Aqueous shunt devices compared with trabeculectomy with Mitomycin-C for children in the first two years of life.
To compare the outcomes of children 24 months of age or younger treated with aqueous shunt devices or with mitomycin-C (MMC) trabeculectomy. Retrospective, age-matched, comparative case series. Forty-six eyes of 32 patients with mean age of 7.0 +/- 5.1 month (range, 1 to 22 months) and uncontrolled glaucoma, which received an aqueous shunt device (Ahmed glaucoma valve or Baerveldt implant), compared with 24 eyes of 19 patients with mean age of 5.3 +/- 4.8 months (range, 0.5 to 24 months), which received an MMC trabeculectomy. Surgical success was defined as intraocular pressure < 23 mm Hg on maximal glaucoma medication, no further glaucoma surgery performed or recommended, no devastating complication, and stable ocular dimensions (axial length and corneal diameter). Cumulative probabilities of success were 87% +/- 5.0% for the aqueous shunt group compared with 36% +/- 8.0% success in the trabeculectomy group at 12 months and 53% +/- 12% in the aqueous shunt group compared with 19% +/- 7% in the trabeculectomy group at 72 months (chi(2) of 23.5, P <.0001). Aqueous shunt implantation was associated with significantly more postoperative complications requiring a return to the operating room (21 of 46 eyes, 45.7%) compared with trabeculectomy with MMC (3 of 24 eyes, 12.5%, P =.0074). The most common postoperative procedure in the aqueous shunt group was tube repositioning, performed in 16 of 46 eyes (34.8%). Aqueous shunt implantation offers a significantly greater chance of successful glaucoma control in the first 2 years of life, compared with trabeculectomy with MMC. However, the enhanced success with aqueous shunt devices is associated with a higher likelihood of postoperative complications requiring surgical revision, most commonly tube repositioning.


En Route Care Provided by US Navy Nurses in Iraq and Afghanistan.
US Navy nurses provide en route care for critically injured combat casualties without having a formal program for training, utilization, or evaluation. Little is known about missions supported by Navy nurses. To characterize the number and types of patients transported and skill sets required by Navy nurses during 2 combat support deployments. All interfacility casualty transfers between 2 separate facilities in Iraq and Afghanistan were assessed. Number of patients treated, number transported, en route care provider type, transport priority level and duration, injury severity, indication for critical care transport, en route care interventions, and vital signs were evaluated. Of 1550 casualties, 630 required medical evacuation to a higher level of care. Of those, 133 (21%) were transported by a Navy nurse, with 131 (98.5%) classified as "urgent," accounting for 46% of all urgent transports. The primary indication for en route care nursing was mechanical ventilation of intubated patients (97%). Mean (SD) patient transport time was 29.8 (7.9) minutes (range, 17-61 minutes). The most common en route care interventions were administration of intravenous sedation (80%), neuromuscular blockade (79%), and opioids (48%); transfusions (18%); and ventilation changes (11%). No intubations, cricothyroidotomies, chest tube placements, or needle decompressions were performed en route. No deaths occurred during transport. US Navy nurses successfully transported critically injured patients without observed adverse events. Establishing en route care as a program of record in the Navy will facilitate continuous process improvement to ensure that future casualties receive optimized en route care.


Early-stage primary school children attending a school in the Malawian School Feeding Program (SFP) have better reversal learning and lean muscle mass growth than those attending a non-SFP school.
In developing countries, schoolchildren encounter a number of challenges, including failure to complete school, poor health and nutrition, and poor academic performance. Implementation of school feeding programs (SFPs) in less developed countries is increasing and yet there is mixed evidence regarding their positive effects on nutrition, education, and cognition at the population level. This study evaluated cognitive and anthropometric outcomes in entry-level primary school children in Malawi with the aim of generating evidence for the ongoing debate about SFPs in Malawi and other developing countries. A total of 226 schoolchildren aged 6-8 y in 2 rural Malawian public primary schools were followed for one school year. Children attending one school (SFP school) received a daily ration of corn-soy blend porridge, while those attending the other (non-SFP school) did not. Baseline and post-baseline outcomes included the Cambridge Neurological Test Automated Battery cognitive tests of paired associate learning, rapid visual information processing and intra-extra dimensional shift, and anthropometric measurements of weight, height, and mid-upper arm circumference (MUAC). At follow-up, the SFP subcohort had a greater reduction than the non-SFP subcohort in the number of intra-extra predimensional shift errors made (mean 18.5 and 24.9, respectively; P-interaction = 0.02) and also showed an increase in MUAC (from 16.3 to 17.0; P-interaction <0.0001). The results indicate that the SFP in Malawi is associated with an improvement in reversal learning and catch-up growth in lean muscle mass in children in the SFP school compared with children in the non-SFP school. These findings suggest that the Malawian SFP, if well managed and ration sizes are sustained, may have the potential to improve nutritional and cognitive indicators of the most disadvantaged children.


Use of antiarrhythmic drug therapy and clinical outcomes in older patients with concomitant atrial fibrillation and coronary artery disease.
Atrial fibrillation (AF) and coronary artery disease (CAD) are common in older patients. We aimed to describe the use of antiarrhythmic drug (AAD) therapy and clinical outcomes in these patients. We analysed AAD therapy and outcomes in 1738 older patients (age ≥65) with AF and CAD in the Duke Databank for cardiovascular disease. The primary outcomes were mortality and rehospitalization at 1 and 5 years. Overall, 35% of patients received an AAD at baseline, 43% were female and 85% were white. Prior myocardial infarction (MI, 31%) and heart failure (41%) were common. Amiodarone was the most common AAD (21%), followed by pure Class III agents (sotalol 6.3%, dofetilide 2.2%). Persistence of AAD was low (35% at 1 year). After adjustment, baseline AAD use was not associated with 1-year mortality [adjusted hazard ratio (HR) 1.23, 95% confidence interval (CI) 0.94-1.60] or cardiovascular mortality (adjusted HR 1.27, 95% CI 0.90-1.80). However, AAD use was associated with increased all-cause rehospitalization (adjusted HR 1.20, 95% CI 1.03-1.39) and cardiovascular rehospitalization (adjusted HR 1.20, 95% CI 1.01-1.43) at 1 year. This association did not persist at 5 years; however, these patients were at very high risk of death (55% for those >75 and on AAD) and all-cause rehospitalization (87% for those >75 and on AAD) at 5 years. In older patients with AF and CAD, antiarrhythmic therapy was associated with increased rehospitalization at 1 year. Overall, these patients are at high risk of longer-term hospitalization and death. Safer, better-tolerated, and more effective therapies for symptom control in this high-risk population are warranted.


Diagnosis of extramammary malignancy metastatic to the breast by fine needle biopsy.
To review and illustrate the findings in fine needle biopsy (FNB) of extramammary malignancies presenting with breast metastases (MMB). We reviewed 32 cases of MMB diagnosed on breast FNB. The clinical data, with particular attention to the history of a known primary malignancy, previous systemic metastatic disease in other sites and presentation with extramammary disease in addition to a breast mass were examined. The morphological appearances were reviewed and are illustrated, focusing on those features which allow the pathologist to recognise the possibility of metastatic disease and undertake appropriate steps to investigate this. The 32 cases included metastases from a wide range of sites, including cutaneous melanoma (10), lung (8), non-Hodgkin's lymphoma (5), soft tissue (4), colon (2), endometrium, ovary and bladder. There was a history of extramammary malignancy in 26, while in six patients the breast mass was detected at initial presentation with malignant disease. Of the latter six patients, four had evidence of widespread metastases, while one presented with multiple breast masses. In 16 cases the cytological features allowed the possibility of metastases to be recognised without clinical data, while in the other 16 there was sufficient overlap with primary mammary carcinoma that the possibility of metastases could be missed. Only one case was initially mistaken for a primary tumour, in this case the history of prior malignancy with systemic metastases was not provided to the reporting pathologist. The majority (81%) of cases of MMB have a history of primary malignancy, although only a minority have a history of systemic metastases at other sites. Of those patients without known prior malignancy, the majority present with systemic disease or multiple breast lesions. The cytological features allow metastatic disease to be suspected in half of the cases, although in the others, particularly patients with metastatic adenocarcinoma, diagnosis without recourse to immunohistochemistry is difficult or impossible. A combination of complete clinical history, attention to the cytological features and suspicion in cases with metastatic disease beyond the axilla should allow most cases of MMB to be suspected, and suitable material for ancillary confirmatory testing to be obtained.


Mechanisms of Suppression of {alpha}-Synuclein Neurotoxicity by Geldanamycin in Drosophila.
Parkinson's disease is a common neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of the protein alpha-synuclein into aggregates called Lewy bodies and Lewy neurites. Parkinson's disease can be modeled in Drosophila where directed expression of alpha-synuclein induces compromise of dopaminergic neurons and the formation of Lewy body-like aggregates. The molecular chaperone Hsp70 protects cells from the deleterious effects of alpha-synuclein, indicating a potential therapeutic approach to enhance neuron survival in Parkinson's disease. We have now investigated the molecular mechanisms by which the drug geldanamycin protects neurons against alpha-synuclein toxicity. Our studies show that geldanamycin sensitizes the stress response within normal physiological parameters to enhance chaperone activation, offering protection against alpha-synuclein neurotoxicity. Further, geldanamycin uncouples neuronal toxicity from Lewy body and Lewy neurite formation such that dopaminergic neurons are protected from the effects of alpha-synuclein expression despite the continued presence of (and even increase in) inclusion pathology. These studies indicate that compounds that modulate the stress response are a promising approach to treat Parkinson's disease.


