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INTRODUCTION: Alopecia areata (AA) in its extensive and severe forms is treatment-challenging, especially in pediatrics. METHOD: A PRISMA-compliant systematic review of seven electronic databases was searched by the terms alopecia areata," "pediatric," "topical immunotherapy," "Anthralin," and "light therapy" from inception until March 2021. All the alternative names of the disease and therapies have been included in the search terms. 790 articles went to title abstract review by two independent reviewers. In the subsequent level, a review of the full text of studies was conducted. RESULTS: Finally, 10 relevant articles in terms of content structure, subject coverage, and purpose, were selected for further review. The highest percentages of complete hair regrowth were 79.6% and 63.61% by SADBE (topical immunotherapy) and laser therapy. By Anthralin (contact sensitization), the complete response rate was below 50% (between 30 and 35%). Regarding average response, the most effective methods were local immunotherapy (with an average effectiveness of 53.8%), laser therapy (52.55%), and the use of Anthralin-induced contact dermatitis (30.86%), respectively. However, recurrence rate-after treatment with induced contact dermatitis by topical medications like Anthralin (contact sensitization)-was lower (mean 43.53%) in comparison with local immunotherapy (57%). In topical immunotherapy, light base therapy, and contact sensitization, the highest percentage of complete hair regrowth and the average response rate were (63.61% and 52.55%), (79.6% and 53.8%) and (32% and 30.8%), respectively. These methods are considered safe in children. CONCLUSION: A high and more than 50% efficacy in hair regrowth could be expected by topical immunotherapy and light/laser therapy method. No serious side effects have been observed by these methods that are well tolerated in children. Therefore, a combination of local immunotherapy and light/laser therapy could be suggested for the treatment of extensive AA in children. The use of Anthralin could be associated with a lower but more durable response. These points are important for patient selection in individualized situations." | Anthralin |
Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS). TMEV induces a biphasic disease in susceptible mouse strains. During the acute phase, 1 week after infection, TMEV causes polioencephalomyelitis characterized by infection and apoptosis of neurons in the gray matter of the brain. During the chronic phase, about 1 month after infection, virus infects glial cells and macrophages, and induces inflammatory demyelination with oligodendrocyte apoptosis and axonal degeneration in the white matter of the spinal cord. Although antibody, CD4(+), and CD8(+) T cell responses against TMEV capsid proteins play important roles in neuropathogenesis, infectious virus with persistence is necessary to induce demyelination; in general, adoptive transfer of antibody or T cells alone did not induce central nervous system (CNS) disease. The TMEV model can be useful for testing new therapeutic strategies specifically as a viral model for MS. Therapies targeting adhesion molecules, axonal degeneration, and immunosuppression can be beneficial for pure autoimmune CNS demyelinating diseases, such as experimental autoimmune encephalomyelitis, but could be detrimental in virus-induced demyelinating diseases, such as progressive multifocal leukoencephalopathy. | Cardiovirus Infections |
There are few effective antimicrobial agents against Balantidium coli infection. The effect of paromomycin sulfate (PS) against B. coli was confirmed in this study of 596 captive cynomolgus monkeys. In several trials, the minimum dose and duration of oral administration of PS were 25 mg/day for 5 + 5 days, with a 2-day withdrawal interval. To facilitate daily PS administration, pumpkin cakes supplemented with PS were made, which not only resulted in precise effects but also increased the efficiency of preparation and administration of PS by the animal care staff. No cysts or trophozoites were detected at 14 or 16 days after the last treatments. There were no obvious differences in blood and biochemical parameters between before and after administration of PS. These results indicate that PS is effective for elimination of B. coli without hematological side effects. These data could contribute to the control of microbiological pathogens during veterinary care and colony management in primate facilities. | Kinetofragminophorea |
OBJECTIVE: To examine the incidence and natural history of middle ear disease in children with congenital velopharyngeal insufficiency (VPI) without cleft palate. SETTING AND SUBJECTS: Children with congenital VPI attending the combined cleft clinic at a tertiary cleft center. The diagnosis of congenital VPI in all cases was confirmed be the observation of hypernasality, nasal air escape, or both by a speech and language therapist and the demonstration of incompetence of the velopharyngeal sphincter by means of nasoendoscopy or videofluoroscopy. Children with overt cleft palate or postsurgical VPI were excluded. DESIGN: The children's medical records were reviewed, and a questionnaire regarding history of ear problems was sent to all parents. Children were divided into those with Pruzansky type I VPI (showing bifid uvula, midline diastasis of soft palate, or submucous cleft of the hard palate) and Pruzansky type II VPI (no visible stigmata). MAIN OUTCOME MEASURES: Incidence of reported ear problems, ear infections, hearing loss, and surgical intervention for middle ear disease in the whole group and in each of the subgroups. RESULTS: Seventy-one parents returned completed questionnaires. The overall incidence of middle ear disease was 63%, with 28% reported to have below-normal hearing. There was no significant difference between children with Pruzansky types I and II VPI with respect to incidence of otopathology or hearing loss. CONCLUSIONS: Irrespective of the presence of any visible palatal abnormalities, children with congenital VPI showed a substantial incidence of otopathology and should thus be closely monitored. | Velopharyngeal Insufficiency |
This paper concerns the dynamics of transference-countertransference as they reveal themselves in object relations and specifically in the psychoanalytic process. It is postulated that transference and countertransference cannot be viewed separately, that both analyst and patient exhibit transference-countertransference reactions, and that they are normal ingredients of the psychoanalytic process. Brief clinical illustrations are provided. Attention is called to special problems when the patient's defenses are primitive, and to the therapeutic value of the analyst's countertransference. | Transference, Psychology |
Nifuratel (CAS 4936-47-4) is a furane-derivative provided with a strong trichomonicidal activity equivalent to that of metronidazole (CAS 443-48-1); it has a broad antibacterial spectrum of action, including both Gram-negative and Gram-positive organisms. It is active against Chlamydia trachomatis and Mycoplasma spp. and has also some degree of activity against Candida spp. and mycetes. Its broad spectrum of action, confirmed by in vitro and in vivo studies, covers virtually all the micro-organisms responsible for the infections of the genito-urinary tract. Nifuratel has a very safe toxicological profile. It is practically non-toxic in acute tests in mice and rats and is also well tolerated after repeated oral and intravaginal administrations. Nifuratel is devoid of teratogenic effects. The comparison among past and recent clinical studies confirms that, in contrast to metronidazole, no resistance phenomena to the treatment with nifuratel are reported. The drug can be used during pregnancy due to the absence of teratogenic effects. In conclusion, nifuratel shows a very favourable risk/benefit ratio for the treatment of patients with vulvo-vaginal infections. | Nifuratel |
PURPOSE: To describe the optical coherence tomography features of vitamin A deficiency. METHODS: Case series includes three male patients aged 50 to 66 years with vitamin A deficiency and visual symptoms ranging from 2 to 8 months. Examination included optical coherence tomography (OCT), fundus autofluorescence imaging, full-field electroretinography6 and laboratory work-up. RESULTS: Patient 1 had inoperable pancreatic neuroendocrine tumor and presented with worsening nyctalopia. The electroretinography showed absent rod function 2 months after the onset of symptoms, followed by a decrease of the cone function eight months after the onset. Optical coherence tomography showed poorly distinguishable outer segments of the photoreceptors with the disappearance of the interdigitation zone. At that time, vitamin A deficiency along with several other deficiencies was confirmed. After the initiation of parenteral nutrition, a substantial improvement of the patient's overall well-being was noted and the OCT showed normalization of the retinal structure. Two other patients were diagnosed with vitamin A deficiency based on similar OCT features. CONCLUSION: Disruption of the outer segments of the photoreceptors and the disappearance of the interdigitation zone on OCT may be helpful in recognition of vitamin A deficiency. Early detection and malnutrition evaluation are especially important in patients with a history of gastrointestinal disorders who may have several other underlying deficiencies. Treatment with either enteral or parenteral nutrition not only leads to resolution of visual symptoms but vastly improves their general condition and quality of life. | Vitamin A Deficiency |
LRSAM1, a RING-type E3 ubiquitin ligase, is essential for regulating cargo sorting, signaling pathways, cell adhesion and anti-bacterial autophagy. It is important to elucidate the mechanism that underlies the regulation of LRSAM1 E3 ligase activity. Here, we reported that LRSAM1 exhibited self-association in vitro and in vivo. We found the self-association of LRSAM1 promotes intermolecular ubiquitination and proved a potential N-terminal ubiquitination. The E3 activity of LRSAM1 is amplified when the RING domain is present in tandem with its N-terminal domain(s). Furthermore, we found that the CC2-SAM domain had a strong inhibitory effect on the E3 activity of LRSAM1 in vitro and blocked ubiquitination of TSG101 in vivo; the tandem CC1 domain, but not the individual CC1 domain, could counteract this inhibition. Collectively, our data characterized the self-association of LRSAM1 and showed how its domains may contribute to its overall activity. | Ubiquitin-Protein Ligases |
BACKGROUND: Dermatofibrosarcoma protuberans of the scalp (DFSP) is a rare soft tissue neoplasm originating from the dermal layer of the skin, usually affecting the adults. CASE REPORT: The current case report presents a 48-year old male with a huge lump on the right side of parietal region. A wide local excision of the tumor was performed and the excised specimen was sent for histopathological examination. Histopathology and Immunohistochemistry was suggestive of DFSP. CONCLUSION: Dermatofibrosarcoma protuberans is a rare neoplasm affecting the head and neck region. This unusual entity is more likely to recur when a small margin of surgical excision is performed. Wide local excision is the gold standard treatment and radiotherapy is preferred in recurrent diseases. | Dermatofibrosarcoma |
Titanium dioxide (TiO(2)) nanostructures are one of the most plentiful compounds that have emerged in various fields of technology such as medicine, energy and biosensing. Various TiO(2) nanostructures (nanotubes [NTs] and nanowires) have been employed in photoelectrochemical (PEC) biosensing applications, greatly enhancing the detection of targets. TiO(2) nanostructures, used as reinforced material or coatings for the bare surface of titanium implants, are excellent additive materials to compensate titanium implants deficiencies-like poor surface interaction with surrounding tissues-by providing nanoporous surfaces and hierarchical structures. These nanostructures can also be loaded by diversified drugs-like osteoporosis drugs, anticancer and antibiotics-and used as local drug delivery systems. Furthermore, TiO(2) nanostructures and their derivatives are new emerging antimicrobial agents to overcome human pathogenic microorganisms. However, like all other nanomaterials, toxicity and biocompatibility of TiO(2) nanostructures must be considered. This review highlights recent advances, along with the properties and numerous applications of TiO(2)-based nanostructure compounds in nano biosensing, medical implants, drug delivery and antibacterial fields. Moreover, in the present study, some recent advances accomplished on the pharmaceutical applications of TiO(2) nanostructures, as well as its toxicity and biocompatibility, are presented. | Titanium |
The unpredictable future of the managed care industry has led to strategic planning paralysis in some organizations. The lack of a strategic plan can be damaging to an organization's long-term viability. In developing a managed care strategic plan, an organization should have a basic understanding of its environment and its ability to make changes as indicated by its structure and information system capabilities. If the organization is both strong and flexible in these two areas, it is well positioned to thrive in the turbulent managed care environment. Strategic plans need to consider alternate futures, reinforce the organization's vision, support the organization's long-term financial viability, and incorporate the reality of the industry's uncertain future. | Managed Care Programs |
Constant observation is a method used to insure the safety of suicidal inpatients. It involves structure and control as well as flexibility and the development of a relationship between the observer and the patient. It has been found that important observations may go unnoticed by the observer or fail to be communicated to the multidisciplinary team because of a lack of sufficient training and systematic documentation. We therefore conducted a Delphi survey to collect opinions on what would be important to observe during constant observation of suicidal patients. A panel of experienced clinicians, service users and researchers reached consensus on 37 of 40 observation items (92%). Of these, 28 were rated as the most important. As a result, we developed a form for systematic observer documentation in clinical practice, the Suicidal Patient Observation Chart. The Suicidal Patient Observation Chart includes the 28 items and covers 24 separate observation periods. | Observation |
