Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis.
MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress.


Unified performance evaluation of health centers with integrated model of data envelopment analysis and bargaining game.
This paper introduces a new integrated approach to measure unified efficiency of the healthcare systems. Health centers as an important part of the healthcare systems are considered for evaluation. For this purpose, we define two categories of inputs to measure performance of health centers based on medical human resources and characteristics of spatial information by using geographic information system (GIS). Catching the balance in the spatial distribution of populations and services is one of the main problems in health centers evaluation. On the other hand, data envelopment analysis (DEA) is widely applied for measuring efficiency of the healthcare systems. But, the conventional DEA models may fail to integrated several categories of measures. In this paper, DEA and bargaining game model are integrated for evaluation of health centers. In other words, two categories of measures are used to measure unified efficiency for each health center in the competitive environment. Two models according to constant return to scale (CRS) and variable return to scale (VRS) assumptions are developed. The case study of health centers under supervising of Tehran university of medical sciences (TMUS) is presented to show the abilities of the proposed approach.


Suppression of human growth hormone secretion by cyproheptadine.
In order to determine whether or not a serotoninergic mechanism is involved in the secretion of the growth hormone (GH), a study was made of the effect of cyproheptadine, an antiserotonin agent, on plasma GH levels in normal children. The oral administration of cyproheptadine (12 mg daily) reduced GH responses to both L-dopa and glucagon; similarly, the mean GH response to oral glucose administration was significantly reduced after cyproheptadine administration. Plasma glucose values during the tests were not altered by cyproheptadine therapy. These results suggest that the serotoninergic mechanism might be involved in L-dopa-, glucagon-, and glucose-induced GH release.


Amplification of KRAS and its heterogeneity in non-Asian gastric adenocarcinomas.
Gastric cancer is one of the deadliest cancer entities worldwide. While surgery is the only curative treatment option in early tumors, for locally advanced and metastatic patients further therapeutic targets are needed. Several studies not only reported mutations but also amplifications of the KRAS locus in different cancer entities. More recently, KRAS amplification was discussed as a new therapeutic target. Little is known about the (prognostic) relevance and (heterogenic) distribution of KRAS amplification in gastric adenocarcinomas, especially in Non-Asian patients. Amplification of the KRAS locus and corresponding protein expression was analyzed in 582 gastric adenocarcinomas employing fluorescence in-situ hybridization (FISH) and immunohistochemistry. Amplification status was correlated with clinico-pathological features, clinical outcome and molecular tumor data including a correlation to the TCGA subtypes of gastric carcinoma. KRAS amplification was detected in 27 out of 470 analysable tumors (5.7%) and correlated with protein expression of KRAS in all amplified tumors. Within the KRAS amplified gastric tumors 14/27 (51.9%) showed a heterogeneous distribution with also KRAS non-amplified tumor parts. According to TCGA 24 tumors (88.8%) were related to chromosomal instable tumors (CIN). The survival analysis of the entire patient cohort did not show any difference in overall survival in dependence on the KRAS status. However, a significant survival difference with a worse outcome for patients with KRAS amplified tumors was identified when analysing patients without neoadjuvant pre-treatment. We confirm the unfavorable prognosis of KRAS amplified tumors reported by other studies in (Asian) patient groups, at least in patients without neoadjuvant pre-treatment. Within KRAS amplified tumors we revealed intratumoral heterogeneity that may define a (more aggressive) tumor cell population which is more frequently observed in patients with lymph node metastases. Despite the heterogeneous distribution of KRAS amplified tumor clones, KRAS amplified locally advanced or metastasized gastric adenocarcinomas represent a therapeutically highly relevant tumor subgroup.


(Multiple) Isotope probing approaches to trace the fate of environmental chemicals and the formation of non-extractable 'bound' residues.
Procedures for the analysis of turnover of chemicals (and of natural compounds) are well developed using radio or stable isotope labelled tracer compounds in various standardized OECD tests. Due to the analytical focus on the isotope label the chemical speciation of the so-called non-extractable residues (NER) in soils and sediments often remains unknown. These NER may stem from parent compounds, metabolites, microbial biomass, or from precipitated carbonates after productive microbial degradation. Fate studies mostly do not describe the link to phylogenetic assignment of degraders and microbial ecology although in these fields various isotope tracer applications are well developed, too. We present several options for integrating both approaches in environmental biotechnology and how they can be used to improve knowledge in microbial ecology.


Importance of Standardizing Analytical Characterization Methodology for Improved Reliability of the Nanomedicine Literature.
Understanding the interaction between biological structures and nanoscale technologies, dubbed the nano-bio interface, is required for successful development of safe and efficient nanomedicine products. The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliability and reproducibility in the nanomedicine literature. As such, there is a strong need to establish a characterization system to support the reproducibility of nanoscience data particularly for studies seeking clinical translation. Here, we discuss the existing key standards for addressing robust characterization of nanomaterials based on their intended use in medical devices or as pharmaceuticals. We also discuss the challenges surrounding implementation of such standard protocols and their implication for translation of nanotechnology into clinical practice. We, however, emphasize that practical implementation of standard protocols in experimental laboratories requires long-term planning through integration of stakeholders including institutions and funding agencies.


Frontiers in electron probe microanalysis: application to cell physiology.
The application of electron probe microanalysis techniques, using X-ray and electron energy loss instruments, to problems in cell physiology is reviewed. The details of the special methodological requirements for the analysis of cryosections at high spatial resolution in an analytical electron microscope are discussed together with a comprehensive review of data obtained on major organ systems and cell types.


[The contribution of medical community into elaboration of theoretical problems of health care in the sixties of XIX century].
The article considers activity of medical societies in 1860s related to theoretical development of problems of organization of Zemstvo medicine, sanitary statistics, medical topographical studies, preventive course of public medicine. It is demonstrated that results of these activities hereinafter were widely applied in the course of health care reforms of the second half of XIX century.


Mental health status of the general population, healthcare professionals, and university students during 2019 coronavirus disease outbreak in Jordan: A cross-sectional study.
The emergence of COVID-19 global pandemic coupled with high transmission rate and mortality has created an unprecedented state of emergency worldwide. This global situation may have a negative impact on the psychological well-being of individuals which in turn impacts individuals' performance. This study aims to explore the prevalence of depression and anxiety among the GP, HCPs, and USs during COVID-19 outbreak, and to identify key population(s) who might need psychological intervention. A cross-sectional study using an online survey was conducted in Jordan between 22 and 28 March 2020 to explore the mental health status (depression and anxiety) of the general population, healthcare professionals, and university students during the COVID-19 outbreak. The Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were used to assess depression and anxiety among the study participants. Logistic regression analysis was used to identify predictors of depression and anxiety. The prevalence of depression and anxiety among the entire study participants was 23.8% and 13.1%, respectively. Anxiety was most prevalent across university students 21.5%, followed by healthcare professionals 11.3%, and general population 8.8%. Females among healthcare professionals and university students, divorced healthcare professionals, pulmonologists, and university students with history of chronic disease were at higher risk of developing depression. Females, divorced participants among the general population, and university students with history of chronic disease and those with high income (≥1,500 JD) were at higher risk of developing anxiety. During outbreaks, individuals are put under extreme stressful condition resulting in higher risk of developing anxiety and depression particularly for students and healthcare professionals. Policymakers and mental healthcare providers are advised to provide further mental support to these vulnerable groups during this pandemic.


Atypical lipomatous tumor/well-differentiated liposarcoma: what is it?
Liposarcoma (LPS) is the most common soft tissue sarcoma, frequently found in the thigh and retroperitoneum. LPS is commonly classified into well-differentiated LPS and dedifferentiated LPS. Histologic subtype, tumor location, and completeness of surgical resection are important prognostic indicators for LPS. Magnetic resonance imaging best characterizes extremity lesions, whereas computed tomography is most often used for intra-abdominal and retroperitoneal tumors. Surgical resection is the mainstay of treatment. Adjuvant radiation is considered for close margins. Survival for extremity tumors is favorable. However, difficulty in obtaining wide margins in the retroperitoneum predisposes to local recurrence and, ultimately, death from unresectable disease.


Cryoablation is associated with shorter length of stay and reduced opioid use in pectus excavatum repair.
The use of intercostal nerve cryoablation (INC) is becoming increasingly common in patients undergoing pectus excavatum (PE) repair. This study sought to evaluate the use of INC compared to traditional use of thoracic epidural (TE). A retrospective review of 79 patients undergoing PE repair with either INC or TE from May 2009 to December 2019 was conducted. The operations were performed by four surgeons who worked together at four different hospitals and have the same standardized practice. The primary outcome measure was hospital length of stay (LOS). Secondary variables included surgical time, total operating room time, operating room time cost, total hospital cost, inpatient opioid use, long-term opioid use after discharge, and postoperative complications. LOS decreased to 2.5 days in the INC group compared to 5 days in the TE group (p < 0.0001). Surgical time was increased in the INC group, but there was no difference in total OR time. The INC group experienced significantly lower hospital costs. Total hospital opioid administration was significantly lower in INC group, and there was a significant decrease in long-term opioid use in the INC group. INC is a newer modality that decreases LOS, controls pain, and results in overall cost savings. We recommend that INC be included in the current practice for postoperative pain control in PE patients undergoing Nuss procedure.


Insight updating of the molecular hallmarks in ovarian carcinoma.
Ovarian cancer (OC) is the deadliest gynaecologic cancer characterised by a high heterogeneity not only at the clinical point of view but also at the molecular level. This review focuses on the new insights about the OC molecular classification. We performed a bibliographic search for different indexed articles focused on the new molecular classification of OC. All of them have been published in PubMed and included information about the most frequent molecular alterations in OC confirmed by omics approaches. In addition, we have extracted information about the role of liquid biopsy in the OC diagnosis and prognosis. New molecular insights into OC have allowed novel clinical entities to be defined. Among OC, high-grade serous ovarian carcinoma (HGSOC) which is the most common OC is characterised by omics approaches, mutations in TP53 and in other genes involved in the homologous recombination repair, especially BRCA1/2. Recent studies in HGSOC have allowed a new molecular classification in subgroups according to their mutational, transcriptional, methylation and copy number variation signatures with a real impact in the characterisation of new therapeutic targets for OC to be defined. Furthermore, despite the intrinsic intra-tumour heterogeneity, the advances in next generation sequencing (NGS) analyses of ascetic liquid from OC have opened new ways for its characterisation and treatment. The advances in genomic approaches have been used for the identification of new molecular profiling techniques which define OC subgroups and has supposed advances in the diagnosis and in the personalised treatment of OC.