Conformations of cytochrome oxidase: thermodynamic evaluation of the interconversion of the 418- and 428-nm forms.
Oxidized cytochrome c oxidase exists in two reasonably well-defined conformations, a high-spin conformation with maximal absorption at 418 nm and a low-spin conformation with maximal absorption at 428 nm. The equilibrium between these two conformations has been studied as a function of pH, pressure, and temperature. pH effects the equilibrium between the two conformations, the maximum fraction of the 418-nm form being found at about pH 6.8. Increasing pressure displaced the equilibrium toward the 428-nm form; the molar volume changes found are independent of pH but strongly dependent on temperature. Increasing temperature over the range -20 to 25 degrees C displaces the equilibrium toward the 428-nm form; the van't Hoff plots that result show a discontinuity at about 10 degrees C. Above 10 degrees C, delta H is relatively constant as a function of pH; below 10 degrees C, delta H is strongly pH dependent. Delta G, delta H, delta S, and delta V have been evaluated for the equilibrium.


The impact of access to immunization information on vaccine acceptance in three countries.
Vaccine acceptance is a critical component of sustainable immunization programs, yet rates of vaccine hesitancy are rising. Increased access to misinformation through media and anti-vaccine advocacy is an important contributor to hesitancy in the United States and other high-income nations with robust immunization programs. Little is known about the content and effect of information sources on attitudes toward vaccination in settings with rapidly changing or unstable immunization programs. The objective of this study was to explore knowledge and attitudes regarding vaccines and vaccine-preventable diseases among caregivers and immunization providers in Botswana, the Dominican Republic, and Greece and examine how access to information impacts reported vaccine acceptance. We conducted 37 focus groups and 14 semi-structured interviews with 96 providers and 153 caregivers in Botswana, the Dominican Republic, and Greece. Focus groups were conducted in Setswana, English, Spanish, or Greek; digitally recorded; and transcribed. Transcripts were translated into English, coded in qualitative data analysis software (NVivo 10, QSR International, Melbourne, Australia), and analyzed for common themes. Dominant themes in all three countries included identification of health care providers or medical literature as the primary source of vaccine information, yet participants reported insufficient communication about vaccines was available. Comments about level of trust in the health care system and government contrasted between sites, with the highest level of trust reported in Botswana but lower levels of trust in Greece. In Botswana, the Dominican Republic, and Greece, participants expressed reliance on health care providers for information and demonstrated a need for more communication about vaccines. Trust in the government and health care system influenced vaccine acceptance differently in each country, demonstrating the need for country-specific data that focus on vaccine acceptance to fully understand which drivers can be leveraged to improve implementation of immunization programs.


Results of implementation of a fast track pathway for diagnosis of colorectal cancer.
fast track pathways for diagnosis of cancer intend to decrease delays in diagnosis and treatment of cancer. It is recommended to initiate treatment in a period no longer than 30 days since admission in these circuits. to know the characteristics and fluency of our Fast Track Diagnostic Pathway (FTDP) for Colorectal Cancer (CRC), with special attention to those patients selected for surgical treatment as a first choice. all patients who entered the FTDP for CRC during a period of 2 years (2008-2009) were analyzed as well as the rest of patients also diagnosed with CRC but never seen in the FTDP. of the 316 patients referred to the FTDP only 78 (24.7%) were diagnosed as having some kind of cancer derived from the digestive system. At the end 61 patients (19.3%) were diagnosed with CCR. The time interval from entry into the FTDP to the first hospital visit was 3 days (range 1-8), and the interval until colonoscopy was performed was 11.5 days (range 1-41). Fourteen (41.1%) of those patients chosen for surgery were operated on in a period lesser than 30 days while 28 patients (82.3%) underwent surgery before day 45 since admission into the circuit. though the functioning of the FTDP is acceptable, any increase in number of patients can generate delays. For this reason it is advisable to have a team to assure a good functioning of the FTDP. A proper follow-up of the whole process will possibly avoid unnecessary delays and it will improve coordination of the different phases of the fast track pathway and treatment. As the diagnostic outcome is poor it is mandatory to implement alternatives programs like screening of asymptomatic population, allowing an early detection of this condition.


MicrO: an ontology of phenotypic and metabolic characters, assays, and culture media found in prokaryotic taxonomic descriptions.
MicrO is an ontology of microbiological terms, including prokaryotic qualities and processes, material entities (such as cell components), chemical entities (such as microbiological culture media and medium ingredients), and assays. The ontology was built to support the ongoing development of a natural language processing algorithm, MicroPIE (or, Microbial Phenomics Information Extractor). During the MicroPIE design process, we realized there was a need for a prokaryotic ontology which would capture the evolutionary diversity of phenotypes and metabolic processes across the tree of life, capture the diversity of synonyms and information contained in the taxonomic literature, and relate microbiological entities and processes to terms in a large number of other ontologies, most particularly the Gene Ontology (GO), the Phenotypic Quality Ontology (PATO), and the Chemical Entities of Biological Interest (ChEBI). We thus constructed MicrO to be rich in logical axioms and synonyms gathered from the taxonomic literature. MicrO currently has ~14550 classes (~2550 of which are new, the remainder being microbiologically-relevant classes imported from other ontologies), connected by ~24,130 logical axioms (5,446 of which are new), and is available at (http://purl.obolibrary.org/obo/MicrO.owl) and on the project website at https://github.com/carrineblank/MicrO. MicrO has been integrated into the OBO Foundry Library (http://www.obofoundry.org/ontology/micro.html), so that other ontologies can borrow and re-use classes. Term requests and user feedback can be made using MicrO's Issue Tracker in GitHub. We designed MicrO such that it can support the ongoing and future development of algorithms that can leverage the controlled vocabulary and logical inference power provided by the ontology. By connecting microbial classes with large numbers of chemical entities, material entities, biological processes, molecular functions, and qualities using a dense array of logical axioms, we intend MicrO to be a powerful new tool to increase the computing power of bioinformatics tools such as the automated text mining of prokaryotic taxonomic descriptions using natural language processing. We also intend MicrO to support the development of new bioinformatics tools that aim to develop new connections between microbial phenotypes and genotypes (i.e., the gene content in genomes). Future ontology development will include incorporation of pathogenic phenotypes and prokaryotic habitats.


Patient and Physician Decisional Factors Regarding Hypercalcemia of Malignancy Treatment: A Novel Mixed-Methods Study.
Integrating shared decision making between patients and physicians and incorporating their values and preferences in the development of clinical practice guidelines (CPGs) is of critical importance to optimize CPG implementation and treatment adherence. This applies to many debilitating diseases, including hypercalcemia of malignancy (HCM). Evaluate patient and physician values, preferences, and attitudes to better inform CPGs to treat HCM in adults. We followed a mixed-methods approach. We conducted a systematic review using 5 databases to identify studies reporting on patient and physician values, costs and resources, feasibility, acceptability, and equity regarding HCM treatment. We also gathered data from different countries on the cost of multiple treatment modalities. We collected data on outcome prioritization from the CPG Working Group. Similarly, we collected data from patients with HCM regarding outcome prioritization and administered a questionnaire to evaluate their attitudes and perceptions toward treatment as well as treatment acceptability and feasibility. In the systematic review, we included 2 cross-sectional surveys conducted on the same population of physicians who agreed that treating HCM alleviates symptoms and improves quality of life; however, harms and benefits should be thoroughly considered when deciding on the duration of treatment. We also included 2 studies on cost showing that intravenous (IV) bisphosphonate is more cost-effective than a combination of IV bisphosphonate and calcitonin and administration of IV zoledronic acid at home is more cost-effective than other IV bisphosphonates. The cost of zoledronic acid, denosumab, and cinacalcet varied widely among countries and types (brand vs generic). Both the CPG Working Group and patients with HCM agreed that the most important outcomes when deciding on treatment were survival and resolution of HCM, but there was some variability in the ratings for other outcomes. Using mixed methods, CPG developers can obtain meaningful information regarding evidence to decision criteria. In the case of HCM CPGs, this approach has provided the required contextual information and supported the development of evidence-based recommendations.


Methods to control for unmeasured confounding in pharmacoepidemiology: an overview.
Background Unmeasured confounding is one of the principal problems in pharmacoepidemiologic studies. Several methods have been proposed to detect or control for unmeasured confounding either at the study design phase or the data analysis phase. Aim of the Review To provide an overview of commonly used methods to detect or control for unmeasured confounding and to provide recommendations for proper application in pharmacoepidemiology. Methods/Results Methods to control for unmeasured confounding in the design phase of a study are case only designs (e.g., case-crossover, case-time control, self-controlled case series) and the prior event rate ratio adjustment method. Methods that can be applied in the data analysis phase include, negative control method, perturbation variable method, instrumental variable methods, sensitivity analysis, and ecological analysis. A separate group of methods are those in which additional information on confounders is collected from a substudy. The latter group includes external adjustment, propensity score calibration, two-stage sampling, and multiple imputation. Conclusion As the performance and application of the methods to handle unmeasured confounding may differ across studies and across databases, we stress the importance of using both statistical evidence and substantial clinical knowledge for interpretation of the study results.


Infra-red laser ablative micromachining of parylene-C on SiO2 substrates for rapid prototyping, high yield, human neuronal cell patterning.
Cell patterning commonly employs photolithographic methods for the micro fabrication of structures on silicon chips. These require expensive photo-mask development and complex photolithographic processing. Laser based patterning of cells has been studied in vitro and laser ablation of polymers is an active area of research promising high aspect ratios. This paper disseminates how 800 nm femtosecond infrared (IR) laser radiation can be successfully used to perform laser ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes (derived from the human teratocarcinoma cell line (hNT)) whilst 248 nm nanosecond ultra-violet laser radiation produces photo-oxidization of the parylene-C and destroys cell patterning. In this work, we report the laser ablation methods used and the ablation characteristics of parylene-C for IR pulse fluences. Results follow that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells. We disseminate the variation in yield of patterned hNT astrocytes on parylene-C with laser pulse spacing, pulse number, pulse fluence and parylene-C strip width. The findings demonstrate how laser ablative micromachining of parylene-C on SiO2 substrates can offer an accessible alternative for rapid prototyping, high yield cell patterning with broad application to multi-electrode arrays, cellular micro-arrays and microfluidics.


