Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates.
Protein aggregates are a potential risk factor for immunogenicity. The measurement, characterization, and control of protein aggregates in drug products are indispensable for the development of biopharmaceuticals, including therapeutic mAbs. In this study, Fcγ receptor (FcγR)-expressing reporter cell lines were used to analyze the FcγR-activation properties of mAb aggregates. Comparison of aggregates of mAbs harboring different IgG subclasses revealed that the FcγR-activation profiles of the mAb aggregates were dependent on IgG subclass. In addition, aggregates of Fc-engineered mAb with enhanced FcγR-activation properties exhibited stronger activation of FcγRs than was observed in the wild-type aggregates, whereas aggregates of Fc-engineered mAb with decreased FcγR-activation properties showed reduced activation. These results suggest that FcγR activation by mAb aggregates depends greatly on the Fc functions of the native (nonaggregated) mAbs. We also showed that aggregates of mAbs smaller than 1 μm in size have the potential to directly activate FcγRs. Unintended immune cell activation can be induced on account of FcγR activation by mAb aggregates and such FcγR activation may contribute to immunogenicity, and therefore, analysis of the FcγR-activation properties of mAb aggregates using FcγR-expressing reporter cell lines is a promising approach for the characterization of mAb aggregates.


Reversal of anterior cervical discectomy and fusion with cervical artificial disc replacement: regain motion after 9 years fusion.
Case report and review of the literature. To present a conversion of an anterior cervical discectomy and fusion (ACDF) with a cervical artificial disc replacement in a 39-year-old woman and to review the relevant literature. Return of functional spinal unit motion 9 years after attempted fusion is extremely rare. The patient underwent an attempted anterior cervical discectomy and fusion 9 years earlier for bilateral hand numbness and leg weakness. Most of her neurological deficits had resolved after the index operation, but returned 2 months before the second operation and were unresponsive to nonoperative treatment. Computed tomography (CT) myelography showed recurrence of cervical disc herniation at the cephalad adjacent segment, which compressed the spinal cord. There was still some osteophyte at the C5/6 level that was also causing compression to the spinal cord. A solid fusion was suspected at this level. Surgery was performed to take down the grafted region and replace both levels with artificial disks. The range of motion (ROM) of the revised level at the 6-month follow-up was well preserved, there was no sign of instability at either operated level. The 6-month follow-up CT scan shows that, there was no obvious compression in the spinal canal. The remobilized facet joints of C5/6 segment have not demonstrated further degeneration. The patient's neck symptom and neurological function were significantly recovered. This case demonstrates application of a cervical artificial disc replacement to restore motion at a level that was previously grafted and fused. In select cases, cervical artificial disc replacement may represent a reasonable alternative to a repeated attempt at fusion. It is imperative that preoperatively lack of fusion of the facet joints be demonstrated on reconstructed CT scanning.


Hyposplenism, Hashimoto's Autoimmune Thyroiditis and Overlap Syndrome (Celiac Disease and Autoimmune Hepatitis Type 1).
Hyposplenism is associated with autoimmune diseases, inflammatory bowel disease, severe celiac disease, autoimmune thyroiditis, untreated HIV infection and chronic graft-versus-host disease. The aim of this study was to review the existing data on hyposplenism associated with celiac disease and Hashimoto's autoimmune thyroiditis. Our research was based on a clinical case concerning a 41-year-old female who presented with asthenia, fatigue, dyspepsia and chronic diarrhea. The medical history revealed autoimmune Hashimoto's thyroiditis, type 2 diabetes, fatty liver disease, chronic gastritis and thrombocytosis. Multiple investigations showed hyposplenism and complex autoimmune dysfunction with positive serum markers for celiac disease and type 1 autoimmune hepatitis along with minor symptomatology. The intestinal symptomatology of celiac disease is often hid by hypothyroidism-associated autoimmune thyroiditis. Asymptomatic or minimally symptomatic celiac disease associated with Hashimoto's autoimmune thyroiditis is diagnosed by biomarkers. Hyposplenism in celiac disease can occur regardless of the disease stage, latent or symptomatic.


Bereavement After a Child's Death.
The death of a child is a heart-wrenching experience that can have a significant impact on parents, siblings, and families while also often having ripple effects throughout the child's community. Pediatric loss has an impact on family structure and dynamics, individual identity formation, and conceptualization as well as professional practice. This article explores bereavement after a child's death through the lens of the family, the parent, the sibling, the forgotten grievers, and the provider.