Diaphragmatic pacing in infants: techniques and results.
Phrenic nerve pacing was employed in 8 infants with central hypoventilation syndrome. Their ages ranged from 2.5 to 8.5 months. Preoperative diagnosis was established by demonstrating inadequate ventilatory response to hypercapnia and hypoxia. Percutaneous measurements of phrenic nerve conduction time and diaphragmatic action potentials were performed prior to operation to assess the feasibility of diaphragmatic pacing. A single anterolateral thoracotomy incision was used for both electrode placement in the chest and receiver implantation in the flank. The stimulating electrode was inserted around a segment of intrathoracic phrenic nerve isolated with pleura and perineural blood supply. Follow-up is available on all patients six months to 8 years postoperatively. There were no complications or deaths related to the procedure. In all patients, bilateral phrenic nerve stimulation allowed either marked decrease in or discontinuation of positive-pressure ventilation. Phrenic nerve pacing can be performed safely in infants. It provides an effective alternative method for ventilatory support without the drawbacks of positive-pressure ventilation.


Microplastic pollution in the surface waters of Vava'u, Tonga.
Marine plastic pollution, particularly microplastics, has been recognised as a global issue in the recent years, but research efforts in the Pacific are lagging. We carried out research on microplastics contamination of surface waters of the Vava'u archipelago, Tonga. Since microplastics smaller than the standard mesh size (333-335 μm) are readily reported in the literature on microplastics, we used a finer plankton net (100 μm) to determine the proportion of captured microplastics smaller than 300 μm. Isolated microplastics were counted and measured using stereomicroscope with polymer identification performed by FTIR spectroscopy. The analysis revealed high microplastics concentrations (329,299.7 ± 40,994.2 pcs km-2 or 1.05 ± 0.13 pcs m-3). The proportion of particles smaller than 300 μm was 40 %. The predominant type of microplastics in surface waters were small bits of white film, which we associated with cement-filled white bags used to construct docks throughout Vava'u, often heavily eroded.


Detection of intraventricular hemorrhage (IVH) by transcephalic impedance (TCZ) in premature infants.
Transcephalic impedance was measured serially in 45 preterm infants less than 1500 g birth weight in order to test the method for the early detection of intraventricular hemorrhage. TCZ increased in all seventeen (38%) infants who developed IVH diagnosed by CT-scan or autopsy. Five of 8 infants monitored 4-8 weeks following confirmed IVH developed hydrocephalus documented by repeat CT-scans; all 5 were discovered early by the TCZ-method 2-3 weeks before physical findings or an increasing head circumference indicated the possibility of hydrocephalus. TCZ appears to be a useful non-invasive clinical guide to the occurrence and course of IVH in the newborn.


Termination of early gestation with 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2.
Vaginal suppositories containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 were administered to 40 subjects in an attempt to induce an early abortion. All subjects were 49 days or less from their last menstrual period. Ten subjects (Group A) received the 75-mg suppository followed in 6 hours by a 30-mg suppository, ten subjects (Group B) received the 30-mg suppository followed in 2 hours by the 75-mg suppository and twenty subjects (Group C) received a 30-mg suppository followed in 3 hours by a second 30-mg suppository and in three more hours, at the discretion of the principal investigator, they could receive a third 30-mg suppository. Twenty-seven subjects (68%) had a successful termination of their pregnancy using the multiple vaginal prostaglandin suppository regimens. Seven subjects from Group A, 6 subjects from Group B, and 14 subjects from Group C successfully aborted. One subject in Group B and one subject in Group C were lost to follow-up and the remaining 11 subjects (28%) failed to abort. Twenty-six subjects reported side effects which included nausea, emesis, diarrhea, and uterine cramping requiring analgesia. Thirty-four subjects experienced hyperpyrexia of 99.6 degrees or greater and 12 subjects had their body temperature reach 101 degrees or higher. The use of vaginal suppositories containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 did not significantly increase the overall abortifacient efficacy of this method from the 60% rate we previously observed with (15S)-15-methyl-prostaglandin F2 alpha methyl ester suppositories.


On-line monitoring of Aspergillus niger GH1 growth in a bioprocess for the production of ellagic acid and ellagitannase by solid-state fermentation.
The present work describes the monitoring of CO2 production by Aspergillus niger GH1 in a bioprocess for the production of ellagitannase (EAH) and ellagic acid by solid state fermentation. Pomegranate ellagitannins, mainly punicalagin, were used as carbon source and EAH inducer. A second condition, using ellagitannins and maltose as growth promoting carbon source, was tested. The ellagic acid production was quantified and the EAH activity was assayed. The accumulated metabolites were identified by HPLC-ESI-MS/MS. Higher CO2 production (7.79mg/grams of dry material) was reached in media supplemented with maltose. Short-time lag phase (7.79h) and exponential phase (10.42h) were obtained using only ellagitannins, despite its lower CO2 production (3.79mg/grams of dry material). Without the use of maltose lower ellagic acid (11.85mg/L/h) and EAH (21.80U/L/h) productivities were reached. The use of maltose enhances the productivity of EA (33.18mg/L/h) and EAH (33.70U/L/h). Besides of punicalin and ellagic acid, two unknown compounds with mass weight of 702 and 290g/mol (ions 701 and 289m/z in negative mode, respectively) were identified and characterized by HPLC-ESI-MS/MS analysis.


Neurogenic and vascular claudication.
Intermittent claudication from peripheral vascular disease is sometimes difficult to distinguish from similar claudication due to degenerative disease of the lumbar spine. In the present study 26 patients with vascular disease were compared with 23 patients with lumbar degenerative disease. Assessment was by clinical and radiological examination. In the vascular group characteristic distinguishing features were: abnormal foot pulses, arterial bruits, relief of symptoms by standing, a constant claudicating distance and stocking sensory loss. In the lumbar group typical findings were: discomfort on lifting, bending, coughing or sneezing, pain on standing, history of back injury, variable claudicating distance and segmental sensory loss.


Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3.
Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically. We developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.SIRT3-myc [adeno-associated virus expressing myc-tagged SIRT3], which has previously been shown to have disease modifying effects in animal models of Parkinson's disease (PD). The lipid shells of the perfluorocarbon gas MDCs were covalently conjugated to antibodies with binding specificity to AAVs. Following systemic (iv) delivery of AAV.SIRT3-myc MDCs, MR-g-FUS was used to deliver SIRT3-myc to brain regions affected in PD. SIRT3-myc expression was determined post mortem, using immunohistochemistry. An in vitro, SH-SY5Y cell culture model was used to show that the localized destruction of MDCs using ultrasound exposures within biological safety limits dissociated AAV2-GFP (green fluorescent protein) from the MDCs in the targeted area while maintaining their transduction capacity. In rats, MR-g-FUS resulted in BBB permeabilization in the striatum and substantia nigra (SNc). SIRT3-myc was expressed in the striatum, but not the SNc. These studies demonstrate that MDCs combined with MR-g-FUS are an effective method for delivery of viral vector gene therapies, such as AAV.SIRT3, to brain regions affected in PD. This technology may prove useful as a disease-modifying strategy in PD and other neurodegenerative disorders.


Rectally administered diclofenac (Voltaren) reduces vomiting compared with opioid (morphine) after strabismus surgery in children.
Nausea, vomiting and pain are common complications after strabismus surgery in children. Diclofenac, a non-steroid anti-inflammatory drug, is widely used to treat acute and chronic pain but there are few reports of its use given rectally in children undergoing strabismus surgery. This open randomised study was designed to investigate the analgesic and anti-emetic properties of rectally administered diclofenac compared with opioid (morphine) given i.v. in connection with strabismus surgery in children. After obtaining approval from the local ethics committee and written informed consent from the parents, 50 ASA class I-II children, 4-16 years of age, were randomised to receive either rectally administered diclofenac (Voltaren) 1 mg/kg or i.v. opioid (morphine) 0.05 mg/kg perioperatively. The children were consecutively operated upon from May 1999 to January 2001. Anaesthesia was induced with fentanyl and propofol and maintained with propofol. Nitrous oxide was omitted. The postoperative pain was assessed after arrival at the post anaesthesia care unit (PACU) by using the validated Wong and Baker scale (FACES) Pain Rating Scale. Postoperative nausea and vomiting (PONV) was assessed by measuring the frequency of vomiting and the degree of nausea. In the diclofenac group the incidence of PONV during the first 24 h was 12% (of which one child had severe vomiting). The incidence of PONV was much higher, 72% (P = 0.0000), in the morphine group, where 56% of the children also had severe vomiting. There were no difference in pain score between the two groups. Recovery time at the PACU was longer (P < 0.002) and the postoperative analgesic requirement higher in the morphine group (10 vs. 5 children). No children needed overnight admission to the hospital. Diclofenac given rectally is an effective analgesic for this kind of surgery and gives less postoperative nausea than i.v. morphine. No serious adverse events were observed.


[Implications of nicotine detected in autopsy cases of newborn babies and infants from the perspective of social medicine].
Smoking by pregnant and parturient women is generally suspected to increase nicotine levels in fetal and infant blood. Supportive data of nicotine levels in infants is, however, inadequate. We investigated blood and muscle nicotine and cotinine levels in 14 autopsy cases of newborn babies and infants using gas chromatography. Among the 14 cases investigated, nicotine or cotinine was detected in six cases (42.9%). In each of these six cases, the mother was a smoker. Route of exposure to nicotine originating from smoking was transplacental in three cases, via breast milk in one case and secondhand smoke in two cases. Nicotine and cotinine levels in blood from the two cases with placental exposure were 10.6-84.4 ng/ml and 20.3-183 ng/ml, and levels in muscle from one case were 43.9 ng/g and 308 ng/g, respectively. Nicotine and cotinine levels in blood from exposure via breast milk were 19.1 ng/ml and 87.1 ng/ml, and from secondhand smoke were 0 ng/ml and 14.6-20.1 ng/ml. Mean concentrations of blood nicotine and cotinine in 68 autopsy cases of adult habitual smokers were 30.0 ng/ml and 247 ng/ml. Our data for nicotine and cotinine levels in infant blood seem to indicate that some infants who are born and develop under exposure to smoking by family members, particularly the mother, may show high nicotine levels in blood and experience possible health risks.


