein kinase C from cytosolic to membrane fractions was also observed. Our findings provide the first direct evidence that protein kinase C may play a potentially important role in the regulation of cardiac functions.


Alprazolam effects in children with anxiety disorders.
Children with overanxious and/or avoidant disorder (DSM-III) were treated with alprazolam (Xanax, Upjohn) to determine its safety, clinical and cognitive effects. Ten male and two female patients (age range 8.8 to 16.5 years; mean 11.5) participated in an open clinical trial consisting of a baseline placebo period (1 week), alprazolam therapy (4 weeks), a drug-tapering period (1 week), and a post-drug placebo period (1 week). There was a drug-free follow-up approximately 4 weeks after termination of the study. Dosages were individually adjusted and the daily maximum ranged from 0.50 mg to 1.5 mg. Evaluations included clinical assessments, parent, teacher and self ratings, and cognitive tests. Clinical global improvement with alprazolam therapy was marked in 1 patient, moderate in 6, minimal in 4, and none in 1. Clinician ratings indicated significant improvements of anxiety, depression, and psychomotor excitation. Parent questionnaires indicated significant improvements of anxiety and hyperactivity while teacher questionnaires showed significant improvement of an anxious-passive factor. Significant improvements in the paired associate learning tasks, maze task and the block design tasks were maintained after drug withdrawal suggesting a practice effect. Adverse effects were infrequent, mild and transient. There were no clinically significant changes of laboratory values, blood pressure, pulse or respiration during the 4 weeks of alprazolam administration. Body weight increased significantly (mean increase was 0.87 kg). Double-blind trials with alprazolam are recommended in child psychiatry disorders.


Tools for coproducing multiple proteins in mammalian cells.
Structural and functional studies of many mammalian systems are critically dependent on abundant supplies of recombinant multiprotein complexes. Mammalian cells are often the most ideal, if not the only suitable host for such experiments. This is due to their intrinsic capability to generate functional mammalian proteins. This advantage is frequently countered by problems with yields in expression, time required to generate overexpressing lines, and elevated costs. Coexpression of multiple proteins adds another level of complexity to these experiments, as cells need to be screened and selected for expression of suitable levels of each component. Here, we present an efficient fluorescence marking procedure for establishing stable cell lines that overexpress two proteins in coordination, and we validate the method in the production of recombinant monoclonal antibody Fab fragments. This procedure may readily be expanded to systems of greater complexity, comprising more than two components.


Successful treatment with nivolumab for SMARCA4-deficient non-small cell lung carcinoma with a high tumor mutation burden: A case report.
SMARCA4 is a subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin-remodeling complex. An effective treatment for SMARCA4-deficient non-small cell lung carcinoma (NSCLC) has not yet been established. Correlations between a response to immune checkpoint inhibitors and the SWI/SNF complex have been suggested, but little is known about the efficacy of immune checkpoint inhibitors against SMARCA4-deficient NSCLC. A 43-year-old man underwent left upper lobe lung resection and was diagnosed with SMARCA4-deficient lung adenocarcinoma. Two months after surgery, multiple lung metastases appeared. Immunohistochemical analysis showed no PD-L1 expression. Whole-exon sequencing revealed a relatively high tumor mutation burden at 396. After the failure of three standard chemotherapy regimens, the patient was treated with nivolumab as fourth-line treatment. An obvious reduction in the lung metastases was obtained for more than 14 months. We report the first case of SMARCA4-deficient NSCLC with a high tumor mutation burden successfully treated with nivolumab. Anti-PD-1 antibodies might be a promising treatment strategy for patients with SMARCA4-deficient NSCLC.


Co-firing of pine chips with Turkish lignites in 750kWth circulating fluidized bed combustion system.
Two Turkish lignites which have different sulfur levels (2-2.9% dry) and ash levels (17-25% dry) were combusted with a Turkish forest red pine chips in a 750kW-thermal capacity circulating fluidized bed combustor (CFBC) system. The combustion temperature was held at 850±50°C. Flue gas emissions were measured by Gasmet DX-4000 flue gas analyzer. Two lignites were combusted alone, and then limestone was added to lignites to reduce SO2 emissions. Ca/S=3 was used. 30% percent of red pine chips were added to the lignites for co-firing experiments without limestone in order to see the biomass effects. The results showed that with limestone addition SO2 concentration was reduced below the limit values for all lignites. CO emissions are high at low excess air ratios, gets lower as the excess air ratio increases. During co-firing experiments the temperature in the freeboard was 100-150°C higher as compared to coal combustion experiments.