[Liver neoplasms in children].
Presentation is made of 27 cases of liver neoplasms in infancy and childhood that were admitted to the Pediatric Hospital of the National Medical Center of the IMSS, through a period of 15 years. Sixteen cases were diagnosed as hepatoblastoma, 2 as hepatocellular carcinoma, 4 as mesenchymal hamartoma, 2 as hemangioendothelioma of infantile type, 2 were embryonal rhabdomyosarcoma of the intrahepatic bile-ducts and one case of multiple bile-ducts hamartoma. The hepatoblastoma and the mesenchymal hamartoma are neoplasms that appear more frequently before the age of 2 years; the hepatocellular carcinoma, after 5 years of age and the infantile hemangioendothelioma generally appears before 6 months old. In all, benign and malignant cases, the clinical manifestations were non specific and did not help to establish the diagnoses. The mesenchymal hamartomas were characterized by the fast growth that led to think in neoplasms of malignant nature. The selective treatment is lobectomy with a better prognosis if the neoplasm is located in the left lobe. The right lobe was the most frequently affected by the benign tumors, as well as by the malignant, and the lung was the organ wherein metastases more often were found.


Optimizing Reconstruction with Periorbital Transplantation: Clinical Indications and Anatomic Considerations.
Complex periorbital subunit reconstruction is challenging because the goals of effective reconstruction vary from one individual to another. The purpose of this article is to explore the indications and anatomic feasibility of periorbital transplantation by reviewing our institutional repository of facial injury. Institutional review board approval was obtained at the R Adams Cowley Shock Trauma Center for a retrospective chart review conducted on patients with periorbital defects. Patient history, facial defects, visual acuity, and periorbital function were critically reviewed to identify indications for periorbital or total face (incorporating the periorbital subunit) vascularized composite allotransplantation. Cadaveric allograft harvest was then designed and performed for specific patient defects to determine anatomic feasibility. Disease conditions not captured by our patient population warranting consideration were reviewed. A total of 7 facial or periorbital transplant candidates representing 6 different etiologies were selected as suitable indications for periorbital transplantation. Etiologies included trauma, burn, animal attack, and tumor, whereas proposed transplants included isolated periorbital and total face transplants. Allograft recovery was successfully completed in 4 periorbital subunits and 1 full face. Dual vascular supply was achieved in 5 of 6 periorbital subunits (superficial temporal and facial vessels). Transplantation of isolated periorbital structures or full face transplantation including periorbital structures is technically feasible. The goal of periorbital transplantation is to re-establish protective mechanisms of the eye, to prevent deterioration of visual acuity, and to optimize aesthetic outcomes. Criteria necessary for candidate selection and allograft design are identified by periorbital defect, periorbital function, ophthalmologic evaluation, and defect etiology.


Characterization of the novel murine monoclonal anti-von Willebrand factor (vWf) antibody GUR76-23 which inhibits vWf interaction with alpha IIb beta 3 but not alpha v beta 3 integrin.
von Willebrand factor (vWf) is known to interact with the two beta 3 integrins, alpha IIb beta 3 and alpha v beta 3, in an RGD-dependent manner. We characterized a novel murine monoclonal antibody to human vWf, GUR76-23, which recognized a site within the carboxy-terminal half of the molecule containing the RGD sequence. This antibody inhibited high shear-induced platelet aggregation and blocked adhesion of ADP plus epinephrine-stimulated platelets to vWf, indicating that it interferes with the interaction with alpha IIb beta 3. Unlike antibodies against the RGD site, however, the antibody was without effect on adhesion of cultured human umbilical vein endothelial cells to vWf, a phenomenon known to involve the interaction with alpha v beta 3. GUR76-23 binding was not displaced by anti-RGD antibodies. These results suggest that the adhesive interaction of vWf with these two beta 3 integrins may be differentially modulated by a site(s) other than the common RGD module.


Protective effect of Ginkgo biloba leaf extract on learning and memory deficit induced by aluminum in model rats.
To examine the protective effect of Ginkgo biloba leaf extract (GbE) on learning and memory deficit induced by aluminum chloride (AlCl(3)), and explore its mechanisms. The rat models with learning and memory deficit were induced by administering via gastrogavage and drinking of AlCl(3) solution. And the model rats were treated with GbE at the dose of 50, 100, 200 mg/kg every day for 2 months accompanied with drinking of AlCl(3) solution, respectively. Their abilities of spatial learning and memory were tested by Morris water maze, and the acetylcholinesterase (AChE) activity in serum was assayed with chemical method, the AChE expression in hippocampus was observed by immunohistochemistry assay, and then quantitative analysis was done by BI 2000 image analysis system. Learning and memory deficit of rats could be induced by AlCl(3) solution (P < 0.01), and AChE expressions in rats hippocampus were increased (P < 0.01); GbE ameliorated learning and memory deficit and reduced AChE expression in rats hippocampus in a dose-dependent manner, while GbE significantly increased serum AChE activity at the dose of 200 mg/kg each day (P < 0.05). GbE can ameliorate learning and memory deficit induced by AlCl(3), which may be due to its inhibition of the AChE expression in hippocampus.


Semantics derived automatically from language corpora contain human-like biases.
Machine learning is a means to derive artificial intelligence by discovering patterns in existing data. Here, we show that applying machine learning to ordinary human language results in human-like semantic biases. We replicated a spectrum of known biases, as measured by the Implicit Association Test, using a widely used, purely statistical machine-learning model trained on a standard corpus of text from the World Wide Web. Our results indicate that text corpora contain recoverable and accurate imprints of our historic biases, whether morally neutral as toward insects or flowers, problematic as toward race or gender, or even simply veridical, reflecting the status quo distribution of gender with respect to careers or first names. Our methods hold promise for identifying and addressing sources of bias in culture, including technology.


Methylthioadenosine phosphorylase cDNA transfection alters sensitivity to depletion of purine and methionine in A549 lung cancer cells.
Methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and methionine metabolism, is present in all normal tissues but is frequently deficient in a variety of cancers. It has been suggested that this metabolic difference between normal and cancer cells may be exploited to selectively treat MTAP-negative cancers by inhibiting de novo purine synthesis and by depleting L-methionine. However, these therapeutic strategies have only been tested in naturally occurring MTAP-positive and -negative cell lines, which might have additional genetic alterations that affect chemotherapeutic sensitivity. Therefore, it is of importance to examine the feasibility of enzyme-selective treatment using paired cell lines that have an identical genotype except for MTAP status. MTAP-negative A549 lung cancer cells were transfected with eukaryotic expression vectors encoding MTAP cDNA in sense and antisense orientations. The resultant stable transfectomas were treated with inhibitors of de novo purine synthesis such as methotrexate, 5,10-dideazatetrahydrofolate, and L-alanosine and by methionine depletion. The A549 cells transfected with an antisense construct (antisense transfectoma) expressed no MTAP protein and were more sensitive to both purine and methionine depletion than were cells expressing MTAP protein (sense transfectoma). Methylthioadenosine was able to completely rescue the sense transfectoma but not the antisense transfectoma from growth inhibition by depletion of purine and methionine. These results prove that MTAP deficiency contributes directly to the sensitivity of cancer cells to purine or methionine depletion. Inhibition of de novo purine synthesis, combined with methionine depletion in the presence of methylthioadenosine, is a highly selective treatment for MTAP-negative cancers.


Clinical comparison between a percutaneous hydraulic pressure delivery system and balloon tamp system using high-viscosity cement for the treatment of osteoporotic vertebral compression fractures.
Osteoporotic vertebral compression fractures (OVCFs) affect the elderly population, especially postmenopausal women. Percutaneous kyphoplasty is designed to treat painful vertebral compression fractures for which conservative therapy has been unsuccessful. High-viscosity cement can be injected by either a hydraulic pressure delivery system (HPDS) or a balloon tamp system (BTS). Therefore, the purpose of this study was to compare the safety and clinical outcomes of these two systems. A random, multicenter, prospective study was performed. Clinical and radiological assessments were carried out, including assessments of general surgery information, visual analog scale, quality of life, cement leakage, and height and angle restoration. Using either the HPDS or BTS to inject high-viscosity cement effectively relieved pain and improved the patients' quality of life immediately, and these effects lasted at least two years. The HPDS using high-viscosity cement reduced cost, surgery time, and radiation exposure and showed similar clinical results to those of the BTS. In addition, the leakage rate and the incidence of adjacent vertebral fractures after the HPDS treatment were reduced compared with those after treatment using the classic vertebroplasty devices. However, the BTS had better height and angle restoration abilities. The percutaneous HPDS with high-viscosity cement has similar clinical outcomes to those of traditional procedures in the treatment of vertebral fractures in the elderly. The HPDS with high-viscosity cement is better than the BTS in the treatment of mild and moderate OVCFs and could be an alternative method for the treatment of severe OVCFs.


Adapting an Isobaric Tag-Labeled Yeast Peptide Standard to Develop Targeted Proteomics Assays.
Targeted proteomics strategies present a streamlined hypothesis-driven approach to analyze specific sets of pathways or disease related proteins. goDig is a quantitative, targeted tandem mass tag (TMT)-based assay that can measure the relative abundance differences for hundreds of proteins directly from unfractionated mixtures. Specific protein groups or entire pathways of up to 200 proteins can be selected for quantitative profiling, while leveraging sample multiplexing permits the simultaneous analysis of up to 18 samples. Despite these benefits, implementing goDig is not without challenges, as it requires access to an instrument application programming interface (iAPI), an elution order and spectral library, a web-based method builder, and dedicated companion software. In addition, the absence of an example test assay may dissuade researchers from testing or implementing goDig. Here, we repurpose the TKO11 standard─which is commercially available but may also be assembled in-lab─and establish it as a de facto test assay for goDig. We build a proteome-wide goDig yeast library, quantify protein expression across several gene ontology (GO) categories, and compare these results to a fully fractionated yeast gold-standard data set. Essentially, we provide a guide detailing the goDig-based quantification of TKO11, which can also be used as a template for user-defined assays in other species.