H-reflexes are less depressed following muscle stretch in spastic spinal cord injured patients than in healthy subjects.
The size of the soleus H-reflex was measured after a slow (17 deg/s) passive stretch of ankle plantarflexors and compared to its control size without muscle stretch in ten neurologically healthy subjects and in six spastic spinal-cord-injured patients. Two seconds after the end of the stretch, the size of the H-reflex was reduced to about 30% of its pre-stretch size in the healthy subjects. The depression remained for 10-15 s. In the spastic, spinal-cord-injured patients, stretch caused significantly less reduction in the size of the H-reflex. The H-reflex also regained its pre-stretch size much faster than in healthy subjects. We suggest that the smaller depression of the H-reflex observed in spastic patients may be involved in the pathophysiology of spasticity.


Treatment of the primary tooth: an online study guide.
The Editorial Board of the Journal of Endodontics has developed a literature-based study guide of topical areas related to endodontics. This study guide is intended to give the reader a focused review of the essential endodontic literature and does not cite all possible articles related to each topic. Although citing all articles would be comprehensive, it would defeat the idea of a study guide. The topics presented in this section are formocresol pulpotomy, electrosurgical pulpotomy, and pulpectomy in primary teeth.


Guide-lines in the design of new antiestrogens and cytotoxic-linked estrogens for the treatment of breast cancer.
Antiestrogens (Tamoxifen) are used for the treatment of breast cancer. However these compounds are also weak estrogens that may stimulate tumor growth. Cytotoxic-linked estrogens (Estradiol Mustard, Estracyt) are devoid of major therapeutic activity. This led to search for new antiestrogens devoid of estrogenicity and for active cytotoxic-estrogens. Hydroxylation of C-4 of triphenylethylene antiestrogens (tamoxifen, CI 628 and U 23,469) largely increases their binding affinity for the estrogen receptor (ER). Hydroxylation also increases the in vitro antitumor activity of the drugs as shown by their higher ability to inhibit the growth of the ER-positive cell line MCF-7. Triphenylethylene antiestrogens contain an aminoethoxy side chain which appears essential for their physiological activity. Removal of the chain of tamoxifen suppresses its antiestrogenicity and antitumor activity. The grafting of side chains on a weak estrogen of the gem-diphenylethylene category produces "symmetrical" antiestrogens devoid of estrogenic activity. This observation raises the question of the role played by the third phenyl ring of the triphenylethylenes since the trans-isomers of the latter display antiestrogenicity and the cis-isomers estrogenicity. Comparison of the binding affinity for ER and antitumor activity of di- and triphenylethylene antiestrogens suggests that this third phenyl ring increases the interaction with ER of the 4-phenolic group of the drugs and/or their aminoethoxy side chain. An analogue of this chain is without any biological activity suggesting that the di-(tri)pheny-lalkene structure is required for promoting the interaction of the chain with ER. New chemical structures yielding antiestrogens with antitumor activity are also reviewed. New cytotoxic estrogens designed for producing lethal damage of DNA show a low binding affinity for ER. Moreover, there is no evidence suggesting specific antitumor activity. Such activity may be more easily obtained with estrogens bearing reagents for proteins rather than DNA. The biological properties of a 2-mesylate derivative of estrone irreversibly interacting with ER supports the concept. On MCF-7 cells, the drug displays a strong antitumor activity which can only be suppressed by high, equimolar, concentrations of estradiol. It is devoid of cytotoxic activity on the ER-negative cell line Evsa-T suggesting that ER is involved in its action.


Getting under the skin of epidermal morphogenesis.
At the surface of the skin, the epidermis serves as the armour for the body. Scientists are now closer than ever to understanding how the epidermis accomplishes this extraordinary feat, and is able to survive and replenish itself under the harshest conditions that face any tissue. By combining genetic engineering with cell-biological studies and with human genome data analyses, skin biologists are discovering the mechanisms that underlie the development and differentiation of the epidermis and hair follicles of the skin. This explosion of knowledge paves the way for new discoveries into the genetic bases of human skin disorders and for developing new therapeutics.


Confirmation of Gelsemium elegans poisoning by UHPLC-MS/MS analysis of koumine, gelsemine, and gelsenicine in hair.
A sensitive, accurate, simple, and rapid analytical UHPLC-MS/MS method was developed for identification and quantification of koumine, gelsemine, and gelsenicine in human hair. Approximately 10 mg of hair was extracted with methanol by cryogenic grinding. The limits of detection (LODs) ranged from 1 to 5 pg/mg, and the limits of quantitation (LOQs) ranged from 2 to 10 pg/mg. The method was linear over a concentration range from the LOQs to 1000 pg/mg, and the linear correlation (R2) of the calibration curves was above 0.998 for all three analytes. The bias varied from -6.5-13.1%, while the intra- and inter-day precision relative standard deviation (RSD) values were 4.3-12.4% and 3.7-13.2%, respectively. Recoveries ranged from 79.3% to 103.5%, and matrix effects ranged from 74.3% to 105.5%. The described method was used for the quantitative determination of koumine, gelsemine, and gelsenicine in a human hair sample from a Gelsemium elegans poisoning case. The highest concentrations of koumine, gelsemine, and gelsenicine were 27.2, 18.1, and 4.2 pg/mg, respectively, and corresponded to the segment associated with the ingestion period. To our knowledge, this is the first study to describe hair analysis in a G. elegans poisoning case and to provide quantitative toxicological findings.


Strategy for elucidating differentially expressed genes in leiomyomata identified by microarray technology.
cDNA microarray technology identifies genes that are differentially expressed between tissues. Our previous study identified several genes that might contribute to the fibroid phenotype. We therefore sought to confirm genes involved in three distinct signal transduction pathways. Evaluation of differential mRNA and protein expression of Dlk, Frizzled-2, and CD-24 in fibroids compared with adjacent myometrium. University hospital. Five women undergoing medically indicated hysterectomy for symptomatic fibroids. Microarray analysis of up to 33000 genes, reverse transcriptase-polymerase chain reaction (RT-PCR), real-time RT-PCR, Western blot, and immunohistochemistry. Expression of mRNA transcripts and protein in fibroid compared with myometrium.A more extensive microarray confirmed differential expression of Frizzled-2 and CD-24 but did not confirm Dlk overexpression. RT-PCR and real-time PCR demonstrated equivalent Dlk mRNA expression between fibroid and myometrium (ratio, 1.02), a slight Frizzled-2 overexpression (ratio, 2.09), and robust CD-24 overexpression in fibroids (ratio, 12.35). Western blot and immunohistochemistry confirmed Frizzled-2 overexpression, but did not confirm Dlk overexpression. Microarray technology is the first phase of tissue evaluation, but changes in gene expression must be confirmed. Confirmed genes can then be used to generate hypotheses testing their involvement in fibroid development.


Switch Pocket Kinase: An Emerging Therapeutic Target for the Design of Anticancer Agents.
Protein kinases are amongst the most focused enzymes in the current century to design, synthesize and formulate drugs that ought to be effective in the treatment of various disordered and diseased states involving either overexpression or deficiency situations. The ATP pocket on the kinases is the active binding site for most of the kinase inhibitors. However, the kinase mutations prevent the binding of kinase inhibitors to the ATP pocket. The enzyme becomes inactive even in the mutated state when the switch pocket site on the enzyme is occupied by switch pocket inhibitors. This review comprises detailed information regarding various classical protein kinases and switch pocket kinase inhibitors with their mechanism of action so that new molecules can be designed to encounter mutations in the kinase enzyme.


Is central venous access in childhood osteomyelitis associated with increased morbidity?
Children with osteomyelitis need treatment with intravenous antibiotics for protracted periods. An implanted central venous line (CVL) is a good method to deliver this treatment. Between 1992 and 1996, 17 patients with osteomyelitis had 20 surgically inserted Hickmann-type CVLs. The outcome of these lines was studied. Patients ranged from 1 month to 14 years of age and the duration of use of the CVL ranged from 6 to 180 days. One CVL was removed because of line sepsis and 1 was removed because of exit-site infection. We conclude that surgically inserted Hickmann-type CVLs in children with a pre-existing focus of infection in the form of osteomyelitis did not result in increased morbidity in terms of line sepsis, and served the purpose of prolonged administration of antibiotics very well.


Ventilation, thermal noise, and errors in cardiac output measurements after cardiopulmonary bypass.
The authors observed transient increases in the amplitude of respiratory variations in pulmonary artery blood temperature in many patients after cardiopulmonary bypass (CPB). This increased "thermal noise" may significantly influence measurements of thermodilution cardiac outputs (TDCO) performed during this time. The authors recorded the peak-to-peak amplitude of respiratory variations in pulmonary artery blood temperature in 15 patients during the first 35 min after CPB. Possible relationships between the amplitude of these variations and the magnitude of temperature differences between commonly monitored body temperature sites (nasopharyngeal, rectal, bladder, and pulmonary artery) were also examined. In ten additional patients, the authors investigated the influence of these increased respiratory variations on TDCO measurements by correlating the maximum variation in three successive TDCO measurements with the peak-to-peak amplitude of the respiratory variations in pulmonary artery blood temperature. Potential error in TDCO measurements caused by these increased respiratory variations in pulmonary artery blood temperature were also examined using model calculations of the effects of respiratory variations in pulmonary artery blood temperature on measured TDCO thermal areas. In the first 15 patients, the mean amplitude of respiratory variations in pulmonary artery blood temperature after CPB (mean +/- SEM) were: (1) within 5 min after CPB, 0.037 +/- 0.004 degrees C; (2) 10 min after #1, 0.025 +/- 0.003 degrees C; (3) 20 min after #1, 0.019 +/- 0.003 degrees C; and (4) 30 min after #1, 0.012 +/- 0.002 degrees C. There were no significant correlations between the magnitude of the respiratory variation in pulmonary artery blood temperature and the observed temperature differences between body sites. Four patients had pulmonary artery blood temperature variations in excess of the maximum amplitude previously reported in man (0.05 degrees C). In the next ten patients, the maximum variation between three successive TDCO measurements taken at specified times in the respiratory cycle (end inspiration, end exhalation, and 3 s after end exhalation) was significantly correlated with the amplitude of respiratory variations in pulmonary artery blood temperature (r = 0.83, P < 0.001). Four patients with increased respiratory variations in pulmonary artery blood temperature had variations in TDCO measurements exceeding 2 l/min. Subsequent model calculations demonstrated that the magnitude of potential error in TDCO measurements is dependent on both the amplitude of the respiratory variations in pulmonary artery blood temperature and the baseline cardiac output. On the basis of these thermal area calculations, potential errors of 15-50% could be caused by respiratory variations in pulmonary artery blood temperature > 0.05 degrees C. The authors concluded that respiratory variations in pulmonary artery blood temperature are transiently increased in many patients after CPB, and that this increased "thermal noise" may cause significant errors in TDCO measurements.


