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Oral submucous fibrosis (OSMF) is one of the most poorly understood and unsatisfactorily treated diseases. Various medical and surgical treatments have been used but with limited benefits. However, with advent of lasers, oral surgeons are provided with new modality for treating OSMF. This case report highlights the pioneering effort in treating a moderate case of bilateral OSMF with Erbium Chromium Yttrium Scandium Gallium Garnet (ErCr:YSGG) laser showing promising result during follow-up. | Oral Surgical Procedures |
N-hydroxyphthalimide (NHPI), which is best known as an organocatalyst for efficient C-H activation, has been found to be oxidized by quinoid compounds to its corresponding catalytically active nitroxide-radical. Here, we found that NHPI can be isomerized into isatoic anhydride by an unusually facile two-step method using tetrachloro-1,4-benzoquinone (TCBQ, p-chloranil), accompanied by a two-step hydrolytic dechlorination of highly toxic TCBQ into the much less toxic dihydroxylation product, 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid). Interestingly, through the complementary application of oxygen-18 isotope-labeling, HPLC combined with electrospray ionization quadrupole time-of-flight and high resolution Fourier transform ion cyclotron resonance mass spectrometric studies, we determined that water was the source and origin of oxygen for isatoic anhydride. Based on these data, we proposed that nucleophilic attack with a subsequent water-assisted Lossen rearrangement coupled with rapid intramolecular addition and cyclization in two consecutive steps was responsible for this unusual structural isomerization of NHPI and concurrent hydroxylation/detoxication of TCBQ. This is the first report of an exceptionally facile double-isomerization of NHPI via an unprecedented water-assisted double-Lossen rearrangement under normal physiological conditions. Our findings may have broad implications for future research on hydroxamic acids and polyhalogenated quinoid carcinogens, two important classes of compounds of major chemical and biological interest. | Chloranil |
Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis in the US, Europe and in many other parts of the world, including parts of sub-Saharan Africa (known as the African 'meningitis belt'). There are > 500000 cases of meningococcal disease annually with an estimated death toll of 135000 worldwide. Approximately 10 - 15 % of survivors experience significant morbidity in the form of neurological sequelae, including hearing loss, speech disorders, loss of limbs, mental retardation and paralysis. Disease is usually caused by N. meningitidis serogroups A, B, C, Y or W-135. Prevention of meningococcal disease includes isolation, chemoprophylaxis and vaccination with available polysaccharide vaccines. However, the polysaccharide meningococcal vaccines (i.e., A and C; A, C and W-135; or A, C, Y and W-135) initially developed in the 1970s are generally poorly immunogenic in children or require repeated doses and do not produce long-lasting immunity. Conjugate vaccine technology has been very successfully used in childhood vaccines for the prevention of other bacterial meningitis pathogens, including vaccines against Haemophilus influenzae serotype b (Hib) and more recently, the seven- and nine-valent conjugate pneumococcal vaccines. Newly released meningococcal conjugate vaccines against N. meningitidis serogroup C have been highly efficacious in young children and adolescents, with minimal side effects. Conjugate vaccines targeting other important meningococcal serogroups (e.g., N. meningitidis serogroup A, responsible for the large pandemic outbreaks and the majority of disease in sub-Saharan Africa and serogroups Y and W-135) are under development and together with the serogroup C conjugates, have the potential to significantly impact worldwide sporadic and epidemic meningococcal disease. The search for an effective serogroup B meningococcal vaccine remains elusive. This manuscript reviews the conjugate meningococcal vaccines and their potential for meningococcal disease prevention. | Meningitis, Meningococcal |
OBJECTIVE: To explore the role of fetuin B-AMPK/ACC signaling pathway in mediating the effect of puerarin on hepatic insulin resistance in mice with type 2 diabetes mellitus (T2DM). OBJECTIVE: Forty C57BL/6J mouse models of T2DM induced by high-fat diet and intraperitoneal injection of streptozotocin were randomized into diabetic model (HFD) group and 3 puerarin groups for treatment with low-, moderate- and high- dose puerarin (50, 100 and 200 mg/kg, respectively), with another 10 mice fed a normal diet as the control group. After treatment for 8 weeks, the mice were examined for fasting blood glucose (FBG), fasting insulin (FINS), liver triglycerides (TG), cholesterol (TC) and free fatty acids (FFA) levels. The expression of fetuin B in the liver was detected by immunohistochemistry. RT-qPCR was used to detect the expressions of fetuin B, AMPK, and ACC mRNA in the liver, and the protein expressions of fetuin B, AMPKalpha1, ACC, P-AMPKalphaT183/T172, and P-ACC S79 were determined with Western blotting. OBJECTIVE: Treatment with moderate- and high-dose puerarin significantly lowered TG, TC, FFA and FBG levels in diabetic mice (P < 0.01). Puerarin at all the 3 doses significantly lowered FINS and HOMA-IR of the mice (P < 0.01). In diabetic mice, hepatic expressions of fetuin B and ACC mRNA increased and AMPK mRNA decreased significantly (P < 0.01); the protein expressions of fetuin B and ACC increased while those of AMPKalpha1, P-AMPKalphaT183/T172 and P-ACC S79 decreased significantly (P < 0.01). Puerarin dose-dependently inhibited the mRNA and protein expressions of fetuin B and ACC, increased AMPK mRNA and protein expressions of AMPKalpha1, P-AMPKalphaT183/ T172, and P-ACC S79, and lowered fetuin B content in the liver of diabetic mice (P < 0.01). OBJECTIVE: Puerarin alleviates insulin resistance and improves glucolipid metabolism in T2DM mice by modulating hepatic fetuin B-AMPK/ACC signaling pathway. | Fetuin-B |
Viability means the quality or state of being able to live, grow and develop." Limit of viability has been changed along with the advancement of perinatal and neonatal medicine. The viability limit defined in the Japanese Motherhood Protection Act was amended from 24 to 22 completed weeks of gestation in 1991 based on the survival rate of extremely preterm infants. Survival rates of infants at 22 and 23 weeks' gestation born between 2002 and 2004 in Japan were 31% and 56%, respectively. Though medical data are the most important means to define viability, socio-economical and ethical factors should be also considered, especially when we discuss the group of marginally viable infants. We think there are two different categories of viability limits, one from biological survival limit and another from social agreement of providing active medical intervention. Currently in Japan, the former viability definition based on purely medical data is 22 completed weeks and the latter definition is the social consensus of about 24-28 weeks' gestation." | Neonatology |
Early facial rejuvenation focused largely on the upper and lower thirds of the face. More recently, improvements in understanding of midfacial aging and anatomy have paralleled the development of endoscopic and minimally invasive surgical techniques. The midface is now understood to include both the lower lid subunit and the cheek down to the nasolabial fold. Many surgical techniques for midface rejuvenation have been used, including skin tightening with direct excision, skin-muscle flaps, isolated fat pad transposition, and subperiosteal lifting. The methods of endoscopic subperiosteal midface lifting and endoscopic malar fat pad lifting are discussed. | Rhytidoplasty |
E-, P-, and L-selectin counterreceptor activities, leukocyte trafficking, and lymphocyte homing are controlled prominently but incompletely by alpha(1,3)fucosyltransferase FucT-VII-dependent fucosylation. Molecular determinants for FucT-VII-independent leukocyte trafficking are not defined, and evidence for contributions by or requirements for other FucTs in leukocyte recruitment is contradictory and incomplete. We show here that inflammation-dependent leukocyte recruitment retained in FucT-VII deficiency is extinguished in FucT-IV(-/-)/FucT-VII(-/-) mice. Double deficiency yields an extreme leukocytosis characterized by decreased neutrophil turnover and increased neutrophil production. FucT-IV also contributes to HEV-born L-selectin ligands, since lymphocyte homing retained in FucT-VII(-/-) mice is revoked in FucT-IV(-/-)/FucT-VII(-/-) mice. These observations reveal essential FucT-IV-dependent contributions to E-, P-, and L-selectin ligand synthesis and to the control of leukocyte recruitment and lymphocyte homing. | Fucosyltransferases |
Interpretation of trends in disease rates using conventional age-period-cohort analyses is made difficult by the lack of a unique set of parameters specifying any given model. Because of difficulties inherent in age-period-cohort models, neither the magnitude nor the direction of a linear trend in birth cohort effects or calendar period effects can be determined unambiguously. This leads to considerable uncertainty in making inferences regarding disease etiology based on birth cohort or calendar period trends. In this paper, the authors demonstrate that changes in the direction or magnitude of long term trends can be identified unequivocally in age-period-cohort analyses, and they provide parametric methods for evaluating such changes in trend within the usual Poisson regression framework. Such changes can have important implications for disease etiology. This is demonstrated in applications of the proposed methods to the investigation of birth cohort trends in female breast cancer mortality rates obtained from the National Center for Health Statistics for the United States (1970-1989) and from the World Health Organization for Japan (1955-1979). | Cohort Effect |
The high mobility group AT-hook (HMGA) proteins, a family of DNA architectural factors, are highly expressed during embryogenesis and play a crucial role in several different biological processes, as well as in tumorigenesis of a wide range of tissues, including pituitary. Indeed, HMGA2 has been found rearranged and amplified in human prolactinomas, and transgenic mice overexpressing either Hmga1 or Hmga2 develop pituitary adenomas secreting prolactin and growth hormone. Here, we overview HMGA proteins in human tumours, focusing on pituitary adenomas and the mechanisms by which the HMGA proteins are involved in their onset and development. Different HMGA-dependent potential drives of pituitary oncogenesis are discussed as future research directions in the field. | HMGA1c Protein |
Protein folding is a topic of fundamental interest since it concerns the mechanisms by which the genetic message is translated into the three-dimensional and functional structure of proteins. In these post-genomic times, the knowledge of the fundamental principles are required in the exploitation of the information contained in the increasing number of sequenced genomes. Protein folding also has practical applications in the understanding of different pathologies and the development of novel therapeutics to prevent diseases associated with protein misfolding and aggregation. Significant advances have been made ranging from the Anfinsen postulate to the new view" which describes the folding process in terms of an energy landscape. These new insights arise from both theoretical and experimental studies. The problem of folding in the cellular environment is briefly discussed. The modern view of misfolding and aggregation processes that are involved in several pathologies such as prion and Alzheimer diseases. Several approaches of structure prediction, which is a very active field of research, are described." | Chaperonin 60 |
AIM: Clinical pharmacology at the Leiden University Medical Centre is primarily taught by the Teaching Resource Centre's (TRC) Pharmacology database. The TRC program contains schematic graphics using a unique icon language, explanation texts and feedback questions to explain pharmacology as it pertains to pathophysiology. Nearly each course of the curriculum has a chapter in the TRC database offered for self-study. Since using the TRC program is not compulsory, the question remains whether students benefit from using it. METHODS: We compared the parameters of log-in attempts and time spent at each topic with students' final exam grades. Instead of looking at the regression of time spent on TRC on grade for one course, we looked at the individual student regression of time spent on TRC for different courses on grades. Spending more time using the TRC being associated with higher grades within an individual is a more powerful result than between students within a course, as better students are likely to spend more time using the TRC. RESULTS: Students increasingly used the program throughout the curriculum. More importantly, the time spent using the program showed that increased TRC use by an individual student is associated with a (small) increase in grade. As expected for a noncompulsory activity, better students (those with higher than average exam scores) logged in to the TRC more frequently, but poorer students appeared to have a larger benefit. CONCLUSIONS: An increase in TRC use by an individual student correlates with an increase in course grades. | Pharmacology |
We constructed a yeast artificial chromosome (YAC) framework map of human chromosome 4 by screening a YAC library with 63 polymorphic DNA markers located on the chromosome. These genetic markers are from two framework meiotic maps that had previously been constructed by two research groups, and are placed on the two maps with odds for their order of 1000:1 or greater. In addition to isolating and determining the sizes of 141 YAC clones for 54 of these markers, we combined the two framework meiotic maps to produce a single integrated map. These combined maps and the YAC clones provide a set of extended DNA loci ordered at high odds that can be used to isolate additional polymorphic loci and genes, and to serve as a framework for obtaining a higher resolution physical map of the chromosome." | Chromosomes, Artificial, Yeast |