Tardive dyskinesia and positive symptoms of schizophrenia.
Positive symptoms and movement disorders were rated in 44 schizophrenic inpatients. A significant negative correlation was demonstrated between tardive dyskinesia and positive symptoms. Possible explanatory mechanisms are discussed.


Food Insecurity in a Pediatric Emergency Department and the Feasibility of Universal Screening.
Children with food insecurity (FI) experience adverse health outcomes due to inadequate quantity or quality of food. Food insecurity may be high among families seeking emergency care. The Hunger Vital Sign (HVS) is a two-question validated tool used to screen families for FI. Our goal in this study was to assess prevalence of FI among emergency department (ED) patients, patient-level risk factors for FI, and the feasibility of screening. This was a cross-sectional analysis of FI in the ED. Parents or guardians of ED patients and adult patients (18 years or older) were approached for screening using the HVS during screening periods spanning weekdays/weekends and days/evenings. All ED patients were eligible, excluding siblings, repeat visits, critically ill patients, minors without a guardian, and families that healthcare staff asked us not to disturb. Families answered the HVS questions verbally or in writing, based on preference. Families with positive screens received information about food resources. We summarized patient and visit characteristics and defined medical complexity using a published algorithm. Multivariable logistic regression was used to assess FI risk factors. In July-August 2019, 527 patients presented during screening periods: 439 agreed to screening, 18 declined, 19 met exclusions, and 51 were missed. On average the screening tool required five minutes (range 3-10 minutes) to complete. Most families (328; 75%) preferred to answer in writing rather than verbally. Overall, 77 participants (17.5%) screened positive for FI. In regression analyses, FI was associated with self-reported race/ethnicity (combined variable) of African American or Black (odds ratio [OR] 5.21, 95% confidence interval [CI], 2.13-12.77), Hispanic (OR 3.47, 95% CI, 1.48-8.15), or mixed/other (OR 3.81, 95% CI, 1.54-9.39), compared to non-Hispanic white. FI was also associated with public insurance type (OR 5.74, 95% CI, 2.52-13.07, reference: private insurance), and each year of increasing patient age (OR 1.05, 95% CI, 1.01-1.09). There were no associations between FI and medical complexity or preferred language. Food insecurity was common among our ED patients. Race and ethnicity, insurance status, and increasing patient age were associated with increased odds of FI. Efforts to include universal FI screening for ED patients with immediate connection to resources will enhance overall care quality and address important health needs.


Venous thromboembolism in patients with COVID-19 (SARS-CoV-2 infection) - a position paper of the German Society of Angiology (DGA).
As observed in other infections with a systemic inflammatory response, severe COVID-19 is associated with hypercoagulability and a prothrombotic state. Currently, there is growing evidence that pulmonary embolism and thrombosis contribute to adverse outcomes and increased mortality in critically ill patients with COVID-19. The optimal thromboprophylactic regimen for patients with COVID-19 is not known. Whereas pharmacologic thromboprophylaxis is generally recommended for all hospitalized COVID-19 patients, adequate dosing of anticoagulants remains a controversial issue. Therefore, we summarize current evidence from the available literature and, on behalf of the German Society of Angiology (DGA), we aim to provide advice to establish an improved and more uniform strategy for thromboprophylaxis in patients with COVID-19.


Causes of Rapid Carrion Beetle (Coleoptera: Silphidae) Death in Flooded Pitfall Traps, Response to Soil Flooding, Immersion Tolerance, and Swimming Behavior.
Terrestrial insects in water can often delay or escape drowning by floating and swimming. However, we observed that flooding of pitfall traps baited with rotting carrion results in high overnight mortality of captured beetles and reasoned that this risk may be enhanced by microbial respiration. By assessing carrion beetle (Coleoptera: Silphidae) response to flooding, tolerance to immersion, and swimming behavior, we offer insights to this cause of death and beetle behavioral physiology. Response of buried Nicrophorus orbicollis Say to soil flooding resulted in beetles moving to the soil surface. The lethal time to 50% mortality (LT50 (immersion); mean ± 95% CI) for Nicrophorus investigator Zetterstedt, Nicrophorus marginatus F., Necrodes surinamensis F., and Thanatophilus lapponicus Herbst was 14.8 ± 2.3, 9.0 ± 3.3, 3.2 ± 1.1, and 12.1 ± 2.5 h, respectively. Swimming behavior and survival time of N. investigator was tested using yeast:sucrose (Y:S) solutions to create a eutrophic, severely hypoxic aqueous environment. LT50 (swimming) for N. investigator was 7.5 ± 1.4, 6.0 ± 1.7, and 4.2 ± 1.2 h for the low, medium, and high Y:S solutions, respectively, and >24.0 h in control treatments. Nicrophorus investigator survived nearly twice as long when completely immersed in deoxygenated water, as might occur in flooded burrows, than when swimming on the surface. We document for the first time, the rapid induction of hypoxic coma and death for a terrestrial insect from enhanced microbial activity and CO2 production of an aqueous environment, as well as suggestions on trapping protocols related to the federally endangered Nicrophorus americanus Olivier.


Peptide self-assembly: from toxins to amyloid fibrils and nanotubes.
The process of self-assembly is universal and lies at the heart of biological structures and function. Peptide aggregation, while considered a nuisance in peptide chemistry, soon gained interest with the discovery of pore-forming peptide toxins and had been an area of intense research during last century and even to date. This has also resulted in the increasing use of the more respectable term peptide self-assembly. The discovery of amyloid forming peptides has rekindled the interest in peptide self-assembly since such aggregates are directly implicated in many debilitating diseases in human and animals. Amyloid aggregates have posed many fundamental questions to researchers. In addition, self-assembly of peptides has emerged as a bottom-up strategy for the fabrication of nanostructures owing to highly ordered nature of the process and considerable degree of flexibility and diversity provided by peptides as starting materials. This review provides a brief account of the progress in the field of peptide self-assembly from pore-forming toxins to amyloid forming peptides and those forming nanostructures.


The Kindergarten Hotspot: Literacy Skill Convergence Between Boston Prekindergarten Enrollees and Nonenrollees.
Preschool improves children's kindergarten readiness, but the cognitive outcomes of preschool enrollees and nonenrollees tend to converge partially or fully in elementary school. In older programs, most of this convergence occurs in kindergarten (Li et al., 2016), but evidence from today's programs is sparse. Using data on 4,971 children who applied to the Boston Public School Prekindergarten program and a quasi-experimental approach, we examine convergence in kindergarten through third grade (K-3) literacy outcomes of prekindergarten enrollees and nonenrollees. Consistent with previous literature, most of the convergence in K-3 literacy outcomes occurred in kindergarten. Our findings suggest that detailed investigations into the kindergarten teaching and learning context may be particularly important for solving the widely noted preschool convergence pattern.


PCR detection of Streptococcus mutans and S. sobrinus in dental plaque samples from Japanese pre-school children.
Streptococcus mutans and S. sobrinus are associated with the development of dental caries. These bacteria were detected by PCR and then their presence was compared with the incidence of dental caries in 77 Japanese pre-school children. Plaque samples were collected from all erupted tooth sites in the subjects, aged 3-5 years old and each with primary dentition, with a sterile toothbrush. A dental examination was performed for dmft (decayed, missing, filled, total) with the WHO caries diagnostic criteria. In all subjects, the prevalence of S. mutans and S. sobrinus was 72.8% and 61.1%, respectively; 19 (24.7%) were positive for S. mutans alone, 10 (13.0%) were positive for S. sobrinus alone, 37 (48.1%) were positive for both S. mutans and S. sobrinus, and 11 (14.3%) were negative for both S. mutans and S. sobrinus. The dmft scores of children positive for both S. mutans and S. sobrinus were significantly higher than those positive for S. mutans alone. These results indicate that children harbouring both S. mutans and S. sobrinus have a significantly higher incidence of dental caries than those with S. mutans alone.


A randomized study of two different schedules of methyl CCNU, 5-FU and vincristine for metastatic colorectal carcinoma.
Sixty-seven patients with measurable colorectal carcinoma were randomized to receive two different schedules of Methyl CCNU, 5-FU and Vincristine (MOF). The treatment schedule consisted of Methyl CCNU 150 mg/m2 po q 70 days, 5-FU 300 mg/m2 iv for 5 consecutive days q 35 days, and Vincristine 1 mg/m2 IV q 35 days. The same total dose was used in each arm; in MOF A, the Methyl CCNU was given on day 1, while in MOF B, the Methyl CCNU was divided and given over 5 consecutive days. In MOF A, there was a 10% partial response rate and a 10% minor response rate. In MOF B, the partial response rate was 12% and the minor response rate was 21%. This difference is not statistically significant, but the patients in MOF B experienced less gastrointestinal toxicity (p less than .001).


Imaging approach to COVID-19 associated pulmonary embolism.
The novel coronavirus disease-2019 (COVID-19) illness and deaths, caused by the severe acute respiratory syndrome coronavirus-2, continue to increase. Multiple reports highlight the thromboembolic complications, such as pulmonary embolism (PE), in COVID-19. Imaging plays an essential role in the diagnosis and management of COVID-19 patients with PE. There continues to be a rapid evolution of knowledge related to COVID-19 associated PE. This review summarises the current understanding of prevalence, pathophysiology, role of diagnostic imaging modalities, and management, including catheter-directed therapy for COVID-19 associated PE. It also describes infection control considerations for the radiology department while providing care for patients with COVID-19 associated PE.