Design, synthesis and drug resistance reversal potential of novel curcumin mimics Van D: Synergy potential of curcumin mimics.
Being crucial part of plant-based novel discovery of drug from natural resources, a study was done to explore the antibacterial potential of curcumin mimics in combination with antibiotics against multidrug resistant isolates of Pseudomonas aeruginosa. The best candidate Van D, a curcumin mimics reduced the MIC of tetracycline (TET) up to 16 folds against multidrug resistant clinical isolates. VanD further inhibited the efflux pumps as evident by ethidium bromide efflux and by in-silico docking studies. In another experiment, it was also found that Van D inhibits biofilm synthesis. This derivative kills the KG-P2, an isolate of P. aeruginosa in a time dependent manner, the post-antibiotic effect (PAE) of tetracycline was extended as well as mutant prevention concentration (MPC) of TET was also decreased. In Swiss albino mice, Van D reduced the proinflammatory cytokines concentration. In acute oral toxicity study, this derivative was well tolerated and found to be safe up to 1000 mg/kg dose. To the best of our knowledge, this is the first report on curcumin mimics as synergistic agent via inhibition of efflux pump.


Adoptive immunotherapy and radiotherapy in the treatment of urinary bladder cancer.
Thirty-one patients with invasive transitional cell carcinoma of the urinary bladder were treated either by infusion of tumour immune pig mesenteric lymph node cells into the tumour blood supply, followed 6 weeks later by 5500 rad, or by radiotherapy alone. The patients were paired prior to treatment, using 4 criteria: age (nearest decade), sex, clinical stage (T3 or T4) and histological grade (average or high). The first patient in each pair then received combined treatment and the second radiotherapy alone. Administration of pig cells before radiotherapy offered no advantage to the patient in terms of the incidence of remission or the length of survival after treatment.


Influence of soil drying on root development, water relations and leaf growth of Ceratonia siliqua L.
Seedlings of Ceratonia siliqua L., an evergreen sclerophyll species native to the Mediterranean region, were grown in 30-cm deep tubes of John Innes II potting compost in a growth cabinet maintained at 15° C during a 12-h day where PAR was 400 μmol m-2 s-1. After a period of acclimatisation to the conditions in the cabinet during which plants were watered every day, water was withheld from the soil in some tubes for 24 days. These conditions may be regarded as a simulation of the natural situation. Estimates of leaf and root water potential and solute potential, leaf growth and root development were made at intervals during the soil drying cycle on both watered and unwatered plants. Water potential and solute potential measurements were made both on young expanding and on fully expanded leaves. During the experimental period, root growth of C. siliqua was not much affected by soil drying, and roots in both the watered and the unwatered columns penetrated to the bottom of the soil tubes by the end of the drying treatment. Expanded leaves showed significant limitation in stomatal conductance as soil drying progressed. Leaf water potential of fully expanded leaves of unwatered plants declined substantially. In contrast, water potential of young expanding leaves on unwatered plants declined to only a limited extent and turgor was sustained. As the soil dried, stomatal conductance of young leaves was always higher than that of mature leaves; also, placticity and elasticity of young leaves slowly decreased whereas mature leaves became stiff. Changing leaf cell wall properties may determine different patterns of water use as the leaves age. A mechanism of continuous diffusion of water through the soil towards the tip and pumping towards the young leaves is proposed.


Recovery of hypothalamic-pituitary-gonadal function with low dose testosterone treatment in a male with congenital hypogonadotropic hypogonadism.
Congenital hypogonadotropic hypogonadism (CHH) is a rare disease caused by deficiency or action of gonadotropin-releasing hormone. While generally considered a long-life condition, CHH can be reversible in about 5%-20% of cases, but mechanisms of reversibility are unknown. We report the case of a male with CHH who began treatment with low dose (20 mg/day) transdermal testosterone to induce pubertal development at age 17. Following the start of treatment, he experienced testicular growth and his serum testosterone concentrations increased beyond the expectations in relation to the dose. Treatment was withdrawn, but this led to the reappearance of symptoms of hypogonadism and a drop in testosterone levels. Testosterone was again prescribed at the same dose and, for the subsequent years, he completed full puberty, including attainment of 20 cc testicular volume, mature secondary sexual characteristics, normal levels of testosterone and only partially arrested germinal function, as demonstrated by inhibin B levels and spermogram. Testosterone treatment was withdrawn three more times, but hypogonadism resumed on each occasion. This case suggests that low-dose testosterone treatment can induce reversal of CHH through the activation, albeit non-permanent, of the hypothalamic-pituitary-gonadal axis, indicating that testosterone administration might be a reliable therapeutic option for reverting GnRH deficiency.


Met and unmet care needs of home-living people with dementia in China: An observational study using the Camberwell Assessment of Need for the Elderly.
The goal of the study was to investigate the patterns of needs in older individuals with mild-to-moderate dementia living at home using the Camberwell Assessment of Need for the Elderly questionnaire. This was a cross-sectional study. A total of 378 home-living residents served as the sample. The Camberwell Assessment of Need for the Elderly questionnaire was used to analyze the needs of those receiving adequate interventions (met needs) and those without appropriate supports (unmet needs). Thereafter, the factors that correlated with total needs were determined using demographic characteristics. Persons with dementia (PWD) had a mean care needs of 18.5 ± 5.4 (range 5-35). Unmet needs were most common in caring for someone (65.1%), looking after the home (63.5%), self-care (58.7%) and intimate relationships (44.4%) domains. Higher needs were significantly related to living with others than a spouse, longer length of diagnosis, older age and higher cognitive function. Unmet needs are common in home-living PWD. Home-based dementia care can identify and address PWD's unmet needs by focusing on care recipients and caregivers to enable PWD to remain safely at home and improve their quality of life. Geriatr Gerontol Int 2021; 21: 102-107.


The Diagnostic Utility of Serum Metal Ion Markers for High-Grade Aseptic Lymphocyte-Dominated Vasculitis-Associated Lesions (ALVALs) in Revision Hip and Knee Arthroplasty: An International Multicenter Study.
Aseptic lymphocyte-dominated vasculitis-associated lesions (ALVALs) are typically described in the context of metal-on-metal (MoM) hip bearings. This study explores the diagnostic utility of preoperative serum cobalt and chromium ion levels in determining the histological grade of ALVAL in revision hip and knee arthroplasty. This was a multicenter retrospective review of 26 hips and 13 knees assessing the correlation between preoperative ion levels (mg/L (ppb)) and the histological grade of ALVAL from intraoperative specimens. The diagnostic ability of preoperative serum cobalt and chromium levels to determine high-grade ALVAL was assessed using a receiver operating characteristic (ROC) curve. In the knee cohort, there was a higher serum cobalt level in high-grade ALVAL cases (10.2 mg/L (ppb) versus 3.1 mg/L (ppb)) (P = .0002). The Area Under the Curve (AUC) was 1.00 (95% confidence interval (CI) 1.00 to 1.00). There was a higher serum chromium level in high-grade ALVAL cases (12.25 mg/L (ppb) versus 7.77 mg/L (ppb)) (P = .0002). The AUC was 0.806 (95% CI 0.555 to 1.00). In the hip cohort, there was a higher serum cobalt level in high-grade ALVAL cases (333.5 mg/L (ppb) versus 119.9 mg/L (ppb)) (P = .0831). The AUC was 0.619 (95% CI 0.388 to 0.849). There was a higher serum chromium level in high-grade ALVAL cases (186.4 mg/L (ppb) versus 79.3 mg/L (ppb)) (P = .183). The AUC was 0.595 (95% CI 0.365 to 0.824). Histologically, high-grade ALVAL has significantly higher preoperative serum cobalt and chromium ion levels in revision TKA. Preoperative serum ion levels have excellent diagnostic utility in revision TKA. Cobalt levels in revision THA have a fair diagnostic ability and chromium levels had a poor diagnostic ability.


Right ureteral injury after radiofrequency ablation for atrial fibrillation.
Percutaneous radiofrequency ablation is a common procedure to treat atrial fibrillation. We describe a patient without a urologic history who had immediate abdominal pain after this treatment. Computed tomography scan and cystoscopy/retrograde pyelography confirmed a right proximal ureteral injury with urinary extravasation. The patient was treated with right ureteral stent placement and urethral catheter drainage. This case appears to be the first report of percutaneous radiofrequency ablation complicated by spontaneous ureteral injury related to blunt injury during manipulation of the transseptal sheaths or intracardiac catheters.


The Australian community overwhelmingly approves IVF to treat subfertility, with increasing support over three decades.
Fifteen Australia-wide interview surveys between July 1981 and February 2011 on the community's attitudes to in vitro fertilisation (IVF) were carried out as part of regular Morgan polls. Each survey involved between 650 and 1000 respondents in urban and rural locations. The proportion of respondents who 'approved' or 'disapproved' of various aspects of IVF treatment were determined. Support for IVF to help infertile married couples increased from 77% in 1981 to 91% in 2011. Approval for IVF procedures being supported by Medicare funding rose from 70% in 1981 to 79% in 2000 and was unchanged in 2011. There has also been a marked increase in the support for single women and lesbians using donor sperm.