The practice guideline 'The intrauterine device' from the Dutch College of General Practitioners, first published in 2000, has been revised. Copper and hormonal IUDs have more or less the same level of reliability with respect to preventing pregnancy. During the use of a copper IUD, menstruation tends to be longer with a greater loss of blood; in 70% of women who use a hormonal IUD oligomenorrhea or even amenorrhoea develops. Women with a history of venous thromboembolism can use a hormonal IUD safely. In the first weeks after IUD insertion, there is an increased risk of pelvic inflammatory disease (PID). Therefore prior to insertion, the general practitioner should enquire about the risk of a SOA being present and, if necessary, perform SOA tests. In the Netherlands, IUD insertion can usually be performed at a general practice. | Intrauterine Devices |
BACKGROUND: Optimal synchronization delay (SD) for triggering the implanted cardiomyostimulators in patients undergoing latissimus dorsi dynamic cardiomyoplasty has not been clearly defined. Generally a synchronization delay time of 45 to 60 ms is used in the current practice, in which the implanted cardiomyostimulator stimulates the latissimus dorsi muscle 45 to 60 ms after mitral valve closure acquired with M-mode echocardiography. We investigated the effect of shortening or prolonging the delay time on cardiac functions. METHODS: We studied 10 patients who were in their first 2 years postoperatively. Three values for SD (SD = 0 ms, 45 to 60 ms, and 150 to 160 ms) were echocardiographically evaluated for their influence on both systolic and diastolic left ventricular parameters. RESULTS: Ejection fractions were 0.27 +/- 0.07, 0.28 +/- 0.07, and 0.32 +/- 0.06; peak aortic velocities were 0.85 +/- 0.8, 0.86 +/- 0.11, and 0.92 +/- 0.8 m/s; and velocity-time integrals were 0.16 +/- 0.03, 0.16 +/- 0.03, and 0.19 +/- 0.03 m for the SD values of 0, 45 to 60 ms, and 150 to 160 ms, respectively. Diastolic parameters were also measured. Isovolumetric diastolic relaxation time was 97.5 +/- 49, 97.20 +/- 44, and 111.8 +/- 49 ms; deceleration time was 83.67 +/- 32, 88.48 +/- 35, and 92.68 +/- 34 ms; and ratio or velocity-time integral of e wave to velocity-time integral of a wave was 3.09 +/- 0.98, 2.48 +/- 0.69, and 2.38 +/- 0.65 for the SD values of 0, 45 to 60 ms, and 150 to 160 ms, respectively. Systolic functions were better when SD was set at 150 to 160 ms, but there was a diastolic compromise. On the other hand, diastolic parameters were more favorable when SD = 0 (i.e., cardiomyostimulator triggered without delay) but the systolic assist was suboptimal. Systolic and diastolic parameters seemed relatively well-balanced with the current practice of setting the synchronization delay at 45 to 60 ms. CONCLUSIONS: The most favorable systolic effects were obtained with a prolonged delay of synchronization (150 to 160 ms), at some expense of diastolic functions. On the other hand, with a short or absent delay, diastolic parameters were improved but systolic parameters became suboptimal. Therefore, the current practice of setting the SD between 45 and 60 ms after echocardiographic mitral valve closure is suggested for the optimal timing for cardiomyostimulator stimulation in patients who have undergone latissimus dorsi dynamic cardiomyoplasty. Yet a great deal of individualization is necessary, and fixed preset values cannot definitely be determined because one setting does not fit all patients. | Skeletal Muscle Ventricle |
Partial-denitrification (PD, NO(3)(-)-N --> NO(2)(-)-N) is emerging as a promising approach for application of anaerobic ammonium oxidation (anammox) process. In this study, stable PD with high nitrite (NO(2)(-)-N) accumulation was achieved by modulating nitrate (NO(3)(-)-N) reduction activity and carbon metabolism. With the influent NO(3)(-)-N increasing from 30 to 200 mg/L, specific NO(3)(-)-N reduction rates (r(no3)) were significantly improved, corresponding to the nitrate-to-nitrite transforming ratio (NTR) increasing rapidly to 80.0% within just 70 days. The required COD/NO(3)(-)-N decreased from 4.5 to 2.0 and the carbon flux was more shared in NO(3)(-)-N reduction to NO(2)(-)-N. Notably, Thauera spp. as core denitrifying bacteria was highly enriched with the relative abundance of 70.5% approximately 82.1% despite different inoculations. This study provided a new insight into inducing high NO(2)(-)-N accumulation and promoting practical application of anammox technology. | Thauera |
A major review of the literature of syringocystadenoma papilliferum's (SCAP's) presentation and management is presented. In addition, a case report of this unique diagnosis presenting as a corneal abrasion in a 66-year-old-male is included. This benign adnexal tumor of the apocrine glands is most commonly found in the face and neck. When found on the eyelids, these lesions are commonly misdiagnosed as basal cell carcinoma or cysts. Diagnosis is made based on histopathology. Treatment is complete excision of the lesion and this has a low recurrence rate. While predominantly benign, there have been cases of basal cell carcinoma development or other malignant transformations. Of the 26 reported cases of SCAP of the eyelids, none have caused a corneal abrasion. The authors present the only known presentation of eyelid SCAP, causing corneal abrasions, and provide a review of literature with discussion of clinical presentation, natural history, diagnosis, and treatment of this rare, eyelid lesion with potential for malignant transformation. | Tubular Sweat Gland Adenomas |
OBJECTIVE: To determine whether messenger RNA for the gonadal LH/hCG receptor is present in human endometrium with the use of reverse-transcriptase polymerase chain reaction. DESIGN: In vitro experiment. SETTING: Academic medical center. PATIENT(S): Premenopausal women who were not receiving hormonally active medications and who were undergoing hysterectomy for uterine leiomyomas, menorrhagia, pelvic pain, or uterine prolapse. INTERVENTION(S): Tissue from hysterectomy specimens was processed for RNA and treated with deoxyribonuclease where appropriate, and RNA was reverse-transcribed to complementary DNA. MAIN OUTCOME MEASURE(S): An appropriately sized band after reverse-transcriptase polymerase chain reaction, followed by sequencing to confirm the results. RESULT(S): A primer pair that spanned the extracellular domain was unable to amplify receptor complementary DNA from human endometrial tissue. For a primer pair that spanned transmembrane regions 2-6 of the receptor and was contained wholly in exon 11, a 552-base pair fragment was amplified successfully in 19 of 25 human endometrial samples. CONCLUSION(S): The traditional gonadal LH/hCG receptor does not appear to be present in human endometrial tissue. The presence of a portion of the transmembrane part of the molecule suggests that human endometrium may express a truncated or variant form of the receptor. | Receptors, LH |
BACKGROUND: Hyperoxaluria may be idiopathic, secondary, or due to primary hyperoxaluria (PH). Hepatic alanine:glyoxylate aminotransferase (AGT) or glyoxylate/hydroxypyruvate reductase (GR/HPR) deficiency causes PHI or PHII, respectively. Hepatic glycolate oxidase (GO) is a candidate enzyme for a third form of inherited hyperoxaluria. METHODS: Six children were identified with marked hyperoxaluria, urolithiasis, and normal hepatic AGT (N = 5) and GR/HPR (N = 4). HPR was below normal and GR not measured in one. Of an affected sibling pair, only one underwent biopsy. GO mutation screening was performed, and dietary oxalate (Diet(ox)), enteric oxalate absorption (EOA) measured using [13C2] oxalate, renal clearance (GFR), fractional oxalate excretion (FE(ox)) in the children, and urine oxalate in first-degree relatives (FDR) to understand the etiology of the hyperoxaluria. RESULTS: Mean presenting age was 19.2 months and urine oxalate 1.3 +/- 0.5 mmol/1.73 m2/24 h (mean +/- SD). Two GO sequence changes (T754C, IVS3 - 49 C>G) were detected which were not linked to the hyperoxaluria. Diet(ox) was 42 +/- 31 mg/day. EOA was 9.4 +/- 3.6%, compared with 7.6 +/- 1.2% in age-matched controls (P = 0.33). GFR was 90 +/- 19 mL/min/1.73 m2 and FE(ox) 4.2 +/- 1.4. Aside from the two brothers, hyperoxaluria was not found in FDR. CONCLUSIONS: These patients illustrate a novel form of hyperoxaluria and urolithiasis, without excess Diet(ox), enteric hyper-absorption, or hepatic AGT, GR/HPR deficiency. Alterations in pathways of oxalate synthesis, in liver or kidney, or in renal tubular oxalate handling are possible explanations. The affected sibling pair suggests an inherited basis. | Hyperoxaluria |
The catalytic domains of protein kinases are commonly treated as independent modular units with distinct biological functions. Here, the interactions between the catalytic and juxtamembrane domains of VEGFR2 are studied. Highly purified preparations of the receptor tyrosine kinase VEGFR2 catalytic domain without (VEGFR2-CD) and with (VEGFR2-CD/JM) the juxtamembrane (JM) domain were characterized by kinetic, biophysical, and structural methods. Although the catalytic parameters for both constructs were similar, the autophosphorylation rate of VEGFR2-CD/JM was substantially faster than VEGFR2-CD. The first event in the autophosphorylation reaction was phosphorylation of JM residue Y801 followed by phosphorylation of activation loop residues in the CD. The rates of activation loop autophosphorylation for the two constructs were determined to be similar. The autophosphorylation rate of Y801 was invariant on enzyme concentration, which is consistent with an intramolecular reaction. In addition, the first biochemical characterization of the advanced clinical compound axitinib is reported. Axitinib was found to have 40-fold enhanced biochemical potency toward VEGFR2-CD/JM (K(i) = 28 pM) compared to VEGFR2-CD, which correlates better with cellular potency. Calorimetric studies, including a novel ITC compound displacement method, confirmed the potency and provided insight into the thermodynamic origin of the potency differences. A structural model for the VEGFR2-CD/JM is proposed based on the experimental findings reported here and on the JM position in c-Kit, FLT3, and CSF1/cFMS. The described studies identify potential functions of the VEGFR2 JM domain with implications to both receptor biology and inhibitor design." | Vascular Endothelial Growth Factor Receptor-2 |
The potential genotoxic effect of a time-varying magnetic field (MF) on human cells was investigated. Upon continuous exposure of human primary fibroblast and cervical cancer cells to a 60 Hz MF at 7 mT for 10-60 min, no significant change in cell viability was observed. However, deoxyribonucleic acid (DNA) double-strand breaks (DSBs) were detected, and the DNA damage checkpoint pathway was activated in these cells without programmed cell death (called apoptosis). The exposure of human cells to a 60 Hz MF did not induce intracellular reactive oxygen species (ROS) production, suggesting that the observed DNA DSBs are not directly caused by ROS. We also compared the position and time dependency of DNA DSBs with numerical simulation of MFs. The Lorentz force and eddy currents in these experiments were numerically calculated to investigate the influence of each factor on DNA DSBs. The DNA DSBs mainly occurred at the central region, where the MF was strongest, after a 30-min exposure. After 90 min, however, the amount of DNA DSBs increased rapidly in the outer regions, where the eddy current and Lorentz force were strong. | Magnetic Fields |
AIMS: We aimed to investigate the frequency of serotonin toxicity following overdose of antidepressants that inhibit serotonin reuptake and the factors that influence the probability of serotonin toxicity occurring. METHODS: This was a retrospective cohort study of overdoses that included selective serotonin reuptake inhibitors (SSRIs) (70%) and serotonin norepinephrine reuptake inhibitors (SNRIs) (30%) admitted to a tertiary toxicology unit over 23 years. A multivariate mixed effects logistic regression model using NONMEM (7.2.0) was used to determine factors that influenced the probability of serotonin toxicity occurring. RESULTS: There were 1978 overdoses in 1520 patients; median age 33 y (range: 13-86 years) and 64% female. Median defined daily dose equivalent (DDD) was 15 (1-420). Co-ingestants were taken in 1678/1978 (85%) overdoses: 11 co-ingested the monoamine oxidase-A inhibitor (MAOI) moclobemide, 99 (5%) co-ingested olanzapine, 58 (3%) co-ingested risperidone and 417 co-ingested a benzodiazepine (21%). Serotonin toxicity occurred in 269 overdoses (13.6%). The probability of serotonin toxicity increased slightly per 10 DDD units dose [OR, 1.01; 95% confidence intervals (CIs): 0.93-1.10], increased for an SNRI vs. an SSRI [OR, 1.07; 95% CI: 0.99-1.15], and markedly increased with co-ingestion of moclobemide [OR, 33.12; 95% CI: 7.5-147]. The probability decreased per 10 y age [OR, 0.84; 95% CI: 0.74-0.95], and with co-ingestion of the serotonin 2 A receptor (5-HT(2A)) antagonists olanzapine [OR, 0.40; 95% CI: 0.17-0.94] or risperidone [OR, 0.13; 95% CI: 0.02-0.99]. The probability of serotonin toxicity was 12.5% at 1 DDD (therapeutic), 12.7% at 15 DDDs and 19% at 420 DDDs. In overdoses of the median dose of 15 DDDs, co-ingestion of moclobemide increased the probability to 83%, and co-ingestion of olanzapine or risperidone decreased it to 5.5% and 1.8%, respectively. CONCLUSIONS: Serotonin toxicity is common following SSRI/SNRI overdose. Although dose increases probability, this was only a small effect. Co-ingestion with olanzapine or risperidone reduced the risk 2-6-fold, and moclobemide increased the risk 5-fold. | Moclobemide |
The presentation of a subset of learned items as retrieval cues can have detrimental effects on recall of the remaining items. For 2 types of encoding conditions, the authors examined in 3 experiments whether such part-list cuing is a transient or a lasting phenomenon. Across the experiments, the detrimental effect of part-list cues was consistently found to be transient with a high degree of interim associations and lasting with a low degree. These results indicate that the persistence of part-list cuing depends on encoding, thus challenging both strategy disruption and retrieval inhibition as general accounts of part-list cuing. A 2-mechanism account is provided according to which the 2 mechanisms mediate the effect in different encoding conditions. | Verbal Learning |
Chromomycosis is a chronic, localized infection of the cutaneous and subcutaneous tissues caused by dematiaceous fungi of several genera. It has distinctive clinical, pathological and mycological characteristics. Exophiala spinifera is a well-established aetiological agent of phaeohyphomycosis, but there are only two reported cases worldwide of this dematiaceous fungus causing chromomycosis. We report the first known case in the UK of E. spinifera causing chromomycosis. | Exophiala |