Hybrid endovascular repair in aortic arch pathologies: a retrospective study.
The aortic arch presents specific challenges to endovascular repair. Hybrid repair is increasingly evolving as an alternative option for selected patients, and promising initial results have been reported. The aim of this study was to introduce our experiences and evaluate mid-term results of supra aortic transpositions for extended endovascular repair of aortic arch pathologies. From December 2002 to January 2008, 25 patients with thoracic aortic aneurysms and dissections involving the aortic arch were treated with hybrid endovascular treatment in our center. Of the 25 cases, 14 were atherosclerotic thoracic aortic aneurysms and 11 were thoracic aortic dissection. The hybrid repair method included total-arch transpositions (15 cases) or hemi-arch transpositions (10 cases), and endovascular procedures. All hybrid endovascular procedures were completed successfully. Three early residual type-I endoleaks and one type-II endoleak were observed. Stroke occurred in three patients (8%) during the in-hospital stage. The perioperative mortality rate was 4%; one patients died post-operatively from catheter related complications. The average follow-up period was 15 ± 5.8 months (range, 1-41 months). The overall crude survival rate at 15 months was 92% (23/25). During follow-up, new late endoleaks and stent-raft related complications were not observed. One case (4%) developed a unilateral lower limb deficit at 17 days and was readmitted to hospital. In conclusion, the results are encouraging for endovascular aortic arch repair in combination with supra-aortic transposition in high risk cases. Aortic endografting offers good mid-term results. Mid-term results of the hybrid approach in elderly patients with aortic arch pathologies are satisfying.


Auxin responses in mutants of the Arabidopsis CONSTITUTIVE PHOTOMORPHOGENIC9 signalosome.
The CONSTITUTIVE PHOTOMORPHOGENIC9 (COP9) signalosome (CSN) is an evolutionarily conserved multiprotein complex that interacts with cullin-RING type E3 ubiquitin ligases (CRLs). CSN subunit 5 (CSN5), which, when incorporated into CSN, can deconjugate the NEDD8 modification from the cullin subunit of CRLs, is essential for CSN's role in controlling CRL activity. Whether the CSN5 monomer, which is maintained in csn mutants such as csn3 or csn4, has a functional role, remains to be established. We performed a comparative gene expression-profiling experiment with Arabidopsis (Arabidopsis thaliana) csn3, csn4, and csn5 mutants, and we show here that these mutants cannot be distinguished at the transcriptional level. Furthermore, we show that csn3 csn5 mutants are morphologically indistinguishable from csn3 or csn5 mutants. Taken together, these data suggest that the CSN5 monomer does not have a function that leads to transcriptional or morphological changes in the csn mutants. We further examined auxin responses in csn mutants. Whereas CSN had previously been shown to be required for the auxin response-regulatory E3 complexes, specifically SCF(TIR1), the csn mutant phenotype suggests that CSN is not essential for auxin responses. We present physiological and genetic data that indicate that auxin responses are indeed only partially impaired in csn mutants and that this is not the result of maternally contributed CSN. Finally, we discuss these findings in the context of the current understanding of the role of neddylation and CSN-mediated deneddylation for CRL activity.


Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms.
Seven human Sir2 homologues (sirtuin) have been identified to date. In this study, we clarified the mechanism of subcellular localization of two SIRT5 isoforms (i.e., SIRT5(iso1) and SIRT5(iso2) ) encoded by the human SIRT5 gene and whose C-termini slightly differ from each other. Although both isoforms contain cleavable mitochondrial targeting signals at their N-termini, we found that the cleaved SIRT5(iso2) was localized mainly in mitochondria, whereas the cleaved SIRT5(iso1) was localized in both mitochondria and cytoplasm. SIRT5ΔC, which is composed of only the common domain, showed the same mitochondrial localization as that of SIRT5(iso2) . These results suggest that the cytoplasmic localization of cleaved SIRT5(iso1) is dependent on the SIRT5(iso1) -specific C-terminus. Further analysis showed that the C-terminus of SIRT5(iso2) , which is rich in hydrophobic amino acid residues, functions as a mitochondrial membrane insertion signal. In addition, a de novo protein synthesis inhibition experiment using cycloheximide showed that the SIRT5(iso1) -specific C-terminus is necessary for maintaining the stability of SIRT5(iso1) . Moreover, genome sequence analysis from each organism examined indicated that SIRT5(iso2) is a primate-specific isoform. Taken together, these results indicate that human SIRT5 potentially controls various primate-specific functions via two isoforms with different intracellular localizations or stabilities.


Electrical detection of cellular penetration during microinjection with carbon nanopipettes.
The carbon nanopipette (CNP) is comprised of a pulled-glass pipette terminating with a nanoscale (tens to hundreds of nm) diameter carbon pipe. The entire inner glass surface of the CNP is coated with a carbon film, providing an electrically conductive path from the carbon tip to the distal, macroscopic end of the pipette. The CNP can double as a nanoelectrode, enabling electrical measurements through its carbon lining, and as a nanoinjector, facilitating reagent injection through its hollow bore. With the aid of a lock-in amplifier, we measured, in real time and with millisecond resolution, variations in impedance and interfacial capacitance as the CNP penetrated into the cytoplasm and nucleus of adherent human osteosarcoma (U20S) cells during microinjection. The capacitance change associated with nucleus penetration was, on average, 1.5 times greater than the one associated with cell membrane penetration. The experimental data was compared and favorably agreed with theoretical predictions based on a simple electrical network model. As a proof of concept, the cytoplasm and nucleus were transfected with fluorescent tRNA, enabling real-time monitoring of tRNA trafficking across the nuclear membrane. The CNP provides a robust and reliable means to detect cell and nucleus penetration, and trigger injection, thereby enabling the automation of cell injection.


Phosphorylation of C-protein in intact amphibian cardiac muscle. Correlation between 32P incorporation and twitch relaxation.
The molecular mechanisms by which neurotransmitters modulate the force of contraction of cardiac muscle are incompletely understood. Hartzell and Titus (1982. J. Biol. Chem. 257:2111-2120) have recently reported that C-protein, an integral component of the thick filament, is reversibly phosphorylated in response to ionotropic agents. In this communication, C-protein phosphorylation (as measured by isotopic labeling with 32P) is correlated with changes in the rate of relaxation of twitch tension. On the average, isoproterenol simultaneously increases peak systolic tension twofold, decreases twitch relaxation time from a control value of approximately 450 to approximately 300 ms, and increases C-protein phosphorylation two- to threefold, with a maximum effect occurring less than 60 s after addition of 1 microM isoproterenol. Carbamylcholine, in contrast, decreases peak systolic tension more rapidly than it affects relaxation or C-protein phosphorylation. The maximum decrease in peak tension (60%) occurs within 1 min of addition of 0.5 microM carbamylcholine, but relaxation time increases slowly to 800 ms over approximately 6 min. The increase in relaxation time correlates well with the decrease in 32P incorporation into C-protein (r = 0.94). Changing beat frequency between 0.2 and 1/s has no effect on C-protein phosphorylation but does alter relaxation time (relaxation time decreases approximately 100 ms when beat frequency is changed from 0.5 to 1/s) and thus alters the quantitative relationship between C-protein phosphorylation and relaxation rate. These results suggest that two separate processes affect relaxation. It is proposed that the level of C-protein phosphorylation sets the boundaries over which relaxation is regulated by a second process that is dependent upon beat frequency and probably involves changes in intracellular Ca.


Impact of hypertension on angiographic findings in patients with coronary artery disease.
The aim of this study was to assess the impact of hypertension on angiographic results in Iraqi patients with coronary artery disease. Six hundred and fifty seven patients with coronary artery disease (CAD) were submitted to routine coronary angiography in the period from January 2008 to December 2010. A comparison and evaluation have been divided into 2 stages. There was no significant association between patients with CAD who had a history of hypertension only with the number and distribution of coronary artery vessels involvement, as well as with morphological severity of coronary lesions. But, there was a statistically significant association between hypertension associated with other cardiac risk factors with multiple coronary lesions. Hypertension was significantly associated with multiple coronary artery lesions when combined with other cardiac risk factors.


Recent advances in personalized cancer immunotherapy with immune checkpoint inhibitors, T cells and vaccines.
The results of genomic and molecular profiling of cancer patients can be effectively applied to immunotherapy agents, including immune checkpoint inhibitors (ICI), to select the most appropriate treatment. In addition, accurate prediction of neoantigens facilitates the development of individualized cancer vaccines and T-cell therapy. This review summarizes the biomarker(s) predicting responses to ICIs and focuses on current strategies to identify and isolate neoantigen-reactive T cells as well as the clinical development of neoantigen-based therapeutics. The results suggest that maximal T-cell stimulation and expansion can be achieved with combination therapies that enhance antigen-presenting cells' function and optimal T-cell priming in lymph nodes.


Psychological aspects of nipple pain in lactating women.
The aim of the study was to assess the psychological impact of nipple pain in lactating women. Forty-eight lactating women with nipple pain completed mood scales at their first visit and following resolution of their pain, and 65 lactating women without nipple pain completed one set of mood scales. At the first visit, the mean score on the Edinburgh Postnatal Depression Scale (EPDS) in the nipple pain group was 12.4 and the control group was 7.6 (p < 0.0001). Eighteen women (38%) scored above the threshold for depression (> 12), compared to nine in the control group (14%): p < 0.01. Following pain resolution, the mean score on the EPDS decreased to 7.3 (p < 0.001); and six women (16%) scored 13 or over on the EPDS, significantly less than initially (p < 0.05). Similarly, on the Profile of Mood States (POMS), the nipple pain group scored significantly higher than control group on all mood factors (Tension, Depression, Fatigue, Confusion, Vigor [lower]), except Anger which did not reach a level of significance. After pain resolution, POMS scores returned to similar levels as the control group. In conclusion, both the EPDS and POMS indicated women with nipple pain were experiencing high levels of emotional distress. However, once the pain had resolved their distress also resolved.


"ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane".
Mitochondrial ATAD3A is an ATPase Associated with diverse cellular Activities (AAA) domain containing enzyme, involved in the structural organization of the inner mitochondrial membrane and of increasing importance in childhood disease. In humans, two ATAD3A paralogs arose by gene duplication during evolution: ATAD3B and ATAD3C. Here we investigate the cellular activities of the ATAD3C paralog that has been considered a pseudogene. We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. Overexpression of ATAD3C, but not of ATAD3A, in fibroblasts caused a decrease in cell proliferation and oxygen consumption rate, and an increase of cellular ROS. This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes. Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell.