Granuloma annulare photoinduced by paroxetine.
Granuloma annulare (GA) is a benign granulomatous skin disease with several clinical manifestations and characteristic histological findings. GA located in photoexposed areas is a rare finding and its association to a drug-induced systemic photosensitivity is even less common. To the best of our knowledge, only one case of systemic drug photosensitivity manifesting as a GA has been reported. We describe a patient with systemic photosensitivity to paroxetine with clinical and histological manifestations of GA, which was confirmed by the photobiological study. The phototest revealed a reduction of the minimal erythematous dose for UVB while taking the paroxetine and its normalization after its withdrawal, which was accompanied by the clinical resolution of the skin eruption. The manifestation of systemic drug photosensitivity as a GA like in our case is exceptional.


Biological differences between two allopatric populations of Amblyomma cajennense (Acari: Ixodidae) in Argentina.
The fertility of hybrids from two distinct populations of Amblyomma cajennense from different ecological regions of Northern Argentina was analyzed. Two colonies of A. cajennense from El Rey National Park (RNP), Salta Province (24º41'S, 64º36'W), and Copo National Park (CNP), Santiago del Estero Province (25º55'S, 61º43'W) were established infesting rabbits with adults collected from vegetation. Reproductive parameters of the first generation in laboratory of each colony and their crosses were evaluated considering engorged weight of females, engorged period of females, pre-oviposition period of females, minimum egg incubation period, reproductive efficiency index [REI = number of eggs laid/weight of the females in mg], and fertility efficiency index [FEI = number of hatched larvae/weight of the females in mg]. Infestations were made as follows: Group 1) RNP males and females; Group 2) CNP males and females; Group 3) males from CNP and females from RNP; Group 4) males from RNP and females from CNP. The engorgement weight of the females from CNP that mated with males from RNP was significantly lighter than those of the engorged females obtained in the other 3 crosses, and the engorged period of the females from CNP that mated with males from RNP was significantly longer that the engorged period of the females belonging to the remaining groups. The females from group 3 and 4 had a FEI extremely low in comparison with the FEI obtained from the engorged females originated from the groups 1 and 2. Biological implication of these findings is discussed.


What's in a name?
Numerous concerns have been raised about the sustainability of the biomedical research enterprise in the United States. Improving the postdoctoral training experience is seen as a priority in addressing these concerns, but even identifying who the postdocs are is made difficult by the multitude of different job titles they can carry. Here, we summarize the detrimental effects that current employment structures have on training, compensation and benefits for postdocs, and argue that academic research institutions should standardize the categorization and treatment of postdocs. We also present brief case studies of two institutions that have addressed these challenges and can provide models for other institutions attempting to enhance their postdoctoral workforces and improve the sustainability of the biomedical research enterprise.


Assessment of ambulatory blood pressure recorders: accuracy and clinical performance.
There are now more than ten different manufacturers of non-invasive, portable blood pressure monitors in North America, Europe, and Japan. These ambulatory blood pressure recorders measure blood pressure by either auscultatory or oscillometric methodology. Technologic advances in the recorders have resulted in reduction in monitor size, reduction in or absence of motor noise during cuff inflation, ability to program the recorder without an external computer system, and enhanced precision. Recently, there has been concern that more structured validation protocols have not been implemented prior to the widespread marking of ambulatory blood pressure recorders. There is a need for proper assessment of recorders prior to use in clinical research or practice. Data on several existing recorders suggest that while most are reasonably accurate during resting measurements, many lose this accuracy during motion, and clinical performance may vary among the monitors. Validation studies of ambulatory recorders should include comparison with mercury column and intra-arterial determinations, resting and motion measurements, and assessment of clinical performance in hypertensive patients.