Ozone treatment inactivates common bacteria and fungi associated with selected crop seeds and ornamental bulbs.
The use of disease-free seeds or bulbs is very crucial to ensure sustainable and profitable agricultural production. Seed-borne pathogens which are responsible for significant yield losses in various crops need to be successfully eliminated with appropriate seed treatments. In this study, we investigated the efficacy of gaseous ozone (O3) and ozonated water treatments on the inactivation of seed-borne fungal and bacterial pathogens of widely cultivated vegetable and cereal seeds, and ornamental bulbs. We demonstrated that O3 application to tomato and cucumber seeds inactivates Fusarium oxysporum f. sp. lycopersici, Fusarium oxysporum f. sp. radicis-lycopersici, Clavibacter michiganensis subsp. michiganensis, Pseuodomonas syringae pv. tomato, and Pseudomonas syringae pv. lachrymans, respectively, with no negative effect on seed germination rate. The sterilization capacity of O3 has substantially increased when the seeds were soaked in water before the treatments. The saprophytic fungal load and the infection rate of Pectobacterium carotovorum subsp. carotovorum on several species and cultivars of ornamental bulbs were suppressed by O3 treatment. A strong decrease in the infection rate of Tilletia caries was also shown in O3-treated wheat seeds under field conditions. Overall, the current study indicated that O3 treatment has great potential in ensuring the use of disease-free seeds or other propagation materials, which is indispensable at the beginning of crop production.


Unusual fatty acid isomers of triacylglycerols and polar lipids in female limpet gonads of Cellana grata.
To investigate the occurrence of positional isomers of unsaturated fatty acids (FA) in triacylglycerols (TAG) and polar lipids (PL) in the female gonads of a dominant limpet, Cellana grata, fatty acid methyl esters (FAME) were fractionated according to the degree of their unsaturation by argentation thin-layer chromatography. Their structures were elucidated by gas chromatography-mass spectrometry of a combination of their FAME and picolinyl esters. A total of 125 different FA ranging from 12 to 24 carbon atoms were identified, and 105 unsaturated FA, including 34 nonmethylene-interrupted FA as minor components, were recognized. Although the major FA 16:0 and 18:1n-7, which accounted for more than 20 and 10%, respectively, of total FA, were present in TAG and PL, higher amounts of 20:4n-6 and 20:5n-3 were present in PL. Unsaturated FA consisting of more than five different positional isomers were 17:1, 19:1, 18:2, 19:2, 20:2, 21:2, 22:2, 20:3, and 22:3, most of which were present in TAG. Furthermore, a larger variety of nonmethylene-interrupted FA was found in TAG than in PL. This limpet gonad had a diverse assortment of unsaturated FA that comprised a wide range of unusual positional isomers with one to five double bonds.


Interactions between cell death induced by statins and 7-ketocholesterol in rabbit aorta smooth muscle cells.
7-Ketocholesterol, an oxysterol present in atherosclerotic lesions, induces smooth muscle cell (SMC) death, thereby destabilizing plaques. Statins protect patients from myocardial infarction, though they induce SMC apoptosis. We investigated whether statins and 7-ketocholesterol exerted additive cell death effects. Cultured rabbit aorta SMCs (passage 2-6) were exposed to 7-ketocholesterol with or without fluvastatin, simvastatin or pravastatin. Uptake of neutral red (NR), monolayer protein, cleavage of the pan-caspase substrate Asp-Glu-Val-Asp-rhodamine110, cell morphology (light and electron microscopy) and processing of microtubule-associated protein 1 light chain 3 (LC3, immunoblot) were determined. NR uptake declined upon 18 h exposure to 25 microM 7-ketocholesterol (-41+/-3%, n=13), 100 microM fluvastatin (-59%) or 30-100 microM simvastatin (-28 to -74%). Oxysterol and high statin concentrations exerted additive effects, but lower concentrations (fluvastatin 10-30 microM, simvastatin 1-10 microM) partly reversed viability loss. 7-Ketocholesterol caused intense cytoplasmic vacuolization, processing of LC3-I to LC3-II, but little caspase activation (increase 29.5%). Fluvastatin (10-100 microM, 70-545% increase) and simvastatin (3-100 microM 43-322% increase) induced caspase activation without LC3 processing, but failed to activate caspases in 7-ketocholesterol-treated SMCs. Pravastatin up to 100 microM was always inactive. 7-Ketocholesterol caused SMC death, mainly via autophagic vesicle formation with LC3 processing, whereas lipophilic statins evoked SMC apoptosis. Cell death following 7-ketocholesterol and low statin concentrations were not additive, presumably because the autophagic process interfered with statin-induced caspase activation. This further illustrates that drug effects in normal SMCs are not necessarily predictive for activities in atherosclerotic settings.


[Analysis of urinary stone composition by infrared spectroscopy in the population of the European part of Russia].
Urolithiasis is one of the most common urological diseases, which affect at least 3% of the population. To study the epidemiology of urolithiasis in the European part of the Russian Federation and to determine the composition of urinary stones in order to understand the pathogenetic mechanisms of urinary stones formation. Urinary stone were obtained from 2888 patients with urolithiasis and the composition of kidney stones was analyzed using the method of infrared spectroscopy. The predominance of oxalate stones was seen in kidney stones with mixed composition (83%) and the prevalence of uric acid stones (54%) was revealed in "pure" kidney stones. Urinary stones with a predominance of oxalates had significantly less impurities (12,4%) than stones with a predominance of uric acid, phosphates and carbonates with average amount of impurities more than 24%. Conslusion. The analysis of stone composition with a consideration of pathogenic factor showed that disorders of calcium metabolism in the population of the European part of the Russian Federation prevailed (88%).


[New techniques in the operative treatment of calcaneal fractures].
The ideal treatment of displaced intra-articular calcaneal fractures is still controversially discussed. Because of the variable fracture patterns and the vulnerable soft tissue coverage an individual treatment concept is advisable. In order to minimize wound edge necrosis associated with extended lateral approaches, selected fractures may be treated percutaneously or in a less invasive manner while controlling joint reduction via a sinus tarsi approach. Fixation in these cases is achieved with screws, intramedullary locking nails or modified plates that are slid in subcutaneously. A thorough knowledge of the three dimensional calcaneal anatomy and open reduction maneuvers is a prerequisite for good results with less invasive techniques. Early functional follow-up treatment aims at early rehabilitation independent of the kind of fixation. Peripheral fractures of the talus and calcaneus frequently result from subluxation and dislocation at the subtalar and Chopart joints. They are still regularly overlooked and result in painful arthritis if left untreated. If an exact anatomical reduction of these intra-articular fractures is impossible, resection of small fragments is indicated.


Thalidomide Inhibits Angiogenesis via Downregulation of VEGF and Angiopoietin-2 in Crohn's Disease.
Immune-mediated angiogenesis is important in the pathogenesis of inflammatory bowel disease and targeted treatment could alleviate the disease. Thalidomide is an effective drug in inflammatory bowel disease, which might be related to its multiple role in anti-inflammatory, immunoregulatory, and anti-angiogenesis. This study is to investigate the effect of thalidomide on angiogenesis in tissues from patients and in vitro cells. Angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), VEGF, and CD31 expressions in intestinal mucosa from pediatric CD patients before and after thalidomide treatment were measured by immunohistochemistry. Western blotting and polymerase chain reaction were performed to characterize the change of angiogenic factors before and after treatment in remission. Human umbilical vein endothelial cells (HUVECs) treated by thalidomide were used to examine its effect on endothelial cell proliferation and migration and capillary-like structures. Results showed that VEGF and Ang-2 levels were significantly greater in CD patients over controls. Thalidomide produced a significant reduction in protein expression of Ang-2 and VEGF, along with a decrease in mRNA expression of Ang-2. While, Ang-1 level did not show a statistically significant change. Thalidomide significantly inhibited cell proliferation in a dose-dependent manner. It also suppressed VEGF- and Ang-2-induced cell migration and capillary-like tube formation in HUVECs. Therefore, our study suggests that VEGF and Ang-2 levels are up-regulated in pediatric CD patients. It also indicated that thalidomide can be able to deactivate endothelium by the downregulation effect on angiogenic factors by targeting VEGF and Ang-2.


Somatotroph and corticotroph pituitary adenoma (double adenoma) in a cat with diabetes mellitus and hyperadrenocorticism.
A 9-year-old castrated male European shorthair cat with insulin-resistant diabetes was referred with the preliminary diagnosis of pituitary-dependent hyperadrenocorticism, based on measurements of urinary corticoids. Further studies revealed not only resistance of plasma concentrations of cortisol, adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) to suppression by a low dose of dexamethasone, but also elevated plasma concentrations of growth hormone (GH) and insulin-like growth factor I (IGF-I). Pituitary imaging with dynamic contrast-enhanced computed tomography demonstrated an enlarged pituitary gland and an adenoma. The cat underwent trans-sphenoidal hypophysectomy after which the insulin resistance disappeared. On histopathological and immunocytochemical examination of the surgical specimen a double adenoma was found, consisting of a corticotroph adenoma and a somatotroph adenoma separated by unaffected pituitary tissue.


The LGI1 protein: molecular structure, physiological functions and disruption-related seizures.
Leucine-rich, glioma inactivated 1 (LGI1) is a secreted glycoprotein, mainly expressed in the brain, and involved in central nervous system development and physiology. Mutations of LGI1 have been linked to autosomal dominant lateral temporal lobe epilepsy (ADLTE). Recently auto-antibodies against LGI1 have been described as the basis for an autoimmune encephalitis, associated with specific motor and limbic epileptic seizures. It is the second most common cause of autoimmune encephalitis. This review presents details on the molecular structure, expression and physiological functions of LGI1, and examines how their disruption underlies human pathologies. Knock-down of LGI1 in rodents reveals that this protein is necessary for normal brain development. In mature brains, LGI1 is associated with Kv1 channels and AMPA receptors, via domain-specific interaction with membrane anchoring proteins and contributes to regulation of the expression and function of these channels. Loss of function, due to mutations or autoantibodies, of this key protein in the control of neuronal activity is a common feature in the genesis of epileptic seizures in ADLTE and anti-LGI1 autoimmune encephalitis.