Feeding Artemia nauplii as the main nutrition source for zebrafish is a common practice for many research facilities. Culturing live feed can be time-consuming and requires additional equipment to be purchased, maintained, and cleaned. Nonhatching decapsulated Artemia cysts (decaps) are a commercially available product that can be fed directly to fish. Several other ornamental fish species have been successfully cultured using decaps. Replacing Artemia nauplii with decaps could reduce the overall time and costs associated with the operation of a zebrafish facility. The objective of this study was to determine if decaps could be a suitable replacement to Artemia nauplii in juvenile and adult zebrafish culture. Wild-type zebrafish were fed one of three dietary treatments: decaps only, nauplii only, or a standard consisting of nauplii plus a commercially prepared pellet food. Survival, growth (length and weight), and embryo production were analyzed between the treatments. Fish receiving the decap diet demonstrated a significantly higher growth and embryo production when compared to the fish receiving the nauplii-only diet. When comparing the decap fish to the standard fish, no significant difference was found in mean survival, mean weight at 90 days postfertilization, or mean embryo production. It was determined that nonhatching decapsulated Artemia cysts can be used as a suitable replacement to Artemia nauplii in juvenile and adult zebrafish culture. | Artemia |
Chronic subdural hematoma (CSDH) is a common neurosurgical condition that has a high incidence in the increasing elderly population of many countries. Pathologically, it is defined as a persistent liquefied hematoma in the subdural space more than 3 weeks old that is generally encased by a membraneous capsule. CSDHs likely originate after minor head trauma, with a key factor in its development being the potential for a subdural cavity to permit its expansion within, which is usually due to craniocerebral disproportion. The pathogenesis of CSDH has been attributed to osmotic or oncotic pressure differences, although measurements of these factors in the CSDH fluid do not support this theory. Current belief is that CSDH arises from recurrent bleeding in the subdural space, caused by a cycle of local angiogenesis, inflammation, coagulation and ongoing fibrinolysis. However, because of a lack of detailed knowledge about the precise mechanisms, treatment is often limited to surgical interventions that are invasive and often prone to recurrence. Thus, it is possible that an easily reproducible and representative animal model of CSDH would facilitate research in the pathogenesis of CSDH and aid with development of treatment options. | Hematoma, Subdural, Chronic |
BACKGROUND: Preclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy. METHODS: This phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naive to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon's two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. RESULTS: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced >/=1 treatment-emergent adverse event. Grade>/=3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells. CONCLUSIONS: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC. TRIAL REGISTRATION NUMBERS: NCT03367819. | ADP-ribosyl Cyclase 1 |
AIMS: An increased risk of adenocarcinoma of the oesophagus has been demonstrated in patients with long segments of Barrett's mucosa. The risk of cancer associated with short segments of metaplasia of the oesophagogastric junction is not known. METHODS AND RESULTS: We report a case of early adenocarcinoma of the oesophagus arising on short tongues of Barrett's mucosa associated with an oesophageal cyst. The patient was a 68-year-old man with no previous clinical history of gastro-oesophageal reflux disease. The fortuitous discovery of an oesophageal cyst lead to the diagnosis of short tongues of Barrett's mucosa with high-grade dysplasia. On pathological examination of the resected specimen, an early adenocarcinoma had developed in Barrett's mucosa, localized just above the oesophageal cyst. CONCLUSIONS: As oesophageal cysts can cause symptoms suggestive of reflux, we hypothesize that this association may not be fortuitous. | Esophageal Cyst |
Coxsackievirus A24 variant (CVA24v) is a major pathogen that causes continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC). In China, the first confirmed outbreak of CVA24v-related AHC occurred in Beijing in 1988, followed by another two significant outbreaks respectively in 1994 and 2007, which coincides with the three-stage dynamic distribution of AHC in the world after 1970s. To illustrate the genetic characteristics of CVA24v in different periods, a total of 23 strains were isolated from those three outbreaks and the whole genome of those isolations were sequenced and analyzed. Compared with the prototype strain, the 23 strains shared four nucleotide deletions in the 5' UTR except the 0744 strain isolated in 2007. And at the 98th site, one nucleotide insertion was found in all the strains collected from 2007. From 1994 to 2007, amino acid polarity in the VP1 region at the 25th and the 32nd site were changed. Both the 3C and VP1 phylogenetic tree indicated that isolates from 1988 and 1994 belonged to Genotype III (GIII), and 2007 strains to Genotype IV (GIV). According to the Bayesian analysis based on complete genome sequence, the most recent common ancestors for the isolates in 1988, 1994 and 2007 were respectively estimated around October 1987, February 1993 and December 2004. The evolutionary rate of the CVA24v was estimated to be 7.45 âÂÂx âÂÂ10(-3) substitutions/site/year. Our study indicated that the early epidemic of CVA24v in Chinese mainland was the GIII. Point mutations and amino acid changes in different genotypes of CVA24v may generate intensity differences of the AHC outbreak. CVA24v has been evolving constantly with a relatively rapid rate." | Conjunctivitis, Acute Hemorrhagic |
OBJECTIVE: The objective of this literature review was to summarise current research regarding how consumers seek health-related information from social media. Primarily, we hope to reveal characteristics of existing studies investigating the health topics that consumers have discussed in social media, ascertaining the roles social media have played in consumers' information-seeking processes and discussing the potential benefits and concerns of accessing consumer health information in social media. METHODS: The Web of Science Core Collection database was searched for existing literature on consumer health information seeking in social media. The search returned 214 articles, of which 21 met the eligibility criteria following review of full-text documents. CONCLUSION: Between 2011 and 2016, twenty-one studies published explored various topics related to consumer information seeking in social media. These ranged from online discussions on specific diseases (e.g. diabetes) to public health concerns (e.g. pesticide residues). Consumers' information needs vary depending on the health issues of interest. Benefits of health seeking on social media, in addition to filling a need for health information, include the social and emotional support health consumers gain from peer-to-peer interactions. These benefits, however, are tempered by concerns of information quality and authority and lead to decreased consumer engagement. | Consumer Health Information |
The transcription factor retinoic acid receptor-related orphan receptor gammat (RORgammat) is an attractive drug target for some autoimmune diseases owing to its roles in the differentiation of human T helper 17 (Th17) cells which produce pro-inflammatory cytokine interleukin (IL)-17. RORgammat agonists and inverse agonists are classically targeted to the hydrophobic and highly conserved orthosteric binding pocket of RORgammat ligand binding domain (LBD). Although successful, this approach also brings some challenges, including off-target effects due to lack of selectivity over other nuclear receptors (NRs). Allosteric regulation of RORgammat by synthetic small molecules has recently emerged as novel research interests for its interesting modes of action (MOA), satisfying bioactivity profile and improved selectivity. In this review, we delineated the discovery and identification of the allosteric pocket of RORgammat. Subsequently, we focused on examples of small molecules that allosterically inhibit RORgammat, with a central attention on structural-activity-relationship (SAR) information, biological activity, pharmacokinetic (PK) property, and the ligand binding mode of these compounds. We also discussed the potential role of RORgammat allosteric inverse agonists as small molecule therapeutics for autoimmune diseases." | Nuclear Receptor Subfamily 1, Group F, Member 3 |
Ovine pulmonary adenocarcinoma is a naturally occurring lung cancer in sheep induced by the Jaagsiekte sheep retrovirus (JSRV). Its envelope glycoprotein (Env) carries oncogenic properties, and its expression is sufficient to induce in vitro cell transformation and in vivo lung adenocarcinoma. The identification of cellular partners of the JSRV envelope remains crucial for deciphering mechanisms leading to cell transformation. We initially identified RALBP1 (RalA binding protein 1; also known as RLIP76 or RIP), a cellular protein implicated in the ras pathway, as a partner of JSRV Env by yeast two-hybrid screening and confirmed formation of RALBP1/Env complexes in mammalian cells. Expression of the RALBP1 protein was repressed in tumoral lungs and in tumor-derived alveolar type II cells. Through its inhibition using specific small interfering RNA (siRNA), we showed that RALBP1 was involved in envelope-induced cell transformation and in modulation of the mTOR (mammalian target of rapamycin)/p70S6K pathway by the retroviral envelope. IMPORTANCE: JSRV-induced lung adenocarcinoma is of importance for the sheep industry. While the envelope has been reported as the oncogenic determinant of the virus, the cellular proteins directly interacting with Env are still not known. Our report on the formation of RALBP/Env complexes and the role of this interaction in cell transformation opens up a new hypothesis for the dysregulation observed upon virus infection in sheep. | Jaagsiekte sheep retrovirus |
PURPOSE: To investigate the impact of typical scan score (TSS) on discriminating glaucomatous and healthy eyes by scanning laser polarimetry and spectral domain optical coherence tomography (SD-OCT) in 32 peripapillary sectors. PATIENTS AND METHODS: One hundred two glaucoma patients and 32 healthy controls underwent standard automated perimetry, 24-hour intraocular pressure profile, optic disc photography, GDxVCC, and SD-OCT measurements. For controls, only very typical scans (TSS=100) were accepted. Glaucoma patients were divided into 3 subgroups (very typical: TSS=100; typical: 99>/=TSS>/=80, atypical: TSS<80). Receiver operating characteristic curves were constructed for mean retinal nerve fiber layer values, sector data, and nerve fiber indicator (NFI). Sensitivity was estimated at >/=90% specificity to compare the discriminating ability of each imaging modality. RESULTS: For discrimination between healthy and glaucomatous eyes with very typical scans, the NFI and inferior sector analyses 26 to 27 demonstrated the highest sensitivity at >/=90% specificity in GDxVCC and SD-OCT, respectively. For the typical and atypical groups, sensitivity at >/=90% specificity decreased for all 32 peripapillary sectors on an average by 10.9% and 17.9% for GDxVCC and by 4.9% and 0.8% for SD-OCT. For GDxVCC, diagnostic performance of peripapillary sectors decreased with lower TSS, especially in temporosuperior and inferotemporal sectors (sensitivity at >/=90% specificity decreased by 55.3% and by 37.8% in the atypical group). CONCLUSIONS: Diagnostic accuracy is comparable for SD-OCT and GDxVCC if typical scans (TSS=100) are investigated. Decreasing TSS is associated with a decrease in diagnostic accuracy for discriminating healthy and glaucomatous eyes by scanning laser polarimetry. NFI is less influenced than the global or sector retinal nerve fiber layer thickness. The TSS score should be included in the standard printout. Diagnostic accuracy of SD-OCT is barely influenced by low TSS. | Scanning Laser Polarimetry |
Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs, associated with sicca syndrome but also with systemic involvement with varying degrees of severity. Despite their importance, some systemic manifestations, mainly liver, gastrointestinal, and pancreatic are not routinely evaluated. To address these manifestations, the Sjogren's Syndrome Committee of the Brazilian Society of Rheumatology conducted a broad systematic review of the literature on studies investigating prevalence and diagnosis of these symptoms in Sjogren s patients and made recommendations based on the findings. Agreement between the experts was achieved using the Delphi method. This is the second part of this guideline, providing 6 recommendations for liver, gastrointestinal, and pancreatic care of SS patients. | Sjogren's Syndrome |
Sequence features of genes and their flanking regulatory regions are determinants of RNA transcript isoform expression and have been used as context-independent plug-and-play modules in synthetic biology. However, genetic context-including the adjacent transcriptional environment-also influences transcript isoform expression levels and boundaries. We used synthetic yeast strains with stochastically repositioned genes to systematically disentangle the effects of sequence and context. Profiling 120 million full-length transcript molecules across 612 genomic perturbations, we observed sequence-independent alterations to gene expression levels and transcript isoform boundaries that were influenced by neighboring transcription. We identified features of transcriptional context that could predict these alterations and used these features to engineer a synthetic circuit where transcript length was controlled by neighboring transcription. This demonstrates how positional context can be leveraged in synthetic genome engineering. | RNA, Fungal |
This was a double-blind, radomized, crossover study of adult subjects to evaluate the effect of a test mouthrinse (Cepacol) on plaque accumulation. The study was divided into two parts, four weeks each, one in which only a mouthwash was used (part I) and the other in which a mouthwash and toothbrushing were used (part II). 1. The test mouthrinse produced a satistically significant reduction in dental plaque when compared to a placebo rinse. 2. The GI averaged approximately 1.0 throughout the study regardless of which mouthrinse was used. 3. A possible carryover effect of the test mouthrinse was noted. 4. A lower plaque score was seen in 67 to 75% of all patients during the period in which the test mouthrinse was used as compared to the placebo. 5. Ten subjects reported a burning sensation of the tongue with the test mouthrinse. No objective adverse effects were seen. | Mouthwashes |