The crystal structure of the anaerobic complex of Pseudomonas putida protocatechuate 3,4-dioxygenase (3,4-PCD) bound with the alternative substrate, 3,4-dihydroxyphenylacetate (HPCA), is reported at 2.4 A resolution and refined to an R factor of 0.17. Formation of the active site Fe(III).HPCA chelated complex causes the endogenous axial tyrosinate, Tyr447 (147beta), to dissociate from the iron and rotate into an alternative orientation analogous to that previously observed in the anaerobic 3,4-PCD.3,4-dihydroxybenzoate complex (3, 4-PCD.PCA) [Orville, A. M., Lipscomb, J. D., & Ohlendorf, D. H. (1997) Biochemistry 36, 10052-10066]. Two orientations of the aromatic ring of HPCA related by an approximate 180 degrees rotation within the active site are consistent with the electron density. Resonance Raman (rR) spectroscopic data from Brevibacteriumfuscum 3,4-PCD.HPCA complex in solution reveals low frequency rR vibrational bands between 500 and 650 cm-1 as well as a band at approximately 1320 cm-1 which are diagnostic of a HPCA. Fe(III) chelate complex. 18O labeling of HPCA at either the C4 or C3 hydroxyl group unambiguously establishes the vibrational coupling modes associated with the five-membered chelate ring system. Analysis of these data suggests that the Fe(III)-HPCAO4 bond is shorter than the Fe(III)-HPCAO3 bond. This consequently favors the model for the crystal structure in which the C3 phenolic function occupies the Fe3+ ligand site opposite the endogenous ligand Tyr408(Oeta) (108beta). This is essentially the same binding orientation as proposed for PCA in the crystal structure of the anaerobic 3,4-PCD.PCA complex based solely on direct modeling of the 2Fo - Fc electron density and suggests that this is the conformation required for catalysis." | Protocatechuate-3,4-Dioxygenase |
MICs were determined for an investigational ketolide, CEM-101, and azithromycin, telithromycin, doxycycline, levofloxacin, clindamycin, and linezolid against 36 Mycoplasma pneumoniae, 5 Mycoplasma genitalium, 13 Mycoplasma hominis, 15 Mycoplasma fermentans, and 20 Ureaplasma isolates. All isolates, including two macrolide-resistant M. pneumoniae isolates, were inhibited by CEM-101 at < or = 0.5 microg/ml, making CEM-101 the most potent compound tested. | Mycoplasmatales |
Certain spatial distributions of water inside partially filled containers can significantly reduce the bounce of the container. In experiments with containers filled to a volume fraction varphi, we show that rotation offers control and high efficiency in setting such distributions and, consequently, in altering bounce markedly. High-speed imaging evidences the physics of the phenomenon and reveals a rich sequence of fluid-dynamics processes, which we translate into a model that captures our overall experimental findings. | Hydrodynamics |
The pathophysiology of angina pectoris is best understood as an imbalance between oxygen supply and demand. The primary determinants of myocardial oxygen demand are heart rate, arterial pressure, heart size, myocardial contractility, and myocardial mass. The medical therapy of angina pectoris is directed toward reducing myocardial oxygen demand by reducing the workload of the heart and the specific determinants listed. The most common medications used in the treatment of angina pectoris are nitroglycerin and propranolol. Nitroglycerin reduces myocardial oxygen demand primarily by reducing heart size and arterial pressure. Propranolol reduces oxygen demand primarily by reducing heart rate. Medical therapy is generally effective in controlling the symptoms of angina pectoris in 80% or more of the patients and allows them to lead useful and productive lives. | Erythrityl Tetranitrate |
Examination under anesthesia, particularly in children, is a common practice in ophthalmology. It may yield valuable information as to the cause and management regimen of the condition under study. The proper equipment should be available to the clinician to expedite the examination. Rapid and useful information thus obtained can justify the risk and expense incurred when this modality is used. Efficient use of the equipment is essential to yield the best examination. | Refraction, Ocular |
OBJECTIVE: This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS-specific therapies and emerging disease-modifying treatments. METHODS: A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease-modifying therapies) and nominated the 31-member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. RESULTS: There was strong consensus that infants 2-15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first- to third-line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease-modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. SIGNIFICANCE: This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease-modifying therapies. | Epileptic Syndromes |
Chemical and spectroscopic investigation of the bulbs of Drimia pancration resulted in the isolation of one known flavonol (1), never isolated from this plant species, and of three previously described steroidal saponins (2-4), but whose configuration at their stereogenic centres was not clearly determined. By mean of (1)H NMR, (13)C NMR, nuclear overhauser effects (NOE) and two-dimensional NMR spectra the full stereochemical structures of compounds 2-4 were proved and all the (1)H and (13)C signals were assigned. Furthermore, the methanol and butanol extracts of D. pancration were tested against adults of Stegobium paniceum beetles. Despite the non-significant results regarding the repellent activity and contact toxicity, promising results were obtained from the feeding tests. | Drimia |
3-Methylindole (3MI) damages nasal olfactory epithelium in mice. Lesions were studied histologically from 30 minutes to 28 days after intraperitoneal injection of 400 mg 3MI/kg. Cellular swelling was apparent in olfactory epithelium by 6 hours after injection of 3MI, while respiratory epithelium was normal. Necrosis of olfactory epithelium and subepithelial glands was diffuse by 48 hours. Subsequent ulceration resulted in epithelial hyperplasia, squamous metaplasia, fibroplasia, and ossification. Partially occlusive intranasal fibrous and osseous tissue persisted through 28 days after 3MI injection. | Skatole |
A quantitative description of carrier-mediated nuclear export in live cells is presented. To this end, we fused a prototypical leucine-rich nuclear export signal (NES) to GFP as a cargo model and expressed the fluorescent chimera in live CHO-K1 cells. By modeling FRAP data, we calculate the NES affinity for the export machinery and the maximum rate of nuclear export achievable at saturation of endogenous carriers. The measured active-export time through the Nuclear Pore Complex (NPC) is 18 ms, remarkably similar to the previously determined active-import rate. Also, our results reveal that active export/import and active export/passive diffusion fluxes are uncoupled, thus complementing previous reports on active import/passive diffusion uncoupling. These findings suggest differential gating at the NPC level. | Nuclear Export Signals |
Dry ice is used by meat and poultry processors for temperature reduction during processing and for temperature maintenance during transportation. ALIGAL Blue Ice (ABI), which combines the antimicrobial effect of ozone (O(3)) along with the high cooling capacity of dry ice, was investigated for its effect on bacterial reduction in air, in liquid, and on food and glass surfaces. Through proprietary means, O(3) was introduced to produce dry ice pellets to a concentration of 20 parts per million (ppm) by total weight. The ABI sublimation rate was similar to that of dry ice pellets under identical conditions, and ABI was able to hold the O(3) concentration throughout the normal shelf life of the product. Challenge studies were performed using different microorganisms, including E. coli, Campylobacter jejuni, Salmonella, and Listeria, that are critical to food safety. ABI showed significant (P < 0.05) microbial reduction during bioaerosol contamination (up to 5-log reduction of E. coli and Listeria), on chicken breast (approximately 1.3-log reduction of C. jejuni), on contact surfaces (approximately 3.9 log reduction of C. jejuni), and in liquid (2-log reduction of C. jejuni). Considering the stability of O(3), ease of use, and antimicrobial efficacy against foodborne pathogens, our results suggest that ABI is a better alternative, especially for meat and poultry processors, as compared to dry ice. Further, ABI can potentially serve as an additional processing hurdle to guard against pathogens during processing, transportation, distribution, and/or storage. | Dry Ice |
OBJECTIVE: To establish the clinical relevance of S-carboxymethylcysteine in the treatment of glue ear in children using measures approximating those saving a child from operation for grommet insertion. DATA SOURCES: Cochrane Library, MEDLINE, EMBASE, PubMed, reference lists and reviews were used for randomised controlled trials comparing S-carboxymethylcysteine with placebo. Seven trials involving 283 children and 146 ears were found. REVIEW METHODS: Studies were randomised, double-blind comparisons of S-carboxymethylcysteine (any dose and duration) with placebo in otitis media with effusion. Quality of trial reporting and validity of methods were assessed and used in sensitivity analysis. Main outcomes were relative benefit and number-needed-to-treat to prevent one grommet operation compared with placebo. RESULTS: Successful outcomes were obtained in 17% of children given placebo (range 5% to 38% in individual studies) and in 35% of children given S-carboxymethylcysteine (range 22 to 80%). For combined data (children and ears) the relative benefit was 2.0 (95%CI 1.4 to 2.8) and number-needed-to-treat 5.5 (95% confidence interval 3.8 to 9.8). Pooled data from trials of higher reporting quality (4/7) or methodological validity (3/7) tended to have lower efficacy but were not statistically different from those of lower quality or validity. CONCLUSION: S-carboxymethylcysteine is effective in the treatment of children with glue ear. For every five or six children treated with S-carboxymethylcysteine over one to three months, one will not undergo surgery for grommet insertion who would have done had they been given placebo. The confidence in this conclusion is limited because studies included relatively few children. | Carbocysteine |
PURPOSE: Prior models of glaucoma filtration surgery assess bleb morphology, which does not always reflect function. Our aim is to establish a model that directly measures tissue hydraulic conductivity of postsurgical outflow in rabbit bleb capsules following experimental glaucoma filtration surgery. METHODS: Nine rabbits underwent insertion of a single-plate pediatric Molteno implant into the anterior chamber of their left eye. Right eyes were used as controls. The rabbits were then allocated to one of two groups. Group one had outflow measurements performed at 1 week after surgery (n = 5), and group two had measurements performed at 4 weeks (n = 4). Measurements were performed by cannulating the drainage tube ostium in situ with a needle attached to a pressure transducer and a fluid column at 15 mm Hg. The drop in the fluid column was measured every minute for 5 minutes. For the control eyes (n = 6), the anterior chamber of the unoperated fellow eye was cannulated. Animals were euthanized with the implant and its surrounding capsule dissected and fixed in 4% paraformaldehyde, and embedded in paraffin before 6-mum sections were cut for histologic staining. RESULTS: By 7 days after surgery, tube outflow was 0.117 +/- 0.036 muL/min/mm Hg at 15 mm Hg (mean +/- SEM), whereas at 28 days, it was 0.009 +/- 0.003 muL/min/mm Hg. Control eyes had an outflow of 0.136 +/- 0.007 muL/min/mm Hg (P = 0.004, one-way ANOVA). Hematoxylin and eosin staining demonstrated a thinner and looser arrangement of collagenous tissue in the capsules at 1 week compared with that at 4 weeks, which had thicker and more densely arranged collagen. CONCLUSIONS: We describe a new model to directly measure hydraulic conductivity in a rabbit glaucoma surgery implant model. The principal physiologic endpoint of glaucoma surgery can be reliably quantified and consistently measured with this model. At 28 days post glaucoma filtration surgery, a rabbit bleb capsule has significantly reduced tissue hydraulic conductivity, in line with loss of implant outflow facility, and increased thickness and density of fibrous encapsulation. | Molteno Implants |
AIM: To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data. METHODS: Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase-4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims-EHR-linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances. RESULTS: From a claims-based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims-based characteristics in the EHR-linked and EHR-unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR-linked subset. The balance of claims-based and EHR-based patient characteristics appeared to be reasonable before PS-matching and generally improved in the PS-matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding. CONCLUSION: In the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new-user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely." | Administrative Claims, Healthcare |
The diagnosis of autoimmune hemolytic anemia (AHA) requires evidence of shortened red blood cell (RBC) survival mediated by autoantibodies directed against autologous RBCs. About 80 percent of patients with AHA have warm-reactive antibodies of the IgG isotype; the remainder exhibit cold-reactive autoantibodies. Typical patients exhibit anemia, reticulocytosis, spherocytes and polychromasia on the blood film and a positive direct antiglobulin test (DAT). Increased indirect serum bilirubin, urinary urobilinogen and serum lactate dehydrogenase (LDH), and decreased serum haptoglobin are not required for the diagnosis, but are frequently present. Patients with AHA and no underlying associated disease are said to have primary or idiopathic AHA. AHA in patients with associated autoimmune disease and certain malignant or infectious diseases is classified as secondary. The etiology of AHA is unknown. Patients with symptomatic anemia require transfusion of RBCs. Prednisone and splenectomy may provide long term remission. Rituximab, intravenous immunoglobulin, immunosuppressive drugs and danazol have been effective in refractory cases and for patients who are poor candidates for surgery. | Spherocytes |