Reducing hypoglycemia from overtreatment of type 2 diabetes in older adults: The HypoPrevent study.
Hypoglycemia from overtreatment is a serious but underrecognized complication among older adults with type 2 diabetes. However, diabetes treatment is seldom deintensified. We assessed the effectiveness of a Clinical Decision Support (CDS) tool and shared decision-making (SDM) in decreasing the number of patients at risk for hypoglycemia and reducing the impact of non-severe hypoglycemic events. HypoPrevent was a pre-post, single arm study at a five-site primary care practice. We identified at-risk patients (≥65 years-old, with type 2 diabetes, treated with insulin or sulfonylureas, and HbA1c < 7.0%). During three clinic visits over 6 months, clinicians used the CDS tool and SDM to assess hypoglycemic risk, set individualized HbA1c goals, and adjust use of hypoglycemic agents. We assessed the number of patients setting individualized HbA1c goals or modifying medication use, changes in the population at risk for hypoglycemia, and changes in impact of non-severe hypoglycemic events using a validated patient-reported outcome tool (TRIM-HYPO). We enrolled 94 patients (mean age-74; mean HbA1c (±SD)-6.36% ± 0.43), of whom 94% set an individualized HbA1c goal at either the baseline or first follow-up visit. Ninety patients completed the study. Insulin or sulfonylurea use was decreased or eliminated in 20%. An HbA1c level before and after goal setting was obtained in 53% (N = 50). Among these patients, the mean HbA1c increased 0.53% (p < 0.0001) and the number of patients at-risk decreased by 46% (p < 0.0001). Statistically significant reductions in the impact of hypoglycemia during daily activities occurred in both the total score and each functional domain of TRIM-HYPO. In a population of older patients at risk for hypoglycemia, the use of a CDS tool and SDM reduced the population at risk and decreased the use of insulin and sulfonylureas. Using a patient-reported outcome tool, we demonstrated significant reductions in the impact of hypoglycemia on daily life.


Cycling of RNAs on Hfq.
The RNA chaperone Hfq is a key player in small RNA (sRNA)-mediated regulation of target mRNAs in many bacteria. The absence of this protein causes pleiotropic phenotypes such as impaired stress regulation and, occasionally, loss of virulence. Hfq promotes rapid sRNA-target mRNA base pairing to allow for fast, adaptive responses. For this to happen, sRNAs and/or mRNAs must be bound by Hfq. However, when the intra- or extracellular environment changes, so does the intracellular RNA pool, and this, in turn, requires a correspondingly rapid change in the pool of Hfq-bound RNAs. Biochemical studies have suggested tight binding of Hfq to many RNAs, indicating very slow dissociation rates. In contrast, the changing pool of binding-competent RNAs must compete for access to this helper protein in a minute time frame (known response time for regulation). How rapid exchange of RNAs on Hfq in vivo can be reconciled with biochemically stable and very slowly dissociating Hfq-RNA complexes is the topic of this review. Several recent reports suggest that the time scale discrepancy can be resolved by an "active cycling" model: rapid exchange of RNAs on Hfq is not limited by slow intrinsic dissociation rates, but is driven by the concentration of free RNA. Thus, transient binding of competitor RNA to Hfq-RNA complexes increases cycling rates and solves the strong binding/high turnover paradox.


Maternal and Fetal Outcomes in Pregnant Women with Pulmonary Arterial Hypertension: A Single-Center Experience and Review of Current Literature.
Although pregnancy in women with pulmonary arterial hypertension has been considered a high-risk condition, current data regarding pregnancy with pulmonary arterial hypertension are scarce. In this study, we aimed to evaluate our single-center data on maternal and fetal outcomes in pregnant women with PAH and review currently available risk-based management strategies. Our single-center study group comprised 35 women who became pregnant after the diagnosis of pulmonary arterial hypertension or in whom pulmonary arterial hypertension was diagnosed within early post-partum period. Clinical, laboratory, echocardiographic, and hemodynamic characteristics of pregnant and non-pregnant productive women with pulmonary arterial hypertension were compared, and similar comparison was also repeated for survivors and non-survivors in pregnant patient group. Pregnancy was noted in 15% of the 228 females with pulmonary arterial hypertension who were of hormonally productive ages, generally well-tolerated until delivery. Elective abortion and pre-term delivery were documented in 1 (2.8%) and 12 (35.3%) pregnant women, respectively. Switching to sildenafil was the standard medication during pregnancy. Cesarian section was the preferred method of delivery in all pregnant women with pulmonary arterial hypertension and was performed without any complication. Clinic deteoriation within the first week of delivery was observed in 5 (41.6%) patients. Maternal mortality was noted in 13 (37.1%) patients and was documented to cumulate within the first month of delivery. However, any sign predicting post-partum clinical deterioration was not found. No fetal mortality was observed. Despite the development of advanced therapies, pregnancy in pulmonary arterial hypertension still carries a high mortality risk and requires multi-disciplinary expert center care with more proactive management strategies.


Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene.
We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.


Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation.
Peptidoglycan recognition proteins (PGRPs) are conserved from insects to mammals and function in antibacterial immunity. We have revealed a novel mechanism of bacterial killing by innate immune system, in which mammalian PGRPs bind to bacterial cell wall or outer membrane and exploit bacterial stress defense response to kill bacteria. PGRPs enter Gram-positive cell wall at the site of daughter cell separation during cell division. In Bacillus subtilis PGRPs activate the CssR-CssS two-component system that detects and disposes of misfolded proteins exported out of bacterial cells. This activation results in membrane depolarization, production of hydroxyl radicals, and cessation of intracellular peptidoglycan, protein, RNA, and DNA synthesis, which are responsible for bacterial death. PGRPs also bind to the outer membrane in Escherichia coli and activate functionally homologous CpxA-CpxR two-component system, which also results in bacterial death. We excluded other potential bactericidal mechanisms, such as inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan, and membrane permeabilization. In vivo, mammalian PGRPs are expressed in polymorphonuclear leukocytes, skin, salivary glands, oral cavity, intestinal tract, eyes, and liver. They control acquisition and maintenance of beneficial normal gut microflora, which protects the host from enhanced inflammation, tissue damage, and colitis.


Conventional respiratory viruses recovered from immunocompromised patients: clinical considerations.
Lower respiratory tract infection is the most common complication in the immunocompromised patient. From January 1991 to December 1995, 785 consecutive patients with suspected respiratory tract infections were studied. One hundred ninety-nine viruses were isolated from 182 (23%) of 785 bronchoalveolar lavage fluid specimens. Cytomegalovirus was isolated from 131 patients, herpes simplex virus was recovered from 31, and conventional respiratory viruses (CRVs) were recovered from 36. There were 9 influenza A viruses, 2 influenza B viruses, 7 parainfluenza viruses, 5 respiratory syncytial viruses, 5 adenoviruses, 6 enteroviruses, and 3 rhinoviruses. We identified 22 patients from whom a CRV was the only microorganism recovered; 13 patients developed pneumonia, 10 had acute respiratory failure, 5 required support with mechanical ventilation, and 5 (23%) died. In conclusion, CRVs are frequent causes of respiratory illnesses and are associated with high rates of morbidity and mortality among immunocompromised patients.


Community cognitive interviewing to inform local adaptations of an e-mental health intervention in Lebanon.
Lebanon has a need for innovative approaches to increase access to mental health care to meet the country's current high demand. E-mental health has been included in its national mental health strategy while in parallel the World Health Organization has produced an online intervention called 'Step-by-Step' to treat symptoms of depression that is being tested in Lebanon over the coming years. The primary aim of this study is to conduct bottom-up, community-driven qualitative cognitive interviewing from a multi-stakeholder perspective to inform the cultural adaptation of an Internet-delivered mental health intervention based on behavioural activation in Lebanon. National Mental Health Programme staff conducted a total of 11 key informant interviews with three mental health professionals, six front-line workers in primary health care centres (PHCCs) and two community members. Also, eight focus group discussions, one with seven front-line workers and seven others with a total of 66 community members (Lebanese, Syrians and Palestinians) were conducted in several PHCCs to inform the adaptation of Step-by-Step. Results were transcribed and analysed thematically by the project coordinator and two research assistants. Feedback generated from the cognitive interviewing mainly revolved around amending the story, illustrations and the delivery methods to ensure relevance and sensitivity to the local context. The results obtained have informed major edits to the content of Step-by-Step and also to the model of provision. Notably, the intervention was made approximately 30% shorter; it includes additional videos of content alongside the originally proposed comic book-style delivery; there is less emphasis on total inactivity as a symptom of low mood and more focus on enjoyable activities to lift mood; the story and ways to contact participants to provide support were updated in line with local gender norms; and many of the suggested or featured activities have been revised in line with suggestions from community members. These findings promote and advocate the use of community-driven adaptation of evidence-based psychological interventions. Some of the phenomena recorded mirror findings from other research about barriers to care seeking in the region and so changes made to the intervention should be useful in improving utility and uptake of 'Step-by-Step'.