One of the major causes of aquatic biodiversity loss is the contamination of the environment by pesticides. Even though there is a considerable amount of studies on the subject, there are still few that deal with the effects of carbofuran on native species in Brazil. Although carbofuran is widely used in Brazil, its action on native organisms, such as the Atlantic Forest lambari Deuterodon iguape, has not yet been studied. This work aimed to evaluate the effects of exposure to carbofuran on the fish D. iguape, considering the behavior and specific oxygen consumption as end points. Opercular movements, dorsal fin movements, and swimming speed were analyzed as behavioral parameters. To assess specific oxygen consumption, fish were subjected to concentrations of 0.0, 0.05, 0.1, 0.25, and 0.5 mg/L, for 24 h. For behavior analysis, fish remained exposed to carbofuran at concentrations of 0.0, 0.01, 0.05, 0.1, and 0.5 mg/L, in periods of 0, 2, 24, and 48 h. The behavior was studied through filming, analyzed with the free software, Tracker 4.92 (Open Source Physics). The results demonstrate an increase in opercular movements (18% +/- 2.65) and a decrease in dorsal fin movements (- 21.2% +/- 2.97), as well as in swimming speed (- 58.3% +/- 1.83) of the experimental groups compared to the control group. There was an increase in oxygen consumption of 58.4% in fish exposed to the highest concentration of carbofuran. Thus, it is concluded that carbofuran altered D. iguape's behavior and oxygen consumption. The species was sensitive to carbofuran concentrations and can be used as a bioindicator. | Carbofuran |
Quantitative analysis of medical liability's influence on medical practice is a small but growing field. The three foregoing articles illustrate three of the possible analytic approaches: case study of technological diffusion, survey of physician responses to detailed clinical scenarios, and multivariate analysis of the relation of physicians' scenario responses to objective liability experience. The articles also offer a good picture of the state of the art: Many difficulties hamper research in this area, and these articles, like others, offer considerable illumination but leave much uncovered. Defensive medicine surely exists, but its effects on health care spending and access are unclear. The most important lessons for public policy are that tort reform may be necessary but not sufficient to reduce the problems associated with defensive medicine, and that the major malpractice problem continues to be malpractice. | Defensive Medicine |
The Bcl-2 protein blocks a distal step in an evolutionarily conserved pathway for programmed cell death and apoptosis. To gain better understanding of how this protein functions, we have undertaken a structure-function analysis of this protein, focusing on domains within Bcl-2 that are required for function and for interactions with other proteins. Four conserved domains are present in Bcl-2 and several of its homologs: BH1 (residues 136-155), BH2 (187-202), BH3 (93-107) and BH4 (10-30). Deletion of the BH1, BH2, or BH4 domains of Bcl-2 abolishes its ability to suppress cell death in mammalian cells and prevents homodimerization of these mutant proteins, though these mutants can still bind to the wild-type Bcl-2 protein. These mutants also fail to bind to BAG-1 and Raf-1, two proteins that we have shown can associate with protein complexes containing Bcl-2 and which cooperate with Bcl-2 to suppress cell death. Deletion of either BH1 or BH2 nullifies the ability of Bcl-2 to: (a) suppress death in mammalian cells: (b) block Bax-induced lethality in yeast; and (c) heterodimerize with Bax. In contrast, deletion of the BH4 domain of Bcl-2 nullifies anti-apoptotic function and homodimerization, but does not impair binding to the pro-apoptotic protein Bax. Taken together, the data suggest the possibility that both Bcl-2/Bcl-2 homodimerization and Bcl-2/Bax heterodimerization are necessary but insufficient for the anti-apoptotic function of the Bcl-2 protein. Homodimerization of Bcl-2 with itself involves a head-to-tail interaction, in which an N-terminal domain where BH4 resides interacts with the more distal region of Bcl-2 where BH1, BH2, and BH3 are located. In contrast, Bcl-2/Bax heterodimerization involves a tail-to-tail interaction, that requires the portion of Bcl-2 where BH1, BH2, and BH3 reside and a central region in Bax where the BH3 domain is located. The BH3 domain of Bax is also required for Bax/Bax homodimerization and pro-apoptotic function in both yeast and mammalian cells. Thus, Bcl-2 may suppress cell death at least in part by binding to Bax via the BH3 domain and thereby preventing formation of Bax/Bax homodimers. Further studies however are required to delineate the full significance of Bcl-2/Bcl-2, Bcl-2/Bax, and Bax/Bax dimers and the biochemical mechanisms by which Bcl-2 family proteins ultimately control cell life and death. | Proto-Oncogene Proteins |
A longstanding goal in the fields of molecular genetics and biochemistry has been to explain how naturally occurring mutations associated with human metabolic disease impair activity of the enzymes involved. This goal is particularly complex for enzymes composed of multiple subunits, because single mutations may exert both intra- and intersubunit effects on holoenzyme structure and function. We have previously applied a yeast coexpression system for human galactose-1-phosphate uridylyltransferase, a dimeric enzyme associated with galactosemia, to investigate the impact of naturally occurring mutations on subunit association and holoenzyme function (). Here we describe the purification and characterization of two heterodimers, R333W/wild type (WT) and Q188R/WT, revealing that although the first exhibits approximately 50% wild-type activity, the second exhibits only approximately 15% wild-type activity. Neither heterodimer varied significantly from the wild type with regard to apparent Km for either substrate, although Q188R/WT but not R333W/WT heterodimers demonstrated significantly increased thermal sensitivity relative to the wild-type enzyme. These results demonstrate for the first time a partial dominant negative effect caused by a naturally occurring mutation in human galactose-1-phosphate uridylyltransferase." | UTP-Hexose-1-Phosphate Uridylyltransferase |
Since its discovery more than 20 years ago, a lot has been revealed about the biochemistry and physiological behaviour of carboxypeptidase U (CPU). Recent advances in CPU research include the unravelling of the crystal structure of proCPU and revealing the molecular mechanisms for the marked instability of the active enzyme, CPU. The recent development of two highly sensitive assays has cleared the path toward the direct measurement of CPU in circulation or the determination of CPU generation, rather than the measurement of total proCPU concentration in plasma. Finally, since CPU is known to have a prominent bridging function between coagulation and fibrinolysis, the development of CPU inhibitors as profibrinolytic agents is an attractive new concept and has gained a lot of interest from several research groups and from the pharmaceutical industry. These recent advances in CPU research are reviewed in this literature update. | Metalloexopeptidases |
CONTEXT: In 1992, the West Virginia School of Osteopathic Medicine (WVSOM) created a task force as part of an institution-wide initiative to integrate osteopathic principles and practice (OPP) across its entire curriculum. The goals of the initiative, which was implemented with the graduating class of 1997, were to create a clearly distinct osteopathic curriculum and preserve the use of osteopathic manipulative treatment (OMT) by WVSOM alumni. OBJECTIVE: To evaluate outcomes of the Osteopathic Principles and Practices Integration Project among WVSOM alumni. METHODS: A survey was mailed on a staggered timeline to WVSOM alumni who had graduated at least 5 years earlier. Data from the graduating classes of 1995 and 1996 (preintervention) were compared with data from the graduating classes of 1997 through 2002 (postintervention). RESULTS: After excluding responses from alumni still in residencies, responses from 52 (41.9%) of 124 alumni in the preintervention group and 155 (40.9%) of 379 alumni in the postintervention group were analyzed. Comparisons of preintervention group to postintervention group, based on the chi(2) test, revealed significant improvement in the proportion of alumni who agreed that basic sciences faculty at WVSOM provided exposure to osteopathic philosophy (P=.020); that basic sciences faculty at WVSOM taught OMT (P=.019); and that alumni were exposed to osteopathic philosophy during rotations with DOs (P=.031). Approximately 53% of alumni in both groups reported daily OMT use in treating patients. Posthoc analysis using the McNemar test for correlated proportions revealed that the proportion of all alumni rating themselves as prepared" in OMT and OPP at the end of the second year of the WVSOM curriculum was 92.7%, significantly higher than the 76.1% rating of preparation at graduation (P<.001). CONCLUSION: Survey results indicate that WVSOM's Osteopathic Principles and Practices Integration Project has created a distinctly osteopathic curriculum and has helped alumni maintain use of OMT in clinical practice." | Osteopathic Medicine |
Fomitopsis pinicola (F. pinicola) is a kind of medicinal fungi, and few studies has been carried out on F. pinicola polysaccharides from liquid submerged cultivation. The characterization and antioxidant activities of extracellular polysaccharide (EPS) and intracellular polysaccharide (IPS) isolated from F. pinicola were investigated. The results showed that the molecular weight of EPS was 2.30x10(4)Da, and EPS was composed of mannose, rhamnose, xylose and galactose with the molar ratio of 0.1:1.0:0.3:0.5. The molecular weight of IPS was 4.07x10(5)Da, and the monosaccharide compositions included glucose, mannose, rhamnose, xylose and galactose with the molar ratio of 1.0:0.9:0.9:0.8:1.1. Antioxidant activities of both EPS and IPS including in vitro scavenging activities on 1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radicals, cellular protective effects on yeast cells from ultraviolet (UV) radiation and H2O2 oxidative damage were tested. Both EPS and IPS showed antioxidant activities in a dose dependent manner, and IPS had higher antioxidant activity than EPS. So EPS and IPS could be potential novel antioxidants for functional food. | Coriolaceae |
This study systematically compared the mechanical performances and polymerization shrinkage of two novel dual-cured resin composites (DCRC) with one conventional packable light-cured resin composite (LCRC) for their application as core build-up material by micro-hardness test, flexural strength test, push-out test, and digital image correlation analysis. The LCRC had a significantly higher micro-hardness (p<0.05) whereas the bond strength demonstrated no difference. The mean values of three materials ranged from 35.16 and 64.82 for the Vickers hardness and from 4.66 MPa to 11.53 MPa for the bond strength. The flexure strength of the three materials was not statistically different from each other. LCRC demonstrated 1.88% of volumetric shrinkage while the two DCRC showed 5.06% and 4.91%, respectively. In general, the DCRC demonstrated a comparable flexural strength and bond strength as the LCRC, however, the significant polymerization shrinkage of DCRC should be emphasized. | Hardness Tests |
To investigate the mechanisms by which Helicobacter pylori (Hp) induces gastric mucosal damage, gastric epithelial apoptotic index (AI) of normal gastric mucosa and Hp positive gastritis before and after anti-Hp treatment was studied with the method of terminal transferase mediated dUTP nick end labeling. The results showed that AI in Hp positive gastritis was higher than that in normal mucosa (P < 0.001). After the eradication of Hp, AI fell significantly to the normal level (P < 0.001). AI in persisting Hp positive gastritis had no statistically significant decrease after the anti-Hp treatment. There was no correlation between AI and the severity of gastritis. These results indicated that Hp could induce gastric epithelial apoptosis, which may be an important mechanism involved in gastric mucosal damage. | Josamycin |
OpenMRS is an open-source, robust electronic health record (EHR) platform that is supported by a large global network and used in over forty countries. We explored what factors lead to successful implementation of OpenMRS in resource constrained settings. Data sources included in-person and telephone key informant interviews, focus groups and responses to an electronic survey from 10 sites in 7 countries. Qualitative data was coded through independent coding, discussion and consensus. The most common perceived benefits of implementation were for providing clinical care, reporting to funders, managing operations and research. Successful implementation factors include securing adequate infrastructure, and sociotechnical system factors, particularly adequate staffing, computers, and ability to use software. Strategic and tactical planning were successful strategies, including understanding and addressing the infrastructure and human costs involved, training or hiring personnel technically capable of modifying the software and integrating it into the daily work flow to meet clinicians' needs." | Medical Records Systems, Computerized |
The identification of novel bacterial cell-to-cell communication (quorum sensing) systems based on diffusible signal molecules, such as indole and the LuxS autoinducer-2, requires discrimination between true signalling molecules and metabolites present in culture supernatants. This depends on rigorous chemical characterisation and demonstration that the molecule controls cellular responses beyond those required to metabolise or detoxify the signal. | Homoserine |
Recent studies have revealed multiple mechanisms that can lead to heterogeneity in ribosomal composition. This heterogeneity can lead to preferential translation of specific panels of mRNAs, and is defined in large part by the ribosomal protein (RP) content, amongst other things. However, it is currently unknown to what extent ribosomal composition is heterogeneous across tissues, which is compounded by a lack of tools available to study it. Here we present dripARF, a method for detecting differential RP incorporation into the ribosome using Ribosome Profiling (Ribo-seq) data. We combine the 'waste' rRNA fragment data generated in Ribo-seq with the known 3D structure of the human ribosome to predict differences in the composition of ribosomes in the material being studied. We have validated this approach using publicly available data, and have revealed a potential role for eS25/RPS25 in development. Our results indicate that ribosome heterogeneity can be detected in Ribo-seq data, providing a new method to study this phenomenon. Furthermore, with dripARF, previously published Ribo-seq data provides a wealth of new information, allowing the identification of RPs of interest in many disease and normal contexts. dripARF is available as part of the ARF R package and can be accessed through https://github.com/fallerlab/ARF. | Ribosomes |