The mutagenicity of CI-921, the 4-methyl-5-(N-methyl)carboxamide derivative of the clinical antileukaemia agent, amsacrine, has been assessed using both bacterial and mammalian cells. CI-921 is distinguished from amsacrine in its high activity against some experimental tumours and is currently undergoing phase I clinical trial. Like 9-aminoacridine and amsacrine, CI-921 is mutagenic to the Salmonella typhimurium frameshift tester strain TA1537, but shows no sign of inducing base pair changes in strain TA100. In Chinese hamster cell culture, however, it differs from 9-aminoacridine in causing extensive chromosomal aberrations and an increase in mutations at the hypoxanthine-guanine phosphoribosyltransferase locus. It induces the formation of tightly packed and multilayered colonies in treated cultures of C3H/10T1/2 cells, but its action differs from that of benzo[a]pyrene, which induces type III fibroblastic multilayered colonies. Side-by-side comparison of the mutagenic properties of CI-921 and amsacrine showed no substantial differences at similar toxicity, suggesting that the increased lipophilicity and DNA-binding affinity of CI-921, which are thought to contribute to its increased antitumour activity, do not concomitantly increase the efficiency of in vitro mutagenesis or cell transformation. | Amsacrine |
Brown adipocytes (BAs) play important roles in body temperature regulation, energy balance, and carbohydrate and lipid metabolism. Activities of BAs are remarkably diminished in obese and diabetic patients, providing possibilities of transplanting functional BAs resulting in therapeutic benefit. Here, we show generation of functional BAs by cellular reprogramming procedures. Transduction of the PRDM16 gene into iPSC-derived embryoid bodies induced BA phenotypes (iBAs). Moreover, normal human fibroblasts were directly converted into BAs (dBAs) by C/EBP-beta and C-MYC gene transduction. Approximately 90% of the fibroblasts were successfully converted within 12 days. The dBAs were highly active in mitochondrial biogenesis and oxidative metabolism. Mouse dBAs were induced by Prdm16, C/ebp-beta, and L-myc genes, and after transplantation, they significantly reduced diet-induced obesity and insulin resistance in an UCP1-dependent manner. Thus, highly functional BAs can be generated by cellular reprogramming, suggesting a promising tailor-made cell therapy against metabolic disorders including type 2 diabetes mellitus. | Adipocytes, Brown |
Barn owls are nocturnal predators which have evolved specific sensory and morphological adaptations to a life in dim light. Here, some of the most fundamental properties of spatial vision in barn owls are reviewed. The eye with its tubular shape is rigidly integrated in the skull so that eye movements are very much restricted. The eyes are oriented frontally, allowing for a large binocular overlap. Accommodation, but not pupil dilation, is coupled between the two eyes. The retina is rod dominated and lacks a visible fovea. Retinal ganglion cells form a marked region of highest density that extends to a horizontally oriented visual streak. Behavioural visual acuity and contrast sensitivity are poor, although the optical quality of the ocular media is excellent. A low f-number allows high image quality at low light levels. Vernier acuity was found to be a hyperacute percept. Owls have global stereopsis with hyperacute stereo acuity thresholds. Neurons of the visual Wulst are sensitive to binocular disparities. Orientation based saliency was demonstrated in a visual-search experiment, and higher cognitive abilities were shown when the owl's were able to use illusory contours for object discrimination. | Strigiformes |
Perianal streptococcal dermatitis is a childhood disorder caused by group A beta-hemolytic streptococci which was first described by Amren in 1966. The incidence of this dermatosis, characterized by well defined erythema in the perianal area, has certainly been underestimated and to the authors' knowledge there have still been no reports of this pathology in Italy. Perianal streptococcal dermatitis merits attention given that affected subjects do not always receive appropriate treatment and on average there is a 6-month lapse between the appearance of symptoms and diagnosis. The authors present two cases which were recently referred to their attention and discuss the methods of contagion, the difficulties of clinical diagnosis, associations with other streptococcal disorders and the treatment of this morbid condition. | Erythema |
An evolutionarily conserved gene network regulates the expression of genes involved in lysosome biogenesis, autophagy, and lipid metabolism. In mammals, TFEB and other members of the MiTF-TFE family of transcription factors control this network. Here we report that the lysosomal-autophagy pathway is controlled by Mitf gene in Drosophila melanogaster. Mitf is the single MiTF-TFE family member in Drosophila and prior to this work was known only for its function in eye development. We show that Mitf regulates the expression of genes encoding V-ATPase subunits as well as many additional genes involved in the lysosomal-autophagy pathway. Reduction of Mitf function leads to abnormal lysosomes and impairs autophagosome fusion and lipid breakdown during the response to starvation. In contrast, elevated Mitf levels increase the number of lysosomes, autophagosomes and autolysosomes, and decrease the size of lipid droplets. Inhibition of Drosophila MTORC1 induces Mitf translocation to the nucleus, underscoring conserved regulatory mechanisms between Drosophila and mammalian systems. Furthermore, we show Mitf-mediated clearance of cytosolic and nuclear expanded ATXN1 (ataxin 1) in a cellular model of spinocerebellar ataxia type 1 (SCA1). This remarkable observation illustrates the potential of the lysosomal-autophagy system to prevent toxic protein aggregation in both the cytoplasmic and nuclear compartments. We anticipate that the genetics of the Drosophila model and the absence of redundant MIT transcription factors will be exploited to investigate the regulation and function of the lysosomal-autophagy gene network. | Ataxin-1 |
Previous studies have confirmed that docetaxel (DTX) treatment increases TNF-alpha production in cancer cells, but its mechanism of action remains unclear. Therefore, this study aimed to determine the signaling axis by which DTX induced the expression of TNF-alpha in U937 leukemia and MCF-7 breast carcinoma cells. DTX treatment promoted Ca(2+)-controlled autophagy and SIDT2 expression, resulting in lysosomal degradation of miR-25 in U937 cells. Downregulation of miR-25 increased NOX4 mRNA stability and protein expression. NOX4-stimulated ROS generation led to JNK-mediated phosphorylation of cytosolic HuR at Ser221, thereby increasing TNF-alpha protein expression by stabilizing TNF-alpha mRNA. Consequently, DTX induced TNF-alpha-dependent death in U937 cells. Depletion of HuR using siRNA or abolishment of JNK activation reduced TNF-alpha expression and eliminated DTX-mediated cytotoxicity. Knockdown of SIDT2 or pretreatment with chloroquine (a lysosome inhibitor) reduced DTX-induced NOX4 and TNF-alpha expression and mitigated JNK-mediated HuR phosphorylation. Altogether, our data indicate that DTX triggers HuR-mediated TNF-alpha mRNA stabilization through the Ca(2+)/SIDT2/NOX4/ROS/JNK axis, thereby inducing TNF-alpha-dependent apoptosis in U937 cells. In addition, DTX induces apoptosis in MCF-7 cells through SIDT2/NOX4/JNK/HuR axis-mediated TNF-alpha expression. | Nucleotide Transport Proteins |
Physiological hypoxic conditions in the tumor microenvironment and consequential overexpression of carbonic anhydrase IX (CA IX) are two characteristics shared by numerous types of solid malignant tumors. Early detection with hypoxia assessment is crucial to improve the prognosis and therapy outcomes of hypoxia tumors. Herein, using acetazolamide (AZA) as a CA IX-targeting moiety, we design and synthesize an Mn(II)-based MR imaging probe (named AZA-TA-Mn) incorporating AZA and two Mn(II) chelates of Mn-TyEDTA on a rigid triazine (TA) scaffold. The per Mn relaxivity of AZA-TA-Mn is 2-fold higher than its monomeric Mn-TyEDTA, which allows it for low-dose imaging of hypoxic tumors. In a xenograft mice model of esophageal squamous cell carcinoma (ESCC), a low dosage of AZA-TA-Mn (0.05 mmol/kg) can selectively produce prolonged and stronger contrast enhancement in the tumor compared to the non-specific Gd-DTPA (0.1 mmol/kg). A competition study of co-injection of free AZA and Mn(II) probes confirms the in vivo tumor selectivity of AZA-TA-Mn, resulting in a more than 2.5-fold decreased tumor-to-muscle contrast-to-noise ratio (DeltaCNR) at 60 min post-injection. MR imaging results were further supported by the quantitative analysis of Mn tissue levels, as the co-injection of free AZA resulted in significantly reduced Mn accumulation in tumor tissues. Finally, immunofluorescence staining of tissue sections confirms the positive correlation between the tumor accumulation of AZA-TA-Mn and CA IX overexpression. Hence, using CA IX as the hypoxia biomarker, our results illustrate a practical strategy for the development of novel imaging probes for hypoxic tumors. | Carbonic Anhydrase IX |
Murine typhus, a neglected rickettsiosis caused by Rickettsia typhi, is a common disease in several Latin-American countries. The sylvatic life cycle of R. typhi encompasses the presence of several wild mammals, particularly opossums of the genus Didelphis and their associated fleas. Due to the colonization of wild environments by human populations, the increase in contact with opossum fleas has generated the presence of urban outbreaks of typhus. For this reason, the aim of our study was to identify the presence and diversity of Rickettsia sp. in fleas collected from opossums of an urban reserve in Mexico City. Opossums were captured from February to September 2017. For the detection of Rickettsia DNA, fragments of 800 bp of the citrate synthase (gltA) and the outer membrane protein B (ompB) were amplified. A total of 141 fleas (111 female symbol, 30 male symbol) of a single species (Ctenocephalides felis felis) were recovered from 31 Didelphis virginiana. Rickettsia DNA was detected in 17.7% (25/141) of the analysed fleas, recovered from seven infested opossums. The Maximum likelihood of sequences exhibited an identity of 99%-100% with sequences of R. typhi from southern United States. This work represents the first record of R. typhi in fleas from opossums in Mexico. | Typhus, Endemic Flea-Borne |
Mastocytosis is a rare condition in which mast cells accumulate throughout various organs of the body-the most common subtype being confined to the skin. We present an unusual case of cutaneous mastocytosis localized to the unilateral breast of a young woman with partial involvement of the areola. Previously diagnosed as nipple eczema, the patient failed appropriate treatment with class III and IV topical corticosteroids. Given it was adult onset, failed appropriate treatment, and had an atypical clinical appearance, a biopsy was pursued that revealed mastocytosis in skin. This is another clinical diagnosis dermatologists may consider in their differential diagnosis of nipple dermatitis. | Mastocytoma, Skin |
The pathways of pectin and galacturonate catabolism in Erwinia chrysanthemi converge to form a common intermediate, 2-keto-3-deoxygluconate, which is phosphorylated to form 2-keto-3-deoxy-6-phosphogluconate (KDGP) and then cleaved by the aldolase encoded by the kdgA gene. We cloned the kdgA gene of the E. chrysanthemi strain 3937 by complementing an Escherichia coli kdgA mutation, using an RP4-derivative plasmid. Restriction mapping of the kdgA region and isolation of kdgA-lac fusions allowed the more precise localization of the kdgA gene and determination of its transcriptional direction. The nucleotide sequence of the kdgA region indicated that the kdgA reading frame is 639 bases long, corresponding to a protein of 213 amino acids with a molecular mass of 22,187 Da. Comparison of the deduced primary amino acid sequences of the E. chrysanthemi KDGP-aldolase to the E. coli, Zymomonas mobilis and Pseudomonas putida enzymes showed that they are highly conserved. The E. chrysanthemi kdgA structural gene begins 153 bases downstream of an open reading frame that has a high homology with the zwf E. coli gene encoding glucose-6-phosphate dehydrogenase. The zwf gene is also linked to eda (kdgA) in E. coli and P. putida but genetic organization is different. Regulation of zwf and kdgA expression in E. chrysanthemi was analysed using lacZ fusions. The expression of zwf is independent of the growth rate, but is repressed in the presence of glucose. Induction of kdgA by pectin-degradation products is mediated in vivo by the negative regulatory gene kdgR, which also controls all the steps of pectin degradation.(ABSTRACT TRUNCATED AT 250 WORDS) | Dickeya chrysanthemi |
Host defense peptides such as defensins are components of innate immunity and have retained antibiotic activity throughout evolution. Their activity is thought to be due to amphipathic structures, which enable binding and disruption of microbial cytoplasmic membranes. Contrary to this, we show that plectasin, a fungal defensin, acts by directly binding the bacterial cell-wall precursor Lipid II. A wide range of genetic and biochemical approaches identify cell-wall biosynthesis as the pathway targeted by plectasin. In vitro assays for cell-wall synthesis identified Lipid II as the specific cellular target. Consistently, binding studies confirmed the formation of an equimolar stoichiometric complex between Lipid II and plectasin. Furthermore, key residues in plectasin involved in complex formation were identified using nuclear magnetic resonance spectroscopy and computational modeling." | Uridine Diphosphate N-Acetylmuramic Acid |
Published information on the properties of two proteins from chicken muscle, creatine kinase (MM-creatine kinase) and an M-line protein, suggested that they might be identical molecules. Different published procedures were used to purify the two proteins to homogeneity, and the properties of the two preparations were compared. Creatine kinase specific activity increased during purification of M-line protein, reaching a value comparable to that of purified MM-creatine kinase. The two proteins migrated identically in two electrophoretic systems and, after electrophoresis, both could be stained for creatine kinase activity. Double immunodiffusion tests with antibody prepared against MM-creatine kinase established the serological identity of the two protein preparations. Immunofluorescent studies showed that antiserum against MM-creatine kinase was bound in a regular pattern at the centers of the A-band regions of isolated myofibrils. These data show conclusively that the M-line protein and MM-creatine kinase are identical. | Creatine Kinase |