Diagnosis of myocardial contusion in blunt chest trauma.
Of 20 patients with blunt chest trauma who underwent cardiac scanning, serial electrocardiography and cardiac monitoring to rule out myocardial contusion, four had positive cardiac scans. All four had electrocardiographic abnormalities: three had nonspecific ST-T wave changes, and the fourth had electrocardiographic evidence of an acute subendocardial infarction. Of the 16 patients with negative scans, five had normal electrocardiograms. In the remaining 11 patients, factors other than myocardial contusion were suspected causes of electrocardiographic abnormalities. On the basis of this data, electrocardiogram changes in the traumatized patient have various causes. Cardiac scanning appears to be a useful adjunct to electrocardiography in confirming the presence of myocardial contusion.


Osnabrueck hand eczema severity index--a study of the interobserver reliability of a scoring system assessing skin diseases of the hands.
An easy-to-use standardized instrument is needed for the clinical assessment of the severity of occupational hand eczema by dermatologists as well as occupational physicians. The Osnabrueck hand eczema severity index (OHSI) was developed for this purpose and the interobserver reliability investigated. The clinical severity was evaluated on the basis of the extension or clinical characteristics of six morphological characteristics. For the validation of the OHSI, hand eczema in 28 patients was investigated independently by one dermatologist and 2 occupational physicians. The agreement between the observers was determined by using kappa values, Kendall's coefficient of concordance, the intraclass correlation coefficient (ICC) and the 95% limits of agreement. The ICC for the total OHSI was 0.80 and the estimated limits of agreement (-3.6 and 3.0) were sufficiently small to expect that ratings according to OHSI performed by independent observers of different medical specialities should produce similar results. It could be demonstrated that the use of the OHSI is simple and practicable. The interobserver reliability for the summary score is good. OHSI seems a reliable tool for assessing the severity of occupational hand eczema.


Magnetic resonance colonography in severe attacks of ulcerative colitis.
To evaluate the ability of MR colonography (MRC) to detect lesions in severe attacks of ulcerative colitis (UC) and to assess its concordance with rectosigmoidoscopy. Eighteen patients underwent MRC and rectosigmoidoscopy. MRC consisted of a water-filled colonic procedure followed by T1/T2w images. Image quality was recorded. Inflammatory lesions and the existence of signs of severity were analysed. We calculated MR accuracy in the diagnosis of inflammatory lesions, as well as per segment and per patient concordance depending on the presence or absence of severe lesions. The MR image quality of the 108 segments was satisfactory. Endoscopy was used to study 36 segments (rectum and sigmoid). MRC had a positive predictive value of 100% and a sensitivity of 64% in the diagnosis of inflammatory lesions. Concordance for the diagnosis of severe lesions was excellent for the rectum (k = 0.85) and good for the sigmoid (k = 0.64). MRC diagnosed signs of severity in all patients affected at endoscopy. MRC also disclosed signs of severity located higher in the colon in four patients with nonsevere lesions at rectosigmoidoscopy. MRC can accurately diagnose inflammatory lesions in severe attacks of UC and significantly correlates with rectosigmoidoscopy in the diagnosis of severe lesions.


Dynamics of membrane lipid domains in neuronal cells differentiated in culture.
Treatment with methyl-beta-cyclodextrin (MCD) induced a time- and dose-dependent efflux of cholesterol, sphingolipids, and phosphatidylcholine (PC) from cerebellar neurons differentiated in culture. With a "mild" treatment, the loss of cell lipids induced a deep reorganization of the remaining membrane lipids. In fact, the amount of PC associated with a Triton X-100-insoluble membrane fraction (highly enriched in sphingolipids and cholesterol in nontreated cells) was lowered by the treatment. This suggested a reduction of the lipid domain area. However, the cholesterol and sphingolipid enrichment of this fraction remained substantially unchanged, suggesting the existence of dynamic processes aimed at preserving the segregation of cholesterol and sphingolipids in membrane domains. Under these conditions, the lipid membrane domains retained the ability to sort signaling proteins, such as Lyn and c-Src, but cells displayed deep alterations in their membrane permeability. However, normal membrane permeability was restored by loading cells with cholesterol. When MCD treatment was more stringent, a large loss of cell lipids occurred, and the lipid domains were much less enriched in cholesterol and lost the ability to sort specific proteins. The loss of the integrity and properties of lipid domains was accompanied by severe changes in the membrane permeability, distress, and eventually cell death.


Protocol for estimating the impact of climate change on economic growth and inequality under climate policies.
The impact of climate change on economic inequality has attracted increasing attention from both government and academia. Here, we present a protocol for estimating both the impact of climate change on economic growth and economic growth inequality under multiple climate policies. We describe steps for constructing an uncertainty analysis framework, collecting and pre-processing data, and estimating the climate-economic response. We then detail procedures of predicting climate policy impact and calculating inter-country economic growth inequality. For complete details on the use and execution of this protocol, please refer to Tang et al. (2023).1.


Steroid modulation of the strychnine-sensitive glycine receptor.
Electrophysiological responses to glycine (0.25-5 mM) were obtained on preparations of rat optic nerve. The log dose-response curve for glycine was shifted to the left by a factor of 2 by 1 microM 20 alpha-dihydrocortisol and by a factor of about 1.5 by 1 microM alpha-cortol and 10 microM hydrocortisone. A similar effect was obtained with 100 microM chlormethiazole but the GABA-potentiating steroid alphaxalone (1 microM) was ineffective on responses to glycine. 20 alpha-Dihydrocortisol and chlormethiazole also appeared to increase the antagonistic potency of strychnine against glycine. These observations suggest that the active steroids and chlormethiazole increase the functional interaction of both glycine and strychnine with the glycine-gated chloride channel.


Early surgery for ruptured cerebral arteriovenous malformations.
Acute surgery on cerebral arteriovenous malformations (AVMs) has seldom been reported or used. We reviewed 49 patients of ages 2 months to 78 years (mean 32.8 years), 32 male (65%) and 17 female (35%), treated acutely (within 4 days of bleed) in Helsinki Neurosurgery during 1997-2002. The following variables were assessed in regards to the outcome (Glasgow outcome score; GOS; 2-3 months after bleed): age, sex, Hunt and Hess Grade (HH), Spetzler-Martin Grade (SMG), location of AVM, size of intraparenchymal haematoma (ICH), and presence of intraventricular haemorrhage (IVH). Most of the patients were in a poor clinical condition on admission (two thirds were HH 4-5). 45 (92%) patients underwent extirpation of AVM and evacuation of ICH, within 4 days after bleed. Over 55% had good functional outcome. GOS correlated significantly with HH (p = 0.001), age (p = 0.006), and IVH (p = 0.049). On the other hand, SMG, location of AVM, and size of haematoma did not significantly predict the outcome. Microneurosurgery with preoperative embolization has made possible the excision of 90% of AVMs. It is our experience that it can be done acute and early, and it saves lives as compared to natural history of cerebral AVMs or late surgery, and accelerates rehabilitation of the patients.


Fused Raman spectroscopic analysis of blood and saliva delivers high accuracy for head and neck cancer diagnostics.
As a rapid, label-free, non-destructive analytical measurement requiring little to no sample preparation, Raman spectroscopy shows great promise for liquid biopsy cancer detection and diagnosis. We carried out Raman analysis and mass spectrometry of plasma and saliva from more than 50 subjects in a cohort of head and neck cancer patients and benign controls (e.g., patients with benign oral masses). Unsupervised data models were built to assess diagnostic performance. Raman spectra collected from either biofluid provided moderate performance to discriminate cancer samples. However, by fusing together the Raman spectra of plasma and saliva for each patient, subsequent analytical models delivered an impressive sensitivity, specificity, and accuracy of 96.3%, 85.7%, and 91.7%, respectively. We further confirmed that the metabolites driving the differences in Raman spectra for our models are among the same ones that drive mass spectrometry models, unifying the two techniques and validating the underlying ability of Raman to assess metabolite composition. This study bolsters the relevance of Raman to provide additive value by probing the unique chemical compositions across biofluid sources. Ultimately, we show that a simple data augmentation routine of fusing plasma and saliva spectra provided significantly higher clinical value than either biofluid alone, pushing forward the potential of clinical translation of Raman spectroscopy for liquid biopsy cancer diagnostics.


Scanning electron microscopic observations on cells grown in vitro. IV. HeLa cells do not have an upperside-underside polarity.
Small glass particles are added to HeLa monolayer cell cultures. Landing on top of a flattened cell fingerlike protrusions are surrounding the particles. Later on leading lamellae are formed on the upperside of the cell and the glass becomes more and more surrounded until it appears to be "incorporated" completely. The glass particles become attached so firmly that by detaching them the cell surface is destroyed. This speaks against the assumption that cells in monolayers are polarized.


Bacterial alginate production: an overview of its biosynthesis and potential industrial production.
Alginate is a linear polysaccharide that can be used for different applications in the food and pharmaceutical industries. These polysaccharides have a chemical structure composed of subunits of (1-4)-β-D-mannuronic acid (M) and its C-5 epimer α-L-guluronic acid (G). The monomer composition and molecular weight of alginates are known to have effects on their properties. Currently, these polysaccharides are commercially extracted from seaweed but can also be produced by Azotobacter vinelandii and Pseudomonas spp. as an extracellular polymer. One strategy to produce alginates with different molecular weights and with reproducible physicochemical characteristics is through the manipulation of the culture conditions during fermentation. This mini-review provides a comparative analysis of the metabolic pathways and molecular mechanisms involved in alginate polymerization from A. vinelandii and Pseudomonas spp. Different fermentation strategies used to produce alginates at a bioreactor laboratory scale are described.