Saxagliptin: a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus.
The pharmacology, pharmacokinetics, efficacy, safety, and dosage and administration of saxagliptin are reviewed. Saxagliptin is a selective, reversible inhibitor of dipeptidyl peptidase-4 (DPP-4) approved for the treatment of type 2 diabetes mellitus in adults. By inhibiting DPP-4, saxagliptin reduces the degradation of endogenous incretin hormones, resulting in increased glucose-dependent insulin release and decreased glucagon secretion from the pancreas. Saxagliptin is rapidly absorbed after oral administration, and its pharmacokinetic profile allows for once-daily oral administration. Clinical trials of saxagliptin as monotherapy and as combination therapy with other oral antidiabetic medications including metformin, glyburide, pioglitazone, and rosiglitazone have demonstrated clinical benefits in various glycemic endpoints, including glycosylated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), and postprandial glucose (PPG) levels over 24 to 102 weeks of therapy. Due to its glucose-dependent mechanism of action, saxagliptin as monotherapy or in combination with metformin results in a low risk for hypoglycemia in patients with type 2 diabetes. Saxagliptin was generally well tolerated in clinical trials, with headache, upper-respiratory-tract infection, and urinary tract infection being the most common adverse events. Saxagliptin has demonstrated a low risk for drug-drug interactions. For patients with moderate or severe renal impairment or end-stage renal disease or patients taking a strong inhibitor of cytochrome P-450 isoenzyme 3A4 or 3A5, the recommended dosage is 2.5 mg once daily. Saxagliptin, a DPP-4 inhibitor approved for the treatment of type 2 diabetes, demonstrated safety and efficacy in lowering HbA(1c), FPG, and PPG levels as both monotherapy and in combination with other oral antidiabetic medications.


Autonomic regulation of heart rate and peripheral circulation: comparison of high altitude and sea level residents.
1. To evaluate the activity of the autonomic nervous system on the heart and peripheral circulation in native high-altitude residents, during a Himalayan expedition we studied 12 men (age: 48 +/- 4, mean +/- SEM), life-long resident in a village at 4800 m (Sumdo village, Zanskar, India) and 7 healthy sea-level residents (age: 37 +/- 4) after 7 days of acclimatization (acclimatized lowlanders) at the same altitude. Furthermore 25 sea level residents (age: 46 +/- 2) underwent the same protocol at sea level. 2. R-R interval (RR), respiratory signal, non-invasive blood pressure, and skin arteriolar blood flow were evaluated in three different conditions: during free breathing in supine position and during controlled breathing (at 0.15 Hz), in supine and upright position, and analysed by autoregressive spectral analysis [low- (around 0.1 Hz) and high-frequency (respiratory) fluctuations, LF and HF, markers of sympathetic and vagal activity, respectively]. 3. High-altitude residents showed in supine position a higher RR than acclimatized lowlanders, similar to sea-level residents. RR variability was reduced in acclimatized lowlanders compared to both high-altitude residents and sea level residents. Systolic blood pressure (SBP) did not show significant differences between the three groups. High altitude residents showed in supine lower LF in RR signal compared to sea-level residents, and, compared to acclimatized lowlanders, higher HF and lower LF/HF ratio; high-altitude residents showed a reduction in skin microcirculation variability compared to sea-level residents, but this was eight fold greater than in acclimatized lowlander, thus indicating a much greater vasoconstriction in acclimatized lowlanders than in high-altitude residents. 4. In upright position, high-altitude residents showed the same behaviour as sea-level residents, with increase in LF-RR, and decrease in HF and LF-SBP. Acclimatized lowlanders showed similar directional trends though not significant changes for RR-LF. 5. After one week of acclimatization, lowlanders still manifested sympathetic activation and skin vasoconstriction; high-altitude residents did not show reduced vagal tone compared to sea-level residents, but a mild vasoconstriction appeared to be present. In conclusion, normal or enhanced vagal tone and preserved vasomotion are probably evidence of adaptation at high altitude hypoxia.


Dynamic Optical Coherence Tomography in Dermatology.
Optical coherence tomography (OCT) represents a non-invasive imaging technology, which may be applied to the diagnosis of non-melanoma skin cancer and which has recently been shown to improve the diagnostic accuracy of basal cell carcinoma. Technical developments of OCT continue to expand the applicability of OCT for different neoplastic and inflammatory skin diseases. Of these, dynamic OCT (D-OCT) based on speckle variance OCT is of special interest as it allows the in vivo evaluation of blood vessels and their distribution within specific lesions, providing additional functional information and consequently greater density of data. In an effort to assess the potential of D-OCT for future scientific and clinical studies, we have therefore reviewed the literature and preliminary unpublished data on the visualization of the microvasculature using D-OCT. Information on D-OCT in skin cancers including melanoma, as well as in a variety of other skin diseases, is presented in an atlas. Possible diagnostic features are suggested, although these require additional validation.