In a tertiary hospital, Legionella spp were isolated from taps and from ward dishwashers connected to contaminated tap piping. Our investigation revealed favorable conditions for growth of Legionella, and showed that Legionella pneumophila SG6 isolates from the taps and dishwashers were all genetically identical by repetitive-element polymerase chain reaction. These results suggest that contaminated dishwashers might be a potential reservoir for the spread of Legionella in health care facilities. | Legionellaceae |
The voltage-gated sodium channel isoform Na(V)1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function Na(V)1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate Na(V)1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting Na(V)1.7 have been advanced to clinical development, no Na(V)1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a Na(V)1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC(50) of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, Na(V)1.1-1.6 and Na(V)1.8. In contrast to other Na(V)1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting Na(V)1.7." | NAV1.7 Voltage-Gated Sodium Channel |
Although Evidence-based medicine (EBM) and Patient-centered medicine (PCM) are often perceived as two conflicting paradigms that speak the language of populations and the language of individuals, respectively, both share the common objective of improving the care of individual patients. As physicians should not practice an EBM that is away from the individual patient nor a PCM that is not based on the best available evidence, it is crucial to connect and combine both movements, promoting the fruitful and natural interaction between research and care. Achieving such interaction requires developing new individual-patient centric research methods. In this commentary, we propose an innovative clinical research design oriented to personalize point-of-care trials-integrating clinical research and medical care-through the incorporation of individual patients' preferences to build personalized research protocols. Building on the framework of N-of-1 studies, in "individual point-of-care trials," each protocol could be personalized for each patient so that the therapeutic objectives, the outcome variables analyzed, and the (operationalization of the) compared interventions would be based not only on the clinical and biological characteristics of each patient but also on their individual preferences, goals, and values. If patient preferences are being progressively integrated into medical practice, it makes sense that they also are incorporated into clinical trials embedded in care delivery. The proposal to perform individual point of care trials may be an optimal way to combine EBM and PCM while preserving their foundational principles, and to ensure the connection between "personalized" and "personal" care." | Pragmatic Clinical Trials as Topic |
Besides a series of known sterols and triterpenoids, a new resorcinol (1) and a known resorcinol (2) have been isolated from ethanol extract of Ardisia maculosa for the first time. The structures of these resorcinol derivatives were elucidated as 2-methyl-5-(Z-heptadec-8-enyl) resorcinol and 5-Z-heptadec-8-enyl) resorcinol by HRESI-MS, NMR ((1)H, (13)C, HSQC, HMBC) experiments. In our in vitro assay, compounds 1 and 2 showed no antimicrobial activities, however, compound 2 exhibited cytotoxity activity against human cancer cell line with GI(50) value of 2.14 x 10(- 4) mmol/ml. | Resorcinols |
Congenital mesoblastic nephroma (CMN) and infantile fibrosarcoma (IFS) are two pediatric tumors arising in the kidneys and soft tissues of infants, respectively. Recently, a t(12;15)(p13;q25) resulting in ETV6-NTRK3 gene fusion was detected in patients with IFS and in patients with the cellular type of CMN, suggesting a common pathogenetic pathway. We investigated the presence or absence of ETV6 rearrangements and numerical abnormalities of chromosome 11 by using fluorescence in situ hybridization on paraffin-embedded material from five cases of IFS, two of CMN, and one of mixed type (CMN and IFS) found in our files. In three cases of IFS, we found ETV6 gene rearrangement but a normal copy number of chromosome 11. One case each of IFS, the cellular type of CMN, and the mixed type (CMN and IFS) had both abnormalities. In a case of classic CMN, neither trisomy 11 nor gene rearrangement was found. It is possible that trisomy 11 is a later, nonessential event in the pathogenetic process or that this secondary aberration is associated with still-unrecognized clinical or biological characteristics. We confirmed that IFS and the cellular type of CMN are cytogenetically related and can occur synchronously in the same organ. | Nephroma, Mesoblastic |
The treatment of minor wounds makes up a significant proportion of the workload in the A&E department. Valerie Small examines the treatment options available. | Skin Care |
(1) Recurrent parotitis is probably caused by a congenital abnormality of the salivary gland ducts with recurrent attacks of ascending infection, perhaps aided by dehydration. The parotid gland is predominantly affected probably because of its lower rate of secretion compared with the submandibular gland. (2) The condition mainly affects children between the ages of 3 and 6, with males being more commonly affected. The symptoms peak in the first year of school, and usually, but not invariably, begin to subside at puberty. By the age of 22, most patients are completely symptom-free. When the disease starts after puberty, females are predominantly affected. (3) Ultrasound is the appropriate initial investigation, and is usually supplemented by sialography. The sialography may itself cause a resolution of symptoms. (4) Treatment is conservative in the first instance, and an expectant policy is indicated. More aggressive treatment is justified only for those adults with persistent problems. This may be parotid duct ligation, parotidectomy, or tympanic neurectomy, depending upon the preference and experience of the treating physician. | Parotid Diseases |
Intracellular parasites use various strategies to invade cells and to subvert cellular signaling pathways and, thus, to gain a foothold against host defenses. Efficient cell entry, ability to exploit intracellular niches, and persistence make these parasites treacherous pathogens. Most intracellular parasites gain entry via host-mediated processes, but apicomplexans use a system of adhesion-based motility called gliding" to actively penetrate host cells. Actin polymerization-dependent motility facilitates parasite migration across cellular barriers, enables dissemination within tissues, and powers invasion of host cells. Efficient invasion has brought widespread success to this group, which includes Toxoplasma, Plasmodium, and Cryptosporidium." | Apicomplexa |
This article addresses the current lack of research on uxoricides in non-Western societies by examining the phenomenon in Ghana, West Africa. Analysis of data from the 60 husband-wife killings reported in a national daily newspaper reveals that jealousy and suspicion of infidelity overwhelmingly provided the basis for wife murders. The findings also indicate that assailants and victims were of low socioeconomic background and the murders predominantly occurred in the rural areas of the country. Posthomicidal suicide by the assailant occurred in about one fourth of the cases. Overall, the results demonstrate that the patterns of uxoricide in Ghana are congruous in many significant ways with those noted in Western industrialized societies. It is concluded that additional research in non-Western societies is warranted to contribute to the development of sound conclusions about and remedies for uxoricide. | Spouses |
GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl(-)](i)) levels. The control of [Cl(-)](i) levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials. | Bumetanide |
AIMS: To determine the long-term outcome of patients with endomyocardial fibrosis and to compare echocardiographic and haemodynamic data before and after ventricular endocardial resection. PATIENTS: Seventeen patients (11 women and six men; mean age 35.5 years) diagnosed with endomyocardial fibrosis at the University Hospital in Zurich, Switzerland from 1971 to 1995. Twelve patients (70%) had partial obliteration of both ventricles and in five patients (30%) the fibrotic lesions were limited to the left ventricle. METHODS: Fourteen of the 17 patients had surgical resection: fibrosis was resected from both ventricles in five patients and from the left ventricle only in nine patients. Ten patients had mitral valve replacement and two had tricuspid valve replacement. Left ventricle endocardial resection was done without reconstruction or replacement of the atrioventricular valve in three patients. Preoperative and postoperative echocardiographic data were available for 11 patients and haemodynamic data for six patients. Patients were followed up for 0.4-19 years (mean 8.6). RESULTS: Preoperatively four patients were NYHA functional class IV and 10 were class III; postoperatively one patient was class III, seven class II, and six class I. Preoperatively, echocardiography showed obliteration of the left ventricular apex and inflow tract in all patients, which decreased or disappeared after surgery. Left ventricular end diastolic pressure decreased from 25 mm Hg before surgery to 14 mm Hg after successful resection of the fibrosis. Left ventricular and diastolic volume (normal 93 (17) ml/m2) increased from 65 ml/m2 to 97 ml/m2 (p < 0.05) after surgery. Ejection fraction was normal preoperatively (57%) and decreased slightly (52%) after surgery. One patient died five months after surgery from heart failure. Four surgically treated patients died during the follow up period: one each from systolic dysfunction, recurrence of endomyocardial fibrosis, pneumonia, and food poisoning. Overall survival was 65% at five years and 59% at 10 years; the survival rates of the operated patients was 72% and 68%, respectively. Only one of the medically treated patients survived longer than three years from diagnosis. CONCLUSIONS: Endomyocardial fibrosis is a rare disease in European countries and is found mainly in women. The clinical picture is characterised by severe congestive heart failure but heart size is only moderately increased. Systolic performance is normal or only slightly depressed despite severe restriction to filling, atrioventricular valve regurgitation or both. Partial obliteration of the right and/or left ventricle may be detected by echocardiography. Endocardial resection with atrioventricular valve replacement is the treatment of choice with appreciable postoperative improvement and 10 year survival of approximately 70%. | Endomyocardial Fibrosis |
The differentiation between premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) has been widely discussed. PMDD is listed as a mental disorder in the DSM-5, whereas PMS is not considered as a mental disorder in any diagnostic manual. Consequently, PMS is operationalized in different ways. Keeping a symptom diary is required to diagnose PMDD but is also recommended for PMS. The aim of our study was, therefore, to operationalize PMS and PMDD within a DSM-5-based symptom diary. We developed a symptom-intensity-score (SI-score) and an interference-score (INT-score) to evaluate the symptom diary. Ninety-eight women (aged 20-45 years) completed a symptom diary over two menstrual cycles, a retrospective screening for premenstrual symptoms, and answered additional impairment questionnaires from August 2013 to August 2015. The scores revealed moderate to good reliability (Cronbach's alpha = 0.83-0.96). Convergent validity was shown by significant correlations with a retrospective screening, the Pain Disability Index, and the German PMS-Impact Questionnaire. Discriminant validity was indicated by low correlations with the Big Five Inventory-10. These scores may facilitate the evaluation of prospective symptom ratings in research and clinical practice. Future research should focus on continuing to validate the scores (e.g., in an ambulatory setting)." | Premenstrual Dysphoric Disorder |
Pyoderma faciale is a distinctive entity. Twenty-nine patients with this process were seen in the Mayo Clinic from 1969 to 1980. Twenty-seven patients had follow-up that ranged from 1 month to 11 years, and twenty-two had follow-up of 3 years or more. Clinical features that characterize the patients were (1) female predominance, (2) onset later than teenage acne vulgaris, generally at 19 to 40 years of age, (3) rapid onset and progression, (4) facial involvement with sparing of the back and chest, (5) cysts, swelling, and purulent drainage with a lack of comedones, and (6) paucity of systemic complaints. Patients were treated with multiple forms of therapy simultaneously, often including Vleminckx packs, oral antibiotics, incision and drainage, ultraviolet B, and intralesional steroids. Of twenty-five patients available for follow-up at 1 year, twenty-three had achieved remission, though fifteen patients required ongoing treatment to maintain optimal control. Twenty-three patients had scarring as a sequela. Patients with pyoderma faciale represent a subset of patients with acne in whom the outlook is favorable with appropriate therapy. | Pyoderma |
Helper-dependent adenoviral (HDAd) vectors are attractive for liver-directed gene therapy because they can drive sustained high levels of transgene expression without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic delivery because of a nonlinear dose response. Unfortunately, such high doses result in systemic vector dissemination and dose-dependent acute toxicity with potential lethal consequences. We have previously shown in nonhuman primates that delivery of HDAd in surgically isolated livers resulted in a significantly higher hepatic transduction with reduced systemic vector dissemination compared with intravenous delivery and multiyear transgene expression. Encouraged by these data, we have now employed a surgical vector delivery method in the Gunn rat, an animal model for Crigler-Najjar syndrome. After vector delivery into the surgically isolated liver, we show phenotypic correction at the low and clinically relevant vector dose of 1 x 10(11) vp/kg. Correction of hyperbilirubinemia and increased glucuronidation of bilirubin in bile was achieved for up to 1 year after vector administration. Surgical delivery of the vector was well tolerated without signs of acute or chronic toxicity. This method of delivery could thereby be a safer alternative to liver transplantation for long-term treatment of Crigler-Najjar syndrome type I. | Rats, Gunn |
Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes. | Antifibrotic Agents |
Onychomycosis is a fungal infection of the nail plate or nail bed. It does not usually cure itself and it can trigger more infectious lesions in other parts of the body. The reported prevalence of onychomycosis is increasing in Western countries, presumably due to lifestyle changes and the ageing of the population. Approximately 10% of the general population, 20% of the population aged>60 years, up to 50% of people aged>70 years and up to one-third of diabetic individuals have onychomycosis. Care should be taken for the accurate diagnosis and timely treatment of toenail onychomycosis to prevent complications. Current treatment options have relatively limited therapeutic success, particularly long-term. Oral medications are associated with high recurrence rates and treatment failure, and are not suitable for many cases due to potential adverse effects. Topical medications are recommended only for mild to moderate cases. The cost of therapies may also be prohibitive in some cases. In the light of these issues, more research is warranted for the investigation and development of more effective and economical options for the treatment and prophylaxis of toenail onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatry care of toenails and feet should be encouraged. | Foot Dermatoses |
PURPOSE: Laboratory processing of implant-supported prostheses may alter the surface of the abutment in contact with the corresponding surface and thus the interface fit. This study assessed changes in the rotational freedom (R) at the interface of 1 implant ceramic abutments before and after preparation and glass infiltration processes. MATERIALS AND METHODS: The abutment R was assessed for 20 as-received In-Ceram Ceramic Blanks over synOcta abutments and after both preparation and infiltration procedures. RESULTS: Compared with the as-received blanks, there was a statistically significant (P < 0.009) increase of 0.8 minutes in the R after preparation and glass infiltration processes. CONCLUSION: The results of this investigation suggest that, if all laboratory steps are observed carefully, changes at the abutment interface of Ceramic Blanks do not occur. | Dental Prosthesis Retention |
Synaptic dysfunction is a typical pathophysiologic change in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Hintington's disease (HD) and amyotrophic lateral sclerosis (ALS), which involves protein post-translational modifications (PTMs) including L-isoaspartate (L-isoAsp) formed by isomerization of aspartate or deamidation of asparagine. The formation of L-isoAsp could be repaired by protein L-isoaspartyl methyltransferase (PIMT). Some synaptic proteins have been identified as PIMT potential substrates and play an essential role in ensuring synaptic function. In this review, we discuss the role of certain synaptic proteins as PIMT substrates in neurodegenerative disease, thus providing therapeutic synapse-centered targets for the treatment of NDs. | Isoaspartic Acid |
Hybridization may influence evolution in a variety of ways. If hybrids are less fit, the geographical range of ecologically divergent populations may be limited, and prezygotic reproductive isolation may be reinforced. If some hybrid genotypes are fitter than one or both parents, at least in some environments, then hybridization could make a positive contribution. Single alleles that are at an advantage in the alternative environment and genetic background will introgress readily, although such introgression may be hard to detect. 'Hybrid speciation', in which fit combinations of alleles are established, is more problematic; its likelihood depends on how divergent populations meet, and on the structure of epistasis. These issues are illustrated using Fisher's model of stabilizing selection on multiple traits, under which reproductive isolation evolves as a side-effect of adaptation in allopatry. This confirms a priori arguments that while recombinant hybrids are less fit on average, some gene combinations may be fitter than the parents, even in the parental environment. Fisher's model does predict heterosis in diploid F1s, asymmetric incompatibility in reciprocal backcrosses, and (when dominance is included) Haldane's Rule. However, heterosis arises only when traits are additive, whereas the latter two patterns require dominance. Moreover, because adaptation is via substitutions of small effect, Fisher's model does not generate the strong effects of single chromosome regions often observed in species crosses. | Hybrid Vigor |
Single oral doses of 16, 32 and 64 mg oxilofrine as dragees as well as 16mg as drops were given to 12 healthy male volunteers in an open Latin-square design with one week interval between dosing days. Concentrations of unchanged drug were monitored in plasma over 24 hours, in urine concentrations of free and total oxilofrine were monitored over 36 hours. Drug concentrations were measured by a specific high pressure liquid chromatography method with electrochemical detection. Medians of maximum plasma concentrations (Cmax) of oxilofrine were 9.1 ng/ml, 11.4 ng/ml, 31.4 ng/ml and 122.9 ng/ml for 16 mg drops, 16, 32, and 64 mg dragees, respectively. The times to maximum plasma concentration (tmax) were between 0.7 and 1.7 h, respectively. The values for areas under the plasma concentration-time curve (AUC0-24) were 12.8, 17.7, 61.0 and 268.2 ng/ml.h for the four treatments. The results show that both Cmax- and AUC0-24-values increase faster with increasing dosing than a linear first-pass would suggest and give evidence for a saturable first-pass metabolism. There is also evidence for an enterohepatic circulation. About 50% of the administered dose is found in the urine, urinary recovery shows a dose-linear dependency. General tolerability was good; no side-effects were reported. | Ephedrine |
In the liver microsome cyanide (CN)-trapping assays, piperazine-containing compounds formed significant N-methyl piperazine CN adducts. Two pathways for the N-methyl piperazine CN adduct formation were proposed: 1) The alpha-carbon in the N-methyl piperazine is oxidized to form a reactive iminium ion that can react with cyanide ion; 2) N-dealkylation occurs followed by condensation with formaldehyde and dehydration to produce N-methylenepiperazine iminium ion, which then reacts with cyanide ion to form the N-methyl CN adduct. The CN adduct from the second pathway was believed to be an artifact or metabonate. In the present study, a group of 4'-N-alkyl piperazines and 4'-N-[(1)(3)C]methyl-labeled piperazines were used to determine which pathway was predominant. Following microsomal incubations in the presence of cyanide ions, a significant percentage of 4'-N-[(1)(3)C]methyl group in the CN adduct was replaced by an unlabeled natural methyl group, suggesting that the second pathway was predominant. For 4'-N-alkyl piperazine, the level of 4'-N-methyl piperazine CN adduct formation was limited by the extent of prior 4'-N-dealkylation. In a separate study, when 4'-NH-piperaziens were incubated with potassium cyanide and [(1)(3)C]-labeled formaldehyde, 4'-N-[(1)(3)C]methyl piperazine CN-adduct was formed without NADPH or liver microsome suggesting a direct Mannich reaction is involved. However, when [(1)(3)C]-labeled methanol or potassium carbonate was used as the one-carbon donor, 4'-N-[(1)(3)C]methyl piperazine CN adduct was not detected without liver microsome or NADPH present. The biologic and toxicological implications of bioactivation via the second pathway necessitate further investigation because these one-carbon donors for the formation of reactive iminium ions could be endogenous and readily available in vivo. | Cyanides |
The needs of molecular diagnostic laboratories that perform both Food and Drug Administration-cleared as well as laboratory-developed tests are usually not met on a single analytical platform. Furthermore, little information is available about the direct impact of molecular automation on labor costs and efficiency in clinical laboratories. We performed a process impact analysis from time and motion studies of a novel molecular diagnostic robotic system designed to automate sample preparation, extraction, and analysis. All 27 preanalytical tasks were quantified for the amount of time spent preparing 24 specimens for analysis. These steps were completed in 899 s (14 min, 59 s) followed by 7887 s (131 min, 27 s) of instrument operation independent of operator control (walk-away time). Postanalytical results evaluation required 1 min per specimen. The instrument automatically extracted the nucleic acid from the specimen, added the eluted DNA to the amplification reagents, and performed the analysis. Only 12% of the total instrument operations required relatively unskilled human labor. Thus, the availability of automated molecular diagnostic instruments will facilitate the expansion of molecular testing in the clinical laboratory because they reduce operator costs with respect to time and complexity of the tasks they are asked to perform. | Automation, Laboratory |
The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation of vitally important cellular functions. Polyamine analogs and derivatives are a traditional and important instrument for the investigation of the cellular functions of polyamines, enzymes of their metabolism, and the regulation of the biosynthesis of antizyme-a key downregulator of polyamine homeostasis. Here, we describe convenient gram-scale syntheses of a set of C-methylated analogs of Spd. The biochemical properties of these compounds and the possibility for the regulation of their activity by moving a methyl group along the polyamine backbone and by changing the stereochemistry of the chiral center(s) are discussed. | Biogenic Polyamines |
Os odontoideum is a rare entity of the second cervical vertebra, characterized by a circumferentially corticated ossicle separated from the body of C2. The ossicle is a distinct entity from an odontoid fracture or a persistent ossiculum terminale. The diagnosis may be made incidentally on imaging obtained for the workup of neck pain or neurologic signs and symptoms. Diagnosis usually can be made with plain radiographs. MRI and CT can assess spinal cord integrity and C1-C2 instability. The etiology of os odontoideum is a topic of debate, with investigative studies supporting both congenital and traumatic origins. A wide clinical range of symptoms exists. Symptoms may present as nondescript pain or include occipital-cervical pain, myelopathy, or vertebrobasilar ischemia. Asymptomatic cases without evidence of radiologic instability are typically managed with periodic observation and serial imaging. The presence of atlantoaxial instability or neurological dysfunction necessitates surgical intervention with instrumentation and fusion for stability. | Axis, Cervical Vertebra |
PREMISE: Populations of species with large spatial distributions are shaped by complex forces that differ throughout their ranges. To maintain the genetic diversity of species, genepool-based subsets of widespread species must be considered in conservation assessments. METHODS: The population genetics of the lichenized fungus Lobaria pulmonaria and its algal partner, Symbiochloris reticulata, were investigated using microsatellite markers to determine population structure, genetic diversity, and degree of congruency in eastern and western North America. Data loggers measuring temperature and humidity were deployed at selected populations in eastern North America to test for climatic adaptation. To better understand the role Pleistocene glaciations played in shaping population patterns, a North American, range-wide species distribution model was constructed and hindcast to 22,000 years before present and at 500-year time slices from then to the present. RESULTS: The presence of two gene pools with minimal admixture was supported, one in the U.S. Pacific Northwest and one in eastern North America. Western populations were significantly more genetically diverse than eastern populations. There was no evidence for climatic adaptation among eastern populations, though there was evidence for range-wide adaptation to evapotranspiration rates. Hindcast distribution models suggest that observed genetic diversity may be due to a drastic Pleistocene range restriction in eastern North America, whereas a substantial coastal refugial area is inferred in the west. CONCLUSIONS: Taken together the results show different, complex population histories of L. pulmonaria in eastern and western North America, and suggest that conservation planning for each gene pool should be considered separately. | Pulmonaria |
Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-kappaB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs. | Diflunisal |
BACKGROUND: Fruit flies are important economic pests of fruits, vegetables, and nuts all over the world. In this study, a permanent ecological trap, which was created by the ovicidal effect of phytogenic hydrogen cyanide (HCN) liberated from passion fruits due to oviposition by fruit flies and can be used in the pest management, were determined. RESULTS: Observation of fruit fly eggs in Passiflora within the passion fruit cultivation region in southern China, from Aug 2019 to Oct 2020 showed that the exotic Passiflora attracted the native fruit flies to oviposit, but the eggs could not hatch. Using classical staging to categorize embryonic development and fumigation assays, we show that oviposition by fruit fly on passion fruits, release HCN from the cyanogenic mesocarp. Exposure of the eggs to HCN causes arrest of embryonic development and finally the death of eggs. CONCLUSION: Our results reveal that the life cycle of fruit fly in Passiflora is interrupted at the egg stage. Consequently, we predict that this ecological trap may be permanent. Extensive cultivation of the Passiflora vine as a dead-end trap crop may be an effective avenue to reduce populations of fruit fly pests. (c) 2023 Society of Chemical Industry. | Passiflora |