A review for the peripheral nerve interface designer.
Informational density and relative accessibility of the peripheral nervous system make it an attractive site for therapeutic intervention. Electrode-based electrophysiological interfaces with peripheral nerves have been under development since the 1960s and, for several applications, have seen widespread clinical implementation. However, many applications require a combination of neural target resolution and stability which has thus far eluded existing peripheral nerve interfaces (PNIs). With the goal of aiding PNI designers in development of devices that meet the demands of next-generation applications, this review seeks to collect and present practical considerations and best practices which emerge from the literature, including both lessons learned during early PNI development and recent ideas. Fundamental and practical principles guiding PNI design are reviewed, followed by an updated and critical account of existing PNI designs and strategies. Finally, a brief survey of in vitro and in vivo PNI characterization methods is presented.


Epipolar Geometry Estimation for Urban Scenes with Repetitive Structures.
Algorithms for the estimation of epipolar geometry from a pair of images have been very successful in dealing with challenging wide baseline images. In this paper the problem of scenes with repeated structures is addressed, dealing with the common case where the overlap between the images consists mainly of facades of a building. These facades may contain many repeated structures that can not be matched locally, causing state-of-the-art algorithms to fail. Assuming that the repeated structures lie on a planar surface in an ordered fashion the goal is to match them. Our algorithm first rectifies the images such that the facade is fronto-parallel. It then clusters similar features in each of the two images and matches the clusters. From them a set of hypothesized homographies of the facade is generated, using local groups of features. For each homography the epipole is recovered, yielding a fundamental matrix. For the best solution, it then decides whether the fundamental matrix has been recovered reliably and, if not, returns only the homography. The algorithm has been tested on a large number of challenging image pairs of buildings from the benchmark ZuBuD database, outperforming several state-of-the-art algorithms.


Role of zinc in hemostasis: a review.
Zinc is a multi-functional element that is found in almost 300 enzymes where it performs catalytic, co-catalytic, and/or structural functions. In 1982, Gordon et al. (Am J Clin Ntr 35:849-857, 1982) found that a low zinc diet caused poor platelet aggregation and increased bleeding tendency in adult males. This fact drew interest to the role of zinc in blood clotting. It has been shown that hyperzincemia predisposes to increased coagulability, and hypozincemia to poor platelet aggregation and increased bleeding time. The blood clotting disturbances can be regressed by appropriate zinc intake management. Considering the importance of zinc as an essential element, its participation in regulation of the equilibrium between pro- and anti-thrombotic factors originating in platelets and endothelium prompted further investigations.


Biosynthesis of sesquiterpenes in grape berry exocarp of Vitis vinifera L.: evidence for a transport of farnesyl diphosphate precursors from plastids to the cytosol.
The participation of the mevalonic acid (MVA) and 1-deoxy-d-xylulose 5-phosphate/2-C-methyl-d-erythritol-4-phosphate (DOXP/MEP) pathways in sesquiterpene biosynthesis of grape berries was investigated. There is an increasing interest in this class of terpenoids, since the oxygenated sesquiterpene rotundone was identified as the peppery aroma impact compound in Australian Shiraz wines. To investigate precursor supply pathway utilization, in vivo feeding experiments were performed with the deuterium labeled, pathway specific, precursors [5,5-(2)H2]-1-deoxy-d-xylulose and [5,5-(2)H2]-mevalonic acid lactone. Head Space-Solid Phase Micro Extraction-Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS) analysis of the generated volatile metabolites demonstrated that de novo sesquiterpene biosynthesis is mainly located in the grape berry exocarp (skin), with no detectable activity in the mesocarp (flesh) of the Lemberger variety. Interestingly, precursors from both the (primarily) cytosolic MVA and plastidial DOXP/MEP pathways were incorporated into grape sesquiterpenes in the varieties Lemberger, Gewürztraminer and Syrah. Our labeling data provide evidence for a homogenous, cytosolic pool of precursors for sesquiterpene biosynthesis, indicating that a transport of precursors occurs mostly from plastids to the cytosol. The labeling patterns of the sesquiterpene germacrene D were in agreement with a cyclization mechanism analogous to that of a previously cloned enantioselective (R)-germacrene D synthase from Solidago canadensis. This observation was subsequently confirmed by enantioselective GC-MS analysis demonstrating the exclusive presence of (R)-germacrene D, and not the (S)-enantiomer, in grape berries.


Predicting aqueous sorption of organic pollutants on microplastics with machine learning.
Microplastics (MPs) are ubiquitously distributed in freshwater systems and they can determine the environmental fate of organic pollutants (OPs) via sorption interaction. However, the diverse physicochemical properties of MPs and the wide range of OP species make a deeper understanding of sorption mechanisms challenging. Traditional isotherm-based sorption models are limited in their universality since they normally only consider the nature and characteristics of either sorbents or sorbates individually. Therefore, only specific equilibrium concentrations or specific sorption isotherms can be used to predict sorption. To systematically evaluate and predict OP sorption under the influence of both MPs and OPs properties, we collected 475 sorption data from peer-reviewed publications and developed a poly-parameter-linear-free-energy-relationship-embedded machine learning method to analyze the collected sorption datasets. Models of different algorithms were compared, and the genetic algorithm and support vector machine hybrid model displayed the best prediction performance (R2 of 0.93 and root-mean-square-error of 0.07). Finally, comparison results of three feature importance analysis tools (forward step wise method, Shapley method, and global sensitivity analysis) showed that chemical properties of MPs, excess molar refraction, and hydrogen-bonding interaction of OPs contribute the most to sorption, reflecting the dominant sorption mechanisms of hydrophobic partitioning, hydrogen bond formation, and π-π interaction, respectively. This study presents a novel sorbate-sorbent-based ML model with a wide applicability to expand our capacity in understanding the complicated process and mechanism of OP sorption on MPs.


Two-phase surgical treatment of anteromedial knee injuries.
The treatment of severe anteromedial knee injuries over the years has undergone various types of approach, changing from proposals, such as combined surgical repair of the anterior cruciate ligament and medial compartment, to the more current protocol which involves conservative treatment of the peripheral injury and later reconstruction of the anterior cruciate ligament. However, in serious ruptures of the medial ligament compartment, conservative treatment does not make it possible to recover peripheral stability, thus transferring abnormal forces onto the anterior cruciate pro-ligament graft which can gradually deteriorate the transplant itself. Thus in severe anteromedial injuries a treatment with two distinct surgical phases is proposed, using direct immediate suture of the peripheral compartment and, after a period of rehabilitation, later replacement of the anterior cruciate ligament by arthroscope graft. Given the obtained results and the few complications observed in 25 cases, it is probable that this therapeutic scheme can be proposed in selected cases of severe ligament laxity of the medial compartment associated with rupture of the anterior cruciate ligament.


Assessment of Carrot Callus as Biofactories of an Atherosclerosis Oral Vaccine Prototype.
Atherosclerosis is a pathology leading to cardiovascular diseases with high epidemiologic impact; thus, new therapies are required to fight this global health issue. Immunotherapy is a feasible approach to treat atherosclerosis and given that genetically engineered plants are attractive hosts for vaccine development; we previously proved that the plant cell is able to synthesize a chimeric protein called CTB:p210:CETPe, which is composed of the cholera toxin B subunit (CTB) as immunogenic carrier and target epitopes from the cholesteryl ester transfer protein (CETP461-476) and apolipoprotein B100 (p210). Since CTB:p210:CETPe was expressed in tobacco at sufficient levels to evoke humoral responses in mice, its expression in carrot was explored in the present study looking to develop a vaccine in a safe host amenable for oral delivery; avoiding the purification requirement. Carrot cell lines expressing CTB:p210:CETPe were developed, showing accumulation levels up to 6.1 µg/g dry weight. An immunoblot analysis revealed that the carrot-made protein is antigenic and an oral mice immunization scheme led to evidence on the immunogenic activity of this protein; revealing its capability of inducing serum IgG responses against p210 and CETP epitopes. This study represents a step forward in the development of an attractive oral low-cost vaccine to treat atherosclerosis.


Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL.
Acetaminophen (APAP) is one of the most commonly used drugs worldwide, and APAP-induced liver injury is the most frequent cause of acute liver failure in developed countries. However, the mechanisms of APAP-induced hepatotoxicity are not well understood, and treatment options for the disorder are very limited. Here, we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a major mediator of APAP-induced liver injury in mice, and its blockade markedly ameliorates the liver failure. In APAP-treated mice, TRAIL was expressed in the liver, spleen, and peripheral blood primarily by CD11b+Gr1+ neutrophils. The concentration of soluble TRAIL in the blood, and the frequencies of TRAIL+ leukocytes in the spleen and liver positively correlated with the severity of liver injury. APAP sensitized hepatocytes to TRAIL-induced apoptosis by upregulating the expression of the TRAIL receptor DR5 (death receptor 5), presumably through its transcription factor CHOP (C/EBP homologous protein). Importantly, blocking TRAIL with a soluble DR5-Fc fusion protein (sDR5-Fc) significantly attenuated APAP-induced liver injury, the hepatic infiltration of leukocytes, the levels of inflammatory cytokines, and the mortality of mice. When administered alongside N-acetylcysteine, sDR5-Fc further protected against APAP-induced acute liver injury. Thus, the TRAIL-DR5 signaling pathway plays a key role in APAP-induced liver inflammation and failure, and its blockade represents an effective new strategy to treat the liver disease.


FGF-21 Plays a Crucial Role in the Glucose Uptake of Activated Monocytes.
Monocytes display a gradual change in metabolism during inflammation. When activated, the increase in glucose utilization is important for monocytes to participate in immune and inflammatory responses. Further studies on the mechanism underlying this biological phenomenon may provide a new understanding of the relationship between immune response and metabolism. The THP-1 cells were used as a monocyte model. The cells were activated with lipopolysaccharide (LPS). Glucose uptake was measured using flow cytometry. The expression of fibroblast growth factor 21 (FGF-21), glucose transporter 1 (GLUT-1), and other FGF-21 signaling pathway-related factor mRNAs was determined by real-time polymerase chain reaction. Further, the relationship between FGF-21 expression in monocytes and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signaling pathway was determined by Western blotting. LPS elevated FGF-21 expression in monocytic THP-1 cells in vitro. Functional assays showed that the phenomenon in which LPS and FGF-21 stimulated glucose uptake in monocytic THP-1 cells could be inhibited by FGFR inhibitor. The mechanism of elevation of FGF-21 was found to involve the PI3K/Akt signaling pathway. This study indicated that FGF-21 could regulate the immune response indirectly by influencing the glucose uptake of activated monocytes cells.