[Expression of IL-17 in laryngeal squamous cell carcinoma tissues and the clinical significance].
To investigate the expression of interleukin 17 in laryngeal squamous cell carcinoma tissues, and to evaluate the value of interleukin-17 in the biological behavior and prognosis of laryngeal squamous cell carcinoma. Expressions of IL-17 were analyzed in 71 laryngeal squamous cell carcinoma samples and 21 cases of adjacent tissues of carcinoma as control by immunohistochemistry. The expression of IL-17 in laryngeal squamous cell carcinoma tissues was obviously higher than that in adjacent tissues (P < 0.05). The expression of IL-17 was associated with tumor T staging, tumor differentiation, regional lymph node metastasis, distant metastasis and recurrence (P < 0.05). Log-rank test showed that the prognosis of patients was related to the primary tumor site, tumor stage, regional lymph node metastasis, distant metastasis and IL-17 expression (P < 0.05), While Cox multiple factors analysis showed that IL-17 was not an independent prognostic factors. The expression of IL-17 may be the vital index in laryngeal squamous cell carcinoma, and it can provide some theoretical basis for the anti-tumor immunotherapy for laryngeal squamous cell carcinoma.


Driving neural regeneration through the mammalian target of rapamycin.
Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer's disease, and Parkinson's disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin (mTOR). mTOR is a component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence. mTOR through its relationship with phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) and multiple downstream signaling pathways such as p70 ribosomal S6 kinase (p70S6K) and proline rich Akt substrate 40 kDa (PRAS40) promotes neuronal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and β-amyloid toxicity may offer new strategies for disorders such as stroke and Alzheimer's disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clinical efficacy and eliminate any clinical toxic side effects.


On the nonlinear relationship between k(obs) and reductant mass loading in iron batch systems.
A first-order relationship between reaction rate and reductant loading is commonly invoked (but rarely verified) for granular iron batch systems. In this study, a linear relationship between the pseudo-first-order rate constant (k(obs)) for polyhalogenated alkane reduction and iron mass loading (rhom) was only obtained when reduction appeared to be mass-transport-limited. For most alkyl polyhalides, a nonlinear relationship was observed under various experimental conditions, causing surface-area-normalized rate constants (k(SA)) to decrease by as much as an order of magnitude with increasing rhom. While a detailed explanation for this nonlinearity remains unclear, the reaction order in rhom (from plots of log(k(obs)) versus log(rhom)) approached unity as the system pH decreased, suggesting that the behavior may be linked to changes in the thickness of a passive oxide overlayer. We obtained strong linear correlations between k(obs) values and the concentration of aqueous iron(ll) generated over a 24 h period in batch systems with that same rhom. Equally strong correlations were obtained when k(obs) was related to the summed concentration of protons and water reduced over an equivalent time interval at that same rhom. Such correlations suggest a possible link between those sites responsible for proton/water reduction and the surface species participating in alkyl polyhalide reduction by granular iron.


Monolayer Assemblies and Optical Properties of Europium(III) Complexes with beta-Diketones Containing Various Substituents
Europium(III) complexes with beta-diketones containing various substituents were newly synthesized and their monolayer behaviors on the water surface were studied in situ by a Brewster angle microscopy (BAM) together with surface pressure-area isotherms. Some BAM images look like a thin soap film on the flat surface, consisting of gas and liquid phases. The monolayer assemblies of these complexes could be deposited by both LB and horizontal lifting techniques. The emission probability from the excited singlet state 5D1 increased in the film as compared to the lowest excited state 5D0, and the symmetrically forbidden transition 5D0-->7F0 was enhanced in comparison with those in the solutions and the crystallines. This effect on the fluorescence was observed significantly for the complex with an asymmetrically substituted ligand rather than that with a symmetrically substituted one. These results can be ascribed to the fact that the thermal deactivation of the higher excited state is decreased and also the symmetries of these complexes are slightly distored in the monolayer assemblies. Copyright 1997 Academic Press. Copyright 1997Academic Press


The role of perceived speaker identity in F0 normalization of vowels.
In the experiments reported here, perceived speaker identity was controlled by manipulating the fundamental frequency (F0) range of carrier phrases in which speech tokens were embedded. In the first experiment, words from two "hood"-"hud" continua were synthesized with different F0. The words were then embedded in synthetic carrier phrases with intonation contours which reduced perceived speaker identity differences for test items with different F0. The results indicated that when perceived speaker identity differences were reduced, the effect of F0 on vowel identification was also reduced. Experiment 2 indicated that when items presented in carrier phrases are matched for speaker identity and F0 with items in isolation, there is no effect for presentation in a carrier phrase. Experiment 3 involved the presentation of vowels from the "hood"-"hud" continuum in two different intonational contexts which were judged to have been produced by different speakers, even though the F0 of the test word was identical in the two contexts. There was a shift in identification as a result of the intonational context which was interpreted as evidence for the role of perceived identity in vowel normalization. Overall, the experiments suggest that perceived speaker identity is a better predictor of vowel normalization effects than is intrinsic F0. This indicates that the role of F0 in vowel normalization is mediated through perceived speaker identity.