A Synthetic Strong and Constitutive Promoter Derived from the Stellaria media pro-SmAMP1 and pro-SmAMP2 Promoters for Effective Transgene Expression in Plants.
Synthetic promoters are vital for genetic engineering-based strategies for crop improvement, but effective methodologies for their creation and systematic testing are lacking. We report here on the comparative analysis of the promoters pro-SmAMP1 and pro-SmAMP2 from Stellaria media ANTIMICROBIAL PEPTIDE1 (AMP1) and ANTIMICROBIAL PEPTIDE2 (AMP2). These promoters are more effective than the well-known Cauliflower mosaic virus 35S promoter. Although these promoters share about 94% identity, the pro-SmAMP1 promoter demonstrated stronger transient expression of a reporter gene in Agrobacterium infiltration of Nicotiana benthamiana leaves, while the pro-SmAMP2 promoter was more effective for the selection of transgenic tobacco (Nicotiana tabacum) cells when driving a selectable marker. Using the cap analysis of gene expression method, we detected no differences in the structure of the transcription start sites for either promoter in transgenic plants. For both promoters, we used fine-scale deletion analysis to identify 160 bp-long sequences that retain the unique properties of each promoter. With the use of chimeric promoters and directed mutagenesis, we demonstrated that the superiority of the pro-SmAMP1 promoter for Agrobacterium-mediated infiltration is caused by the proline-inducible ACTCAT cis-element strictly positioned relative to the TATA box in the core promoter. Surprisingly, the ACTCAT cis-element not only activated but also suppressed the efficiency of the pro-SmAMP1 promoter under proline stress. The absence of the ACTCAT cis-element and CAANNNNATC motif (negative regulator) in the pro-SmAMP2 promoter provided a more constitutive gene expression profile and better selection of transgenic cells on selective medium. We created a new synthetic promoter that enjoys high effectiveness both in transient expression and in selection of transgenic cells. Intact promoters with differing properties and high degrees of sequence identity may thus be used as a basis for the creation of new synthetic promoters for precise and coordinated gene expression.


LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in LPIN2 and review of literature.
LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519). To date, only 31 individuals from 18 families have been reported with this rare condition. Exome sequencing was done in two affected individuals from two unrelated families. Additionally, phenotypic, and genotypic information from the literature was reviewed. Two novel homozygous missense variants, c.2207G>A p. (Arg736His) and c.1157C>G p. (Ser386Ter) in LPIN2 , were identified in family 1 and family 2 respectively. Chronic recurrent osteomyelitis involving the lower extremities was the most common clinical presentation. LPIN2 -related Majeed syndrome should be considered as a differential diagnosis in an individual with clinical or radiological evidence of recurrent sterile osteomyelitis and chronic anaemia.


Peripherally inserted central venous catheters in critically ill premature neonates.
To evaluate the safety of peripherally inserted central venous catheters (PICCs) and their complications in critically ill premature neonates. A retrospective collection of data of infants with very low birth weight (VLBW) who underwent PICC placement over a 2-year period. Gestational age, birth weight (BW), sex, site of catheter placement, reason for catheter removal, duration of the catheter use, proven sepsis, type of the reported organism and the rate of complications were collected. The infants were classified into two groups according to BWs: Group 1-VLBW infants (BW between 1,000 and 1,500 g) and Group 2-BW <1,000 g (extremely low birth weight, ELBW group). During the study period, 90 VLBW infants were admitted to the neonatal intensive care unit. PICCs were attempted in 71 patients. A PICC was successfully inserted into 62 patients (87.3%). Totally, 68 PICCs were inserted into 62 infants. PICCs placed in either the upper or the lower extremity have no differences in complication rates. The median time of catheter insertion was 10 (1-22) days for Group 1 and 16 (1-47) days for Group 2 (p=0.001). The median duration of PICCs was 9 (2-18) and 12.0 (3-30) days, respectively (p=0.012). There were no significant differences between groups for the reasons for removal (p=0.859). PICCs are convenient for the administration of long course antibiotics and parenteral nutrition for both VLBW and ELBW infants. The risk of catheter complications did not increase in ELBW infants. Although the technique of insertion is easy and using PICCs has many benefits, serious and fatal complications may occur in premature neonates in critical states.


Models for drug absorption from the small intestine: where are we and where are we going?
The small intestine is a complex organ with movements, flora, mucus and flows. Despite this, the most widely used absorption models consider the organ a cylindrical monoepithelial tube. This review presents the recent evolution of models to take into consideration the complex nature of gut physiology. The most commonly encountered issues are ethical (in vivo models) and differences in drug transport as a result of a modified expression of drug transporters or metabolic enzymes compared with human (in vitro and in vivo models). Finally, this review discusses the way forward to reach an ideal equilibrium between reproducibility, predictability and efficiency for predicting permeability. The features of an ideal model are listed as a guideline for future development.


Two sisters with Toriello-Carey syndrome.
Toriello-Carey syndrome comprises agenesis of the corpus callosum, telecanthus, short palpebral fissures, small nose with anteverted nares, Robin sequence, abnormally shaped ears, cardiac defect, and hypotonia. We describe two Japanese sisters with a Toriello-Carey syndrome whose phenotypes were as severe as reported male cases. The younger sister died suddenly at age 4 months. Our patients with a severe phenotype and possible parental consanguinity suggest autosomal recessive inheritance of Toriello-Carey syndrome.


Small proteins in gram-positive bacteria.
Small proteins comprising less than 100 amino acids have been often ignored in bacterial genome annotations. About 10 years ago, focused efforts started to investigate whole peptidomes, which resulted in the discovery of a multitude of small proteins, but only a number of them have been characterized in detail. Generally, small proteins can be either membrane or cytosolic proteins. The latter interact with larger proteins, RNA or even metal ions. Here, we summarize our current knowledge on small proteins from Gram-positive bacteria with a special emphasis on the model organism Bacillus subtilis. Our examples include membrane-bound toxins of type I toxin-antitoxin systems, proteins that block the assembly of higher order structures, regulate sporulation or modulate the RNA degradosome. We do not consider antimicrobial peptides. Furthermore, we present methods for the identification and investigation of such proteins.


Mechanism of inhibition of peroxynitrite-induced oxidation and nitration by [6]-gingerol.
[6]-Gingerol potently inhibits peroxynitrite-induced oxidation and nitration reactions, but its mechanism of action is unclear. In order to discover the mechanism of inhibition, [6]-gingerol was reacted with peroxynitrite and the reaction mixture was analyzed using HPLC. The HPLC chromatogram showed one novel peak, indicative of the formation of a reaction product between [6]-gingerol and peroxynitrite. This compound was purified and identified as a symmetrical dimer of [6]-gingerol covalently linked at the aromatic ring. It has been assumed that this dimer is generated from a phenoxyl radical intermediate produced from [6]-gingerol via one-electron oxidation by peroxynitrite-derived radicals. We propose a mechanism in which [6]-gingerol scavenges peroxynitrite-derived radicals and consequently inhibits peroxynitrite-induced oxidation and nitration reactions.


Report on the 1st international workshop on procedures for the development of evidence-based vaccination recommendations, Berlin, Germany, 22-23 November 2010.
In November 2010, experts from European and North-American countries met in Berlin, Germany, to discuss improved methods for the development of evidence-based vaccination recommendations. The objectives of the workshop were to (i) review current procedures and experiences of National Immunization Technical Advisory Groups (NITAGs) in developing a framework for evidence-based vaccination recommendations, (ii) discuss the applicability of methods like Grading of Recommendations Assessment, Development and Evaluation (GRADE), and (iii) to identify opportunities for international collaboration to support NITAGs in the development of vaccination recommendations at country-level. Recognizing that a systematic and transparent approach is necessary to promote the quality and acceptance of vaccination recommendations, various decision making frameworks have been implemented by national and international advisory groups addressing common key aspects of knowledge, such as the burden of disease or characteristics of the vaccine. There are several challenges when grading the quality of evidence of some immunization-specific topics (e.g. population-level effects of vaccination). This does not, however, necessitate development of an entirely new systematic methodology. The participants concluded that (i) GRADE or a modification of this methodology is suitable for the grading of quality of evidence related to vaccine effectiveness and safety, and that (ii) international cooperation would be beneficial to develop common framework methodologies for certain aspects of national immunization recommendation developments in order to avoid duplication of efforts, to build on existing strengths, and to support NITAGs worldwide.


Model-based Estimators of QT Series Time Delay in Following Heart-Rate Changes.
Sudden cardiac death is the leading cause of death among cardiovascular diseases. Markers for patient risk stratification focusing on QT-interval dynamics in response to heart-rate (HR) changes can be characterized in terms of parametric QT to RR dependence and QT/RR hysteresis. The QT/RR hysteresis can be quantified by the time delay the QT interval takes to accommodate for the HR changes. The exercise stress test has been proposed as a proper test, with large HR dynamics, to evaluate the QT/RR hysteresis. The present study aims at evaluating several time-delay estimators based on noise statistic (Gaussian or Laplacian) and HR changes profile at stress test (gradual transition change). The estimator's performance was assessed on a simulated QT transition contaminated by noise and in a clinical study including patients affected by coronary arteries disease (CAD). As expected, the Laplacian and Gaussian estimators yield the best results when noise follows the respective distribution. Further, the Laplacian estimator showed greater discriminative power in classifying different levels of cardiac risk in CAD patients, suggesting that real data fit better the Laplacian distribution than the Gaussian one. The Laplacian estimator appears to be the choice for time-delay estimation of QT/RR hysteresis lag in response to HR changes in stress test.Clinical Relevance-The proposed time-delay estimator of QT/RR hysteresis lag improves its significance as biomarkers for coronary artery diseases risk stratification.