Pattern of equestrian injuries presenting to a Sydney teaching hospital.
Equestrian activities are associated with a high rate of injury. Attempts to reduce the incidence and severity of injury require accurate characterization of risk factors and pattern of injury. The present study was performed to analyse the injuries seen at an Australian centre where a large number of equestrian injuries present. Data were collected prospectively over a 3 year period on all equestrian injuries presenting to the Prince of Wales -Hospital complex. These data were compared against and combined with retrospectively collected data over the preceding 3 years at the same centre. Two hundred and twenty-one injured equestrians presented (181 consented) in the prospective period of the study, and 208 presented in the retrospective period. Overall, 81% of riders were wearing a helmet at the time of their injury. Helmet use was associated with a significantly lower admission rate (27% vs 55%; P < 0.0001, from combined data). Recreational equestrians had a higher admission rate than professional equestrians, and had a significantly higher head and spine injury rate than the professional group. Rate of helmet use increased from 72% in the retrospective group to 91% in the more recent prospective group, and total admissions decreased from 43% to 14%. Significant and serious injuries are associated with equestrian activities, with the higher risk group being recreational equestrians, and riders not using a helmet. The pattern of injury favours head and spine in recreational and non-helmeted riders, and extremities for professional and helmeted riders. Helmet use is still not universal among riders, although an increase in its use may be contributing to an overall reduction in admission rate. Facial and spinal injuries still occurred in helmeted patients.


Elastic energy in locomotion: Spring-mass vs. poly-articulated models.
The human is often modeled as a Poly-Articulated Model (PAM) with rigid segments while some authors use a Spring Mass Model (SMM) for modeling locomotion. These two models are considered independent, and the objective of this study was to link them in order to enlighten the origin of the elasticity in locomotion. Using the characteristics of the two models, a theoretical relationship demonstrates that the variation of elastic energy of the SMM equals the variation of the internal kinetic energy minus internal forces work of the PAM. This theoretical relationship was experimentally investigated among 19 healthy participants walking and running on a treadmill. The results showed that the equality is verified except during the double support phase at 0.56ms(-1), at high walking speeds (1.67 and 2.22ms(-1)) or during the aerial phase of running. The formal relationship showed that the global stiffness of the SMM is directly related to the work of the internal forces of the PAM, and thus, to the characteristics of the musculoskeletal system. It also showed the relevance of taking into account the participation of each joint in the global stiffness. Finally, the coordination of internal forces work to produce a global stiffness may be considered as a new criterion of movement optimization for clinical purposes or motion planning for humanoid robots.


Ticagrelor versus aspirin and vein graft patency after coronary bypass: A randomized trial.
Antiplatelet therapy prevents saphenous vein graft (SVG) occlusion and improves outcomes after coronary artery bypass graft surgery (CABG). However, the optimal postoperative antiplatelet regimen remains unclear. The goal of the Ticagrelor Antiplatelet Therapy to Reduce Graft Events and Thrombosis (TARGET) trial was to assess whether early postoperative ticagrelor reduces SVG occlusion compared to conventional aspirin therapy. In this multi-center double-blind randomized trial, 250 patients who had CABG with SVG were randomized to receive either aspirin 81 mg twice daily or ticagrelor 90 mg twice daily. The primary outcome was SVG occlusion at 1 year. Altogether, 123 patients were randomized to aspirin and 127 received ticagrelor. One-year graft assessment was performed in 202 patients (80.8%), examining 588 grafts, yielding an overall graft occlusion rate of 10.9%. The primary outcome, SVG occlusion at 1 year, did not significantly differ between the two groups (17.4% vs. 13.2%, aspirin vs. ticagrelor, p = .30). The incidence of vein grafts with any disease (stenosis or occlusion) did not significantly differ between the groups (21.5% vs. 22.3%, aspirin vs. ticagrelor, p = .90), and the number of patients with vein graft disease did not significantly differ between the groups (29.4% vs. 28.0%, aspirin vs. ticagrelor, p = .88). Freedom from major adverse cardiovascular events at 1 year was similar between the groups (p = .60). Compared to conventional aspirin therapy, ticagrelor did not significantly reduce vein graft occlusion 1 year after CABG. Further study will assess the impact of ticagrelor on 2-year graft patency for this cohort.


Contemporary and retrospective investigations of human milk in the trend studies of organochlorine contaminants in Sweden.
Milk from the Mothers' Milk Centre in Stockholm has been analysed for organochlorine contaminants in different time periods between 1967 and 1989. The contemporary investigations showed a decrease of the levels of certain pesticides and polychlorinated biphenyls (PCBs). The changes were related to the prohibitions and restrictions applied on the usage of the compounds. Milk samples, remaining from the contemporary studies, were archived from 1972 and onward. These samples were later reanalyzed and the investigations were extended to also include polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and specific congeners of PCBs, including non-ortho and mono-ortho coplanar PCBs. These retrospective investigations, of the same milk, showed a time related decrease in the concentrations also for these compounds. Calculating the levels by toxic equivalency factors relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) it was found that PCBs contributed the major part of the toxic equivalents in milk.


Cardiovascular Medications in Pregnancy: A Primer.
Cardiovascular disease and cardiovascular disease-related disorders remain among the most common causes of maternal morbidity and mortality in the United States. Due to increased rates of obesity, delayed childbearing, and improvements in medical technology, greater numbers of women are entering pregnancy with preexisting medical comorbidities. Use of cardiovascular medications in pregnancy continues to increase, and medical management of cardiovascular conditions in pregnancy will become increasingly common. Obstetricians and cardiologists must familiarize themselves with the pharmacokinetics of the most commonly used cardiovascular medications in pregnancy and how these medications respond to the physiologic changes related to pregnancy, embryogenesis, and lactation.


The immune system in minimal change nephrotic syndrome.
Numerous examples of abnormal immune responsiveness have been described in minimal change nephrotic syndrome (MCNS). The of MCNS with allergy and with certain genetic markers of immune responsiveness, as well as the excellent response of proteinuria to immunomodulatory agents, has suggested a causal relationship between the immunological and renal abnormalities. However, the nature of this relationship is uncertain. Before it can be clarified, the basic mechanism(s) involved in disturbed immunity in patients with MCNS must be better characterized. Studies of humoral and cellular immune function support the hypothesis that immune regulation is abnormal. However, conclusive evidence of participation by a defined immunoregulatory system in the events leading to immune dysfunction has not been obtained. Thus, considerable work remains to be done in determining the nature and cause of abnormal immunity in MCNS prior to investigating its potential role in the pathogenesis of proteinuria.


Current understanding of adult neurogenesis in the mammalian brain: how does adult neurogenesis decrease with age?
Adult neurogenesis occurs throughout life in restricted brain regions in mammals. However, the number of neural stem cells (NSCs) that generate new neurons steadily decreases with age, resulting in a decrease in neurogenesis. Transplantation of mesenchymal cells or cultured NSCs has been studied as a promising treatment in models of several brain injuries including cerebral infarction and cerebral contusion. Considering the problems of host-versus-graft reactions and the tumorigenicity of transplanted cells, the mobilization of endogenous adult NSCs should be more feasible for the treatment of these brain injuries. However, the number of adult NSCs in the adult brain is limited, and their mitotic potential is low. Here, we outline what we know to date about why the number of NSCs and adult neurogenesis decrease with age. We also discuss issues applicable to regenerative medicine.


Inequality, privacy, and mental health.
The state's mental health power is standardly understood in terms of the state's power to intervene with persons or populations to address mental health problems. This article advances a more expansive view of the state's mental health power, one which seeks to capture those exercises of state power that do not directly concern mental health but that nevertheless can have a profound effect on mental well-being. The article considers two features of contemporary American society that implicate the state in conditions that undermine, or threaten to undermine, mental health. The first concerns the impact of poverty and inequality on mental health. The second concerns the threat to the self posed by measures that would significantly erode privacy. The article argues that a greater commitment to liberal principles of equality and tolerance is crucial to overcoming the perils for mental health that poverty and losses of privacy generate.


Post-traumatic infection of the lower limb caused by rare Enterobacteriaceae and Mucorales in a young healthy male.
Enterobacter amnigenus and Leclercia adecarboxylata are gram-negative aerobic bacilli of the family Enterobacteriaceae that have been isolated from water and, rarely, from various clinical specimens. Absidia is a filamentous fungus of the class Zygomycetes that is ubiquitous in nature and can cause infection, primarily in immunocompromised hosts. Here, we describe an infection of the left lower limb caused by E. amnigenus and L. adecarboxylata with subsequent isolation of Absidia spp. in a patient with multiple traumatic injuries after a major motor vehicle accident. The severity of the clinical picture made amputation necessary, despite aggressive anti-infective therapy with both antibacterial and antifungal agents. Prompt diagnosis and management are mandatory in order to minimize morbidity and even mortality, and reduce the social and economic cost.


Interface Adsorption and Aggregation Behavior of Sulfonate-Based Anionic Silicone Surfactants in Aqueous Solution.
A series of sulfonate silicone surfactants possessing different hydrophobic groups were synthesized. Their adsorption and thermodynamic parameters in aqueous solutions were investigated by surface tension measurements, conductivity, transmission electron microscopy (TEM) and dynamic light scattering (DLS). These sulfonate-based anionic silicone surfactants exhibit significant surface activity and can reduce the surface tension of water to 19.6 mN m-1 at critical micelle concentration. The TEM and DLS results demonstrate that the three sulfonated silicone surfactants self-assemble into homogeneous sized vesicle-like aggregates in aqueous solution. Moreover, the size of the aggregates was determined to be in the range from 80 to 400 nm at 0.05 mol L-1 .


Scombroid fish poisoning syndrome.
Two patients presented to the emergency department with features of a histamine-like reaction and were subsequently determined to have scombroid fish poisoning. It is important to recognize the syndrome as an intoxication rather than an allergic reaction in order that the source of the toxin can be identified and further cases prevented. A review of the features and pathogenesis of the syndrome is presented.