A prospective audit over a six month period of condylar fractures at Chris Hani Baragwanath Hospital.
To determine the frequency of occurrence, patterns, aetiology and outcome of treatment of mandibular condylar fractures at Chris Hani Baragwanath Hospital. All patients with condylar fractures seen at Chris Hani Baragwanath Hospital over a six-month period from January to June 2003 were included in the study. Data was recorded on sex, age, date of injury, cause of trauma, status of the occlusion and presence of associated facial injuries. The type of condylar fracture was recorded and classified following the radiographic examination according to Spiessl and Schroll. The type of treatment rendered and its outcome were also documented. Patients were followed up from 1 week to 6 months post-treatment. The sample comprised 84 patients with 95 condylar fractures; 69 (82%) males and 15(18%) females. 73.8% of the fractures were caused by interpersonal violence followed by road traffic accidents (16,67%) and falls (7.14%). 73 (87%) patients had unilateral fractures and 11 (13%) had bilateral condylar fractures. Of the 95 condylar fractures, there were 16 medially dislocated condylar fractures in 13 patients. Type I, Type II and Type III fractures accounted for 31%, 26% and 25% of the total fractures respectively. A relationship exists between the type of condylar fracture and the cause of the fracture: road traffic accidents and falls produce more bilateral and dislocated fractures than interpersonal violence. Prolonged intermaxillary fixation, failure to use training elastics, absence of active physiotherapy and poor patient compliance results in increased risk of hypomobility.


Effect of the Zwitterion, p(MAO-DMPA), on the Internal Structure, Fouling Characteristics, and Dye Rejection Mechanism of PVDF Membranes.
The zwitterion poly-(maleic anhydride-alt-1-octadecene-3-(dimethylamino)-1-propylamine) (p(MAO-DMPA)) synthesized using a ring-opening reaction was used as a poly(vinylidene fluoride) (PVDF) membrane modifier/additive during phase inversion process. The zwitterion was characterized using proton nuclear magnetic resonance (1HNMR) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Atomic force microscopy (AFM), field emission scanning electron microscope (SEM), FTIR, and contact angle measurements were taken for the membranes. The effect of the zwitterionization content on membrane performance indicators such as pure water flux, membrane fouling, and dye rejection was investigated. The morphology of the membranes showed that the increase in the zwitterion amount led to a general decrease in pore size with a concomitant increase in the number of membrane surface pores. The surface roughness was not particularly affected by the amount of the additive; however, the internal structure was greatly influenced, leading to varying rejection mechanisms for the larger dye molecule. On the other hand, the wettability of the membranes initially decreased with increasing content to a certain point and then increased as the membrane homogeneity changed at higher zwitterion percentages. Flux and fouling properties were enhanced through the addition of zwitterion compared to the pristine PVDF membrane. The high (>90%) rejection of anionic dye, Congo red, indicated that these membranes behaved as ultrafiltration (UF). In comparison, the cationic dye, rhodamine 6G, was only rejected to <70%, with rejection being predominantly electrostatic-based. This work shows that zwitterion addition imparted good membrane performance to PVDF membranes up to an optimum content whereby membrane homogeneity was compromised, leading to poor performance at its higher loading.


(-)Epigallocatechin-3-gallate directly inhibits MT1-MMP activity, leading to accumulation of nonactivated MMP-2 at the cell surface.
Consumption of green tea has been associated with prevention of cancer development, metastasis, and angiogenesis. Given the crucial role of the matrix metallo-proteinase-2 (MMP-2) on the degradation of the extracellular matrix instrumental to invasion, we examined the effect of the main flavanol present, (-)epigallocatechin-3-gallate (EGCG), on membrane-type 1 MMP (MT1-MMP), the receptor/activator of MMP-2. In-solution fluorimetric assay with activated MT1-MMP and gelatin-zymography with MT1-MMP catalytic domain alone and pro-MMP-2 activation by the same domain revealed dose-dependent inhibition of MT1-MMP at EGCG concentrations slightly lower than that reported to inhibit MMP-2 and MMP-9. Cytofluorimetry and immunolocalization revealed that EGCG does not impair MT1-MMP/TIMP-2/MMP-2 presence on the cell membrane. In the membrane extract of HT-1080 human fibrosarcoma cells, 10 micro M EGCG caused a strong increase in MT1-MMP level and accumulation of pro-MMP-2 while leaving activated MMP-2 unchanged. EGCG thus exerts inhibition of MT1-MMP, which restrains activation of MMP-2; this may confer the antiangiogenic and antimetastatic activity associated with green tea.


Activin A regulates porcine follicle-stimulating hormone beta-subunit transcription via cooperative actions of SMADs and FOXL2.
Activins stimulate FSH synthesis and secretion by pituitary gonadotrope cells. Activin A induction of porcine and murine FSHβ (Fshb) gene transcription in immortalized gonadotropes is dependent on homolog of Drosophila mothers against decapentaplegic (SMAD) proteins as well as the forkhead transcription factor L2 (FOXL2). Using both heterologous and homologous cell models, we demonstrate that FOXL2 functionally synergizes with SMAD3/4 to stimulate porcine Fshb promoter-reporter activity. We further show that endogenous FOXL2 and SMAD2/3 physically interact in homologous cells. We identify two composite cis-elements of adjacent FOXL2 and SMAD binding sites in the proximal porcine Fshb promoter that mediate activin A, FOXL2, and SMAD3 actions. FOXL2 can bind these elements independently of SMADs, whereas SMAD3/4 binding requires high-affinity FOXL2 binding. Conversely, FOXL2 alone is insufficient to regulate Fshb transcription and requires SMADs to induce promoter activity. Collectively, our data suggest a model in which activins stimulate formation and nuclear accumulation of SMAD3/4 complexes, which interact with FOXL2 bound to at least two proximal promoter elements. This association stabilizes SMAD3/4 binding to adjacent SMAD binding elements. SMAD-FOXL2 complexes then mediate activation of transcription through a currently unknown mechanism. Conservation of one of the two composite cis-elements suggests that this may form part of a general mechanism whereby activins regulate Fshb subunit transcription and FSH synthesis.


Remediation of Mild, Acute Radiation Dermatitis Using a Stem Cell-Based Topical: A Real-World Case Report.
Wounds of the skin induced by irradiation involve a disruption of skin homeostasis and an increase in inflammation. Physiological renormalization treatment strategies using the molecules released from stem cells that restore proteostasis and regulate the immune system and reduce inflammation may be effective in treating skin conditions. Previous studies of severe radiation dermatitis found a significant reduction in symptoms using a combination product of the secretome from adipose mesenchymal stem cells and dermal fibroblasts, but mild radiation dermatitis has yet to be studied using this product. This is a case report of radiation dermatitis in a patient with an uncommon cutaneous basosquamous cell carcinoma with perineural invasion that warranted radiation therapy. In this study we used S2RM technology, a proprietary combination of stem cell-released molecules from multiple types of skin stem cells, to renormalize homeostasis of the skin, including a renormalization of proteostasis to treat a mild form of radiation dermatitis induced by Intensity Modulated Radiation Therapy. Dramatic reductions in pain, redness, and inflammation, more rapid and complete wound healing, and an overall enhancement of the appearance of the skin were achieved in this patient. The current study demonstrates that as part of the palliative care strategies for cancer patients, the simple topical application of S2RM technology is a powerful means to renormalize homeostasis of the skin and remediate mild radiation dermatitis. The reduction of inflammation in the skin is important to reducing systemic inflammation and related comorbidities.


The Good, the Bad, and the Ugly-Chances, Challenges, and Clinical Implications of Avoidance Research in Psychosomatic Medicine.
Avoidance behaviors are shaped by associative learning processes in response to fear of impending threats, particularly physical harm. As part of a defensive repertoire, avoidance is highly adaptive in case of acute danger, serving a potent protective function. However, persistent or excessive fear and maladaptive avoidance are considered key factors in the etiology and pathophysiology of anxiety- and stress-related psychosomatic disorders. In these overlapping conditions, avoidance can increase the risk of mental comorbidities and interfere with the efficacy of cognitive behavioral treatment approaches built on fear extinction. Despite resurging interest in avoidance research also in the context of psychosomatic medicine, especially in conditions associated with pain, disturbed interoception, and disorders of the gut-brain axis, current study designs and their translation into the clinical context face significant challenges limiting both, the investigation of mechanisms involved in avoidance and the development of novel targeted treatment options. We herein selectively review the conceptual framework of learning and memory processes, emphasizing how classical and operant conditioning, fear extinction, and return of fear shape avoidance behaviors. We further discuss pathological avoidance and safety behaviors as hallmark features in psychosomatic diseases, with a focus on anxiety- and stress-related disorders. Aiming to emphasize chances of improved translational knowledge across clinical conditions, we further point out limitations in current experimental avoidance research. Based on these considerations, we propose means to improve existing avoidance paradigms to broaden our understanding of underlying mechanisms, moderators and mediators of avoidance, and to inspire tailored treatments for patients suffering from psychosomatic disorders.


Comparison of the Cardiac MicroPET Images Obtained Using [(18)F]FPTP and [(13)N]NH3 in Rat Myocardial Infarction Models.
The short half-life of current positron emission tomography (PET) cardiac tracers limits their widespread clinical use. We previously developed a (18)F-labeled phosphonium cation, [(18)F]FPTP, that demonstrated sharply defined myocardial defects in a corresponding infarcted myocardium. The aim of this study was to compare the image properties of PET scans obtained using [(18)F]FPTP with those obtained using [(13)N]NH3 in rat myocardial infarction models. Perfusion abnormality was analyzed in 17 segments of polar map images. The myocardium-to-liver and myocardium-to-lung ratios of [(18)F]FPTP were 10.48 and 2.65 times higher, respectively, than those of [(13)N]NH3 in images acquired 30 min after tracer injection. The myocardial defect size measured by [(18)F]FPTP correlated more closely with the hypoperfused area measured by quantitative 2,3,5-triphenyltetrazolium chloride staining (r = 0.89, P < 0.01) than did [(13)N]NH3 (r = 0.84, P < 0.01). [(18)F]FPTP might be useful as a replacement for the myocardial agent [(13)N]NH3 in cardiac PET/CT applications.


Low-frequency fatigue and neuromuscular performance after exercise-induced damage to elbow flexor muscles.
The purpose of this study was to quantify the association between low-frequency fatigue (LFF) and the increase in EMG and force fluctuations after eccentric exercise of elbow flexor muscles. Ten subjects performed two tasks involving voluntary isometric contractions of elbow flexors: a maximum voluntary contraction (MVC) and a constant-force task at five submaximal target forces (5, 10, 20, 40, 60% MVC) while EMG was recorded from biceps and triceps brachii. A third task involved electrical stimulation of biceps brachii at 12 frequencies (1-100 Hz). These tasks were performed before, after, and 2 h and 24 h after concentric or eccentric exercise. MVC force declined after eccentric exercise (34% decline) and remained depressed 24 h later (22% decline), whereas the reduced force following concentric exercise (32%) was recovered 2 h later. Biceps brachii EMG and force fluctuations during the submaximal voluntary contractions increased after eccentric exercise (both approximately 2x greater) with the greatest effect at low forces. LFF was equivalent immediately after both types of exercise (50-60% reduction in 20:100 Hz force) with a slower recovery following eccentric exercise. A significant association was found between the change in LFF and EMG (r(2) values up to 0.52), with the strongest correlations observed at low forces (20% MVC) and at 2 h after exercise. In contrast, there were no significant associations between LFF and force fluctuations during voluntary or electrically evoked contractions, suggesting that other physiological factors located within the muscle are likely to be playing a major role in the impaired motor performance after eccentric exercise.


Solid-state ring laser gyro behaving like its helium-neon counterpart at low rotation rates.
Nonlinear couplings induced by crystal diffusion and spatial inhomogeneities of the gain have been suppressed over a broad range of angular velocities in a solid-state ring laser gyro by vibrating the gain crystal at 168 kHz and 0.4 microm along the laser cavity axis. This device behaves in the same way as a typical helium-neon ring laser gyro, with a zone of frequency lock-in (or dead band) resulting from the backscattering of light on the cavity mirrors. Furthermore, it is shown that the level of angular random-walk noise in the presence of mechanical dithering depends only on the quality of the cavity mirrors, as is the case with typical helium-neon ring laser gyros.