An atypical pestivirus ('Hobi'-like pestivirus, putative bovine viral diarrhoea 3, BVDV-3) was identified firstly in contaminated foetal calf serum batches and isolated subsequently from an outbreak of respiratory disease in a cattle herd in Italy. The isolation of the novel pestivirus from animals affected clinically posed concerns about the validity of BVDV eradication programs, considering that 'Hobi'-like pestivirus (BVDV-3) is undetected or mistyped by the molecular diagnostic tools currently employed. In this paper, the development of a nested PCR (nPCR) assay for unambiguous typing of all bovine pestiviruses is reported. The assay consisted of a first-round amplification using an oligonucleotide pair which binds to conserved sequences located in the 5' untranslated region and capsid gene, followed by a heminested PCR using virus-specific forward primers. The assay performances were evaluated analytically, showing good sensitivity and specificity. By analysis of 100 BVDV-positive samples typed using a nPCR assay discriminating ruminant pestiviruses, five samples recognised previously as BVDV-2 were not typed when submitted to the new assay (n=2) or reacted as 'Hobi'-like pestivirus BVDV-3 (n=3). Sequence analysis of the first-round amplification products showed that the untyped strains were border disease viruses, whereas the other three strains were true 'Hobi'-like viruses. The development of a molecular assay able to identify simultaneously all bovine pestiviruses known currently will help warrant biosafety of live vaccines and other biological products and assess the molecular epidemiology of 'Hobi'-like pestivirus, thus leading to the improvement of the eradication programs through unambiguous typing of pestiviruses infecting cattle. | Pestivirus Infections |
Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of drugs in medicine and ophthalmology. Several NSAIDs have been commercially available for many years: diclofenac, flurbiprofen, indomethacin, ketorolac and suprofen. The purpose of this chapter is to review the clinical use of earlier and newer pharmacologic agents of the NSAID class. NSAIDs may have a modulating effect on ocular inflammation and pain through the prevention of prostaglandin synthesis via cyclooxygenase inhibition. Newer-generation NSAIDs have emerged in recent years for the treatment of ocular pain and inflammation. Nepafenac ophthalmic suspension 0.1% is a new topical NSAID prodrug that has been approved by the Food and Drug Administration for the treatment of pain and inflammation after cataract surgery. Preliminary data suggest nepafenac may also provide unique efficacy in the posterior segment, since its corneal permeability characteristics are superior to those of other NSAIDs. Nevanac, diclofenac, ketorolac and bromfenac are some notable NSAID candidates which should be investigated intravitreally or topically for retinal pharmacotherapy. In addition, for intraocular surgery, NSAIDs can help to prevent intraoperative miosis, reduce ocular pain, decrease postoperative inflammation and prevent cystoid macular edema. Retinal, choroidal and vitreous diseases may be the target of future nepafenac studies, either as monotherapy or as combination treatments. | Benzeneacetamides |
The presence of the human T cell lymphotropic virus (HTLV-I/II) in South America is well established. Its origin and spectrum in the continent still remain a matter of debate. There are signs now that HTLV-I/II was already present in the Amerindian population coming originally from Asia and that HTLV-I was also introduced with African slave trade and with immigration of individuals from endemic areas of Japan. South America has approximately 350 million inhabitants in its 13 countries. The presence of HTLV-I/II has been reported with impressive numbers in most of them and may be considered endemic in this continent. The distribution of HTLV I/II among native Amerindian populations has shown a geographic clustering of type I in the Andean highlands and Brazilian coast, while type II predominates in lowlands of South America. Although comparability between studies conducted among blood donors in different countries may be difficult, the data indicate that the viruses are also circulating among otherwise healthy individuals. Undoubtedly, HTLV-I/II infection and its related diseases should be considered a public health concern in South America and measures to prevent its spread should be emphasized. | HTLV-II Infections |
In a 42-years-old woman, an abdominal sonography was done, and a 10 x 9-cm solid cystic tumor on the left kidney appeared. Abdominal CT and arteriography showed a retroperitoneal heterogeneous mass surrounding and obstructing the ureteropelvic left junction. Tumor was removed under open surgery and the pathological study showed a benign schwannoma. We present this case because of its rarity 1%-10% of all primary retroperitoneal tumors. | Neurilemmoma |
Validation studies are prerequisites for computational fluid dynamics (CFD) simulations to be accepted as part of clinical decision-making. This paper reports on the 2011 edition of the Virtual Intracranial Stenting Challenge. The challenge aimed to assess the reproducibility with which research groups can simulate the velocity field in an intracranial aneurysm, both untreated and treated with five different configurations of high-porosity stents. Particle imaging velocimetry (PIV) measurements were obtained to validate the untreated velocity field. Six participants, totaling three CFD solvers, were provided with surface meshes of the vascular geometry and the deployed stent geometries, and flow rate boundary conditions for all inlets and outlets. As output, they were invited to submit an abstract to the 8th International Interdisciplinary Cerebrovascular Symposium 2011 (ICS'11), outlining their methods and giving their interpretation of the performance of each stent configuration. After the challenge, all CFD solutions were collected and analyzed. To quantitatively analyze the data, we calculated the root-mean-square error (RMSE) over uniformly distributed nodes on a plane slicing the main flow jet along its axis and normalized it with the maximum velocity on the slice of the untreated case (NRMSE). Good agreement was found between CFD and PIV with a NRMSE of 7.28%. Excellent agreement was found between CFD solutions, both untreated and treated. The maximum difference between any two groups (along a line perpendicular to the main flow jet) was 4.0 mm/s, i.e. 4.1% of the maximum velocity of the untreated case, and the average NRMSE was 0.47% (range 0.28-1.03%). In conclusion, given geometry and flow rates, research groups can accurately simulate the velocity field inside an intracranial aneurysm-as assessed by comparison with in vitro measurements-and find excellent agreement on the hemodynamic effect of different stent configurations. | Patient-Specific Modeling |
A functional scoring method to grade the usefulness and quality of the upper limbs in congenital radial dysplasia is presented. It is based on the author's examinations of 44 arms with congenital deficiency of the radius. The hand (H), wrist (W) and proximal parts (P) of the extremity are each scored from 0 to 10 points for severity. The scoring is expressed similarly to the TNM (tumour, nodes, metastasis) tumour classification, for example as H5W4P2. The maximum severity index is 30 points. A severity grade of mild is between 1 and 8 points, moderate between 9 and 16 points and severe 17 points and over. In the author's series, the grades were mild in eight, moderate in 21 and severe in 15 cases. The functional severity grading should allow better comparison of radially deficient limbs and the results of treatment between groups of patients. | Musculoskeletal Abnormalities |
The current study analyzed 312 caught-in-between fatalities caused by machinery and vehicles. A comprehensive and mutually exclusive coding scheme was developed to analyze and code each caught-in-between fatality in terms of age, gender, experience of the victim, type of industry, source of injury, and causes for these accidents. Boolean algebra analysis was applied on these 312 caught-in-between fatalities to derive minimal cut set (MCS) causes associated with each source of injury. Eventually, contributing factors and common accident patterns associated with (1) special process machinery including textile, printing, packaging machinery, (2) metal, woodworking, and special material machinery, (3) conveyor, (4) vehicle, (5) crane, (6) construction machinery, and (7) elevator can be divided into three major groups through Boolean algebra and MCS analysis. The MCS causes associated with conveyor share the same primary causes as those of the special process machinery including textile, printing, packaging and metal, woodworking, and special material machinery. These fatalities can be eliminated by focusing on the prevention measures associated with lack of safeguards, working on a running machine or process, unintentional activation, unsafe posture or position, unsafe clothing, and defective safeguards. Other precise and effective intervention can be developed based on the identified groups of accident causes associated with each source of injury. | Accidents, Occupational |
Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of 'eat me' signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants. | Phagocytosis |
A percutaneous perineal approach is presented as a further technique for rigid cystoscopy in male dogs. The anatomy of the urethra in the male dog prevents rigid cystoscopy by non-surgical means but a fine flexible fibrescope may be used. Perineal urethrotomy and prepubic percutaneous puncture techniques using rigid endoscopes have been described; however, both have possible serious complications. This new procedure allows access for visual examination, biopsy and resection as necessary and appears to have few adverse sequelae. | Cystoscopes |
The kallikrein-kinin system (KKS) is a complex system produced in various organs. This system includes kininogen (precursor for kinin), kallikreins, and pharmacologically active bradykinin (BK), which is considered to be proinflammatory and/or cardioprotective. It is a proinflammatory polypeptide that is involved in many pathological conditions and can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles, as well as cell proliferation. On the other hand, it has been shown that BK has cardioprotective effects, as all components of KKS are located in the cardiac muscles. Numerous observations have indicated that decreased activity of this system may lead to cardiovascular diseases, such as hypertension, cardiac failure, and myocardial infarction. BK acts on two receptors, B1 and B2, which are linked physiologically through their natural stimuli and their common participation in a variety of inflammatory responses. Recently, numerous BK antagonists have been developed in order to treat several diseases that are due to excessive BK formation. Although BK has many beneficial effects, it has been recognized to have some undesirable effects that can be reversed with BK antagonists. In addition, products of this system have multiple interactions with other important metabolic pathways, such as the renin-angiotensin system. | Kallikrein-Kinin System |
Protein-bound internal water molecules are essential features of the structure and function of microbial rhodopsins. Besides structural stabilization, they act as proton conductors and even proton storage sites. Currently, the most understood model system exhibiting such features is bacteriorhodopsin (bR). During the last 20 years, the importance of water molecules for proton transport has been revealed through this protein. It has been shown that water molecules are as essential as amino acids for proton transport and biological function. In this review, we present an overview of the historical development of this research on bR. We furthermore summarize the recently discovered protein-bound water features associated with proton transport. Specifically, we discuss a pentameric water/amino acid arrangement close to the protonated Schiff base as central proton-binding site, a protonated water cluster as proton storage site at the proton-release site, and a transient linear water chain at the proton uptake site. We highlight how protein conformational changes reposition or reorient internal water molecules, thereby guiding proton transport. Last, we compare the water positions in bR with those in other microbial rhodopsins to elucidate how protein-bound water molecules guide the function of microbial rhodopsins. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks. | Rhodopsins, Microbial |
The human antiapoptotic bcl-2 gene has been discovered in t(14;18) B-cell leukemias/lymphomas because of its overexpression caused at a transcriptional control level by the bcl-2/IgH fusion gene. We were the first to disclose the post-transcriptional control of bcl-2 expression mediated by interactions of an adenine + uracil (AU)-rich element (ARE) in the 3'-UTR of bcl-2 mRNA with AU-binding proteins (AUBPs). Here, we identify and characterize zeta-crystallin as a new bcl-2 AUBP, whose silencing or overexpression has impact on bcl-2 mRNA stability. An increased Bcl-2 level observed in normal phytohemagglutinin (PHA)-activated T lymphocytes, acute lymphatic leukemia (ALL) T-cell lines, and T cells of patients with leukemia in comparison with normal non-PHA-activated T lymphocytes was concomitant with an increase in zeta-crystallin level. The specific association of zeta-crystallin with the bcl-2 ARE was significantly enhanced in T cells of patients with ALL, which accounts for the higher stability of bcl-2 mRNA and suggests a possible contribution of zeta-crystallin to bcl-2 overexpression occurring in this leukemia. | zeta-Crystallins |
BACKGROUND: Treatment of classic pityriasis rubra pilaris, which almost always progresses to a generalized erythroderma with marked, often disabling keratoderma of the palms and soles, remains problematic. OBJECTIVE: Our purpose was to evaluate the results of treatment in a recent period during which the retinoid group of drugs has been available. METHODS: The clinical course of 75 patients with classic pityriasis rubra pilaris seen from 1982 to 1992 was reviewed. RESULTS: Of 15 patients treated with isotretinoin, 10 had complete and 2 had partial clearing. Of six treated with etretinate, four had clearing. All eight patients treated with methotrexate had a favorable response. Other forms of treatment, including Goeckerman regimen, corticosteroids, vitamin A, and cyclosporine, were ineffective. CONCLUSION: Early diagnosis and early treatment with retinoids appear to offer the best chance for clearing of pityriasis rubra pilaris. If retinoids fail or cannot be used, methotrexate should be considered. | Etretinate |