'The money is important but all women anyway go to hospital for childbirth nowadays' - a qualitative exploration of why women participate in a conditional cash transfer program to promote institutional deliveries in Madhya Pradesh, India.
In 2005-06, only 39 % of Indian women delivered in a health facility. Given that deliveries at home increase the risk of maternal mortality, it was in this context in 2005, that the Indian Government implemented the Janani Suraksha Yojana program that incentivizes poor women to give birth in a health facility by providing them with a cash transfer upon discharge. JSY helped raise institutional delivery to 74 % in the eight years since its implementation. Despite the success of the JSY in raising institutional delivery proportions, the large number of beneficiaries (105 million), and the cost of the program, there have been few qualitative studies exploring why women participate (or not) in the program. The objective of this paper was to explore this. In March 2013, we conducted 24 individual in-depth interviews with women who delivered within the previous 12 months in two districts of Madhya Pradesh, India. Qualitative framework analysis was used to analyze the data. Our findings suggest that women's increased participation in the program reflect a shift in the social norm. Drivers of the shift include social pressure from the Accredited Social Health Activist (ASHA) to deliver in a health facility, and a growing individual perception of the importance for 'safe' and 'easy' delivery which was most likely an expression of the new social norm. While the incentive was an important influence on many women's choices, others did not perceive it as an important consideration in their decision to deliver in a health facility. Many women reported procedural difficulties to receive the benefit. Retaining the cash incentive was also an issue due to out-of-pocket expenditures incurred at the facility. Non-participation was often unintentional and caused by personal circumstances, poor geographic access or driven by a perception of poor quality of care provided in program facilities. In summary, while the cash incentive was important for some women in facilitating an institutional birth, the shift in social norm (possibly in part facilitated by the program) and therefore their own perceptions has played a major role in them giving birth in facilities.


Messaging Affects the Behavior of African American Parents with Regards to Soft Bedding in the Infant Sleep Environment: A Randomized Controlled Trial.
To evaluate the impact of specific health messages on the decisions of African American parents regarding soft bedding use, specifically related to the high degree of self-efficacy that African American parents have with regards to preventing infant suffocation vs low self-efficacy with regards to sudden infant death syndrome (SIDS) risk reduction. We conducted a randomized, controlled clinical trial of African American mothers of infants. The control group received standard messaging emphasizing safe sleep practices recommended by the American Academy of Pediatrics for the purposes of SIDS risk reduction. The intervention group received enhanced messaging emphasizing safe sleep practices for both SIDS risk reduction and suffocation prevention. Participants completed interviews at 2-3 weeks, 2-3 months, and 5-6 months after the infant's birth. Of 1194 mothers enrolled, 637 completed all interviews. The use of soft bedding both in the past week and last night declined with age (P < .001). Infants in the enhanced group had a lower rate of use of soft bedding in the past week (P = .006) and last night (P = .013). Mothers who received the enhanced message were more likely to state that they avoided soft bedding to protect their infant from suffocation. African American mothers who receive an enhanced message about SIDS risk reduction and suffocation prevention are less likely to use soft bedding in their infant's sleep environment. ClinicalTrials.gov: NCT01361880.


Multiple Gestations and Hypertensive Disorders of Pregnancy: What Do We Know?
The occurrence of hypertensive disorders of pregnancy (HDP) including gestational hypertension, chronic hypertension, preeclampsia, and eclampsia is proportional to the number of fetuses: singletons 6.5%, twins 12.7%, and triplets 20.0%. Literature on HDP in multifetal gestation is sparse compared with singletons. We aim to summarize the current evidence on HDP, specifically in twins. HDP occurs more frequently, at an earlier gestational age, and can present more severely and atypically in twin pregnancies. HDP in twins carries a higher risk of maternal/fetal morbidity and mortality including renal failure, stroke, cardiac arrest, pulmonary edema, placental abruption, cesarean delivery, fetal growth restriction, and iatrogenic preterm delivery. Low-dose aspirin (60-150 mg) should be initiated in all multifetal pregnancies to reduce the risk of preeclampsia. To improve outcomes and reduce inherent risks associated with multiple gestations, twins should be managed as high-risk pregnancies, and different from singletons.


Comparison of regeneration of the chorda tympani nerve and gustatory function recovery after severing the nerve between pediatric and adult patients.
To compare the incidence of regeneration of the chorda tympani nerve (CTN) and taste function recovery between pediatric and adult patients after severing the CTN. Retrospective study. University hospital. Consecutive 31 pediatric patients and 61 adult patients who underwent staged tympanoplasty (86 patients) or reoperation (6 patients) because of chronic otitis media with (89 patients) or without cholesteatoma (3 patients) and whose CTN was severed during primary surgery were included. