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Human brain development proceeds via a sequentially transforming stem cell population in the ventricular-subventricular zone (V-SVZ). An essential, but understudied, contributor to V-SVZ stem cell niche health is the multi-ciliated ependymal epithelium, which replaces stem cells at the ventricular surface during development. However, reorganization of the V-SVZ stem cell niche and its relationship to ependymogenesis has not been characterized in the human brain. Based on comprehensive comparative spatiotemporal analyses of cytoarchitectural changes along the mouse and human ventricle surface, we uncovered a distinctive stem cell retention pattern in humans as ependymal cells populate the surface of the ventricle in an occipital-to-frontal wave. During perinatal development, ventricle-contacting stem cells are reduced. By 7 months few stem cells are detected, paralleling the decline in neurogenesis. In adolescence and adulthood, stem cells and neurogenesis are not observed along the lateral wall. Volume, surface area and curvature of the lateral ventricles all significantly change during fetal development but stabilize after 1 year, corresponding with the wave of ependymogenesis and stem cell reduction. These findings reveal normal human V-SVZ development, highlighting the consequences of disease pathologies such as congenital hydrocephalus. | Lateral Ventricles |
Analysis of illicit methamphetamine samples revealed the presence of a hitherto unreported impurity. This was identified as N-acetylmethamphetamine by synthesis and GC-MS. This impurity is believed to arise by transesterification of methamphetamine during reflux with propyl acetate. Other circumstantial evidence and intelligence data indicate that propyl acetate was used to increase yields of methamphetamine hydrochloride by azeotropic removal of water remaining after salt formation with aqueous hydrochloric acid. | Methamphetamine |
Polysaccharides were extracted from a wild species of Ornithogalum by using three methods: maceration, ultrasound-assisted extraction, and combination of maceration and ultrasound. Extraction conditions were optimized by using response surface method (RSM) with a central composite design (CCD). The optimal extraction yield was 81.7%, 82.5% and 85.7%, and the optimal polysaccharides yield was 74.7%, 75.7%, and 82.8% under the optimum conditions of maceration, ultrasound-assisted extraction and combined extraction, respectively. These results indicate that the combination method significantly improves the extraction and polysaccharides yields compared to traditional extraction methods. The combination method also allows reducing the time of ultrasound treatment and thus its adverse effects on polysaccharides. In addition, these results well corroborate with the theoretically predicted values. The NMR ((1)H,(13)C, HSQC, HMBC, and COSY) analysis shows that the extract is composed of fructo-polysaccharides with a backbone of (2 --> 6)-linked beta-d-fructofuranosyl (Fruf) and (2 --> 1)-linked beta-d-Fruf branched chains, and terminated with glucose and fructose residues. The antioxidant activities of the extract were evaluated from ABTS radical scavenging activity, total antioxidant capacity, metal-chelating power and beta-carotene bleaching test. Data show that the extract presents outstanding antioxidant activities. | Ornithogalum |
In osteoporosis, both the bisphosphonate alendronate and parathyroid hormone (1-34) (PTH (1-34) ) have been shown to reduce the incidence of fractures. As bisphosphonates and PTH have different mechanisms, it has been proposed that their effects in osteoporosis may be additive. However, a major clinical trial of PTH (1-84) and alendronate in postmenopausal women demonstrated that their effects were not additive. A further trial in men with osteoporosis showed that alendronate impaired the ability of PTH (1-34) to increase bone mineral density. The combination of alendronate and PTH does not have greater benefit than either agent alone, and may even be detrimental, thus should not be used. | Alendronate |
Despite considerable overlap, the confusion hovering over the four common sparing signs can be cleared as follows: Reverse Koebner relates to sparing by physical trauma; isotopic non-response/reverse isotopic response relates to sparing over an already healed dermatosis; Renbok Phenomenon relates to sparing among two concomitant active diseases often with autoimmune etiology; anatopic phenomenon relates to sparing caused by presence of certain infectious diseases of skin. In conclusion, sparing phenomenon of dermatology seems to command our attention by their sheer number, variety, and clinical implications. Therefore, it may be said that astute clinician is the one who will look, not only for the presence of lesions in the patient but also for the conspicuous absence thereof. | Dermatology |
Phytochemical investigations of the methanol extract from Origanum dictamnus L. (Lamiaceae) resulted in the isolation of forty compounds belonging to the classes of terpenes, resorcinol derivatives, flavonoids, depsides, neolignans and jasmonates. Chromatographic isolations were targeted by using two analytical platforms, NMR and HPLC-PDA-MS. In parallel, HPLC-PDA-MS of individual fractions enabled the unambiguous identification of additionally eight components. In total 48 constituents were isolated/identified. Among the isolated constituents are four undescribed compounds, one resorcinol derivative, one monoterpene, one diterpene and one acylated flavonoid glycoside. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR, and HPLC-ESI-MS and HRMS experiments. Representative compounds were tested for their antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa. I4-II7-dicarvacrol was the most potent constituent. | Origanum |
A new catechin derivative named as sterilin A (1), and three known compounds, (+)-catechin (2), kaji-ichigoside F1 (3) and 2alpha,3alpha,19alpha-trihydroxyurs-12-en-28-oic acid-28-O-beta-D-xylopyranosyl-(1 --> 2)-beta-D-glucopyranoside (4), was isolated from the fresh fruits of Rosa sterilis. Their structures were elucidated by means of extensive spectroscopic analysis and by comparison with data reported in the literatures. | Catechin |
Lower-extremity injuries have become increasingly common as sports performance demands have risen. Hyperbaric oxygen therapy is one method used to return athletes to competition as quickly as possible, but it has received criticism and lacks support. This review examines the literature on hyperbaric oxygen therapy and soft-tissue sports injuries. In the various studies, the location of the injury seemed to influence the effectiveness of treatment. Injuries at areas of reduced perfusion such as muscle-tendon junctions and ligaments seemed to benefit more from hyperbaric oxygen treatment than injuries at the muscle belly. Differences in the magnitude of the injury and in the time between injury and treatment may also affect outcomes. The authors sought to explore these variables as they relate to soft-tissue sports injuries and to weigh the benefits of hyperbaric oxygen therapy against its potential risks and high cost. More randomized controlled clinical trials with larger sample sizes must be conducted before hyperbaric oxygen can be established as a safe adjunctive therapy for soft-tissue sports injuries. | Hyperbaric Oxygenation |
We report the molecular cloning and expression of a phosphatidic acid-preferring phospholipase A1 from bovine testis. The open reading frame encoded an 875-amino acid protein with a calculated molecular mass of 97,576 daltons and a pI of 5.61. The sequence included a region similar to a lipase consensus sequence containing the putative active site serine and also included a potential, coiled-coil-forming region. Expression of the open reading frame in COS1 cells resulted in a 20-44-fold increase in phosphatidic acid phospholipase A1 activity over that of control cells. Mutation of the putative active site serine (amino acid 540) demonstrated that it was essential for this increase in enzyme activity. Northern blot analysis revealed at least five different messages with the highest overall message levels in mature testis, but detectable message in all tissues examined. Two possible alternately spliced regions in the open reading frame also were identified. Finally, a search of the data base identified six related proteins: a potential counterpart of the phospholipase A1 in Caenorhabditis elegans, two putative lipases in yeast, and three proteins separately encoded by the Drosophila retinal degeneration B gene and its mouse and human homologues. | Phospholipases A1 |
Our purpose was to develop a method of using a maximal forced expiratory maneuver (MFEM) for the study of bronchoconstriction and bronchial hyperreactivity (BHR) induced in mice by ovalbumin (OA) inhalation challenge. Eight mice (group I) were sensitized and then provocated with OA. Pulmonary function testing (PFT) at baseline and after varying doses of acetylcholine challenge was performed. Eight weight-matched normal mice served as controls (group II). Pulmonary functions include MFEM, dynamic respiratory system compliance (Crs) and respiratory system resistance (Rrs). The results showed that mice treated with OA had worse PFTs than normal controls, characterized by lower MFEF 50%, FEV0.1 and Crs but higher Rrs. The OA-sensitized mice also had more severe bronchoconstriction in response to acetylcholine, characterized by greater decreases in MFEF 50%, FEV0.1 and Crs but a higher Rrs than the controls. There was a good correlation between PD20MFEF50%Ach and PD20FEV0.1Ach with PD20CrsAch and PD20RrsAch. In conclusion, the MFEM can be used to evaluate airway obstruction and BHR induced in mice by allergen challenge. | Maximal Expiratory Flow Rate |
278 consecutive patients with suspected contact dermatitis were patch tested with the European standard series and gold sodium thiosulfate (0.5% pet.): 13 patients (4.6%) had a positive allergic response to gold sodium thiosulfate (GST). All of these patients were female, with a mean age of 37 years. The most frequent site of eczema in these patients was the head and neck (62%). A seborrhoeic distribution of eczema was common. 46% had involvement of the limbs, 15% had a perianal or perivulval rash. The mean duration of eczema in this group of patients was 15.8 months. 54% of patients allergic to gold were also allergic to nickel. Biopsy of positive patch test reactions to GST were consistent with allergic contact dermatitis. | Gold Sodium Thiosulfate |
Bronchospasm and status asthmaticus are two of the most dreaded complications that a pediatric anesthesiologist may face. With the occurrence of severe bronchospasm and the inability to ventilate, children are particularly vulnerable to apnea and ensuing hypoxia because of their smaller airway size, smaller lung functional residual capacity, and higher oxygen consumption rates than adults. Nebulized medication delivery in intubated children is also more difficult because of smaller endotracheal tube internal diameters. This case demonstrates the potentially lifesaving use of a vibrating-mesh membrane nebulizer connected to the anesthesia circuit for treating bronchospasm." | Albuterol, Ipratropium Drug Combination |
Our understanding of the mechanisms governing of Rab and Arf protein function has exploded in recent years with a convergence of information from model genetic organisms, biochemical studies, cell biological observations and protein structural information. However, the list of known Rab and Arf interacting factors still remains small relative to the number of these small GTPases that have been identified through complete genomic sequencing. It can be anticipated that the factors listed and discussed in this review probably represent a small fraction of the Rab and Arf accessory molecules that remain to be discovered. The identification of regulators and accessory molecules for the Rab and Arf families has allowed investigators to elaborate themes and develop a framework for a mechanistic understanding of these proteins. The themes are highlighted in this review, which aims to concentrate on Rab and Arf function in exocytosis." | Monomeric GTP-Binding Proteins |
The isotropic metaphase actin cortex progressively polarizes as the anaphase spindle elongates during mitotic exit. This involves the loss of actomyosin cortex from opposing cell poles and the accumulation of an actomyosin belt at the cell centre. Although these spatially distinct cortical remodelling events are coordinated in time, here we show that they are independent of each other. Thus, actomyosin is lost from opposing poles in anaphase cells that lack an actomyosin ring owing to centralspindlin depletion. In examining potential regulators of this process, we identify a role for Aurora B kinase in actin clearance at cell poles. Upon combining Aurora B inhibition with centralspindlin depletion, cells exiting mitosis fail to change shape and remain completely spherical. Additionally, we demonstrate a requirement for Aurora B in the clearance of cortical actin close to anaphase chromatin in cells exiting mitosis with a bipolar spindle and in monopolar cells forced to divide while flat. Altogether, these data suggest a novel role for Aurora B activity in facilitating DNA-mediated polar relaxation at anaphase, polarization of the actomyosin cortex, and cell division. | Anaphase |
Standard operating procedures for autologous stem cell transplantation (SCT) aim to guarantee best possible engraftment. Three procedures are routinely used for transplant infusion: regular bag infusion (Procedure 1), injection via syringe (Procedure 2), and combination of regular bag infusion and syringe (Procedure 3). We conducted a retrospective analysis of all autologous stem cell transplants done in the hematology department of the Vivantes Clinic Neukoelln in Berlin, Germany, between January 1, 2016 and March 4, 2017. Of the total of 69 patients, 17 underwent Procedure 1, 32 Procedure 2, and 20 Procedure 3. Although speed of transplant reinfusion differed significantly between procedure types, these differences had no effect on duration of leukopenia. However, duration of leukopenia did correlate with need for blood transfusion and use of antibiotics. Our findings contradict the general perception that very rapid reinfusion is necessary. Nevertheless, considering the limitations of this study (retrospective, single center, small sample size) and that longer duration of aplasia is associated with greater need for intervention, efficient transplant reinfusion is advisable. More research is needed regarding timeliness and type of procedure used. | Leukopenia |
For the first time, growth curves are shown for the phytopathogen Xylella fastidiosa on traditional growth media such as PW (periwinkle wilt), BCYE (buffered charcoal yeast extract), and on new ones such as GYE (glutamate yeast extract) and PYE (phosphate yeast extract) that were developed in this work. The optimal growth conditions on solid and liquid media as well as their measurements are presented, by using total protein content and turbidity determinations. The results demonstrated that yeast extract provided sufficient nutrients for X. fastidiosa, since the cells grew well on PYE medium. | Vinca |
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease leading to visual loss, typically in young men, and rarely displays extra-ocular manifestations including spinal cord disease. We report the case of a 57-year-old man who presented with a longitudinally extensive dorsal column lesion as the first manifestation of LHON, with the onset of bilateral progressive optic neuropathy 11 months later, harbouring the m.14484T>C mutation. To our knowledge this is the most extensive cord lesion preceding optic neuropathy traversing the cervical and thoracic cord. We review the literature of all published cases of LHON in which spinal cord involvement was the presenting feature of the disease, summarising the clinical phenotype, demographics, radiological characteristics and genotype. We highlight the importance for diagnostic vigilance in patients with either longitudinally extensive dorsal column myelopathy, optic neuropathy or both." | Optic Atrophy, Hereditary, Leber |
Forty years ago, alcohol was not commonly recognized as a teratogen, an agent that can disrupt the development of a fetus. Today, we understand that prenatal alcohol exposure induces a variety of adverse effects on physical, neurological, and behavioral development. Research supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has contributed to the identification of the range and prevalence of fetal alcohol spectrum disorders (FASD), as well as methods for prevention and treatment of FASD. The worldwide prevalence and high personal and societal costs of FASD speak to the importance of this research. This article briefly examines some of the ways that NIAAA has contributed to our understanding of FASD, the challenges that we still face, and how this research is translated into changes in public policy." | National Institute on Alcohol Abuse and Alcoholism (U.S.) |
Thiamine (T) analogues pyrithiamine, oxythiamine or amprolium in amounts 10-1000 times higher than labelled T, were i.p. injected into rats together with 14C-T (30 microg; 46.25 KBq). The radioactivity associated with T and its phosphoesters in the plasma and cerebral cortex, brainstem, cerebellum, and sciatic nerve were determined at time intervals from 0.25 to 240 h from injection. The experimental data obtained were processed with a mathematical compartmental model that calculated the fractional rate constants. These are the amount of content in a given compartment that is replaced in 1 h and expressed in per hour. The results showed that all three analogues inhibited thiamine entry from plasma. Instead, oxythiamine enhanced T phosphorylation to T pyrophosphate (TPP); amprolium and oxythiamine enhanced TPP dephosphorylation to monophosphate (TMP); pyrithiamine reduced TPP dephosphorylation and TMP formation, while none of the analogues modified TMP dephosphorylation to T. In conclusion, in living rats, the action of T analogues was much more complex than could be expected from their structure and action in vitro. | Amprolium |
Illusions are not errors but erroneous beliefs motivated by wishful ideas and fantasies. To disillusion gender is to challenge the traditional Freudian construction that splits masculinity and femininity into agency versus passivity, the first with power, the second without. Disillusioning femininity as impotent frees up potency and power as generativity. Disillusioning masculinity as phallic and omnipotent opens the masculine subject to permeability and vulnerability. Illusions regarding the transgender include the idea that there are only two gender categories and the idea that gender identity is generated solely from an internal sense of self. The wish to be seen as" or "to pass as" one gender or the other shows that social structures exceed the individual. At least for now, the disillusionment of gender with which we are left marks a tension between the internal sense of gender identity and the social structures of gender." | Gender Identity |
Program development and review are a central part of institutional and industry quality assurance. Traditional approaches, although well established, present several barriers that could undermine the integrity of the process and the quality of outcomes. Here, a new approach to program development and design is explored with the goal of enhancing outcomes for students and institutions. | Program Development |
In this work, we evaluated the effects of Psidium cattleianum (Red Type) (PcRT) fruit extract on metabolic, behavioral, and neurochemical parameters in rats fed with a highly palatable diet (HPD) consisted of sucrose (65% carbohydrates being 34% from condensed milk, 8% from sucrose and 23% from starch, 25% protein and 10% fat). Animals were divided into 4 groups: standard chow, standard chow + PcRT extract (200 mg/Kg/day by gavage), HPD, HPD + extract. The animals were treated for 150 days. Concerning chemical profiling, LC/PDA/MS/MS analysis revealed cyanidin-3-O-glucoside as the only anthocyanin in the PcRT extract. Our results showed that the animals exposed to HPD presented glucose intolerance, increased weight gain and visceral fat, as well as higher serum levels of glucose, triacylglycerol, total cholesterol, LDL-cholesterol and interleukin-6. These alterations were prevented by PcRT. In addition, HPD caused an increase in immobility time in a forced swimming test and the fruit extract prevented this alteration, indicating an antidepressant-like effect. PcRT treatment also prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD consumption. Moreover, PcRT extract was able to restore Ca(2+)-ATPase activity in the prefrontal cortex, hippocampus, and striatum, as well as Na(+),K(+)-ATPase activity in the prefrontal cortex and hippocampus. PcRT treatment decreased thiobarbituric acid-reactive substances, nitrite, and reactive oxygen species levels and prevented the reduction of superoxide dismutase activity in all cerebral structures of the HPD group. Additionally, HPD decreased catalase in the hippocampus and striatum. However, the extract prevented this change in the hippocampus. Our results showed that this berry extract has antihyperglycemic and antihyperlipidemic effects, and neuroprotective properties, proving to be a potential therapeutic agent for individuals with metabolic syndrome. | Diet, Carbohydrate Loading |
CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146(EC-KO)) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146(EC-KO) mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) of CD146(EC-KO) mice. Mechanistic studies further confirmed that VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-kappaB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146(EC-KO) mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis. | CD146 Antigen |
Although it has proven difficult to demonstrate the clinical efficacy of therapeutic vaccination as a monotherapy in advanced cancers, its combination with an immunomodulatory treatment to reduce intra-tumor immunosuppression and improve vaccine efficacy is a very promising strategy. In this context, we are studying the combination of a vaccine composed of peptides of the tumor antigen survivin (SVX vaccine) with the anti-angiogenic agent sunitinib in a colorectal carcinoma model. To this end, we have been focusing on administration scheduling and have highlighted a therapeutic synergy between SVX vaccine and sunitinib when the vaccine was administered at the end of anti-angiogenic treatment. In this setting, a prolonged control of tumor growth associated with an important percentage of complete tumor regression was observed. Studying the remodeling induced by each therapy on the immunological and angiogenic tumor microenvironment over time we observed, during sunitinib treatment, a transient increase in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and a decrease in NK cells in the tumor microenvironment. In contrast, after sunitinib treatment was stopped, a decrease in PMN-MDSC populations has been observed in the tumor, associated with an increase in NK cells, pericyte coverage of tumor vessels and CD8(+) T cell population and functionality. In conclusion, sunitinib treatment results in the promotion of an immune-favorable tumor microenvironment that can guide the optimal sequence of vaccine and anti-angiogenic combination to reinforce their synergy. | Sunitinib |
An unprecedented coupling of a P-C and a C-C bond-forming event in a practical operation was developed to access medicinally relevant phosphinic structures. The strategy relies on an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites to allyl acrylates. This protocol was extended to a more versatile three-component variant that utilizes phosphinic acids, acryloyl chlorides, and allylic alcohols as starting materials. | Phosphinic Acids |
OBJECTIVE: This article reviews the literature concerning the function of the omentum and how omentectomy came to be part of the staging and treatment of epithelial ovarian cancer. METHODS: A review of the English language literature based on a MEDLINE (PubMed) database search using the key words: ovary, cancer, carcinoma, omentum, and omentectomy. An additional collection of reports was found by systematically reviewing all references from retrieved papers. RESULTS: Descriptions of the omentum can be found as far back as the time of the ancient Egyptians. An immunologic role of the omentum was confirmed in 1980s when milky spots" were described. Omentectomy arrived as part of the ovarian cancer guidelines in the 1960s after observing that the omentum was a frequent site of metastasis and that patients with removal of all diseased tissue did better. The exact role of the omentum in immunology and cancer remains incompletely understood. CONCLUSIONS: Historically, occult omental metastases in otherwise early disease have led to the inclusion of omentectomy for the purpose of accurate staging and for a possible therapeutic benefit. Laboratory studies on the role in cancer of the omental fat and milky spots are controversial." | Omentum |
To evaluate the effects of aging on vasoreactivity of pial arterioles to adenosine and barium chloride, an hydraulically intact cranial window preparation was developed in the rat. The microvasculature of anesthetized 3- and 24-month-old Fischer-344 rats was studied during superfusion with artificial cerebrospinal fluid with and without test agents and results determined by videomicroscopy techniques. In both cohorts, the response of pial arterioles to adenosine was both dose and vessel size dependent: arteriolar dilation increased with increasing concentrations of adenosine and at any given concentration the percent increase in diameter was greater in the smaller vessels. During adenosine superfusion the absolute changes and percent increase in vessel caliber were greater in the young rats. Arteriolar vasoconstriction due to barium chloride was vessel size dependent but there were no significant differences in response between young and aged rats. The results indicated an attenuated cerebrovascular response in aged rats to adenosine, but not to barium chloride. This may be due to a difference in the mode of action in these two compounds. Venules did not respond to adenosine at any concentration. | Pia Mater |
Myotonia congenita (Thomsen's disease) is a muscular disorder with autosomal dominant inheritance. The main symptom is muscle stiffness caused by hyperexcitability of the muscle cell membranes. The disorder is noticeable at birth or in early childhood and is progressive. Muscle hypertrophy is a common sign. Recessive generalized myotonia (Becker) resembles myotonia congenita in many respects, but there are also differences, e.g. later onset and transient muscle weakness experienced by many patients during muscle exertion after rest. The clinical signs usually progress over several years and then remain stable. The decisive criterion for the differential diagnosis of Thomsen or Becker type myotonia is the mode of inheritance. Both disorders are caused by defects of the gene, situated on chromosome 7, that is responsible for the normal functioning of the chloride channels in the muscle cell membranes. The differences between the two types of myotonia are probably caused by different mutations of this gene. The present paper also describes two animal models of myotonia (the myotonic goat and the myotonic mouse), which simulate the dominant and recessive types of human myotonia, respectively. The models have been very helpful in research into the origins of myotonia. | Myotonia Congenita |
A functional approach of gene cloning was applied to HeLa cells in an attempt to isolate positive mediators of programmed cell death. The approach was based on random inactivation of genes by transfections with antisense cDNA expression libraries, followed by the selection of cells that survived in the presence of the external apoptotic stimulus. An antisense cDNA fragment identical to human cathepsin D aspartic protease was rescued by this positive selection. The high cathepsin D antisense RNA levels protected the HeLa cells from interferon-gamma- and Fas/APO-1-induced death. Pepstatin A, an inhibitor of cathepsin D, suppressed cell death in these systems and interfered with the TNF-alpha-induced programmed cell death of U937 cells as well. During cell death, expression of cathepsin D was elevated and processing of the protein was affected, which resulted in high steady-state levels of an intermediate, proteolytically active, single chain form of this protease. Overexpression of cathepsin D by ectopic expression induced cell death in the absence of any external stimulus. Altogether, these results suggest that this well-known endoprotease plays an active role in cytokine-induced programmed cell death, thus adding cathepsin D to the growing list of proteases that function as positive mediators of apoptosis. | Cathepsin D |
Dry eye is a common yet complex condition. Intrinsic and extrinsic factors can cause dysfunction of the lids, lacrimal glands, meibomian glands, ocular surface cells, or neural network. These problems would ultimately be expressed at the tear film-ocular surface interface. The manifestations of these problems are experienced as symptoms such as grittiness, discomfort, burning sensation, hyperemia, and secondary epiphora in some cases. Accurate investigation of dry eye is crucial to correct management of the condition. Techniques can be classed according to their investigation of tear production, tear stability, and surface damage (including histological tests). The application, validity, reliability, compatibility, protocols, and indications for these are important. The use of a diagnostic algorithm may lead to more accurate diagnosis and management. The lack of correlation between signs and symptoms seems to favor tear film osmolarity, an objective biomarker, as the best current clue to correct diagnosis. | Tears |
We report three children with hypohidrotic ectodermal dysplasia (HED), which includes two sisters with unaffected parents (and therefore likely autosomal recessive inheritance of HED) and an unrelated boy. Each patient presented with hypohidrosis, sparse hair, oligodontia with conical teeth, periorbital hyperpigmentation, eczematous dermatitis, and facial features that include frontal bossing, a saddle nose, and prominent lips. HED is caused by defects in the ectodysplasin signal transduction pathway. Mutations in the gene encoding the ligand ectodysplasin A (EDA) underlie classic, X-linked recessive HED, whereas mutations in the genes encoding the EDA receptor and (less frequently) the adaptor protein that associates with the EDA receptor's death domain result in autosomal dominant and autosomal recessive forms of HED. | Receptors, Ectodysplasin |
BACKGROUND AND AIMS: The ranunculid model system Aquilegia is notable for the presence of a fifth type of floral organ, the staminode, which appears to be the result of sterilization and modification of the two innermost whorls of stamens. Previous studies have found that the genetic basis for the identity of this new organ is the result of sub- and neofunctionalization of floral organ identity gene paralogues; however, we do not know the extent of developmental and molecular divergence between stamens and staminodes. METHODS: We used histological techniques to describe the development of the Aquilegia coerulea 'Origami' staminode relative to the stamen filament. These results have been compared with four other Aquilegia species and the closely related genera Urophysa and Semiaquilegia. As a complement, RNA sequencing has been conducted at two developmental stages to investigate the molecular divergence of the stamen filaments and staminodes in A. coerulea 'Origami'. KEY RESULTS: Our developmental study has revealed novel features of staminode development, most notably a physical interaction along the lateral margin of adjacent organs that appears to mediate their adhesion. In addition, patterns of abaxial/adaxial differentiation are observed in staminodes but not stamen filaments, including asymmetric lignification of the adaxial epidermis in the staminodes. The comparative transcriptomics are consistent with the observed lignification of staminodes and indicate that stamen filaments are radialized due to overexpression of adaxial identity, while the staminodes are expanded due to the balanced presence of abaxial identity. CONCLUSIONS: These findings suggest a model in which the novel staminode identity programme interacts with the abaxial/adaxial identity pathways to produce two whorls of laterally expanded organs that are highly differentiated along their abaxial/adaxial axis. While the ecological function of Aquilegia staminodes remains to be determined, these data are consistent with a role in protecting the early carpels from herbivory and/or pathogens. | Aquilegia |
Continuous renal replacement therapy (CRRT) is the preferred modality of extracorporeal renal support for critically ill patients with acute kidney injury (AKI). The dose of CRRT is reported as effluent flow in ml/kg body weight per hour (ml/kg/h). Solid evidence supports that the delivered CRRT effluent dose for critically ill patients with AKI should be 20-25 ml/kg/h on average. To account for treatment interruptions and the natural decline in filter efficiency over time, it is recommended to prescribe 25-30 ml/kg/h of effluent dose. However, transient higher doses of CRRT in specific clinical scenarios may be needed to accommodate specific solute control needs of a particular patient at a given time. Consequently, there should be consideration of the potential adverse consequences of non-selective clearance such as undesired antimicrobials and nutrients removal. In this manuscript, we provide a summary of evidence related to CRRT dose, practical aspects for its calculation at the time of prescribing CRRT, and considerations for addressing the expected gap between prescribed and delivered CRRT dose. We also provide a framework for monitoring and implementation of CRRT dose as a quality indicator of CRRT delivery." | Continuous Renal Replacement Therapy |
Serous papillary cystadenofibromas (SPCAFs) of the fallopian tube are very rare benign tumors of the female genital tract. They are usually asymptomatic and are found incidentally. Until now, only 18 cases of this tumor have been reported in the world literature. We report a case of SPCAF of the left fallopian tube in a 30-year-old female who presented with a large abdominal mass and pain. On computed tomography, a diagnosis of ovarian neoplasm was given. However, during surgery the tumor was found to arise from the fallopian tube and was treated with tubal cystectomy with sparing of the ovary. We present this unique case on account of its rarity, unusual presentation, and huge size along with a short review of literature." | Neoplasms, Cystic, Mucinous, and Serous |
OBJECTIVE: To determine the effect of extracranial injury (ECI) on 6-month outcome in patients with mild traumatic brain injury (TBI) versus moderate-to-severe TBI. PARTICIPANTS/SETTING: Patients with TBI (n = 135) or isolated orthopedic injury (n = 25) admitted to a UK major trauma center and healthy volunteers (n = 99). DESIGN: Case-control observational study. MAIN MEASURES: Primary outcomes: (a) Glasgow Outcome Scale Extended (GOSE), (b) depression, (c) quality of life (QOL), and (d) cognitive impairment including verbal fluency, episodic memory, short-term recognition memory, working memory, sustained attention, and attentional flexibility. RESULTS: Outcome was influenced by both TBI severity and concomitant ECI. The influence of ECI was restricted to mild TBI; GOSE, QOL, and depression outcomes were significantly poorer following moderate-to-severe TBI than after isolated mild TBI (but not relative to mild TBI plus ECI). Cognitive impairment was driven solely by TBI severity. General health, bodily pain, semantic verbal fluency, spatial recognition memory, working memory span, and attentional flexibility were unaffected by TBI severity and additional ECI. CONCLUSION: The presence of concomitant ECI ought to be considered alongside brain injury severity when characterizing the functional and neurocognitive effects of TBI, with each presenting challenges to recovery. | Glasgow Outcome Scale |
Concentrated viral suspensions were purified by isopycnic gradients: discontinuous sucrose, continuous Percoll. With Percoll, homogenous buoyant density virus were obtained; hemagglutinating titer, concentration factor, specific activity, and reproducible yield were higher than with sucrose. | Centrifugation, Isopycnic |
Dormancy development in micropropagated plantlets at the acclimatization stage and early growth ex vitro is undesirable as it lowers their survival rate and restricts the efficient year-round production of planting material. Thus far, little is known about the factors and mechanisms involved in the dormancy development of micropropagated herbaceous perennials, including rhubarb. This study determined physiological and molecular changes in the Rheum rhaponticum (culinary rhubarb) 'Raspberry' planting material in response to photoperiod and temperature. We found that the rhubarb plantlets that were grown under a 16-h photoperiod (LD) and a temperature within the normal growth range (17-23 degrees C) showed active growth of leaves and rhizomes and did not develop dormancy. Rapid growth cessation and dormancy development were observed in response to a 10-h photoperiod (SD) or elevated temperature under LD. These morphological changes were accompanied by enhanced abscisic acid (ABA) and starch levels and also the upregulation of various genes involved in carbohydrate synthesis and transport (SUS3, AMY3, BMY3, BGLU17) and ABA synthesis and signaling (ZEP and ABF2). We also found enhanced expression levels of heat shock transcription factors (HSFA2 and HSFA6B), heat shock proteins (HSP22, HSP70.1, HSP90.2 and HSP101) and antioxidant enzymes (PRX12, APX2 and GPX). This may suggest that dormancy induction in micropropagated rhubarb plantlets is a stress response to light deficiency and high temperatures and is endogenously coordinated by the ABA, carbohydrate and ROS pathways. | Rheum |
Proprioception is a vital aspect of motor control and when degraded or lost can have a profound impact on function in diverse clinical populations. This systematic review aimed to identify clinically related tools to measure proprioceptive acuity, to classify the construct(s) underpinning the tools, and to report on the clinimetric properties of the tools. We searched key databases with the pertinent search terms, and from an initial list of 935 articles, we identified 57 of relevance. These articles described 32 different tools or methods to quantify proprioception. There was wide variation in methods, the joints able to be tested, and the populations sampled. The predominant construct was active or passive joint position detection, followed by passive motion detection and motion direction discrimination. The clinimetric properties were mostly poorly evaluated or reported. The Rivermead Assessment of Somatosensory Perception was generally considered to be a valid and reliable tool but with low precision; other tools with higher precision are potentially not clinically feasible. Clinicians and clinical researchers can use the summary tables to make more informed decisions about which tool to use to match their predominant requirements. Further discussion and research is needed to produce measures of proprioception that have improved validity and utility. | Feedback, Sensory |
Herpes zoster is an acute nervous system infection that commonly affects the elderly. Because the causative agent is a virus, herpes zoster is often treated symptomatically in the primary care setting. While this approach is acceptable for immunocompetent patients less than 50 years of age, it can leave older patients at greater risk of developing painful and debilitating complications such as postherpetic neuralgia. There is evidence that appropriate treatment initiated within 48 to 72 hours after the onset of the zoster eruption can decrease healing time, reduce acute pain, decrease ocular complications and may prevent the development of postherpetic neuralgia in this age group. The health care practitioner in a primary care setting is ideally placed to identify elderly clients with herpes zoster in the early stages; to consult with physicians about therapies such as steroids, antiviral agents and sympathetic nerve blocks; to monitor treatment effects; and to provide supportive therapy to those who develop postherpetic neuralgia. | Herpes Zoster |
Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca(2+)) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP(3)R), a homo- or heterotetramer of the IP(3)R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca(2+) from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP(3)R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP(3)R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca(2+) signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca(2+) signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP(3)R3 in IP(3)R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype-phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca(2+) channels and immunodeficiency and identify IP(3)Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca(2+)-associated immunodeficiency from store-operated entry to impaired Ca(2+) mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca(2+) signaling." | Inositol 1,4,5-Trisphosphate Receptors |
Mesenchymal stem cells (MSCs) are the most prominent type of adult stem cells for clinical applications. Three-dimensional (3D) cultivation of MSCs in biomimetic hydrogels provides a more physiologically relevant cultivation microenvironment for in vitro testing and modeling, thus overcoming the limitations of traditional planar cultivation methods. Cellulose nanofibers are an excellent candidate biomaterial for synthesis of hydrogels for this application, due to their biocompatibility, tunable properties, availability, and low cost. Herein, we demonstrate the capacity of hydrogels prepared from 2,2,6,6-tetramethylpiperidine-1-oxyl -oxidized and subsequently individualized cellulose-nanofibrils to support physiologically relevant 3D in vitro cultivation of human MSCs at low solid contents (0.2-0.5 wt %). Our results show that MSCs can spread, proliferate, and migrate inside the cellulose hydrogels, while the metabolic activity and proliferative capacity of the cells as well as their morphological characteristics benefit more in the lower bulk cellulose concentration hydrogels. | Cellulose, Oxidized |
A semi-isolated cockroach heart preparation was used to rapidly determine the activity of cobra cardiotoxin, monitored as a direct response on heart rate. This preparation produced a dose-response curve in the presence of active cardiotoxin and demonstrated that cardiotoxin retained its biological activity after boiling, although cardiotoxin activity was destroyed by heating in the presence of dithiothreitol. Experiments that cross-linked radiolabeled cardiotoxin to solubilized cockroach heart membranes suggested that cardiotoxin bound specifically to a 59,000 mol. wt membrane protein in this tissue. | Cobra Cardiotoxin Proteins |
Differentiation of cholinergic cell line NG108-15 induced by a combination of dibutyryl cyclic AMP (dbcAMP) and dexamethasone enhances the cholinergic phenotype of the cells more than that induced by either agent alone. We investigated the effect of treatment with dbcAMP and dexamethasone on potassium depolarization-evoked influx of calcium and its regulation by the muscarinic agonist carbachol. Depolarization of control cells and of cells differentiated in the presence of dbcAMP or dexamethasone alone, or in the combined presence of dbcAMP and dexamethasone induced, respectively, 2.2-, 4.3-, 2.7- and 10.7-fold increases of the resting [Ca(2+)](i). Dexamethasone alone and the combination of dbcAMP and dexamethasone augmented the number of muscarinic receptors by 25 and 40%, respectively. Inhibitors of N (omega-conotoxin GVIA) or P/Q (omega-agatoxin TK) calcium channels had no effect on Ca(2+) influx in control cells, whereas in cells differentiated in the combined presence of dbcAMP and dexamethasone they significantly diminished the influx of Ca(2+) by 20 and 5%, respectively. Carbachol attenuated calcium influx in differentiated cells in an atropine-insensitive manner if it was present during stimulation. This effect of carbachol was probably due to an open-channel block of L type channels. In the presence of nifedipine, carbachol attenuated the influx of Ca(2+) into cells differentiated with dbcAMP and dexamethasone by 20% in an atropine-sensitive way. Data show that differentiation of NG108-15 cells by dbcAMP and dexamethasone promotes the expression of functional nifedipine-insensitive N and P/Q types of Ca(2+) channels and that the nifedipine-insensitive calcium influx becomes subject to inhibitory regulation by muscarinic receptors. | Calcium Channels, P-Type |
The complete genomic sequences of two geographically distinct isolates of rice tungro bacilliform virus (RTBV) from India were determined. Both the sequences showed equal divergence from previously reported Southeast Asian isolates. Numerous insertions, deletions and substitutions, mostly in the intergenic regions, were found. The genome sizes were 7907 and 7934 bp respectively, 95 and 68 residues short of an infectious clone reported earlier. Between them, both the isolates showed high homology all along the genome, except for a 30-nucleotide insertion/deletion close to the 3' end of ORF III in one of them. Both the isolates indicated an unconventional start codon in ORF I, similar to the type isolate. In addition, as novel features, both the Indian isolates showed an unconventional start codon for ORF IV. Considering the low amounts of genome variability noticed in other RTBV isolates, the Indian isolates show that they have diverged sufficiently from the rest and should be considered belonging to a distinct strain. | Badnavirus |
Electrophoretic patterns of hemoglobins, Root effect, Bohr effect in blood and stripped hemoglobin, Hb-O2 affinity GTP modulation of Astyanax scabripinnis (lambari), caught at three different altitudes in Ribeirao Grande, near Campos do Jordao (Sao Paulo), are described. All populations showed the same electrophoretic patterns: two cathodal components in starch gel. Normal Bohr effect values were found in these three populations both in blood (phi = -0.11) and stripped hemoglobin (phi = -0.12). Different blood O2 affinities collected in fish of these 3 populations were detected. GTP has a large influence on Hb-O2 binding properties in A. scabripinnis. Stripped hemoglobin shows small Root effect. The addition of triphosphated nucleotides increases this effect. GTP is more effective than ATP on enhancing Root effect. Oxygen availability in water can be the factor responsible for differences found in blood O2 affinity. | Hemoglobins |
In the central nervous system (CNS), the inhibitory transmitter GABA interacts with three subtypes of GABA receptors, type A, type B, and type C. Historically, GABA receptors have been classified as either the inotropic GABAA receptors or the metabotropic GABAB receptors. Over the past 10 yr, studies have shown that a third class, called the GABAC receptor, also exists. GABAC receptors are found primarily in the vertebrate retina and to some extent in other parts of the CNS. Although GABAA and GABAC receptors both gate chloride channels, they are pharmacologically, molecularly, and functionally distinct. The rho subunit of the GABAC receptor, which has about 35% amino acid homology to GABAA receptor subunits, was cloned from the retina and, when expressed in Xenopus oocytes, has properties similar to retinal GABAC receptors. There are probably distinct roles for GABAC receptors in the retina, because they are found on only a subset of neurons, whereas GABAA receptors are ubiquitous. This article reviews recent electrophysiological and molecular studies that have characterized the unique properties of GABAC receptors and describes the roles that these receptors may play in visual information processing in the retina. | Receptors, GABA |
Receptor clustering on the cell membrane is critical in the signaling of many immunoreceptors, and this mechanism has previously been attributed to the extracellular and/or the intracellular interactions. Here, we report an unexpected finding that for death receptor 5 (DR5), a receptor in the tumor necrosis factor receptor superfamily, the transmembrane helix (TMH) alone in the receptor directly assembles a higher-order structure to drive signaling and that this structure is inhibited by the unliganded ectodomain. Nuclear magnetic resonance structure of the TMH in bicelles shows distinct trimerization and dimerization faces, allowing formation of dimer-trimer interaction networks. Single-TMH mutations that disrupt either trimerization or dimerization abolish ligand-induced receptor activation. Surprisingly, proteolytic removal of the DR5 ectodomain can fully activate downstream signaling in the absence of ligand. Our data suggest a receptor activation mechanism in which binding of ligand or antibodies to overcome the pre-ligand autoinhibition allows TMH clustering and thus signaling." | Receptors, TNF-Related Apoptosis-Inducing Ligand |
The changes induced in the relative concentrations of the different species of RNA (messenger, ribosomal, transfer and heterogenous) which regulate the metabolic behavior of tissues were studied in the endometrium of normal women and in women wearing a progesterone T IUD for 6-12 months. It was observed that the intrauterine release of progesterone is accompanied by a significant decrease in the content of total RNA (from 78 +or- 8.4 to 64 +or- 6.7 mcg/mg of protein) and in the RNA/DNA ratio (from 0.85 +or- 0.10 to 0.73 +or- 0.08). Although the protein decreased significantly (from 102 +or- 11 to 82 +or- 14 mg/g wet wt.), the DNA content and the Prot/DNA ratio were not altered. Using the affinity chromatography technique in poly(u)Sepharose it was found that the relative concentrations of RNA types were in general drastically modified: mRNA and rRNA decreased (from 2.6 +or- 0.31 to 1.28 +or- 0.15 and from 65.5 +or- 8.0 to 54.8 +or- 6.7 mcg/mg of protein respectively). tRNA content was increased (from 6.2 +or- 0.9 to 11.0 +or- 1.3) while hRNA was unchanged. The probable inhibitory effects of these changes in relation to the normal hormonal stimulation of the human endometrium, as a possible explanation of the mechanism of action of this device, are discussed. | Contraceptive Devices, Female |
We studied the impact of hibernation and food supply on relative telomere length (RTL), an indicator for aging and somatic maintenance, in free-living edible dormice. Small hibernators such as dormice have approximately 50% higher maximum longevity than non-hibernators. Increased longevity could theoretically be due to prolonged torpor directly slowing cellular damage and RTL shortening. However, although mitosis is arrested in mammals at low body temperatures, recent evidence points to accelerated RTL shortening during periodic re-warming (arousal) from torpor. Therefore, we hypothesized that these arousals during hibernation should have a negative effect on RTL. Here, we show that RTL was shortened in all animals over the course of approximately 1 year, during which dormice hibernated for 7.5-11.4 months. The rate of periodic arousals, rather than the time spent euthermic during the hibernation season, was the best predictor of RTL shortening. This finding points to negative effects on RTL of the transition from low torpor to high euthermic body temperature and metabolic rate during arousals, possibly because of increased oxidative stress. The animals were, however, able to elongate their telomeres during the active season, when food availability was increased by supplemental feeding in a year of low natural food abundance. We conclude that in addition to their energetic costs, periodic arousals also lead to accelerated cellular damage in terms of RTL shortening. Although dormice are able to counteract and even over-compensate for the negative effects of hibernation, restoration of RTL appears to be energetically costly. | Myoxidae |
Although exclusive breastfeeding for the first 6 months of infant life is recommended in the UK, there is little information on the extent of exclusive breastfeeding. This study has taken the 1996 and 2003 World Health Organization (WHO) definitions of breastfeeding and investigated breastfeeding rates in the first 6 months of life in infants born to mothers enrolled in a longitudinal, representative, population-based cohort study--the Avon Longitudinal Study of Parents and Children (ALSPAC). Information about breastfeeding and introduction of solids was available for 11 490 infants at 6 months of age (81% of live births). Exclusive breastfeeding declined steadily from 54.8% in the first month to 31% in the third, and fell to 9.6% in the fourth month mainly due to the introduction of solids to the infants. In the first 2 months, complementary feeding (breastmilk and solid/semi-solid foods with any liquid including non-human milk) was used in combination, and declined from 22% in the first month to 16.8% in the second due to a switch to exclusive commercial infant formula feeding. Replacement feeding (exclusive commercial infant formula or combined with any liquid or solid/semi-solid food but excluding breastmilk) increased steadily from 21.9% in the first month to 67.1% by the seventh. This obscured the change from exclusive commercial infant formula feeding only to commercial infant formula feeding plus solids/semi-solids, a change which started in the third month and was complete by the fifth. Using categories in the 1996 and 2003 WHO definitions, such as complementary feeding and replacement feeding, presented difficulties for an analysis of the extent of breastfeeding in this population." | Child Nutritional Physiological Phenomena |
Somites are formed progressively from the presomitic mesoderm (PSM) in a highly regulated process according to a strict periodicity driven by an oscillatory mechanism. The Notch and Wnt pathways are key components in the regulation of this somitic oscillator and data from Xenopus and zebrafish embryos indicate that the Notch-downstream target Nrarp participates in the regulation of both activities. We have analyzed Nrarp/nrarp-a expression in the PSM of chick, mouse and zebrafish embryos, and we show that it cycles in synchrony with other Notch regulated cyclic genes. In the mouse its transcription is both Wnt- and Notch-dependent, whereas in the chick and fish embryo it is simply Notch-dependent. Despite oscillating mRNA levels, Nrarp protein does not oscillate in the PSM. Finally, neither gain nor loss of Nrarp function interferes with the normal expression of Notch-related cyclic genes. | Somites |
A total of 6,500 mosquitoes were identified during a two-year survey (1999-2001) in Lebanon, and these belonged to twelve species: Culex pipiens, Cx. laticinctus, Cx. mimeticus, Cx. hortensis, Cx. judaicus, Aedes aegypti, Ae. cretinus, Ochlerotatus caspius, Oc. geniculatus, Oc. pulchritarsis, Culiseta longiareolata and Anopheles claviger. Culex pipiens was the most predominant species in Lebanon, collected indoors and outdoors. It was continuously abundant and active throughout the year. Culex judaicus was a small and rare mosquito and it is reported to occur for the first time in Lebanon. On the coastal areas, Ochlerotatus caspius was very common, and proved to be a complex of species as two forms were detected. One of the vectors of malaria, Anopheles claviger, was collected from May to September, from eight sites in Lebanon. Its breeding sites were restricted to fresh, cool, and clean water in pools and wells. Most of these breeding sites were in the populated Metn County where a few indigenous cases of malaria were reported from 1997-2000. This shows that the reported malaria cases were not imported, but caused by the bites of locally infected Anopheles females. | Ochlerotatus |
BACKGROUND: A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio((R)) Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. METHODS: In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus((R)) tablets) or the control product (CP: Nexgard Spectra((R)) tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0-41.5 mg/kg bodyweight lotilaner and 0.75-1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. RESULTS: Flea effectiveness of Credelio Plus((R)) after 3 consecutive monthly treatments was 100% against Ctenocephalides felis, C. canis and Pulex irritans. Tick effectiveness of Credelio Plus((R)) over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus (s.l.). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis, C. canis and P. irritans. Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus. Credelio Plus((R)) was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. CONCLUSIONS: This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus((R))) administered orally to dogs naturally infested with fleas and/or ticks. | Flea Infestations |
Mycoplasma pneumoniae (Mpn) is a human pathogen causing acute respiratory diseases and accounts for approximately 30% cases of community-acquired pneumonia. Co-infection with Mycoplasmas compromises the efficacy of anticancer and antiviral nucleoside analog-based drugs due to the presence of Mycoplasma thymidine phosphorylase (TP). In this study, a TP-deficient strain of Mpn was generated in order to study the effect of Mpn TP in the metabolism of nucleoside analogs. Deficiency in TP activity led to increased uptake and incorporation of radiolabeled deoxyuridine and uracil but thymidine uptake was not affected. The activities of enzymes in the salvage of thymidine and deoxyuridine, e.g., thymidine kinase and uracil phosphoribosyltransferase were upregulated in the TP-deficient mutant, which may explain the increased uptake of deoxyuridine and uracil. Thirty FDA-approved anticancer and antiviral nucleoside and nucleobase analogs were used to screen their inhibitory activity toward the TP mutant and the wild type strain. Seven analogs were found to inhibit strongly the growth of both wild type and TP mutant. Differences in the inhibitory effect of several purine analogs between the two strains were observed. Further study is needed in order to understand the mechanism of inhibition caused by these analogs. Our results indicated that TP is not an essential gene for Mpn survival and TP deficiency affects other enzymes in Mpn nucleotide metabolism, and suggested that Mycoplasma nucleotide biosynthesis pathway enzymes are potential targets for future development of antibiotics. | Pyrimidine Phosphorylases |
Central pontine and extrapontine myelinolysis are uncommon disorders characterized by distinctive clinical features and typical findings on neuroimaging. Only a few cases are reported in the pediatric age group. We describe the case of a leukemic, malnourished 14-year-old boy with a high serum sodium concentration that gradually increased to 170 mmol/L. During a septic shock episode, hydration with a low sodium concentration at the rate of 104 mL/h for 24 h was administered. A rapid correction of the high serum sodium occurred, exceeding 0.5 mmol/L/h. The following day the patient developed rapid and progressive neurological impairment with clinical features characteristic of central pontine and extrapontine myelinolysis. Magnetic resonance imaging confirmed the diagnosis 11 days later. The patient was treated with steroids and intravenous immunoglobulins. He achieved an almost full neurological recovery and radiological improvement. The reported case demonstrates that central pontine and extrapontine myelinolysis can occur after excessively rapid correction of hypernatremia. | Myelinolysis, Central Pontine |
Lipid accumulation often leads to lipotoxic injuries to hepatocytes, which can cause nonalcoholic steatohepatitis. The association of inflammation with lipid accumulation in liver tissue has been studied for decades; however, key mechanisms have been identified only recently. In particular, it is still unknown how hepatic inflammation regulates lipid metabolism in hepatocytes. Herein, we found that PA treatment or direct stimulation of STING1 promoted, whereas STING1 deficiency impaired, MTORC1 activation, suggesting that STING1 is involved in PA-induced MTORC1 activation. Mechanistic studies revealed that STING1 interacted with several components of the MTORC1 complex and played an important role in the complex formation of MTORC1 under PA treatment. The involvement of STING1 in MTORC1 activation was dependent on SQSTM1, a key regulator of the MTORC1 pathway. In SQSTM1-deficient cells, the interaction of STING1 with the components of MTORC1 was weak. Furthermore, the impaired activity of MTORC1 via rapamycin treatment or STING1 deficiency decreased the numbers of LDs in cells. PA treatment inhibited lipophagy, which was not observed in STING1-deficient cells or rapamycin-treated cells. Restoration of MTORC1 activity via treatment with amino acids blocked lipophagy and LDs degradation. Finally, increased MTORC1 activation concomitant with STING1 activation was observed in liver tissues of nonalcoholic fatty liver disease patients, which provided clinical evidence for the involvement of STING1 in MTORC1 activation. In summary, we identified a novel regulatory loop of STING1-MTORC1 and explain how hepatic inflammation regulates lipid accumulation. Our findings may facilitate the development of new strategies for clinical treatment of hepatic steatosis.Abbreviations: AA: amino acid; ACTB: actin beta; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; DEPTOR: DEP domain containing MTOR interacting protein; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FFAs: free fatty acids; GFP: green fluorescent protein; HFD: high-fat diet; HT-DNA: herring testis DNA; IL1B: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LDs: lipid droplets; MAP1LC3: microtubule associated protein 1 light chain 3; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MLST8: MTOR associated protein, LST8 homolog; MT-ND1: mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NAFL: nonalcoholic fatty liver; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NPCs: non-parenchymal cells; PA: palmitic acid; PLIN2: perilipin 2; RD: regular diet; RELA: RELA proto-oncogene, NF-kB subunit; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RPTOR: regulatory associated protein of MTOR complex 1; RRAGA: Ras related GTP binding A; RRAGC: Ras related GTP binding C; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGs: triglycerides; TREX1: three prime repair exonuclease 1. | Sequestosome-1 Protein |
Dyspnea is a common symptom and, in most cases, can be effectively managed in the office by the family physician. The differential diagnosis is composed of four general categories: cardiac, pulmonary, mixed cardiac or pulmonary, and noncardiac or nonpulmonary. Most cases of dyspnea are due to cardiac or pulmonary disease, which is readily identified with a careful history and physical examination. Chest radiographs, electrocardiograph and screening spirometry are easily performed diagnostic tests that can provide valuable information. In selected cases where the test results are inconclusive or require clarification, complete pulmonary function testing, arterial blood gas measurement, echocardiography and standard exercise treadmill testing or complete cardiopulmonary exercise testing may be useful. A consultation with a pulmonologist or cardiologist may be helpful to guide the selection and interpretation of second-line testing. | Diagnosis |
Accumulated evidence to date confirms the importance of the C3-CR pathway in the phagocytosis of pathogenic mycobacteria. Detailed receptor-ligand studies for phagocytosis are creating the framework to test the hypothesis that the entry pathway for these bacteria influences the immediate host cell response and their intracellular fate. These types of study are particularly important for improving our understanding of the outcome of primary infection in humans, where the number of bacilli is presumed to be very low. | Complement C2a |
PURPOSE OF REVIEW: Anal fissures are very common. They are easy to diagnose and treat in the office setting. They may coexist with hemorrhoids. In fact 20% of patients with hemorrhoids have anal fissures also. The purpose of this review is to highlight current diagnosis and treatment of anal fissures using diet, ointments and botulinum toxin to enable healing. Medical treatment relies on reducing anal sphincter spasm to allow improved blood flow and healing. RECENT FINDINGS: Many anorectal disorders can be managed in the office. Most anal fissures can be managed without the need for surgery. The need for anorectal examination, including use of anoscopy is stressed in the current literature. The use of calcium channel blockers in preference to nitroglycerin is highlighted as well as the use of botulinum toxin when ointments don't work. SUMMARY: Anal fissure can be managed nonsurgically most of the time and gastroenterologists should be able to manage them. This article should help in preventing unnecessary surgery and its complications, mainly incontinence in a small but significant number. The search for more effective drugs and options for managing this disorder continues. | Fissure in Ano |
OBJECTIVE: To determine the characteristics and outcomes of pregnancy in women with Turner syndrome. DESIGN: Retrospective 20-year cohort study (2000-20). SETTING: Sixteen tertiary referral maternity units in the UK. POPULATION OR SAMPLE: A total of 81 women with Turner syndrome who became pregnant. METHODS: Retrospective chart analysis. MAIN OUTCOME MEASURES: Mode of conception, pregnancy outcomes. RESULTS: We obtained data on 127 pregnancies in 81 women with a Turner phenotype. All non-spontaneous pregnancies (54/127; 42.5%) were by egg donation. Only 9/31 (29%) pregnancies in women with karyotype 45,X were spontaneous, compared with 53/66 (80.3%) pregnancies in women with mosaic karyotype 45,X/46,XX (P < 0.0001). Women with mosaic karyotype 45,X/46,XX were younger at first pregnancy by 5.5-8.5 years compared with other Turner syndrome karyotype groups (P < 0.001), and more likely to have a spontaneous menarche (75.8% versus 50% or less, P = 0.008). There were 17 miscarriages, three terminations of pregnancy, two stillbirths and 105 live births. Two women had aortic dissection (2.5%); both were 45,X karyotype with bicuspid aortic valves and ovum donation pregnancies, one died. Another woman had an aortic root replacement within 6 months of delivery. Ten of 106 (9.4%) births with gestational age data were preterm and 22/96 (22.9%) singleton infants with birthweight/gestational age data weighed less than the tenth centile. The caesarean section rate was 72/107 (67.3%). In only 73/127 (57.4%) pregnancies was there documentation of cardiovascular imaging within the 24 months before conceiving. CONCLUSIONS: Pregnancy in women with Turner syndrome is associated with major maternal cardiovascular risks; these women deserve thorough cardiovascular assessment and counselling before assisted or spontaneous pregnancy managed by a specialist team. TWEETABLE ABSTRACT: Pregnancy in women with Turner syndrome is associated with an increased risk of aortic dissection. | Turner Syndrome |
Aldehydes are important synthons for DNA-encoded library (DEL) construction, but the development of a DNA-compatible method for the oxidation of alcohols to aldehydes remains a significant challenge in the field of DEL chemistry. We report that a copper/TEMPO catalyst system enables the solution-phase DNA-compatible oxidation of DNA-linked primary activated alcohols to aldehydes. The semiaqueous, room-temperature reaction conditions afford oxidation of benzylic, heterobenzylic, and allylic alcohols in high yield, with DNA compatibility verified by mass spectrometry, qPCR, Sanger sequencing, and ligation assays. Subsequent transformations of the resulting aldehydes demonstrate the potential of this method for robust library diversification. | Cyclic N-Oxides |
OBJECTIVES: Default mode network (DMN) connectivity is altered in depression. We evaluated the relationship between changes in within-network DMN connectivity and improvement in depression in a subsample of our parent clinical trial comparing escitalopram/memantine (ESC/MEM) to escitalopram/placebo (ESC/PBO) in older depressed adults (NCT01902004). METHODS: Twenty-six participants with major depression (age > 60 years) and subjective memory complaints underwent treatment with ESC/MEM (n = 13) or ESC/PBO (n = 13), and completed baseline and 3-month follow-up resting state magnetic resonance imaging scans. Multi-block partial least squares correlation analysis was used to evaluate the impact of treatment on within-network DMN connectivity changes and their relationship with symptom improvement at 3 months (controlling for age and sex). RESULTS: A significant latent variable was identified, reflecting within-network DMN connectivity changes correlated with symptom improvement (p = .01). Specifically, although overall group differences in within-network DMN connectivity changes failed to reach significance, increased within-network connectivity of posterior/lateral DMN regions (precuneus, angular gyrus, superior/middle temporal cortex) was more strongly and positively correlated with symptom improvement in the ESC/MEM group (r = 0.97, 95% confidence interval: 0.86-0.98) than in the ESC/PBO group (r = 0.36, 95% confidence interval: 0.13-0.72). CONCLUSIONS: Increased within-network connectivity of core DMN nodes was more strongly correlated with depressive symptom improvement with ESC/MEM than with ESC/PBO, supporting an improved engagement of brain circuitry implicated in the amelioration of depressive symptoms with combined ESC/MEM treatment in older adults with depression and subjective memory complaints. | Default Mode Network |
When unexpected events occur during goal-directed behavior, they automatically trigger an orienting-related cascade of psychological and neural processes through which they influence behavior and cognition. If the unexpected event was caused by an action error, additional error-specific, strategic-related processes have been proposed to follow the initial orienting period. Little is known about the neural interactions between action errors and unexpected perceptual events, two instantiations of unexpected events, in these two putative stages of post-error processing. Here, we aimed to address this by investigating the electrophysiological dynamics associated with action errors and unexpected perceptual events using scalp EEG with a focus on the frontal midline (FM) delta-to-theta oscillations (1-8 Hz) indicative of the performance-monitoring system. Specifically, we examined how the timing of unexpected sounds would influence behavior and neural oscillations after action errors, depending on the length of the intertrial interval (ITI). Our data showed that unexpected sounds aggravated post-error decreases in accuracy when they occurred (1) immediately after errors (i.e., post-error orienting period), regardless of ITI and (2) immediately after the post-error stimulus (i.e., post-error strategic period), at short ITIs. Meanwhile, action errors and unexpected sounds independently produced increased FM delta-to-theta power during the post-error orienting period, regardless of ITIs. However, when unexpected sounds occurred during the post-error strategic period, action errors produced lower FM delta-to-theta power than correct responses, at short ITIs. These differential effects of unexpected events on behavior and FM delta-to-theta dynamics support the notion of the two post-error periods during which different processes are implemented. | Delta Rhythm |
Mastocytosis is a heterogeneous disease of bone marrow origin, characterized by local or diffuse increased growth and accumulation of clonal mast cells in the skin and/or in internal organs. The skin is the organ most frequently involved, but others may be affected as well. The purpose of this article is to present the oral management of a child with urticaria pigmentosa/maculopapulous cutaneous mastocytosis requiring dental treatment under general anesthesia. The multidisciplinary team approach involving the relevant medical specialists is discussed to emphasize the significance of coordinated patient management. | Mastocytosis, Cutaneous |
PURPOSE: To determine whether organic electroluminescence (OLED) screens can be used as visual stimulators to elicit pattern-reversal visual evoked potentials (p-VEPs). METHOD: Checkerboard patterns were generated on a conventional cathode-ray tube (S710, Compaq Computer Co., USA) screen and on an OLED (17 inches, 320 x 230 mm, PVM-1741, Sony, Tokyo, Japan) screen. The time course of the luminance changes of each monitor was measured with a photodiode. The p-VEPs elicited by these two screens were recorded from 15 eyes of 9 healthy volunteers (22.0 +/- 0.8 years). RESULTS: The OLED screen had a constant time delay from the onset of the trigger signal to the start of the luminescence change. The delay during the reversal phase from black to white for the pattern was 1.0 msec on the cathode-ray tube (CRT) screen and 0.5 msec on the OLED screen. No significant differences in the amplitudes of P100 and the implicit times of N75 and P100 were observed in the p-VEPs elicited by the CRT and the OLED screens. CONCLUSION: The OLED screen can be used as a visual stimulator to elicit p-VEPs; however the time delay and the specific properties in the luminance change must be taken into account. | Evoked Potentials, Visual |
Although sclerotherapy as a treatment for hydroceles has gained in popularity during the last few years, there is no consensus on whether it can also be adopted for the treatment of spermatoceles. We examine here the efficacy and safety of ethanolamine oleate sclerotherapy in cases of spermatocele using ultrasound (US) before treatment and during follow-up. Thirty-seven consecutive outpatients aged 36-84 years (mean 61) with symptoms of 40 spermatoceles (1-3 chambers) treated by sclerotherapy were included in the series. It is concluded that US allows multilocular spermatoceles to be differentiated from hydroceles. Post-treatment US findings are typical, including heteroechoic masses with cystic areas extratesticularly, hyperechoic lines peritesticularly (thickened tunicas) and a thickened scrotal wall. All lesions are reversible, however. US is helpful when assessing the need for resclerotherapy. Ethanolamine oleate proved to be effective as a sclerosant, as 83% of the cases were cured or became significantly better. Complications were few and there were no changes in the epididymis. Ethanolamine oleate sclerotherapy can be recommended as an alternative treatment to surgery, especially in older patients with spermatoceles consisting of 1-3 chambers. | Spermatocele |
Parkinson disease (PD) is a progressive neurodegenerative condition characterized by bradykinesia, rigidity, resting tremor, and postural instability. Non-motor symptoms, including pain, fatigue, insomnia, anxiety, and depression to name a few, are increasingly recognized and often just as disabling at motor symptoms. The mainstay of treatment is dopamine replacement; however, the beneficial effects tend to wane over time with disease progression, and patients often experience motor fluctuations and medication side effects. The lack of a disease-modifying intervention and the shortcomings of traditional symptomatic medications have led many patients to pursue complementary therapies to alleviate motor and non-motor symptoms associated with PD. The term complementary implies that the therapy is used along with conventional medicine and may include supplements, manipulative treatments (chiropractic, massage), exercise-based programs, and mind-body practices. As these practices become more widespread in Western medicine, there is a growing interest in evaluating their effects on a number of medical conditions, PD included. In this review, we provide an update on clinical trials that have evaluated the effectiveness of complementary treatments for patients with PD, specifically focusing on acupuncture, Tai Chi, Qi Gong, yoga, and cannabis. | Tai Ji |
A novel synthesis of natural drimanic compounds, (-)-albrassitriol (2) and (-)-6-epi-albrassitriol (3), has been carried out starting from an easily available labdane diterpenoid, (+)-larixol (1). In a two-step procedure, (+)-larixol (1) was converted into 14,15-bisnorlab-7-ene-6,13-dione (9), which was then submitted to a Norrish type II photochemical degradation yielding drim-7,9(11)-diene-6-one (10), whose treatment with OsO4 led selectively to the formation of drim-7-ene-9alpha,11-diol-6-one (12). The same compound was obtained by selective epoxidation of the C(9)-C(11) double bond in drim-7,9(11)-diene-6-one (10) with monoperphtalic acid. Treatment of the resulting mixture of alpha- and beta-epoxides (13 and 14) with HClO4 yielded drim-7-ene-9alpha,11-diol-6-one (12). Reduction of the C6-carbonyl group in drim-7-ene-9alpha,11-diol-6-one (12) with LiAlH4 afforded (-)-albrassitriol (2) and (-)-6-epi-albrassitriol (3), 12.4% and 13.6% overall yields, respectively. | Naphthols |
BACKGROUND: In this study we tried to assess the efficacy of topical emollients in the treatment of patients with PUVA-induced pruritus. MATERIAL AND METHODS: 41 patients over 18 years of age, who received PUVA treatment in the phototherapy unit, were included in the study. Patients were randomly divided into two groups; Group I was administered with a 4% urea lotion and Group II was administered with liquid petrolatum. The follow-up period was minimum 4 weeks. During the first 2 weeks, patients were administered topical emollients and received PUVA treatment together. The next 2 weeks, they continued PUVA treatment without any medication. RESULTS: When time-dependent changes in the visual analogue scale scores for pruritus of both groups were considered, both treatment methods were found to be remarkably successful (p < 0.0001). In addition, an insignificant group-time interaction was identified (p = 0.753). CONCLUSIONS: Topical emollients were found to be effective in the treatment of PUVA-induced pruritus. Both forms of medication can be successfully administered and increase the patient's compliance with medication. | Emollients |
In this study, we examined the effect of tomatidine on tumor necrosis factor (TNF)-alpha-induced apoptosis in C(2)C(12) myoblasts. TNF-alpha treatment increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) protein levels in a dose- and time-dependent manner. Pretreatment of cells with 10 muM tomatidine prevented TNF-alpha-induced apoptosis, caspase 3 cleavage, and PARP cleavage. Cells were treated with 100 ng/mL TNF-alpha for 24 h, and flow cytometry was utilized to assess apoptosis using annexin-V and 7-aminoactinomycin D. TNF-alpha up-regulated activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression. This effect was suppressed by pretreatment with tomatidine. Pretreatment with 4-phenylbutyric acid (a chemical chaperone) also inhibited TNF-alpha-induced cleavage of caspase 3 and PARP and up-regulation of ATF4 and CHOP expression. In addition, tomatidine-mediated inhibition of phosphorylation of c-Jun amino terminal kinase (JNK) attenuated TNF-alpha-induced cleavage of PARP and caspase 3. However, tomatidine did not affect NF-kappaB activation in TNF-alpha-treated C(2)C(12) myoblast cells. Taken together, the present study demonstrates that tomatidine attenuates TNF-alpha-induced apoptosis through down-regulation of CHOP expression and inhibition of JNK activation. | Tomatine |
The quantitative or qualitative decline of high-density lipoprotein (HDL) is linked to the pathogenesis of atherosclerosis because of its antiatherogenic functions, including the mediation of reverse cholesterol transport from the peripheral cells to the liver. We have recently shown that group X secretory phospholipase A(2) (sPLA(2)-X) is involved in the pathogenesis of atherosclerosis via potent lipolysis of low-density lipoprotein (LDL) leading to macrophage foam cell formation. We demonstrate here that sPLA(2)-X as well as group V secretory PLA(2) (sPLA(2)-V), another group of sPLA(2) that can potently hydrolyze phosphatidylcholine (PC), also possess potent hydrolytic potency for PC in HDL linked to the production of a large amount of unsaturated fatty acids and lysophosphatidylcholine (lysoPC). In contrast, the classical types of group IB and IIA secretory PLA(2)s evoked little, if any, lypolytic modification of HDL. Treatment with sPLA(2)-X or -V also caused an increase in the negative charge of HDL with no oxidation and little modification of apolipoprotein AI (apoAI). Modification with sPLA(2)-X or -V resulted in significant decrease in the capacity of HDL to cause cellular cholesterol efflux from lipid-loaded macrophages. Immunohistochemical analysis revealed significant expression of sPLA(2)-X in foam cell lesions in the arterial intima of Watanabe heritable hyperlipidemic (WHHL) rabbit. These findings suggest that lipolytic modification of HDL by sPLA(2)-X or -V causes drastic change of HDL in terms of the production of a large amount of unsaturated fatty acids and lysoPC linked to the reduction of its antiatherogenic functions. These sPLA(2)-mediated modifications of plasma lipoproteins might be relevant to the pathogenesis of atherosclerosis. | Group X Phospholipases A2 |
This cross-over study compares the relative benefits of a standard NHS contracted hearing aid with a high-frequency emphasis commercial aid in subjects with high-frequency hearing loss. Disability questionnaires and free-field speech-in-noise (FAAF II) tests were used to assess subjects unaided and after 6 weeks of wearing each aid. Total FAAF II test scores showed no significant difference with either aid, but analysis of frequency-specific subscores demonstrated less use of low-frequency information when using the high-frequency emphasis aid. Overall questionnaire responses relating to conversation showed more benefit with the high-frequency emphasis aid. Subjects generally preferred this aid, possibly due to less low-tone gain than the standard NHS aid. | Hearing Loss, High-Frequency |
Long-duration space missions will need to rely on the use of plants in bio-regenerative life support systems (BLSSs) because these systems can produce fresh food and oxygen, reduce carbon dioxide levels, recycle metabolic waste, and purify water. In this scenario, the need for new experiments on the effects of altered gravity conditions on plant biological processes is increasing, and significant efforts should be devoted to new ideas aimed at increasing the scientific output and lowering the experimental costs. Here, we report the design of an easy-to-produce and inexpensive device conceived to analyze the effect of interaction between gravity and light on root tropisms. Each unit consisted of a polystyrene multi-slot rack with light-emitting diodes (LEDs), capable of holding Petri dishes and assembled with a particular filter-paper folding. The device was successfully used for the ROOTROPS (for root tropisms) experiment performed in the Large Diameter Centrifuge (LDC) and Random Positioning Machine (RPM) at ESA's European Space Research and Technology centre (ESTEC). During the experiments, four light treatments and six gravity conditions were factorially combined to study their effects on root orientation of Brassica oleracea seedlings. Light treatments (red, blue, and white) and a dark condition were tested under four hypergravity levels (20 g, 15 g, 10 g, 5 g), a 1 g control, and a simulated microgravity (RPM) condition. Results of validation tests showed that after 24 h, the assembled system remained unaltered, no slipping or displacement of seedlings occurred at any hypergravity treatment or on the RPM, and seedlings exhibited robust growth. Overall, the device was effective and reliable in achieving scientific goals, suggesting that it can be used for ground-based research on phototropism-gravitropism interactions. Moreover, the concepts developed can be further expanded for use in future spaceflight experiments with plants. | Hypogravity |
Gap junctions confer interconnectivity of the cytoplasm in neighboring cells via docking of two connexons expressed in each of the adjacent membranes. Undocked connexons, referred to as hemichannels, may open and connect the cytoplasm with the extracellular fluid. The hemichannel configuration of connexins (Cxs) displays isoform-specific permeability profiles that are not directly determined by the size and charge of the permeant. To further explore Ca(2+)-mediated gating and permeability features of connexin hemichannels, we heterologously expressed Cx30 hemichannels in Xenopus laevis oocytes. The sensitivity toward divalent cation-mediated gating differed between small atomic ions (current) and fluorescent dye permeants, indicating that these permeants are distinctly gated. Three aspartate residues in Cx30 (Asp-50, Asp-172, and Asp-179) have been implicated previously in the Ca(2+) sensitivity of other hemichannel isoforms. Although the aspartate at position Asp-50 was indispensable for divalent cation-dependent gating of Cx30 hemichannels, substitutions of the two other residues had no significant effect on gating, illustrating differences in the gating mechanisms between connexin isoforms. Using the substituted cysteine accessibility method (SCAM), we evaluated the role of possible pore-lining residues in the permeation of ions and ethidium through Cx30 hemichannels. Of the cysteine-substituted residues, interaction of a proposed pore-lining cysteine at position 37 with the positively charged compound [2-(trimethylammonium)ethyl] methane thiosulfonate bromide (MTS-ET) increased Cx30-mediated currents with unperturbed ethidium permeability. In summary, our results demonstrate that the permeability of hemichannels is regulated in a permeant-specific manner and underscores that hemichannels are selective rather than non-discriminating and freely diffusable pores. | Connexin 30 |
Salla disease, one of three disease phenotypes that manifest increased urinary excretion of unconjugated sialic acid, is an autosomal recessive condition caused by a mutation in SLC17A5. This gene encodes sialin, a lysosomal membrane transporter for sialic acid. Salla disease is rare outside of individuals of Finnish ancestry. In this report we describe the disorder in non-Finnish monozygous twin siblings, the first reported American cases of Salla disease. | Sialic Acid Storage Disease |
The group VIA PLA2 is a member of the PLA2 superfamily. This enzyme, which is cytosolic and Ca2+-independent, has been designated iPLA2beta to distinguish it from another recently cloned Ca2+-independent PLA2. Features of iPLA2beta molecular structure offer some insight into possible cellular functions of the enzyme. At least two catalytically active iPLA2beta isoforms and additionalsplicing variants are derived from a single gene that consists of at least 17 exons located on human chromosome 22q13.1. Potential tumor suppressor genes also reside at or near this locus. Structural analyses reveal that iPLA2beta contains unique structural features that include a serine lipase consensus motif (GXSXG), a putative ATP-binding domain, an ankyrin-repeat domain, a caspase-3 cleavage motif DVTD138Y/N, a bipartite nuclear localization signal sequence, and a proline-rich region in the human long isoform. iPLA2beta is widely expressed among mammalian tissues, with highest expression in testis and brain. iPLA2beta prefers to hydrolyze fatty acid at the sn-2 fatty acid substituent but also exhibits phospholipase A1, lysophospholipase, PAF acetylhydrolase, and transacylase activities. iPLA2beta may participate in signaling, apoptosis, membrane phospholipid remodeling, membrane homeostasis, arachidonate release, and exocytotic membrane fusion. Structural features and the existence of multiple splicing variants of iPLA2beta suggest that iPLA2beta may be subject to complex regulatory mechanisms that differ among cell types. Further study of its regulation and interaction with other proteins may yield insight into how its structural features are related to its function. | Phospholipases A |
AIMS: Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings. METHODS AND RESULTS: A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement. CONCLUSIONS: It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis. | Mesenchymoma |
The rationale for the use of muscarinic antagonists in bronchopulmonary dysplasia (BPD) is based on the physiology and pharmacology of airway smooth muscle, the pathology of BPD, and the response of infants with BPD to bronchodilators, in vivo and in vitro studies of airway smooth muscle of newborn animals and humans indicate that vagal efferent airway innervation and/or muscarinic receptors are functional at birth, as well as early in gestation. Current concepts regarding muscarinic receptor subtypes suggest that M3 receptors mediate airway smooth muscle contraction, M2 receptors are autoinhibitory and limit vagally-mediated bronchoconstriction, and M1 receptors may play a facilitatory role in ganglionic transmission. Muscarinic receptor subtypes appear to be functionally expressed at birth but may undergo developmental regulation. Infants with BPD have an elevated pulmonary resistance that is accompanied by hypertrophy of airway smooth muscle, b2-agonists cause bronchodilation in BPD as does atropine in infants recovering from severe BPD. The synthetic congener of atropine, ipratropium bromide (IPB) causes bronchodilation in ventilator-dependent infants with BPD in a dose-dependent fashion. Nebulized IPB causes a decrease in respiratory resistance that reaches a maximum of 20% at 175 mg. The bronchodilation seen with muscarinic antagonists suggests that part of the elevated resistance associated with BPD is due to increased muscarinic tone, presumably vagal in origin. When IPB is combined with salbutamol (0.04 mg) the response is increased in magnitude and duration; reaching a slightly larger decreases in resistance (26%) that is now accompanied by an increase in compliance (20%).(ABSTRACT TRUNCATED AT 250 WORDS) | Parasympathomimetics |
Terminal alpha-2,6-sialylation of N-glycans is a humanized glycosylation that affects the properties and efficacy of therapeutic glycoproteins. Fc di-sialylation (a biantennary N-glycan with two alpha-2,6-linked sialic acids) of IgG antibodies imparts them with enhanced anti-inflammatory activity and other roles. However, the microheterogeneity of N-glycoforms presents a challenge for therapeutic development. Therefore, controlled sialylation has drawn considerable attention, but direct access to well-defined di-sialylated antibodies remains limited. Herein, a one-pot three-enzyme protocol was developed by engineering a bacterial sialyltransferase to facilitate the modification of therapeutic antibodies with N-acetylneuraminic acid or its derivatives towards optimized glycosylation. To overcome the low proficiency of bacterial sialyltransferase in antibody remodeling, the Photobacterium sp. JT-ISH-224 alpha-2,6-sialyltransferase (Psp2,6ST) was genetically engineered by terminal truncation and site-directed mutagenesis based on its protein crystal structure. With the optimized reaction conditions and using activity-based screening of various Psp2,6ST variants, a truncated mutant Psp2,6ST (111-511)-His6 A235M/A366G was shown to effectively improve the catalytic efficiency of antibody di-sialylation. Herceptin and the donor substrate promiscuity allow the introduction of bioorthogonal modifications of N-acetylneuraminic acid into antibodies for site-specific conjugation. 2-AB hydrophilic interaction chromatography analysis of the released N-glycans and intact mass characterization confirmed the high di-sialylation of Herceptin via the optimized one-pot three-enzyme reaction. This study established a versatile enzymatic approach for producing highly di-sialylated IgG antibodies. It provides new insights into engineering bacterial sialyltransferase for adaptation to the enzymatic glycoengineering of therapeutic antibodies and the glycosite-specific conjugation of antibodies. | Sialyltransferases |
Extensor tenosynovitis has been reported as a complication of the Arbeitsgemeinschaft fur Osteosynthesefragen/Association for the Study of Internal Fixation (AO/ASIF) pi plate. The authors present a case of extensor tendon rupture after internal fixation with a pi plate after one of the screws in the distal limb loosened. This mechanism of extensor tendon rupture has not been reported previously. With appropriate prevention, monitoring, and intervention this complication could have been avoided. Schnur DP, Chang B. Extensor tendon rupture after internal fixation of a distal radius fracture using a dorsally placed AO/ASIF titanium pi plate. | Bone Plates |
Low-effort, reliable diagnostics of digital dermatitis (DD) are needed, especially for lesions warranting treatment, regardless of milking system or hygienic condition of the feet. The primary aim of this study was to test the association of infrared thermography (IRT) from unwashed hind feet with painful M2 lesions under farm conditions, with lesion detection as ultimate goal. Secondary objectives were to determine the association between IRT from washed feet and M2 lesions, and between IRT from unwashed and washed feet and the presence of any DD lesion. A total of 641 hind feet were given an M-score and IRT images of the plantar pastern were captured. Multivariable logistic regression analyses were done with DD status as dependent variable and maximum infrared temperature (IRTmax), lower leg cleanliness score and locomotion score as independent variables, and farm as fixed effect. To further our understanding of IRTmax within DD status, we divided IRTmax into two groups over the median value of IRTmax in the datasets of unwashed and washed feet, respectively, and repeated the multivariable logistic regression analyses. Higher IRTmax from unwashed hind feet were associated with M2 lesions or DD lesions, in comparison with feet without an M2 lesion or without DD, adjusted odds ratio 1.6 (95% CI 1.2-2.2) and 1.1 (95% CI 1.1-1.2), respectively. Washing of the feet resulted in similar associations. Dichotomization of IRTmax substantially enlarged the 95% CI for the association with feet with M2 lesions indicating that the association becomes less reliable. This makes it unlikely that IRTmax alone can be used for automated detection of feet with an M2 lesion. However, IRTmax can have a role in identifying feet at-risk for compromised foot health that need further examination, and could therefore function as a tool aiding in the automated monitoring of foot health on dairy herds. | Digital Dermatitis |
Micropropagation of Hypoxis hemerocallidea Fisch. and C.A. Mey was used as a model system to study the influence of cytokinins (CKs) on plant regeneration and biochemical accumulation of hydroxybenzoic and hydroxycinnamic acid derivatives in organ and callus cultures and their antioxidant activity. Fourteen free phenolic acids were detected using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) while antioxidant activity was evaluated using oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity. Cytokinins had a significant effect on the biochemical accumulation of hydroxybenzoic and hydroxycinnamic acid derivatives in H. hemerocallidea organ cultures. In particular, meta-topolin-treated organ cultures produced high concentrations of gallic, protocatechuic, gentisic, p-hydroxybenzoic, m-hydroxybenzoic, salicylic, chlorogenic and trans-cinnamic acids. The isoprenoid CK, N(6)-(2-isopentenyl)-adenine significantly increased the accumulation of hydroxycinnamic acid derivatives, namely, caffeic, p-coumaric, sinapic and ferulic acids. Cytokinin-treated organ cultures exhibited a significant increase in antioxidant activity, particularly in the ORAC model. In callus cultures, CKs decreased the concentrations of hydroxycinnamic acid derivatives and antioxidant activity when compared to the control. Overall, both CK type and concentration had a significant effect on plant regeneration, callus proliferation, biochemical accumulation of free phenolic acids and antioxidant activity of the resultant extracts. | Hypoxis |
The Integrated Trauma Program (ITP) is the cooperative trauma triage service of the University of Toronto trauma and burn hospitals and the Ontario Ministry of Health. It provides physicians in referring hospitals direct access to a trauma team leader (TTL) in one of several trauma centers through a single phone number. Three adult trauma centers, one pediatric trauma center, and one burn center, all affiliated with the University of Toronto, participate in this program. This article describes the system during the first two years of operation. From July 1989 to June 1991, 1530 requests for patient transfers from a total of 97 hospitals were processed. Of these transfer requests, 77% were accepted by the TTL to a trauma service as multiple trauma cases, 16% were accepted directly to a surgical service without involving the trauma team, 4% were refused by the TTL as inappropriate referrals, and 3% of requests were cancelled by the referring physician. The transfer requests are distributed to a specific trauma center by request of the referring physician (10%), according to a rotation (70%), or as selected by the ITP (20%) when the scheduled hospital is not readily available. Closure of all adult trauma centers occurred on 43 occasions. During these closures, 48 patients bypassed the Toronto trauma centers and were transferred to other cities. The ITP office also keeps an ongoing data base of patients transferred. The mechanism of injury in the majority of cases is vehicular crashes. The mean Injury Severity Score is 24 for adults and 17 for children.(ABSTRACT TRUNCATED AT 250 WORDS) | Trauma Centers |
BACKGROUND: Serologic data on diseases that are preventable by vaccine are useful to evaluate the success of immunization programs and to identify susceptible subgroups. OBJECTIVE: To provide national estimates of immunity to diphtheria and tetanus by measurement of serum antibody levels. DESIGN: Examination of data from the Third National Health and Nutrition Examination Survey, a representative cross-sectional sample of the U.S. population. SETTING: 89 randomly selected locations throughout the United States. PARTICIPANTS: 18 045 persons 6 years of age or older who were examined from 1988 to 1994. MEASUREMENTS: Serum samples obtained at a single time point were tested for diphtheria and tetanus antitoxin. RESULTS: Overall, 60.5% of Americans 6 years of age or older had fully protective levels of diphtheria antibody (> or =0.10 IU/mL) and 72.3% had protective levels of tetanus antibody (> 0.15 IU/mL). Ninety-one percent of Americans 6 to 11 years of age had protective levels of both diphtheria and tetanus antibody; this proportion decreased to approximately 30% among persons 70 years of age (29.5% for diphtheria and 31.0% for tetanus). Adult Mexican-Americans were slightly less likely to have protective levels of antibody to both toxins. Only 47% of persons 20 years of age or older had levels that were protective against both diseases, and only 63% of adults who were protected against tetanus were also protected against diphtheria. CONCLUSIONS: A substantial proportion of adults in the United States do not have antibody levels that are protective against diphtheria and tetanus. In addition, although the recommended vaccine is a combination of tetanus and diphtheria, only 63% of adults with protective antibody to tetanus also had protective antibody to diphtheria. | Diphtheria-Tetanus Vaccine |
Heterothallic strains of the Closterium peracerosum-strigosum-littorale (C. psl.) complex have two sexes, mating-type plus (mt(+)) and mating-type minus (mt(-)). Conjugation between these two sexes is regulated by two sex pheromones, protoplast-release-inducing protein (PR-IP) and PR-IP Inducer, which are produced by mt(+) and mt(-) cells, respectively. PR-IP mediates the release of protoplasts from mt(-) cells during mating. In this study, we examined the mechanism of action of CpRLP1 (receptor-like protein 1), which was previously identified in a cDNA microarray analysis as one of the PR-IP-inducible genes. Using CRISPR/Cas9 technology, we generated CpRLP1 knockout mutants in mt(-) cells of the C. psl. complex. When the knockout mt(-) cells were mixed with wild-type mt(+) cells, conjugation was severely reduced. Many cells released protoplasts without pairing, suggesting a loss of synchronization between the two mating partners. Furthermore, the knockout mutants were hypersensitive to PR-IP. We conclude that CpRLP1 is a negative regulator of PR-IP that regulates the timing of protoplast release in conjugating C. psl. cells. As the first report of successful gene knockout in the class Charophyceae, this study provides a basis for research aimed at understanding the ancestral roles of genes that are indispensable for the development of land plants. | Desmidiales |