GTP cyclohydrolase II catalyzes the hydrolytic release of formate and pyrophosphate from GTP producing 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate, the first committed intermediate in the biosynthesis of riboflavin. The enzyme was shown to contain one zinc ion per subunit. Replacement of cysteine residue 54, 65 or 67 with serine resulted in proteins devoid of bound zinc and unable to release formate from the imidazole ring of GTP or from the intermediate analog, 2-amino-5-formylamino-6-ribosylamino-4(3H)-pyrimidinone 5'-triphosphate. However, the mutant proteins retained the capacity to release pyrophosphate from GTP and from the formamide-type intermediate analog. The data suggest that the enzyme catalyzes an ordered reaction in which the hydrolytic release of pyrophosphate precedes the hydrolytic attack of the imidazole ring. Ring opening and formate release are both dependent on a zinc ion acting as a Lewis acid, which activates the two water molecules involved in the sequential hydrolysis of two carbon-nitrogen bonds. | GTP Cyclohydrolase |
BACKGROUND: Genetic barcoding provides a high-throughput way to simultaneously track the frequencies of large numbers of competing and evolving microbial lineages. However making inferences about the nature of the evolution that is taking place remains a difficult task. RESULTS: Here we describe an algorithm for the inference of fitness effects and establishment times of beneficial mutations from barcode sequencing data, which builds upon a Bayesian inference method by enforcing self-consistency between the population mean fitness and the individual effects of mutations within lineages. By testing our inference method on a simulation of 40,000 barcoded lineages evolving in serial batch culture, we find that this new method outperforms its predecessor, identifying more adaptive mutations and more accurately inferring their mutational parameters. CONCLUSION: Our new algorithm is particularly suited to inference of mutational parameters when read depth is low. We have made Python code for our serial dilution evolution simulations, as well as both the old and new inference methods, available on GitHub ( https://github.com/FangfeiLi05/FitMut2 ), in the hope that it can find broader use by the microbial evolution community. | Bayes Theorem |
Iron deficiency anemia (IDA) is prevailing around the globe at variable extent. To combat this phenomenon various strategies are popular. One effective strategy is food fortification. A number of reviews are available to discuss the bioavailability of food fortificants exclusively or in special dietary arrangements with specific food vehicles to access their performance in order to overcome the iron deficiency problem. However, little consideration is given to the efficacy studies of these dietary settings. This review is meant for discussing the efficacy of non-heme iron fortified diets. | Nonheme Iron Proteins |
This paper assesses the economic efficiency of Brazilian general hospitals that provide inpatient care for the Unified Health System (SUS). We combined data envelopment analysis (DEA) and spatial analysis to identify predominant clusters, measure hospital inefficiency and analyze the spatial pattern of inefficiency throughout the country. Our findings pointed to a high level of hospital inefficiency, mostly associated with small size and distributed across all Brazilian states. Many of these hospitals could increase production and reduce inputs to achieve higher efficiency standards. These findings suggest room for optimization, but inequalities in access and the matching of demand and supply must be carefully considered in any attempt to reorganize the hospital system in Brazil. | Hospitals, General |
Sea buckthorn (Hippophae rhamnoides L.) pulp oils (SPOs) are rich in a variety of beneficial bioactive ingredients. Nevertheless, SPOs would be exposed to plastic equipment during processing, resulted in increasing phthalates contents and edible risk, as well as affecting oil quality. For these reasons, the effects of two stages steam distillation (SD2) and two stages molecular distillation (MD2) on phthalic acid esters (PAEs) content were investigated and compared in the present work. Compared with SD2, MD2 showed higher removal rates of seven selected PAEs from the SPO. Even if the initial concentration of DBP and DEHP in R-SPO were 1.626 and 10.933â¯mg/kg respectively, the concentration of DBP and DINP could be reduced below the limit set by China government after treated with MD2. Besides that, there was no trans-fatty acids generated in SPO during the distillation process. | Phthalic Acids |
The cellular mechanisms underlying pathological alcohol seeking remain poorly understood. Here, we show an enhancement of nucleus accumbens (NAcb) core action potential firing ex vivo after protracted abstinence from alcohol but not sucrose self-administration. Increased firing is associated with reduced small-conductance calcium-activated potassium channel (SK) currents and decreased SK3 but not SK2 subunit protein expression. Furthermore, SK activation ex vivo produces greater firing suppression in NAcb core neurons from alcohol- versus sucrose-abstinent rats. Accordingly, SK activation in the NAcb core significantly reduces alcohol but not sucrose seeking after abstinence. In contrast, NAcb shell and lateral dorsal striatal firing ex vivo are not altered after abstinence from alcohol, and SK activation in these regions has little effect on alcohol seeking. Thus, decreased NAcb core SK currents and increased excitability represents a critical mechanism that facilitates motivation to seek alcohol after abstinence. | Germinal Center Kinases |
Mitochondrial protein interactions and complexes facilitate mitochondrial function. These complexes range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation complexes I, III, and IV. To improve understanding of mitochondrial function, we used chemical cross-linking mass spectrometry to identify 2,427 cross-linked peptide pairs from 327 mitochondrial proteins in whole, respiring murine mitochondria. In situ interactions were observed in proteins throughout the electron transport chain membrane complexes, ATP synthase, and the mitochondrial contact site and cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical protein structures and delivered complementary constraints for in silico protein docking. These data established direct physical evidence of the assembly of the complex I-III respirasome and enabled prediction of in situ interfacial regions of the complexes. Finally, we established a database and tools to harness the cross-linked interactions we observed as molecular probes, allowing quantification of conformation-dependent protein interfaces and dynamic protein complex assembly." | Electron Transport Chain Complex Proteins |
Sustained low-efficiency dialysis is a hybrid form of kidney replacement therapy that has gained increasing popularity as an alternative to continuous forms of kidney replacement therapy in intensive care unit settings. During the COVID-19 pandemic, the shortage of continuous kidney replacement therapy equipment led to increasing usage of sustained low-efficiency dialysis as an alternative treatment for acute kidney injury. Sustained low-efficiency dialysis is an efficient method for treating hemodynamically unstable patients and is quite widely available, making it especially useful in resource-limited settings. In this review, we aim to discuss the various attributes of sustained low-efficiency dialysis and how it is comparable to continuous kidney replacement therapy in efficacy, in terms of solute kinetics and urea clearance, and the various formulae used to compare intermittent and continuous forms of kidney replacement therapy, along with hemodynamic stability. During the COVID-19 pandemic, there was increased clotting of continuous kidney replacement therapy circuits, which led to increased use of sustained low-efficiency dialysis alone or together with extra corporeal membrane oxygenation circuits. Although sustained low-efficiency dialysis can be delivered with continuous kidney replacement therapy machines, most centers use standard hemodialysis machines or batch dialysis systems. Even though antibiotic dosing differs between continuous kidney replacement therapy and sustained low-efficiency dialysis, reports of patient survival and renal recovery are similar for continuous kidney replacement therapy and sustained low-efficiency dialysis. Health care studies indicate that sustained low-efficiency dialysis has emerged as a cost-effective alternative to continuous kidney replacement therapy. Although there is considerable data to support sustained low-efficiency dialysis treatments for critically ill adult patients with acute kidney injury, there are fewer pediatric data, even so, currently available studies support the use of sustained low-efficiency dialysis for pediatric patients, particularly in resource-limited settings." | Hybrid Renal Replacement Therapy |
Observational data were collected on institutionalized mentally retarded people to determine the relationship between density and behavior in order to discover (a) in what size groups do such persons typically congregate? and (b) what effect does density have on their behavior within that group? Results showed that (a) this population was alone or only with peers more than with staff by a 3:1 ratio; (b) when they were with staff, they were with two or more peers 75 percent of the time; and (c) when they were not with staff, they were with two or more peers more than they were alone or with only one other peer. Results also showed that certain types of behavior changed in frequency as density changed. | Personal Space |
Hemipterans and thysanopterans (Paneoptera: Condylognatha) differ from other insects by having an intestinal perimicrovillar membrane (PMM) which extends from the base of the microvilli to the intestinal lumen. The development and composition of the PMM in hematophagous Reduviidae depend on factors related to diet. The PMM may also allow the human parasite Trypanosoma cruzi, the etiological agent of human Chagas Disease, to establish and develop in this insect vector. We studied the PMM development in the Mexican vector of Chagas Disease, Triatoma (Meccus) pallidipennis. We describe changes in the midgut epithelial cells of insects in response to starvation, and at different times (10, 15 and 20 days) after bloodfeeding. In starved insects, the midguts showed epithelial cells closely connected to each other but apparently free of PMM with some regions being periodic acid-Schiff (PAS-Schiff) positive. In contrast, the PMM was evident and fully developed in the midgut region of insects 15 days after feeding. After this time, the PMM completely covered the microvilli and reached the midgut lumen. At 15 days following feeding the labeled PAS-Schiff increased in the epithelial apex, suggesting an increase in carbohydrates. Lectins as histochemical reagents show the presence of a variety of glycoconjugates including mannose, glucose, galactosamine, N-acetyl-galactosamine. Also present were N-acetyl-glucosamine and sialic acid which contribute to the successful establishment and replication or T. cruzi in its insect vectors. By means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM), the formation and structure of the PMM is confirmed at 15 days post feeding. Our results confirmed the importance of the feeding processes in the formation of the PMM and showed the nature of the biochemical composition of the vectors' intestine in this important Mexican vector of Chagas disease. | Triatoma |
BACKGROUND: Current scientific evidence indicates that anemia in pregnancy, regardless of severity, is associated with an increased risk of maternal and fetal mortality. There is little published information about the bioavailability and bioequivalence of formulations containing both iron and folic acid. However, in vitro dissolution studies can provide important information on the likely relative bioavailability of various formulations. AIM: The objective of our study was to compare the in vitro dissolution of two similar commercially available formulations of iron- and folic acid-containing supplements, Folifer(R) (Bialport - Produtos Farmaceuticos, S.A., Portugal) and Ferroliver(R) (SM Pharma c.a., Venezuela), in order to determine the in vitro availability of their iron content. Folifer(R) and Ferroliver(R) were chosen because they contained similar amounts of elemental iron. METHODS: The amount of iron released from each tablet was evaluated over a 4-hour period in three dissolution media replicating gastric or intestinal juices with pH values ranging from 1.5 to 6.9. The samples were then titrated with a solution of cerium ammonium sulfate in order to calculate the amount of iron released in each specific pH condition. The percentage of dissolved iron was calculated as a cumulative frequency, using the percentage of dissolved iron at all timepoints. The dissolution similarity between the two commercially available formulations was evaluated using the &U0192;(2) statistic formula. RESULTS: During a 4-hour dissolution test, Folifer(R) released 59.4 mg of iron compared with 48.5 mg released by Ferroliver(R). The value obtained for the similarity factor, an indicator of likely bioequivalence, was 41. CONCLUSION: These data suggest that Folifer(R) releases more iron than Ferroliver(R), and that the two formulations are not equivalent in vitro. The superior dissolution of ferrous sulfate with Folifer(R) compared with ferrous fumarate in Ferroliver(R) might be responsible for the observed difference. | Intestinal Secretions |