1 The ability of intravenous L-DOPA to block sympathetic and parsympathetic nerves has been studied in cats and dogs pretreated with a monoamine oxidase inhibitor.2 L-DOPA inhibited positive chronotropic and pressor responses to dimethylphenylpiperazinium (DMPP) and McN-A-343 in dogs, and contractions of the nictitating membrane produced by these ganglion stimulants in cats.3 Responses of the cat nictitating membrane to preganglionic stimulation were inhibited by L-DOPA to a greater extent than those to postganglionic stimulation of the cervical sympathetic chain.4 In dogs, L-DOPA had no vagolytic action, but depressed vasoconstrictor responses elicited in the perfused hind-limb by electrical stimulation of the lumbar sympathetic chain.5 The degree of lumbar sympathetic chain inhibition correlated with the pressor response following L-DOPA, and both effects were prevented by prior decarboxylase inhibition.6 These results suggest that the decarboxylation products of L-DOPA do not impair parasympathetic nerve activity but depress sympathetic nerve function predominantly by inhibiting both muscarinic and nicotinic sites of sympathetic ganglia. | Chlorisondamine |
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a member of the aldehyde dehydrogenase superfamily and is involved with the metabolic processing of aldehydes. ALDH2 plays a cytoprotective role by removing aldehydes produced during normal metabolism. We examined the cytoprotective role of ALDH2 specifically in gastric mucosa cells. Overexpression of ALDH2 increased the viability of gastric mucosa cells treated with H2O2, while knockdown of ALDH2 had an opposite effect. Moreover, overexpression of ALDH2 protected gastric mucosa cells against oxidative stress-induced apoptosis as determined by flow cytometry, Hoechst 33342, and TUNEL assays. Consistently, ALDH2 knockdown had an opposite effect. Additionally, DNA damage was ameliorated in ALDH2-overexpressing gastric mucosa cells treated with H2O2. We further identified that this cytoprotective role of ALDH2 was mediated by metabolism of 4-hydroxynonenal (4-HNE). Consistently, 4-HNE mimicked the oxidative stress induced by H2O2 in gastric mucosa cells. Treatment with 4-HNE increased levels of DNA damage in ALDH2-knockdown GES-1 cells, while overexpression of ALDH2 decreased 4-HNE-induced DNA damage. These findings suggest that ALDH2 can protect gastric mucosa cells against DNA damage caused by oxidative stress by reducing levels of 4-HNE." | Aldehyde Dehydrogenase, Mitochondrial |
This study investigated bacterial diversities in surface water and sediment of the East Lake located in Wuhan, China. Bacterial community of lake water was mainly composed of Proteobacteria (31.1%), Actinobacteria (25.0%), Bacteroidetes (18.6%), Cyanobacteria (18.9%), Planctomycetes (2.4%) and Verrucomicrobia (1.4%), while more abundant and richer bacterial community was found in the sediments, e.g. 46.1% for Proteobacteria, 10.1% for Bacteroidetes, 8.7% for Chloroflexi, 8.4% for Acidobacteria, 5.0% for Cyanobacteria, 3.6% for Firmicutes, 3.1% for Planctomycetes, 2.8% for Actinobacteria and 2.3% for Nitrospirae. The decreased bacterial community richness and abundance was found in poor-quality water. Moreover, Bacterial Eutrophic Index (BEI) was firstly put forward to quantitatively describe the water quality of a freshwater ecosystem, which was defined as the ratio of abundance of Cyanobacteria and Actinobacteria in water. It was demonstrated BEI was well correlated to Carlson's Trophic State Index (TSI) (Spearman's rhoâ¯=â¯0.848, pâ¯<â¯0.01). The average TSI and BEI were determined to be 64 and 0.81, suggesting that East Lake could be classified as a medium eutrophic level. | Planctomycetales |
The dimensional factors of the cervical undercut of the human teeth were measured. The facial and lingual undercuts showed considerable deviations in depth, width, and inclination to the crown axis and the food stream. The proximal undercuts showed a uniform depth of 1 +/- 0.3 mm with some deviations in width and inclination. | Tooth |
PURPOSE: To demonstrate the importance of material properties of the cornea in intraocular pressure (IOP) readings via standard Goldmann applanation tonometry. METHODS: A realistic finite element model of the cornea was developed for the simulation of Goldmann applanation tonometry. A virtual cornea population was generated by randomly sampling material properties, central corneal thickness (CCT), and IOP for comparison with 181 clinical cases. The effect of material properties and CCT on IOP prediction in the virtual population was determined via computational simulation. RESULTS: The results show that corneal biomechanical properties (as characterized in this study by the stiffness parameter Einit) are as important as the CCT in influencing measured (Goldmann) IOP. CONCLUSIONS: This study supports the contention that the observed large scatter in standard correlations of clinical measurements of IOP versus CCT can be largely accounted for by plausible individual variations in corneal biomechanical stiffness properties. | Elasticity |
Sanguinarine, a benzophenanthridine alkaloid, has anticancer potential through induction of cell death. We previously demonstrated that sanguinarine treatment at a low concentration (1.5 microg/ml) induced apoptosis in K562 human erythroleukemia cells, and a high concentration (12.5 microg/ml) induced the morphology of blister formation or oncosis-blister cell death (BCD). Treatment of cells at an intermediate sanguinarine concentration (6.25 microg/ml) induced diffuse swelling or oncosis-diffuse cell swelling (DCS). To assess the underlying mechanism of sanguinarine-induced apoptosis and oncosis-BCD in K562 cells, we studied their response to pre-treatment with two chemical compounds: aurintricarboxylic acid (ATA) and cycloheximide (CHX). The pretreatment effects of both chemical compounds on apoptosis and oncosis-BCD were evaluated by measuring multiple parameters using quantitative morphology, electron microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling and annexin-V-binding. ATA, a DNA endonuclease inhibitor, efficiently prevented DNA nicking and inhibited apoptosis almost completely and oncosis-BCD by about 40%, while CHX, a protein synthesis inhibitor, failed to inhibit both apoptosis and oncosis-BCD. These results demonstrate, first, the importance of endonuclease in sanguinarine-induced apoptosis and to some extent in oncosis-BCD and, second, that this inhibition does not require de novo protein synthesis. | Aurintricarboxylic Acid |
Raman spectroscopy (RS) was used to determine the crystallinity of lactose (a commonly used carrier in dry powder inhaler (DPI) formulations). Samples of alpha-lactose monohydrate and amorphous lactose were prepared using ethanol precipitation and lyophilisation respectively. The anomeric forms were confirmed using DSC at a rate of 10 degrees C/min and heated to 250 degrees C. The Raman spectra of both alpha-lactose monohydrate and amorphous lactose were obtained. Distinguishable differences were seen between the two spectra including peak areas and intensities. Depolarisation ratios (rho) of each form were then determined to identify the crystallinity of the lactose carrier samples. At the prominent Raman bands 865 and 1082 cm-1, significant differences in rho values were observed for crystalline (0.80+/-0.07, 0.89+/-0.06 respectively) and amorphous samples (0.44+/-0.07, 0.51+/-0.10). | Lactose |
Increasing interest in cytochrome P450 2B6 (CYP2B6) genetic polymorphism was stimulated by revelations of a specific CYP2B6 genotype significantly affecting the metabolism of various drugs in common clinical use in terms of increasing drug efficacy and avoiding adverse drug reactions. The present study aimed to determine the frequencies of CYP2B6*4 CYP2B6*5, CYP2B6*6, CYP2B6*7 and CYP2B6*9 alleles in healthy Turkish individuals (n = 172). Frequencies of three single nucleotide polymorphisms were 516G>T (28%), 785A>G (33%), and 1459C>T (12%). The frequencies of CYP2B6*1, *4, *5, *6, *7, and *9 alleles were 54.3 (95% CI 49.04-59.56), 6.4% (95% CI 3.81-8.99), 11% (95% CI 7.69-14.31), 25.3% (95% CI 20.71-29.89), 0.87% (95% CI -0.11-1.85) and 2.0% (95% CI 0.52-3.48), respectively. Allele *6 was more frequent (25.3%) than the other variant alleles in Turkish subjects. The frequencies of CYP2B6*4, *5, *6, *7, and *9 alleles were similar to European populations but significantly different from that reported for Asian populations. This is the first study to document the frequencies of the CYP2B6*4, *5, *6, *7, *9 alleles in the healthy Turkish individuals and our results could provide clinically useful information on drug metabolism by CYP2B6 in Turkish population. | Cytochrome P-450 CYP2B6 |
Virtual and augmented reality have seen increasing employment for teaching within medical and health sciences programs. For disciplines such as physiology and anatomy, these technologies may disrupt the traditional modes of teaching and content delivery. The objective of this systematic review and meta-analysis is to evaluate the impact of virtual reality or augmented reality on knowledge acquisition for students studying preclinical physiology and anatomy. The protocol was submitted to Prospero and literature search undertaken in PubMed, Embase, ERIC, and other databases. Citations were reviewed and articles published in full assessing learning or knowledge acquisition in preclinical physiology and anatomy from virtual or augmented reality were included. Of the 919 records found, 58 eligible articles were reviewed in full-text, with 8 studies meeting full eligibility requirements. There was no significant difference in knowledge scores from combining the eight studies (626 participants), with the pooled difference being a non-significant increase of 2.9 percentage points (95% CI [-2.9; 8.6]). For the four studies comparing virtual reality to traditional teaching, the pooled treatment effect difference was 5.8 percentage points (95% CI [-4.1; 15.7]). For the five studies comparing augmented reality to traditional teaching, the pooled treatment effect difference was 0.07 (95% CI [-7.0; 7.2]). Upon review of the literature, it is apparent that educators could benefit from adopting assessment processes that evaluate three-dimensional spatial understanding as a priority in physiology and anatomy. The overall evidence suggests that although test performance is not significantly enhanced with either mode, both virtual and augmented reality are viable alternatives to traditional methods of education in health sciences and medical courses. | Data Display |
Two new labdane diterpene derivatives, crotondecalvatin A (1) and crotondecalvatin B (2) were obtained from the leaves and twigs of Croton decalvatus. The structures of compounds were established on the basis of extensive spectroscopic data. | Cinnamates |
Single-stage extended replacement from the ascending to the distal descending aorta or beyond is a formidable operation that should be preserved for those who have no other option or those who are physically fit, and should be performed in the experienced centers. Hybrid operations combining open surgical repair with thoracic endovascular aortic repair through a median sternotomy incision are preferable because these operations are less invasive than the extended open aortic repair and the risk of spinal cord ischemia is lower compared with the frozen elephant trunk operation. However, these operations are associated with the inherent demerits of endovascular aneurysm exclusion. When the underlying aortic pathology necessitates extended open aortic repair in a single stage, approaches such as the anterolateral partial sternotomy, straight incision with rib cross, and extended thoracotomy with sternal transection may be useful to provide sufficient exposure for both aortic reconstruction and organ protection, with less surgical stress to the patients. | Dissection, Ascending Aorta |
Inflammatory processes are associated with the rapid migration of dendritic cells (DCs) to regional lymph nodes and depletion of these potent antigen-presenting cells (APCs) from the inflamed tissue. This study examined whether sites of cutaneous inflammation can be repopulated with DCs from a pool of immature DCs circulating in the blood. In adoptive transfer experiments with ex vivo-generated radioactively labeled primary bone marrow-derived DCs injected into mice challenged by an allergic contact dermatitis reaction, immature DCs were actively recruited from the blood to sites of cutaneous inflammation, whereas mature DCs were not. Immature, but not mature, DCs were able to adhere specifically to immobilized recombinant E- and P-selectin under static as well as under flow conditions. P-selectin-dependent adhesion of immature DCs correlates with their higher level of expression of the carbohydrate epitope cutaneous lymphocyte-associated antigen (CLA) and is blocked by a novel inhibitory antibody against mouse P-selectin glycoprotein ligand 1 (PSGL-1). Surprisingly, however, emigration of immature DCs into inflamed skin is retained in the presence of this anti-PSGL-1 antibody and is also normal when immature DCs are generated from fucosyltransferase (Fuc-T) Fuc-TVII-deficient mice. By contrast, emigration of wild-type immature DCs is reduced by adhesion-blocking anti-E- and P-selectin antibodies, and immature DCs generated ex vivo from Fuc-TVII/Fuc-TIV double-deficient mice emigrate poorly. Thus, fucosylated ligands of the endothelial selectins, determined in part by Fuc-TIV, and independent of PSGL-1, are required for extravasation of DCs into sites of cutaneous inflammation. | E-Selectin |
The presence of an abnormal sympathetic vascular tone is assumed in the hindquarters of spontaneously hypertensive rats (SHR) on the basis that ganglionic blockade decreases hindquarter vascular resistance (HQR) in them but not in normotensive control rats (NCR). Hindquarter blood flow (HQF) was observed with an electromagnetic flow probe implanted around the terminal aorta in SHR and NCR in the conscious state. Mean arterial pressure (AP) was also recorded with an indwelling catheter. HQR was calculated as AP divided by HQF. Intravenous bolus injection of chlorpromazine-HCl at 0.5 mg/kg significantly decreased HQR in SHR but not in NCR. Thereafter, in SHR, ganglionic blockade with hexamethonium bromide did not decrease HQR further. Chlorpromazine given to SHR after ganglionic blockade did not decrease HQR either. These findings indicate that the abnormal hindquarter tone in SHR was inhibited by chlorpromazine. It is suggested that dopaminergic neurons are involved in the hindquarter sympathetic tone generation. | Ganglionic Blockers |
A young patient with limited systemic sclerosis and medically resistant bilateral trigeminal neuralgia was successfully treated with microvascular decompression. To our knowledge, this is the first published report of this type of case. | Trigeminal Neuralgia |