Substrate utilization during graded aerobic exercise in rainbow trout.
A biochemical approach was employed to examine the oxidative utilization of carbohydrate and lipid in red muscle of rainbow trout (Oncorhynchus mykiss) during sustained swimming at 30 and 60% of their critical swimming speed (U(crit); for 2, 15 and 240 min) and during non-sustainable swimming at 90% U(crit) (for 2, 15 and 45 min). Measurements included pyruvate dehydrogenase (PDH) activity, creatine phosphate, ATP, glycogen, glycolytic intermediates, acetyl-CoA, acetyl-, total-, free-, short-chain fatty acyl- and long-chain fatty acyl- carnitine, intramuscular triacylglycerol and malonyl-CoA concentrations, and whole body oxygen consumption ((O)(2)). During the first 2 min at 30 and 60% U(crit), oxidation of endogenous glycogen by PDH activation increased 4- and 8-fold, respectively, yielding 1.5- to 2.5-fold increases in acetyl-CoA and 2- to 6-fold increases in acetyl-carnitine concentrations. Within 15 min, PDH activity returned to control values (153.9+/-30.1 nmol g(-1) wet tissue min(-1)); after 240 min there were small 1.7- to 2.6-fold increases in long-chain fatty acyl-carnitine and approx. 50% decreases in malonyl-CoA concentrations, indicating an overall enhancement of lipid oxidation. Sustainable swimming at 30 and 60% U(crit) was further characterized by 1.5- and 2.2-fold increases in M(O(2)), respectively. Non-sustainable swimming at 90% U(crit) was characterized by a sustained tenfold (approx.) elevation of red muscle PDH activity (approx. 1600 nmol g(-1) wet tissue min(-1)). Significant 67% decreases in white muscle creatine phosphate and 73% decreases in glycogen levels, without matching increases in lactate levels, point to significant recruitment of white muscle during high-speed swimming for power production, and the potential export of white muscle lactate to red muscle for oxidation. Overall, sustainable exercise at 30 and 60% U(crit) is supported by approximately equal contributions of carbohydrate (approx. 45%) and lipid (approx. 35%) oxidation, whereas non-sustainable swimming is supported primarily by carbohydrate oxidation with only moderate contributions from lipid oxidation.


High-resolution elasticity imaging for tissue engineering.
An elasticity microscope provides high resolution images of tissue elasticity. With this instrument, it may be possible to monitor cell growth and tissue development in tissue engineering. To test this hypothesis, elasticity micrographs were obtained in two model systems commonly used for tissue engineering. In the first, strain images of a tissue-engineered smooth muscle sample clearly identified a several hundred micron thick cell layer from its supporting matrix. Because a one-dimensional mechanical model was appropriate for this system, strain images alone were sufficient to image the elastic properties. In contrast, a second system was investigated in which a simple one-dimensional mechanical model was inadequate. Uncultured collagen microspheres embedded in an otherwise homogeneous gel were imaged with the elasticity microscope. Strain images alone did not clearly depict the elastic properties of the hard spherical cell carriers. However, reconstructed elasticity images could differentiate the hard inclusion from the background gel. These results strongly suggest that the elasticity microscope may be a valuable tool for tissue engineering and other applications requiring the elastic properties of soft tissue at high spatial resolution (75 microm or less).


Diagnostic value of magnetic resonance imaging for malignant tumors in the oral and maxillofacial region.
The purpose of this study was to clarify the diagnostic value of magnetic resonance imaging for malignant tumors in the oral and maxillofacial region. Computed tomography and magnetic resonance images of 25 patients with malignant tumors of the oral and maxillofacial region were evaluated. Computed tomography scans were performed with intravenous contrast enhancement. A 0.2-Tesla (Hitachi Medical Corp., Tokyo, Japan) permanent magnetic resonance unit was used to obtain T1-, T2-, and proton-density-weighted images with spin-echo pulse sequences. Gadolinium-diethylene-triamine-pentaacetic acid was administered in 11 cases. Severe artifacts influencing image interpretation were observed in 10 (40%) cases on computed tomography but only in 5 (20%) cases on magnetic resonance imaging. There was no difference in the detectability of bone invasion between images from the two systems. Contrast enhancement with gadolinium-diethylene-triamine-pentaacetic acid provided additional useful information in only 3 of 11 cases compared with nonenhanced magnetic resonance images. Malignant tumors showed a higher signal intensity than that of muscle on T2-weighted images in all cases and on proton-density-weighted images in 23 (92%) cases. On T1-weighted images, an intermediate signal intensity similar to that of muscle was seen in 16 (64%) cases and a hyperintense signal in 9 (36%) cases. There was poor correlation between signal intensity and pathologic diagnosis of the tumors. These results suggest that in cases with severe artifacts that disturb the interpretation of the images on computed tomography, magnetic resonance examinations are preferable for defining the exact extent of the primary lesion.


Retinaldehyde alleviates rosacea.
Anecdotal observations suggest that retinoic acid may be effective in mild rosacea. Our aim was to investigate, by an exploratory clinical and instrumental study, the effects of a topical formulation with the retinoic acid precursor retinaldehyde, in patients with vascular signs of facial rosacea. Female patients were treated with a 0.05% retinaldehyde cream that was applied once daily for 6 months. Clinical assessments of persistent erythema and telangiectasia were performed every month, using a 4-point severity score (absent to severe). The clinical response for each parameter was defined as a decrease of at least 1 grade in the severity score. In addition, erythema was further evaluated by measurement of the a* parameter, using a spectrophotometer on lesional and nonlesional areas. A total of 23 women comprised the study population. At baseline, 10 patients had diffuse erythema, 3 patients had isolated telangiectasia and 10 patients had both. During retinaldehyde treatment, a clinical response was revealed in about 75% of the patients with erythema, after 5 months (p < 0.05). Similarly, isolated telangiectasia responded to retinaldehyde, although to a lesser extent and after a longer period of treatment (46% responders after 6 months, nonsignificant). Using the spectrophotometer, the a* parameter diminished in patients with erythema by about 15%, after 2 months of treatment (p = 0.001). This study indicates that retinaldehyde has beneficial effects on the vascular component of rosacea.


Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors.
Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1-28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses. Dose limiting toxicities (DLTs) were only assessed during the first cycle of treatment and response evaluation was performed every 2 cycles. The effects of tanibirumab on several angiogenic factors were analyzed. Results From October 2011 to September 2013, a total of 26 patients with refractory solid tumors were enrolled. The median age was 58 years (range, 27-75) and 20 patients were male. The most common tumor type was colorectal cancer (N = 19) and seven patients had a history of previous bevacizumab treatment. As hemangioma continued to occur, the final dose level, 28 mg/kg, was not performed. DLTs were not found, and the MTD was confirmed to be 24 mg/kg. Hemangioma was observed in 16 patients (61.5%), but all were grade 1-2 and disappeared after discontinuation of the study drug. Among the 18 patients in the efficacy set, no objective response was observed, but 11 patients showed stable disease. PKs were characterized by dose-dependent linear exposure and the mean trough concentrations exceeded biologically relevant target levels at 12 mg/kg and above. Serum VEGF, soluble VEGFR-2, and PlGF increased at the 4 mg/kg dose level and above. Conclusions Treatment with tanibirumab showed a tolerable toxicity profile and modest clinical efficacy in patients with refractory solid tumors. A phase II trial of tanibirumab is ongoing now.


Dysregulated metabolites and lipids in serum of patients with acute hepatitis E: A longitudinal study.
Hepatitis E is a disease associated with acute inflammation of the liver. It is related to several dysregulated metabolic pathways and alterations in the concentration of several metabolites. However, longitudinal analysis of the alterations in metabolites and lipids is generally lacking. This study investigated the changes in levels of metabolites and lipids over time in sera from men with acute hepatitis E compared to healthy controls similar in age and gender. Untargeted measurement of levels of various metabolites and lipids was done using mass spectrometry on 65 sera sequentially sampled from 14 patients with acute hepatitis E and 25 serum samples from five controls. Temporal changes in intensities of metabolites and lipids were determined over different times at 3-day periods for the hepatitis E virus (HEV) group. In carbohydrate metabolism, glucose levels, fructose 1-6-bisphosphate and ribulose-5-phosphate were increased in the HEV-infected persons compared to the healthy controls. HEV infection is significantly associated with decreased levels of inosine, guanosine, adenosine and urate in purine metabolism and thymine, uracil and β-aminoisobutyrate in pyrimidine metabolism. Glutamate, alanine and valine levels were significantly lower in the HEV group than in healthy individuals. Homogentisate of tyrosine metabolism and cystathionine of serine metabolism were increased, whereas kynurenate of tryptophan metabolism decreased in the HEV group. Metabolites of the bile acid biosynthesis, urea cycle (arginine and citrulline) and ammonia recycling (urocanate) were significantly altered. Co-enzymes, pantothenate and pyridoxal, and co-factors, lipoamide and FAD, were elevated in the HEV group. The acylcarnitines, sphingomyelins, phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysoPC and lysoPE tended to be lower in the HEV group. In conclusion, acute hepatitis E is associated with altered metabolite and lipid profiles, significantly increased catabolism of carbohydrates, purines/pyrimidines and amino acids, and decreased levels of several glycerophospholipids.


Dexfenfluramine elevates systemic blood pressure by inhibiting potassium currents in vascular smooth muscle cells.
Appetite suppressants, such as dexfenfluramine (dex), are associated with primary pulmonary hypertension, valvular heart disease, and systemic vascular complications, such as coronary, cerebral, or mesenteric ischemia. These drugs suppress appetite by enhancing release and inhibiting reuptake of serotonin in the central nervous system. The effects of dex on the systemic circulation have not been studied. K(+) channels regulate vascular tone in most vascular beds. We hypothesized that dex is a systemic vasoconstrictor acting primarily by inhibiting K(+) channels, independent of effects on serotonin. The effects of clinically relevant concentrations of dex (10(-6) to 10(-4) M) on outward K(+) current and membrane potential were studied with whole-cell patch clamping in freshly isolated smooth muscle cells from rat renal, carotid, and basilar arteries. Tone was measured in tissue baths. Blood pressure, cardiac output, and left ventricular end diastolic pressure were assessed in open- and closed-chest anesthetized rats. At 10(-4) M, dex inhibits outward K(+) current (50%) and increases membrane potential (by >35 mV), an effect comparable with 4-aminopyridine (5 mM). Furthermore, dex constricts rings and acutely elevates systemic pressure (+17 +/- 3 mm Hg) and systemic vascular resistance in the presence of ketanserin. Dex vasoconstriction is dose-dependent (threshold dose 10(-6) M; 156 microg/ml) and enhanced in L-NAME-fed rats. We conclude that dex causes acute systemic vasoconstriction, at least in part by inhibition of voltage-gated K(+) channels, independent of effects on serotonin. To our knowledge, this is the first time that a commonly prescribed drug with voltage-gated K(+) channel-blocking properties is shown to have significant hemodynamic effects in vivo.