In the early 1980s, an atypical" beta-adrenergic receptor was discovered and subsequently called the beta (3)-adrenoceptor (beta(3)-AR). Agonists of the beta(3)-AR were observed to simultaneously increase lipolysis, fat oxidation, energy expenditure and insulin action leading to the belief that this receptor might serve as an attractive target for the treatment of diabetes and obesity. In vivo studies lent credence to this postulate with the finding that stimulation of this receptor by selective agonists lead to glycemic improvements and weight loss in rodent models of diabetes and obesity. This lead to intensive research efforts directed at developing beta(3)-AR selective agonists for the treatment of type 2 diabetes and obesity in humans. Unfortunately, endeavour been largely unsuccessful to date. Major obstacles have included the pharmacological differences between the rodent and human beta(3)-AR, the lack of selectivity of previous compounds for the beta(3)-AR over beta(1)-/beta(2)-ARs, and unsatisfactory oral bioavailability and pharmacokinetic properties. Cloning of the human beta(3)-AR has allowed for the development of novel compounds targeted specifically at the human receptor. Encouraging data has emerged from clinical studies wherein CL-316,243, a highly selective, albeit rodent specific beta(3)-AR agonist was observed to increase lipolysis, fat oxidation and insulin action in humans. More recently, beta(3)-AR agonists directed at the human receptor are showing promising results in their ability to increase energy expenditure in humans following a single dose. However, they do nor appear to be able to sustain their effects when administered chronically. Further clinical testing will be necessary, using compounds with improved oral bioavailability and potency, to help assess the physiology of the beta(3)-AR in humans and its attractiveness as a potential therapeutic for the treatment of type 2 diabetes and obesity." | Adrenergic Agonists |
Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation. Only half of patients with severe acute GVHD respond to first-line treatment with corticosteroids and, for several decades, there was no optimal second-line treatment of patients with corticosteroid-refractory acute GVHD. Ruxolitinib was recently approved for the treatment of corticosteroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Thus, it is important to define the patient population that would now be considered as refractory to ruxolitinib vs ruxolitinib dependent. Here, we propose to define ruxolitinib-refractory acute GVHD as disease that shows: (1) progression of GVHD compared with baseline after at least 5 to 10 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement; (2) lack of improvement in GVHD (partial response or better) compared with baseline after >/=14 days of treatment with ruxolitinib; or (3) loss of response, defined as objective worsening of GVHD determined by increase in stage, grade, or new organ involvement at any time after initial improvement. GVHD manifestations that persist without improvement in patients who had a grade >/=3 treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib would serve as a clinical indication for additional treatment. In addition, absence of complete response or very good partial response at day 28 after ruxolitinib could be considered as an eligibility criterion. | Salvage Therapy |
The European Organisation for External Quality Assurance Providers in Laboratory Medicine (EQALM) was founded in 1996 and currently has members from 29 European countries and 6 countries from outside Europe. EQALM provides a forum for co-operation and exchange of knowledge on quality-related matters in laboratory medicine, especially with regard to external quality assessment (EQA) programs in Europe. In addition, EQALM represent the EQA providers in laboratory medicine at European level vis-r-vis political, professional, scientific and other bodies, including patients' organisations. To this end EQALM promotes activities such as organizing meetings with scientific and practical themes for members and other interested parties, issuing scientific publications, developing EQA projects and representing laboratory medicine EQA activities within other organisations and networks. EQALM is active in scientific and educational activity in different fields such as survey frequency, haematology, haemostasis, microbiology, nomenclature, virtual microscopy, traceability, accreditation, and quality assurance of the total testing process. The aim of this paper is to give an overview of the EQALM organisation. | Medical Laboratory Science |
Hinokitiol (I) and tropolone (II) showed characteristic cytotoxic effects in vitro on five kinds of human and murine cell lines and blastic lymphocytes from mouse splenocytes. The cytotoxic effect of I on the growth of murine and human tumor cell lines, including RL male-1, MH134, HL60, K562 and KATO-III was definite when examined by thymidine incorporation into DNA and its 50% inhibitory concentration (IC50) on all cells was 0.3-0.6 microgram/ml. Compound II also showed comparable cytotoxic effects on these cell lines, indicating a little lower activity when compared to I. Furthermore, I and II also completely suppressed the [3H]thymidine ([3H]TdR) incorporation of mitogen-induced blastic lymphocytes. The suppressive activity on mouse lymphocyte proliferative response to concanavaline-A was also found with both compounds at a low concentration of 0.32 microgram/ml. As compound I is known to be of fairly low toxicity (LD50: 453 + 24 mg/kg in mice), the antitumor and immuno-suppressive effect of hinokitiol (I) should be further investigated. | Tropolone |
Mycoplasma capricolum subsp. capripneumoniae is the causative agent of contagious caprine pleuropneumonia, a devastating disease of goats listed by the World Organization for Animal Health. Here we report the first complete genome sequence of this organism (strain M1601, a clinically isolated strain from China). | Mycoplasma capricolum |
Cutaneous and rhinofacial infections by Pythium insidiosum have previously been reported in sheep in Brazil. In the current study, a new form of pythiosis involving the alimentary tract of 2 nursing lambs from 2 different farms in the semiarid region of Brazil is described. The first lamb showed food regurgitation, lethargy, and anorexia, and died 5 days after the presentation of clinical signs. The second lamb had no history of gastrointestinal disease before death. Necropsy findings were similar in both lambs. The mucosa of the esophagus, reticulum, rumen, omasum, and abomasum showed ulcerated areas covered by yellowish caseous granular exudate. The lesions were transmural and extended to the serosal surfaces, and adhesions were observed between the serosa of the forestomachs and abomasum to the liver and diaphragm. Histologic lesions consisted of pyogranulomatous necrotizing transmural esophagitis, rumenitis, reticulitis, omasitis, and abomasitis with vascular thrombosis and intralesional hyphae. Pythium insidiosum was confirmed as the etiology by immunohistochemistry and culture. The presence of sheep in the vicinity of water ponds during the hot, dry season when forage is not available in the pastures seems to be the main predisposing factor for the occurrence of pythiosis in sheep in the Brazilian semiarid region. | Pythiosis |
Aldehyde oxidoreductases (AORs) are tungsten enzymes catalyzing the oxidation of many different aldehydes to the corresponding carboxylic acids. In contrast to other known AORs, the enzyme from the denitrifying betaproteobacterium Aromatoleum aromaticum (AOR(Aa)) consists of three different subunits (AorABC) and uses nicotinamide adenine dinucleotide (NAD) as an electron acceptor. Here, we reveal that the enzyme forms filaments of repeating AorAB protomers that are capped by a single NAD-binding AorC subunit, based on solving its structure via cryo-electron microscopy. The polyferredoxin-like subunit AorA oligomerizes to an electron-conducting nanowire that is decorated with enzymatically active and W-cofactor (W-co) containing AorB subunits. Our structure further reveals the binding mode of the native substrate benzoate in the AorB active site. This, together with quantum mechanics:molecular mechanics (QM:MM)-based modeling for the coordination of the W-co, enables formulation of a hypothetical catalytic mechanism that paves the way to further engineering for applications in synthetic biology and biotechnology. | Tungsten |
Advanced glycation end products (AGEs) are formed by the nonenzymatic Maillard reaction between sugars and proteins. Low-molecular weight AGEs are filtered by renal glomeruli and then reabsorbed and metabolized by proximal tubule cells (PTCs). High-molecular weight AGEs are also delivered to PTCs in proteinuric states. In patients with diabetes, AGE generation is increased, and the actions of AGEs on PTCs are likely involved in the pathogenesis of diabetic nephropathy. In patients with chronic renal failure (CRF), reduced renal metabolism of AGEs likely accounts for the accumulation of AGEs in serum, leading to uremic complications including dialysis-related amyloidosis. AGE precursors such as reactive carbonyl compounds also accumulate in the sera of patients with CRF. It is likely that PTCs take up AGEs and AGE precursors via specific endocytotic receptors or transporters. Megalin is a multiligand endocytotic receptor that is abundantly expressed on PTCs. There is evidence that megalin is involved in the cellular uptake and degradation of AGEs. We previously reported a cell therapy model involving implantation of megalin-expressing cells into experimental mice with renal failure for elimination of uremic toxin proteins. Further studies are needed to clarify the molecular mechanisms of the metabolism of AGEs and their precursors to develop a strategy for the treatment of diabetic nephropathy and uremic complications of CRF." | Heymann Nephritis Antigenic Complex |
Rectal perforation by migration of an intrauterine device is a rare complication which gynecologists must be aware of. Treatment can associate endoscopic examinations and a surgical procedure. | Intrauterine Device Expulsion |
Carbon dioxide (CO(2) ) is an easily available, renewable carbon source and can be utilized as a comonomer in the catalytic ring-opening polymerization of epoxides to generate aliphatic polycarbonates. Dodecyl glycidyl ether (DDGE) is copolymerized with CO(2) and propylene oxide (PO) to obtain aliphatic poly(dodecyl glycidyl ether carbonate) and poly(propylene carbonate-co-dodecyl glycidyl ether carbonate) copolymers, respectively. The polymerization proceeds at 30 degrees C and high CO(2) pressure utilizing the established binary catalytic system (R,R)-Co(salen)Cl/[PPN]Cl. The copolymers with varying DDGE:PO ratios are characterized via NMR, FT-IR spectroscopy, and SEC, exhibiting high molecular weights between 11 400 and 37 900 g mol(-1) with dispersities (Eth = M (w) /M (n) ) in the range of 1.37-1.61. Copolymers with T (g) s of -11 degrees C or T (m) s from 5 to 15 degrees C and thermal decomposition >200 degrees C depending on the comonomer ratio, are obtained as determined by differential scanning calorimetry/TGA. | Polycarboxylate Cement |
A major challenge in genetic studies of complex diseases is to determine how the action of risk genes is restricted to a tissue or cell type. Here, we investigate tissue specificity of gene action using CRISPR screens from 786 cancer cell lines originating from 24 tissues. We find that the expression pattern of the gene across tissues explains only a minority of cases of tissue-specificity (9%), while gene amplification and the expression levels of paralogs account for 39.5% and 15.5%, respectively. In addition, the transfer of small molecules to mutant cells explains tissue-specific gene action in blood. The tissue-specific genes we found are not specific just for human cancer cell lines: we found that the tissue-specific genes are intolerant to functional mutations in the human population and are associated with human diseases more than genes that are essential across all cell types. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases. | Gene Amplification |
Submitted in the paper are some general results of a many-years' standing experience gained with the use of computer engineering and computer methods in practical activities of a medical institution, concerning in particular organization matters, practical aspects of programme, technical, and cadre maintenance. Advantages are shown together with some results of effectiveness of employment of computer engineering in the therapeutic-and-diagnostic process and cultural aspect of medical activities." | Hospital Bed Capacity, 100 to 299 |
Carotid artery dissection (CAD) is one of the more common causes of stroke in persons younger than 50 years. In this age group and in older persons, CAD is most often associated with trauma. Significant morbidity can be a consequence of CAD, particularly a stroke or other permanent neurologic deficit. Because stroke is the third leading cause of death in the United States, attention has focused in the past decade on understanding the phenomenon of dissection of the carotid artery. This article presents a review of the risk factors associated with CAD, the role of the nurse as a provider of care for these persons, and the approaches to prevent or limit disability related to CAD, the ultimate goal of patient care. Nurses play a crucial role in the detection of CAD and in the prevention of strokes or other neurologic disabilities through recognition of persons at risk, assessment for early signs and symptoms, and implementation of prophylactic measures. Because more than half of persons with CAD have cerebral ischemia, thrombolytic, anticoagulant, and antiplatelet regimens have evolved to limit the development of a thromboembolic event associated with dissection. The administration of these agents, the monitoring for their effectiveness, and the education of patients receiving them are fundamental aspects of care. | Cerebrovascular Trauma |
PURPOSE: The purpose of this study was to investigate the anticancer effects of combined RNA interference (RNAi) of the adenine nucleotide translocase-2 (ANT2) gene and ganciclovir (GCV) therapy for treatment of hepatocellular carcinoma cells (Huh 7) in an animal model. METHODS: The Huh 7/NTG stable cell line was established by transfection of a vector with the human sodium iodide symporter (hNIS), HSV1-sr39 thymidine kinase (tk), and enhanced green florescent protein (EGFP) fusion gene into Huh 7 cells. mRNA expressions of these genes were evaluated by RT-PCR analysis. The functions of hNIS and HSV1-sr39tk were verified with (125)I uptake and (3)H-penciclovir (PCV) uptake tests. EGFP and hNIS expression was confirmed with confocal microscopy after immunocytochemical staining. We treated the tumor cells with ANT2 shRNA or GCV or both ANT2 shRNA and GCV and treated the in vivo mouse model with a Huh 7/NTG tumor xenograft. The therapeutic effects of the in vivo study were assessed with caliper measurements and gamma camera imaging using (99m)Tc-pertechnetate. RESULTS: Huh 7/NTG cells showed a cell number-dependent increase in (125)I uptake and a 24-fold higher (3)H-PCV uptake compared to parent Huh 7 cells. Huh 7/NTG cells transfected with ANT2 shRNA had lower ANT2 mRNA expression and more impaired proliferation activity than cells transfected with scramble shRNA. Proliferation of Huh 7/NTG cells was also inhibited by GCV treatment. Combined GCV and ANT2 shRNA therapy further inhibited cell proliferation in the in vitro study. The combined therapy with GCV and ANT2 shRNA showed a further decrease in tumor growth in the mouse model. CONCLUSIONS: Our results suggest that the combined RNA interference with ANT2 and GCV therapy inhibited hepatocellular carcinoma cell proliferation more than single GCV therapy or ANT2 shRNA therapy in vitro and in vivo. Therefore it could be applied treating incurable hepatocellular carcinoma." | Adenine Nucleotide Translocator 2 |