So far, most cases of hypercholesterolaemia (60-80%) are attributed to pathogenic variants in the LDLR gene. Only 1-5% of cases are caused by variants in the APOB gene, and 0-3% by variants in the PCSK9 gene. There is a large variety in known pathogenic mutations of the LDLR gene, while for those affecting the APOB gene, the highest incidence is p.Arg3527Gln, described predominantly in Central European and North American populations. In the Iberian Peninsula the predominant gene affected is that of the LDL receptor, similar to the rest of the world, with the involvement of the APOB gene being described in individuals from the northwest, and anecdotal in the rest of the territory. A genetics analysis was performed on the population attending the first year of a lipid clinic in southwestern Spain with a 6-point score from the Dutch lipid clinics. The genetic, biochemical and clinical findings are described. The first findings show indications of a possible higher prevalence of patients with mutation in the APOB gene compared to other territories. Historical evidence is presented that could give a possible explanation to this, thus supporting the assumption. | Apolipoprotein B-100 |
INTRODUCTION: Langerhans cell histiocytosis (LCH) is a condition characterized by proliferation of Langerhans cells and wide-range pathologies, ranging from single granulomatous lesions to multi-organ involvement, associated with tissue destruction. LCH pathogenesis remains obscure although association with interleukin (IL)-17A has been reported. We report here a case that illustrates the potential pathogenic role of helper T17 (Th17) cells in LCH-related bone destruction. MATERIALS AND METHODS: The patient was a 66-year-old woman. The clinical course included craniectomy and bone mass excision in X-9, diagnosis of LCH confirmed by histopathology, followed by 26-month chemotherapy. In August X, the patient was diagnosed with complete central diabetes insipidus. Symptoms improved after treatment with desmopressin. Pituitary magnetic resonance imaging showed swelling extending from the suprasellar region to the pituitary stalk, suggestive of LCH recurrence. This was followed by chemotherapy combined with mercaptopurine hydrate. RESULTS: Subsequent peripheral blood lymphocyte analysis showed marked increase in activated Th17 cells (CXCR3(-)CXCR6(+) CD4(+) T cells). Double staining for CD4 and IL-17 by immunofluorescence of pathological tissue samples obtained during temporal bone mass excision, which confirmed the diagnosis of LCH in X-9, showed areas of combined presence of CD4-positive cells and IL-17-positive cells. Chemotherapy resulted in size reduction of the pituitary lesion and decrease in peripheral blood-activated Th17 cells. CONCLUSIONS: We found abundant peripheral blood-activated Th17 cells and high percentages of IL-17-producing cells in osteolytic bone lesions in LCH. This finding, together with the decrease in peripheral blood-activated Th17 cells following chemotherapy, suggests the potential involvement of activated Th17 cells in LCH-related osteolysis. | Receptors, CXCR6 |
OBJECTIVE: To report nine cases of descending necrotizing mediastinitis (DNM) and to summarize the management experience. METHODS: Between December 2005 and December 2008, nine patients (mean age, 55.7 years; age range, 38 to 78 years) with DNM were treated. Eight patients underwent surgical drainage of the involved cervical region and mediastinum (4 with cervical drainage alone; 4 with cervical drainage and right thoracotomy). RESULTS: Two patients died, one of them refused surgical therapy and the other one died of multiorgan failure related to postoperative septic shock. Seven patients recovered. The mortality rate was 22%. CONCLUSIONS: Delayed diagnosis and inadequate drainage are the main causes of high mortality rate of DNM. Aggressive surgical drainage and debridement of the neck and mediastinum by a multidisciplinary team of surgeons are very important in the treatment of DNM. | Focal Infection |
The disarticulation of the knee joint is--in contrary to the above-knee level--a fast and tender method for amputation, resulting in a vigorous, complete weightbearing stump. Without problems the bulky stump is fitted in an exactly moulded plastic or resin socket--eventually combined with a soft socket--, which can be easily put on and off also by older patients suffering from general dysvascular disorders. Nowadays special joints are used for functionally as well as cosmetically satisfying knee-disarticulation-prostheses. The surgical technique with alternative incisions, the peculiarities in dysvascular patients, the postoperative care including immediate or early fitting, the management after wound-healing with a temporary exercise-prosthesis and finally the various possibilities of the definitive prosthetic fitting are stressed in detail. | Disarticulation |
Purification of a lipoxygenase enzyme from the cultivar Tresor of durum wheat semolina (Triticum turgidum var. durum Desf) was reinvestigated furnishing a new procedure. The 895-fold purified homogeneous enzyme showed a monomeric structure with a molecular mass of 95 +/- 5 kDa. Among the substrates tested, linoleic acid showed the highest k(cat)/K(m) value; a beta-carotene bleaching activity was also detected. The enzyme optimal activity was at pH 6. 8 on linoleic acid as substrate and at pH 5.2 for the bleaching activity on beta-carotene, both assayed at 25 degrees C. The dependence of lipoxygenase activity on temperature showed a maximum at 40 degrees C for linoleic acid and at 60 degrees C for bleaching activity on beta-carotene. The amino acid composition showed the presence of only one tryptophan residue per monomer. Far-UV circular dichroism studies carried out at 25 degrees C in acidic, neutral, and basic regions revealed that the protein possesses a secondary structure content with a high percentage of alpha- and beta-structures. Near-UV circular dichroism, at 25 degrees C and at the same pH values, pointed out a strong perturbation of the tertiary structure in the acidic and basic regions compared to the neutral pH condition. Moreover, far-UV CD spectra studying the effects of the temperature on alpha-helix content revealed that the melting point of the alpha-helix is at 60 degrees C at pH 5.0, whereas it was at 50 degrees C at pH 6.8 and 9.0. The NH(2)-terminal sequence allowed a homology comparison with other lipoxygenase sequences from mammalian and vegetable sources. | Lipoxygenases |
Costimulatory molecules of the B7 family regulate the activation of T lymphocytes. T cell activation is promoted by binding of B7 molecules to CD28 and inhibited by binding to CTLA-4 (CD152). The balance between positive signals through CD28 and negative signals through CTLA-4 is critical for the fate of the T cell and is subject to tight regulation. Recent in vitro and in vivo studies have significantly advanced our understanding of the function of the CTLA-4 receptor. The results of these experiments suggest that CTLA-4 is critical for the induction of self-tolerance, and that it may have distinct signaling functions in resting and activated T cells. In resting T cells, CTLA-4 crosslinking leads to cell-cycle arrest, whereas in activated T cells, CTLA-4 crosslinking induces apoptosis. In this article, we will review the physiologic functions of the CTLA-4 receptor. | Antigens, Differentiation |
Myosin-Va, a processive actin-based motor thought to be involved in organelle transport, now stands ready to join myosin-II (from muscle) as one of the most highly characterized members of the myosin superfamily. Recent reports from the laboratories of Goldman and colleagues and Selvin and colleagues have provided unprecedented, high-resolution views of the structural changes that take place while this motor moves along its track. Taken together, the new results indicate that myosin-Va tilts its light chain binding domains to 'walk' along actin in a hand-over-hand fashion. | Myosin Type V |
BACKGROUND: Traumatic stress is a global mental health problem requiring novel, easily implemented treatment solutions. We compared the effectiveness and efficiency of Reconsolidation Therapy (RT) to the well-established antidepressant paroxetine, in reducing symptoms of traumatic stress among patients from Nepal, a low-income country. METHODS: Forty-six adults with posttraumatic stress disorder (PTSD) were randomized to one of two groups. The reconsolidation blocker propranolol was administered 90 min before briefly recalling a traumatic memory with a therapist, weekly for six consecutive weeks. This was compared to daily paroxetine for 26 weeks. Self-reported PTSD symptoms were assessed blindly at the 7th, 13th, and 26th weeks. RESULTS: An intent-to-treat analysis revealed a robust pre- to post-treatment main effect (beta(1) = - 4.83, 95% CI = [- 5.66, - 4.01], p < .001), whereby both groups improved, with Cohen's effect sizes of d = 2.34 (95% CI = [1.57, 3.12]) for paroxetine, and of 2.82 (95% CI = [1.98, 3.66]) for RT after 7 weeks, suggesting treatment effectiveness for both groups in a real-world setting. Three and six-month follow-up yielded further significant improvement in both groups, which did not differ from each other. CONCLUSION: RT also displayed promising efficiency, considering that it had been discontinued weeks earlier while the paroxetine treatment was continued, as recommended. RT could be taught in low-income countries as part of the local therapeutic resources to treat the core symptoms of PTSD, provided that such results are replicated on a broader scale. TRIAL REGISTRATION: ISRCTN34308454 (11/10/2017). | Paroxetine |
Tuberculosis (TB) is responsible for 1.4 million deaths annually. Wide-spread misuse of anti-tubercular drugs over three decades has resulted in emergence of drug resistant TB including multidrug-resistant TB and extensively drug-resistant TB globally. Accurate and rapid diagnosis of drug-resistant TB is one of the paramount importance for instituting appropriate clinical management and infection control measures. The present article provides an overview of the various diagnostic options available for drug resistant TB, by searching PubMed for recent articles. Rapid phenotypic tests still requires days to weeks to obtain final results, requiring biosafety and quality control measures. For newly developed molecular methods, infrastructure, training and quality assurance should be followed. Successful control of drug resistant TB globally will depend upon strengthening TB control programs, wider access to rapid diagnosis and provision of effective treatment. Therefore, political and fund provider commitment is essential to curb the spread of drug resistant TB." | Extensively Drug-Resistant Tuberculosis |
Four tetrathiafulvalene (TTF)-annulated porphyrins 1-4 were synthesized and characterized. All contain a tetraphenylporphyrin (TPP) core onto which four, two, or one TTF subunits were annulated. Absorption and fluorescence spectroscopic studies together with electrochemical investigations reveal that interactions between the porphyrin system and the annulated TTF units take place in solution. The annulation of one or more TTF units to the porphyrin core has a profound effect on the reduction potentials associated with this latter framework, with positive shifts in the range of 0.105 to 0.355 V and 0.200 to 0.370 V for the first and second reduction potential, respectively, compared to the corresponding processes in the model compound TPP, 18. The redox potentials for the first oxidation of the TTF units are considerably shifted in 4 (DeltaE(ox)(1)=+0.285 V) and 2 (DeltaE(ox)(1)=-0.140 V), whereas for 1 and 3 these potentials remain within the region expected for a normal TTF unit. Considerable changes in the second oxidation potential associated with the TTF subunits were seen for 2 (DeltaE(ox)(1)=-0.085) and 3 (DeltaE(ox)(1)=-0.175). The emission spectra of 1-4 revealed that the porphyrin fluorescence is almost quenched in the neutral state of the TTF-annulated porphyrins, a finding that is consistent with substantial electron transfer taking place from the TTF subunits to the porphyrin core. Oxidation of the TTF unit(s) (TTF-->TTF(*+)) present in 1-4 leads to the emission intensity being restored. | Porphyrins |
Serum and urine myoglobin levels were determined on 14 patients with stable chronic renal failure. Serum myoglobin ranged from 38 to 350 ng/mL. Eleven patients had myoglobinuria between 15 and 250 ng/mL; none developed myoglobinuric renal failure. Fractional excretion of myoglobin in the myoglobinuric patients increased as creatinine clearance decreased, although there was no correlation between filtered load and excretion rate of myoglobin. This confirms that renal failure leads to hypermyoglobinemia and usually to myoglobinuria. Surviving nephrons tend to reabsorb less of the filtered load of myoglobin as renal function diminishes. | Myoglobinuria |
Linx is a member of the leucine-rich repeat and immunoglobulin family of membrane proteins which has critical roles in the development of the peripheral nervous system and forebrain connectivity. A previous study showed that Linx is expressed in projection neurons in the cortex and in cells that comprise the passage to the prethalamus that form the internal capsule, indicating the involvement of Linx in axon guidance and cell-cell communication. In this study, we found that Linx-deficient mice develop severe hydrocephalus and die perinatally by unknown mechanisms. Importantly, mice heterozygous for the linx gene exhibited defects in the development of the anterior commissure in addition to hydrocephalus, indicating haploinsufficiency of the linx gene in forebrain development. In N1E-115 neuroblastoma cells and primary cultured hippocampal neurons, Linx depletion led to impaired neurite extension and an increase in cell body size. Consistent with this, but of unknown significance, we found that Linx interacts with and upregulates the activity of Rho-kinase, a modulator of many cellular processes including cytoskeletal organization. These data suggest a role for Linx in the regulation of complex forebrain connectivity, and future identification of its extracellular ligand(s) will help clarify this function. | Axon Guidance |