Introduction: Fetal heart rate monitoring presents one of the few available methods for evaluating the fetus prior to birth. However, current devices on the market have significant shortcomings. We sought to describe the use and experiences with external fetal monitoring (EFM) devices among obstetrical providers.Materials and methods: We performed a cross-sectional survey in an academic medical center between April and July 2017 including nurse, midwife, and physician obstetrical providers (n = 217) who were invited to participate in this study regarding their experiences with the external fetal monitoring (EFM) device utilized by their hospital system in the outpatient, inpatient, and labor and delivery (L&D) settings. Associations between provider characteristics, device use, perception of challenging patients, and potential usefulness of an improved system were assessed by Fisher's exact test.Results: The 137 respondents (63.1%) reported difficulties monitoring obese women (98.5%), multiple gestation pregnancies (90.5%), and early gestational ages (71.5%). Over half (59.5%) of L&D nurses reported interacting with EFM devices for greater than 1-hour during a typical 12-hour shift and fewer than half (42.3%) reported being satisfied with current EFM devices. There were no statistically significant associations between provider age, experience, or time spent utilizing the devices with perception of challenging patient types.Conclusions: In conclusion, obstetrical providers perceive shortcomings of current EFM devices across all levels of provider experience and time utilizing these devices. Nurses reported significant time operating the devices, representing an opportunity to reduce time and costs with an improved device. | Cardiotocography |
Autoimmune diseases usually arise as a result of an aberrant immune system attack on normal tissues of the body, which leads to a cascade of inflammatory reactions. The immune system employs different types of protective and anti-inflammatory cells for the regulation of this process. Curcumin is a known natural anti-inflammatory agent that inhibits pathological autoimmune processes by regulating inflammatory cytokines and their associated signaling pathways in immune cells. Due to the unstable nature of curcumin and its susceptibility to either degradation, or metabolism into other chemical entities (i.e., metabolites), encapsulation of this agent into various nanocarriers would appear to be an appropriate strategy for attaining greater beneficial effects from curcumin as it pertains to immunomodulation. Many studies have focused on the design and development of curcumin nanodelivery systems (micelles, dendrimers, and diverse nanocarriers) and are summarized in this review in order to obtain greater insight into novel drug delivery systems for curcumin and their suitability for the management of autoimmune diseases. | Curcumin |
Formation and emission of dioxins is a great concern during thermal desorption remediation of organic contaminated soil. The differential formation of dioxins from chlorine organic contaminated soil (COCS) and non-chlorine organic contaminated soil (NCOCS) is still unclear and the control technique for the dioxins generated is an urgent need. In this study, the formation and distribution characteristics of dioxins were investigated in the thermal desorption unit combined with flue gas purification system during COCS and NCOCS treatments. Although organic contaminates were well desorbed, de-novo formation of dioxins was observed for both COCS and NCOCS, as well as synthesis from precursors for NCOCS. The gas-phase dioxin in the flue gas purification system continuously decreased during NCOCS thermal desorption, while the dioxin concentration in the quench tower sharply increased from 0.46 to 2.13 ng/Nm(3) through de-novo synthesis during COCS treatment. Furthermore, the emission of dioxins only slightly reduced (for COCS) or even increased (for NCOCS) at 70% operating load. The catalytic adsorption tower within modified activated carbon and V(5)-Mo(5)-Ti catalyst after bag filter can reduce the emission of dioxins up to 91.4% at the condition of secondary combustion chamber closure, demonstrating that the catalytic adsorption tower can replace the secondary combustion chamber for controlling dioxin emission. More importantly, the highly toxic low-chlorinated polychlorinated dibenzodioxins and polychlorinated dibenzofurans (PCDD/PCDFs) were selectively removed from flue gas by the catalytic adsorption tower. These results reveal the differential formation characteristics of dioxins during COCS and NCOCS thermal treatments and highlight V(5)-Mo(5)-Ti/ modified activated carbon as a promising catalytic adsorption material to control the emission of dioxins from the thermal desorption of organic contaminated soil." | Dioxins and Dioxin-like Compounds |
Cancer develops in a multi-step process where environmental carcinogenic exposure is a primary etiological component, and where cell-cell communication governs the biological activities of tissues. Identifying the molecular genes that regulate this process is essential to targeting metastatic breast cancer. Ionizing radiation can modify and damage DNA, RNA, and cell membrane components such as lipids and proteins by direct ionization. Comparing differential gene expression can help to determine the effect of radiation and estrogens on cell adhesion. An in vitro experimental breast cancer model was developed by exposure of the immortalized human breast epithelial cell line MCF-10F to low doses of high linear energy transfer alpha particle radiation and subsequent growth in the presence of 17beta-estradiol. The MCF-10F cell line was analyzed in different stages of transformation that showed gradual phenotypic changes including altered morphology, increase in cell proliferation relative to the control, anchorage-independent growth, and invasive capability before becoming tumorigenic in nude mice. This model was used to determine genes associated with cell adhesion and communication such as E-cadherin, the desmocollin 3, the gap junction protein alpha 1, the Integrin alpha 6, the Integrin beta 6, the Keratin 14, Keratin 16, Keratin 17, Keratin 6B, and the laminin beta 3. Results indicated that most genes had greater expression in the tumorigenic cell line Tumor2 derived from the athymic animal than the Alpha3, a non-tumorigenic cell line exposed only to radiation, indicating that altered expression levels of adhesion molecules depended on estrogen. There is a significant need for experimental model systems that facilitate the study of cell plasticity to assess the importance of estrogens in modulating the biology of cancer cells. | Keratin-16 |
Sphingomonas carotinifaciens strain L9-754(T) (DSM 27347) is a gram-negative, chemoheterotrophic, and rod-shaped endophyte isolated from the stem tissues of Jatropha curcas L. This strain has putative in vitro antagonistic ability against the plant pathogenic fungus Magnaporthe grisea. A draft genome of L9-754T was obtained using the PacBio SMRT cell platform. By analyzing the genome of strain L9-754T, a gene cluster (GQR91_18700 - GQR91_18715) related to an antioxidant enzyme was identified in the obtained draft genome. The information obtained from the draft genome is expected to reveal the putative properties helpful in biocontrol applications. | Jatropha |
We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care." | Voltage-Gated Sodium Channel beta-1 Subunit |
PURPOSE OF REVIEW: Ketone body metabolism is a dynamic and integrated metabolic node in human physiology, whose roles include but extend beyond alternative fuel provision during carbohydrate restriction. Here we discuss the most recent observations suggesting that ketosis coordinates cellular function via epigenomic regulation. RECENT FINDINGS: Ketosis has been linked to covalent modifications, including lysine acetylation, methylation, and hydroxybutyrylation, to key histones that serve as dynamic regulators of chromatin architecture and gene transcription. Although it remains to be fully established whether these changes to the epigenome are attributable to ketone bodies themselves or other aspects of ketotic states, the regulated genes mediate classical responses to carbohydrate restriction. SUMMARY: Direct regulation of gene expression may occur in-vivo via through ketone body-mediated histone modifications during adherence to low-carbohydrate diets, fasting ketosis, exogenous ketone body therapy, and diabetic ketoacidosis. Additional convergent functional genomics, metabolomics, and proteomics studies are required in both animal models and in humans to identify the molecular mechanisms through which ketosis regulates nuclear signaling events in a myriad of conditions relevant to disease, and the contexts in which the benefits of ketosis might outweigh the risks. | Ketone Bodies |
N-terminal methionine removal has been analyzed statistically in a large sample of prokaryotic and eukaryotic cytosolic proteins in an attempt to uncover common sequence determinants. We find that the residue next to the initiator Met is the most important determinant of N-terminal processing: Lys, Arg, Leu and (in prokaryotes) Phe and Ile protect the initiator Met from being removed when next to it in the sequence; Ala, Gly, Pro, Ser, Thr and (in eukaryotes) Val in this position cause its removal. Subsequent acetylation is confirmed to be strongly biased towards Ala, Met and Ser residues; when Met is acetylated, Asp is the predominant penultimate residue in eukaryotes. Also, we find major differences in the relative abundance of the various residues next to the initiator Met between prokaryotes and eukaryotes: prokaryotic proteins are much more biased towards Lys as the Met-protecting residue, and towards Ala when met is to be removed, than eukaryotic ones. Finally, we show that our results can explain a part of the mRNA 'consensus sequence' found around eukaryotic initiator AUG codons. | Methionyl Aminopeptidases |
In this in vitro study, we have investigated the ability of Taraxacum officinale (dandelion) to inhibit adipocyte differentiation and lipogenesis in 3T3-L1 preadipocytes. HPLC analysis of the three plant extracts used in this study-leaf and root extracts and a commercial root powder-identified caffeic and chlorogenic acids as the main phenolic constituents. Oil Red O staining and triglyceride levels analysis showed decreased lipid and triglyceride accumulation, respectively. Cytotoxicity was assessed with the MTT assay showing non-toxic effect among the concentrations tested. DNA microarray analysis showed that the extracts regulated the expression of a number of genes and long non-coding RNAs that play a major role in the control of adipogenesis. Taken together, our results indicate that the dandelion extracts used in this study may play a significant role during adipogenesis and lipid metabolism, and thus, supporting their therapeutic interest as potential candidates for the treatment of obesity. | Taraxacum |
Immature beta cells secrete insulin at a lower glucose threshold compared to mature beta cells. In this issue of Developmental Cell, Huang et al. (2018) show that the increase in glucose threshold during beta cell maturation is achieved through balance between the Ca(2+)-sensitive synaptotagmin 7 and the Ca(2+)-insensitive synaptotagmin 4. | Synaptotagmins |
Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases." | Cell- and Tissue-Based Therapy |
A new arylnaphthalide lignan, prostalidin D (6) was isolated as a minor metabolite from Justicia diffusa var. prostrata. 6 contains a rare catechol unit and its structure was confirmed by total synthesis. In addition, seven known lignans, namely, justicidin E (7), helioxanthin (8), justicidin A (9), medioresinol dimethyl ether (10), medioresinol (11), lariciresinol (12) and 8-methoxyisolariciresinol (13) have also been isolated from the same source and identified by direct comparison with authentic samples. | Lignans |
There is no drug therapy without risk for toxicity. The patient must tolerate some toxic or idiosyncratic adverse events (e. g. hand foot syndrome). After life threatening adverse effects, one needs to screen (hyperkalemia). The sick-day-rule should be communicated with the informed patient as for example stopping SGLT2-inhibitors (loss of appetite, hypotension). The list of prescriptions should regularly criticized for dangerous or superfluous medicines (deprescribing)." | Drug Therapy, Computer-Assisted |
The streptothricin (ST) antibiotics, produced by Streptomyces bacteria, contain L-beta-lysine ((3S)-3,6-diaminohexanoic acid) oligopeptides as pendant chains. Here we describe three unusual nonribosomal peptide synthetases (NRPSs) involved in ST biosynthesis: ORF 5 (a stand-alone adenylation (A) domain), ORF 18 (containing thiolation (T) and condensation (C) domains) and ORF 19 (a stand-alone A domain). We demonstrate that ST biosynthesis begins with adenylation of L-beta-lysine by ORF 5, followed by transfer to the T domain of ORF 18. In contrast, L-beta-lysine molecules adenylated by ORF 19 are used to elongate an L-beta-lysine peptide chain on ORF 18, a reaction unexpectedly catalyzed by ORF 19 itself. Finally, the C domain of ORF 18 catalyzes the condensation of L-beta-lysine oligopeptides covalently bound to ORF 18 with a freely diffusible intermediate to release the ST products. These results highlight an unusual activity for an A domain and unique mechanisms of crosstalk within NRPS machinery. | Streptothricins |
Placebo effects permeate many aspects of the clinical environment. However, little attention has been devoted to placebo effects in the nursing literature. Recent research shows that the promotion of placebo responses can enhance certain patient outcomes. Nurses are situated in an ideal position to take on this task. This article suggests ways for nurses to ethically promote placebo responses in daily practice." | Effect Modifier, Epidemiologic |
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