We report a case of Meningo-angiomatosis, a rare hamartomatous lesion of the cerebral cortex. The main clinical and pathological features of this entity are discussed. | Angiomatosis |
CONTEXT: It is widely understood that reciting a contemporary version of the Hippocratic Oath has two purposes. It constitutes a public commitment on the part of the prospective doctor to preserving the traditional values of the medical profession and to meeting the obligations expected of a doctor. It is also an important symbolic ritual in the process of professional identity formation. METHODS: A portion of the 1964 version of the Hippocratic Oath is examined for its relevance to the current practice of medicine. Its closing paragraph reads: 'If I do not violate this oath, may I enjoy life and art, be respected while I live and remembered with affection thereafter. May I always act to preserve the finest traditions of my calling and may I long experience the joy of healing those who seek my help.' This is interpreted as representing the doctor's expectations of the practice of medicine: job satisfaction; status, and prestige. It also conveys the understanding that enjoying these benefits is contingent upon the doctor's adherence to the terms of the Oath. CONCLUSIONS: Our current understanding of the relationship between medicine and society is that a social contract exists under which members of the profession are granted a privileged position in society on the understanding that they will meet society's reasonable expectations. These expectations entail obligations not only to patients and to the profession, but to wider society. The Oath under consideration, which concentrates on medicine's obligations to patients and to the profession, does not adequately reflect its obligations to society. It is suggested that versions of the Hippocratic Oath used in the future should be updated to better reflect the obligations of both individual doctors and the medical profession to society. | Hippocratic Oath |
Three-dimension (3D) scaffolds for bone tissue regeneration were produced combining three different phases: nanometric hydroxyapatite (HA) was synthesized by precipitation method and the crystals nucleation took place directly within collagen fibrils following a biologically inspired mineralization process; polycaprolactone was employed to give the material a 3D structure. The chemico-physical analysis carried out to test the material's properties and composition revealed a high similarity in composition and morphology with biologically mineralized collagen fibrils and a scaffold degradation pattern suitable for physiological processes. The micro- computerized tomography (micro-CT) showed 53.53% porosity and a 97.86% mean interconnected pores. Computer-aided design and computer-aided manufacturing (CAD-CAM) technology was used for molding the scaffold's volume (design/shape) and for guiding the surgical procedure (cutting guides). The custom made scaffolds were implanted in sheep mandible using prototyped surgical guides and customized bone plates. After three months healing, scanning electron microscopy (SEM) analysis of the explanted scaffold revealed a massive cell seeding of the scaffold, with cell infiltration within the scaffold's interconnected pores. The micro-CT of the explanted construct showed a good match between the scaffold and the adjacent host's bone, to shield the implant primary stability. Histology confirmed cell penetration and widely documented neoangiogenesis within the entire scaffold's volume. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 723-734, 2017. | Mandibular Injuries |
OBJECTIVE: Application of a face mask may provoke the trigeminocardiac reflex, leading to apnoea and bradycardia. This study investigates whether re-application of a face mask in preterm infants at birth alters the risk of apnoea compared with the initial application, and identify factors that influence this risk. METHODS: Resuscitation videos and respiratory function monitor data collected from preterm infants <30 weeks gestation between 2018 and 2020 were reviewed. Breathing and heart rate before and after the initial and subsequent mask applications were analysed. RESULTS: In total, 111 infants were included with 404 mask applications (102 initial and 302 subsequent mask applications). In 254/404 (63%) applications, infants were breathing prior to mask application, followed by apnoea after 67/254 (26%) mask applications. Apnoea and bradycardia occurred significantly more often after the initial mask application compared with subsequent applications (apnoea initial: 32/67 (48%) and subsequent: 44/187 (24%), p<0.001; bradycardia initial: 61% and subsequent 21%, p<0.001). Apnoea was followed by bradycardia in 73% and 71% of the initial and subsequent mask applications, respectively (p=0.607).In a logistic regression model, a lower breathing rate (OR 0.908 (95% CI 0.847 to 0.974), p=0.007) and heart rate (OR 0.935 (95% CI 0.901 to 0.970), p<0.001) prior to mask application were associated with an increased likelihood of becoming apnoeic following subsequent mask applications. CONCLUSION: In preterm infants at birth, apnoea and bradycardia occurs more often after an initial mask application than subsequent applications, with lower heart and breathing rates increasing the risk of apnoea in subsequent applications. | Bradycardia |
This study aimed to develop a novel method for real-time monitoring of the intracellular redox states in a methanotroph Methylococcus capsulatus, using Peredox as a genetically encoded fluorescent sensor of the NADH:NAD(+) ratio. As expected, the fluorescence derived from the Peredox-expressing M. capsulatus transformant increased by supplementation of electron donor compounds (methane and formate), while it decreased by specifically inhibiting the methanol oxidation reaction. Electrochemical measurements confirmed that the Peredox fluorescence reliably represents the intracellular redox changes. This study is the first to construct a reliable redox-monitoring method for methanotrophs, which will facilitate to develop more efficient methane-to-methanol bioconversion processes. | Methylococcus |
Control of gonad development in insects requires juvenile hormone, ecdysteroids, and a peptidic brain gonadotropin(s). Compared to vertebrates, the situation in insects with respect to the molecular structure of gonadotropins is far less uniform. Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) of vertebrates are glycoproteins that are synthezised in the hypothalamus and released from the anterior pituitary. They stimulate gonad development, the production of progesterone or of sex steroids (estrogens, androgens). None of the known insect gonadotropins is a glycoprotein, neither can they be grouped into a single peptide family. In Drosophila, two G-protein coupled receptors, structurally related to the mammalian glycoprotein hormone receptors, have been identified. Nothing is known about their natural ligands. The sex-steroids of insects are likely to be ecdysteroids (20E in females, E in males of some species). Some of the identified gonadotropins speed up vitellogenesis (locust OMP and some -PF/-RFamide peptides) or stimulate ecdysteroid production by the ovaries (locust-OMP and Aedes- OEH) or testis (testis ecdysiotropin of Lymantria). In flies, the only as yet identified gonadotropin is the cAMP-generating peptide of Neobellieria. The seeming absence of uniformity in gonadotropins in insects might be due to a multitude of factors that can stimulate ecdysteroid production and/or to the use of different bioassays. Arch. | Gonadotropins |
Population-level nutritional assessments often rely on self-reported data, which increases the risk of recall bias. Here, we demonstrate that wastewater-based epidemiology can be used for near real-time population dietary assessments. Neighbourhood-level, untreated wastewater samples were collected monthly from within an urban population in the south-western United States from August 2017 to July 2019. Using liquid chromatography-tandem mass spectrometry, we identify recurring seasonal dynamics in phytoestrogen consumption, including dietary changes linked to the winter holiday season. Using 16S ribosomal RNA gene amplicon sequencing, we demonstrated the feasibility of detecting sewage-derived human gut bacterial taxa involved in phytoestrogen metabolism, including Bifidobacterium, Blautia and Romboutsia. Combined metabolomic and genomic wastewater analysis can inform nutritional assessments at population scale, indicating wastewater-based epidemiology as a promising tool for actionable and cost-effective data collection to support public health nutrition." | Wastewater-Based Epidemiological Monitoring |
OBJECTIVE: Spontaneous reports of sexual side effects were infrequent during placebo-controlled clinical trials of selegiline transdermal system (STS). The objective of this study was to examine the impact of STS 6 mg/24 hours on various domains of sexual function in patients with major depressive disorder (MDD), using a patient-rated questionnaire. METHOD: Data from 4 short-term (6 to 8 weeks), randomized, double-blind, placebo-controlled trials of STS in patients with MDD (DSM-IV criteria) were included in the meta-analysis (STS, N = 389; placebo, N = 400). The Medex Sexual Dysfunction Subscale was used to assess sexual interest, arousal, maintenance of interest, orgasm, and satisfaction. Estimates of the average effect of study drug on each item of sexual function and 95% confidence intervals were calculated using a fixed-effects model due to homogeneity of study means. The direct effect of STS versus placebo was estimated using multivariate regression models, with baseline item score as a covariate and controlling for improvement in depression. Analyses were performed on the total population and by gender. Data were collected between January 1997 and April 2000. RESULTS: Estimates of difference between STS and placebo demonstrated a nonsignificant trend toward a positive treatment effect of STS on most sexual function items and significant improvement in sexual satisfaction. For women, there was a significant positive effect on interest, maintaining interest during sex, and satisfaction. The direct effect of STS on changes in individual item scores was minimal in men and showed a trend for improvement in women. CONCLUSION: This meta-analysis suggests that short-term therapy with STS 6 mg/24 hours does not impair any aspect of sexual function in MDD patients as measured using a patient-rated questionnaire. | Selegiline |
Through the Red Wolf Species Survival Plan, the captive red wolf (Canis rufus) population was developed with the intent of reestablishing wild populations. One part of the plan was a survey for diseases that might occur as a result of population homogeneity or that might impede breeding success and reintroduction. For this survey, complete necropsies and histopathologic analyses were performed on 62 red wolves from 1992 to 1996. Major causes of 22 neonatal deaths were parental trauma, parasitic pneumonia, and septicemia. Common neonatal lesions included pododermatitis and systemic ascariasis. Cardiovascular anomalies and systemic parasitism were found in two juveniles. Causes of death in the 38 adults included conspecific trauma, neoplasia, or gastrointestinal diseases such as necrotizing enteritis, intestinal perforation, and gastric volvulus. Lymphosarcoma represented 50% of the fatal neoplasms. Three adults died from cardiovascular failure or hyperthermia during handling, and several adults were euthanized for suspected genetic diseases. Overall, the captive population had few significant health problems, but population fitness might be improved by continued removal of potentially deleterious genes from the breeding population and by modifying the husbandry of neonates and adults. | Cause of Death |
Metachromatic Leukodystrophy (MLD) and Multiple Sulfatase Deficiency (MSD) are rare and ultra-rare lysosomal storage diseases. Due to enzyme defects, patients are unable to split the sulfategroup from the respective substrates. In MSD all sulfatases are affected due to a defect of the Sulfatase Modifying Factor 1 (SUMF1) gene coding for the formylglycine generating enzyme (FGE) necessary for the modification of the active site of sulfatases. In MLD mutations in the arylsulfatase A (ARSA) gene cause ARSA deficiency with subsequent accumulation of 3-sulfogalactocerebroside especially in oligodendrocytes. The clinical consequence is demyelination and a devastating neurological disease. Enzyme replacement therapy (ERT) with recombinant human arylsulfatase A (rhARSA), gene therapy, and stem cell transplantation are suggested as new therapeutic options. The aim of our study was to characterize rhARSA concerning its substrate specificity using analytical isotachophoresis (ITP). Substrate specificity could be demonstrated by sulfate splitting from the natural substrates 3-sulfogalactocerebroside and ascorbyl-2-sulfate and the artificial substrate p-nitrocatecholsulfate, whereas galactose-6-sulfate, a substrate of galactose-6âÂÂsulfurylase, was totally resistant. In contrast, leukocyte extracts of healthy donors were able to split sulfate also from galactose-6-sulfate. The ITP method allows therefore a rapid and simple differentiation between samples of MLD and MSD patients and healthy donors. Therefore, the isotachophoretic diagnostic assay from leukocyte extracts described here provides a fast and efficient way for the diagnosis of MLD and MSD patients and an elegant system to differentiate between these diseases in one assay." | Multiple Sulfatase Deficiency Disease |
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