INTRODUCTION: Spondylolysis can either be asymptomatic or can cause significant low back pain. It is sometimes associated with the translation of one vertebra over another and is termed spondylolisthesis. The aim of the study was to find out the prevalence of spondylolysis among patients without low back pain in a diagnostic centre. METHODS: A descriptive cross-sectional study was carried out in a referral diagnostic centre from 15 December 2018 to 14 December 2021 . Ethical approval was obtained from the Nepal Health Research Council (Reference number: 2903). Images of a computed tomography scan of the abdomen performed for other abdominal causes and without low back pain were reconstructed in the sagittal and coronal plane and evaluated for the presence of spondylolysis and spondylolisthesis in the lumbar spine. Demographic data were taken from the hospital records. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. RESULTS: Among 768 patients without low back pain, spondylolysis was found in 59 (7.68%) (5.80-9.56, 95% Confidence Interval). Spondylolisthesis was found in only 16 (27.1%) individuals with spondylolysis. The majority of spondylolysis cases were encountered in L5 level in 54 (91.53%). The mean age of patients with spondylolysis was 41.9+/-14.46 years. Male to female ratio was 1:1.18. CONCLUSIONS: The prevalence of spondylolysis in our study was found to be similar to other studies done in similar settings. KEYWORDS: low back pain; spondylolisthesis; spondylolysis. | Spondylolysis |
PURPOSE: Primary ciliary dyskinesia (PCD) is a heterogeneous disorder that includes respiratory symptoms, laterality defects, and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance. METHODS: In addition to studies in mouse and planaria, clinical exome sequencing and functional analyses in human were performed. RESULTS: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms. Consistently, we found that Clxn is expressed in mice left-right organizer. Transmission electron microscopy depicted ODA defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1, and DNAI2 from the distal axonemes, and mislocalization or absence of DNAH9. In addition, CLXN was undetectable in ciliary axonemes of individuals with defects in the ODA-docking machinery: ODAD1, ODAD2, ODAD3, and ODAD4. Furthermore, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility. CONCLUSION: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5. | Axonemal Dyneins |
Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin-inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin. | Antithrombins |
BACKGROUND: To determine the repeatability of measurements of ocular surface vessel density in normal and diseased eyes using optical coherence tomography angiography (OCTA). METHODS: Ten normal eyes, 10 pinguecula eyes, and 10 pterygium eyes of 30 volunteers were subjected to OCTA (AngioVue Imaging System, Optovue, Inc.). For scanning, we used the corneal adapter module. Each eye was scanned three times in the nasal and temporal directions, separately. AngioVue software was used to generate the ocular surface vessel density. Ocular surface vessel density was defined as the proportion of vessel area with blood flow to the total measurement area (3 x 3 mm(2)). Intersession repeatability of the measurement was summarized as the coefficient of variation (CV), and intraclass correlation coefficients (ICC) were calculated by variance component models. RESULTS: The CVs were less than 5% in all subjects, and the ICCs exceeded 0.9; thus, all measurements showed good repeatability. The nasal vessels densities differed significantly between healthy eyes and eyes with pterygium (P < 0.05); however, there was no significant difference between healthy eyes and eyes with pinguecula (P = 0.466). CONCLUSIONS: These results suggest that measurement of ocular surface vessel density by OCTA in normal eyes and eyes with pterygium and pinguecula is repeatable. This preliminary research describes a quantitative and visual method for assessing vessel density of the ocular surface with a high level of consistency. | Pinguecula |
ETHNOPHARMACOLOGICAL RELEVANCE: The haemorrhagic dengue fever affects up to 500 million patients, annually causing 20.000 deaths, with no chemotherapeutic agent available. The oleoresin labdanum of Cistus creticus L. has been established as an anti-infective agent since antiquity in Mediterranean ethnopharmacology. MATERIALS AND METHODS: We tested several extracts and fractions of labdanum - standardised on labdane-type diterpenes via GC-MS - on their activity against the dengue virus (DENV-2 strain 00st-22A) in in vitro Vero cell cultures (96-well-plates, 5 days). Preliminary experiments with a labdanum diethyl ether raw-extract did not yield measureable results due to cytotoxic effects against Vero cells. In all following experiments, cell viability was constantly checked using the MTT-test. Fractionation of this raw-extract by liquid-liquid-extraction and column-chromatography on silica-gel (gradient elution with hexane, EtOAc, CHCl(3), MeOH) succeeded in separating the anti-viral activity of labdanum from its cytotoxic effect. RESULTS: In the most active fraction GS5 at 30â¯mug/ml, dengue virus proliferation was 100% suppressed and cell viability was over 90%. Structural elucidation of major constituents of GS5 is currently ongoing, but thin-layer chromatography showed that this fraction is mainly dominated by manoyloxides, a class of labdane-type diterpenes with known antimicrobial activity. Claims concerning the antiviral activity of above ground parts of C. creticus have been made previously, but these generally ascribe this activity to hot water soluble polyphenols and propose an unspecific tanning effect of the viral surface proteins as the mechanism of action. However, the water soluble fraction enhanced viral proliferation. CONCLUSION: We therefore describe a direct, pharmacological, antiviral activity of a diethyl ether extract of labdanum against a virulent haemorrhagic fever like dengue for the first time. | Cistus |
Plasma cell neoplasms are notorious for having diverse morphological presentations, and less frequently, unusual immunophenotypical profiles. This unexpected immunomorphological variability could lead to erroneous impressions upon initial assessment, potentially delaying the generation of a final accurate diagnosis. In this review, we present a concise, yet comprehensive summary of both morphological and immunophenotypical variants of plasma cell neoplasms from the archives of MD Anderson Hematopathology Department, with emphasis on possible diagnostic pitfalls precluding a timely and accurate assessment. | Neoplasms, Plasma Cell |
Cheyne-Stokes respiration is characterized by crescendo-decrescendo fluctuations in tidal volume and respiratory rate interrupted by central apneas. It has long been associated with cardiac disease and has often been cited as a poor prognostic indicator, yet the incidence and immediate significance of CSR in the setting of acute cardiogenic PE is not well defined. Therefore, we studied 95 patients who required MVS because of PE. Breathing patterns were monitored by continuous respiratory inductive plethysmography for a minimum of 12 hours of spontaneous respiration after recovery from PE; CSR was noted in 42 patients (44 percent). There were no significant differences between patients with PE and CSR and those with only PE in regard to LVEF (mean +/- SD, 36 +/- 18 percent vs 33 +/- 16 percent; p = 0.55), reinstitution of MVS within 48 hours (4.8 percent vs 17.0 percent; p = 0.065), or in-hospital mortality (16.7 percent vs 26.4 percent; p = 0.255). We conclude that CSR is a relatively common breathing pattern in patients who required MVS because of cardiogenic PE and does not portend a poor immediate prognosis in this population. | Cheyne-Stokes Respiration |
Protein ubiquitination and protein phosphorylation are two fundamental regulatory post-translational modifications controlling intracellular signalling events. However, the ubiquitin system is vastly more complex compared with phosphorylation. This is due to the ability of ubiquitin to form polymers, i.e. ubiquitin chains, of at least eight different linkages. The linkage type of the ubiquitin chain determines whether a modified protein is degraded by the proteasome or serves to attract proteins to initiate signalling cascades or be internalized. The present review focuses on the emerging complexity of the ubiquitin system. I review what is known about individual chain types, and highlight recent advances that explain how the ubiquitin system achieves its intrinsic specificity. There is much to be learnt from the better-studied phosphorylation system, and many key regulatory mechanisms underlying control by protein phosphorylation may be similarly employed within the ubiquitin system. For example, ubiquitination may have important allosteric roles in protein regulation that are currently not appreciated. | Ubiquitin |
This study aims to investigate the acute protective effect of montelukast sodium in hepatic injury secondary to acetaminophen (APAP) intoxication. This study used 60 rats. The rats were grouped into 6 groups. The control group was administered oral distilled water 10 ml/kg, the APAP group oral APAP 1 g/kg, the montelukast sodium (MK) group oral MK 30 mg/kg, the acetaminophen+N-acetylcysteine (APAP+NAC) group oral APAP 1 g/kg, followed by a single dose of intraperitoneal NAC 1.5 g/kg three hours later, the acetaminophen+montelukast sodium (APAP+MK) group oral APAP 1 g/kg, followed by oral MK 30 mg/kg 3 h later, the acetaminophen+N-acetylcysteine+montelukast sodium (APAP+NAC+MK) group oral APAP 1 g/kg, followed by a single intraperitoneal NAC 1.5 g/kg plus oral MK 30 mg/kg 3 h later. Blood and liver tissue samples were taken 24h after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were studied from the blood samples. Liver tissue samples were used for histopathological examination. Compared with the control group, serum AST and ALT activities were higher in the APAP and APAP+NAC groups. APAP+NAC, APAP+MK, and APAP+NAC+MK groups had reduced serum ALT and AST activities than the group administered APAP alone. APAP+MK and APAP+NAC+MK groups had a lower serum ALP activity than the control group. Histopathologically, there was a difference between the group administered APAP alone and the APAP+MK and APAP+NAC+MK groups. MK is as protective as NAC in liver tissue in APAP intoxication in rats." | Cytochrome P-450 CYP1A2 Inducers |
Gastrointestinal (GI) diseases involving the alimentary tract and hepatobiliary system are common in geriatric dogs and cats. Inflammatory disorders predominate, but motility disturbances and degenerative lesions may also cause GI signs in affected animals. Treatment is directed at correction of the underlying cause and often requires tissue biopsy. The prognosis is good in many diseases with appropriate drug nutritional, and/or surgical therapy. | Digestive System Diseases |
Constipation is a common problem with a considerable negative impact on quality of life in patients who receive palliative care. Over 35% of patients with heart failure, chronic obstructive pulmonary disease or cancer have constipation. In the palliative phase constipation often has multiple causes. Treatment of constipation consists of both medical treatment with laxatives and non-medical treatment. A specific recommendation for the use of laxatives cannot be made because of the lack of comparative trials. The choice of what laxative to use can only be made on the basis of clinical experience, mechanism of action, personal preference of the patient and costs. Prophylactic use of laxatives is indicated to prevent constipation when initiating constipation inducing medication such as opioids. In treatment-resistant constipation prucalopride, colchicine or misoprostol may be effective. Opioid-antagonists such as naloxone and methylnaltrexone are effective in patients with persistent opioid-induced constipation despite the use of laxatives. | Laxatives |
This study identified changes in blood pressure, blood glucose, and cholesterol levels in frail elderly adults who received home health care nursing over 8 years in Korea. Secondary data extracted from nursing records (2010-2018) of a public health center were analyzed using a mixed model of repeated measure. Study participants were elderly people (n = 499) with a mean age of 81.9 +/- 5.56 years. Systolic and diastolic blood pressure decreased by 8.97 and 15.78 mmHg, and by 2.92 and 5.01 mmHg, respectively, at 4-year and 8-year monitoring. This demonstrates that home health care nursing is effective and has both short- and long-term benefits. | Home Health Nursing |
Unlike BCR and secreted Ig, TCR expression is not thought to occur in a bivalent form. The conventional monovalent model of TCR/CD3 is supported by published studies of complexes solubilized in the detergent digitonin, in which bivalency was not observed. We revisited the issue of TCR valency by examining complexes isolated from primary alphabeta T cells after solubilization in digitonin. Using immunoprecipitation followed by flow cytometry, we unexpectedly observed TCR/CD3 complexes that contained two TCRs per complex. Standard anti-TCR Abs, being bivalent themselves, tended to bind with double occupancy to bivalent TCRs; this property masked the presence of the second TCR per complex in certain Ab binding assays, which may partially explain why previous data did not reveal these bivalent complexes. We also found that the prevalence of bivalency among fully assembled, mature TCR/CD3 complexes was sufficient to impact the functional performance of immunoprecipitated TCRs in binding antigenic peptide/MHC-Ig fusion proteins. Both TCR positions per bivalent complex required an Ag-specific TCR to effect optimal binding to these soluble ligands. Therefore, we conclude that in primary T cells, TCR/CD3 complexes can be found that are physically and functionally bivalent. The expression of bivalent TCR/CD3 complexes has implications regarding potential mechanisms by which Ag may trigger signaling. It also suggests the possibility that the potential for bivalent expression could represent a general feature of Ag receptors. | CD3 Complex |
Daptomycin is a lipopeptide antimicrobial with in vitro bactericidal activity against Gram-positive bacteria that was first approved for clinical use in 2004 in the United States. Since this time, significant data have emerged regarding the use of daptomycin for the treatment of serious infections, such as bacteremia and endocarditis, caused by Gram-positive pathogens. However, there are also increasing reports of daptomycin nonsusceptibility, in Staphylococcus aureus and, in particular, Enterococcus faecium and Enterococcus faecalis. Such nonsusceptibility is largely in the context of prolonged treatment courses and infections with high bacterial burdens, but it may occur in the absence of prior daptomycin exposure. Nonsusceptibility in both S. aureus and Enterococcus is mediated by adaptations to cell wall homeostasis and membrane phospholipid metabolism. This review summarizes the data on daptomycin, including daptomycin's unique mode of action and spectrum of activity and mechanisms for nonsusceptibility in key pathogens, including S. aureus, E. faecium, and E. faecalis. The challenges faced by the clinical laboratory in obtaining accurate susceptibility results and reporting daptomycin MICs are also discussed. | Daptomycin |
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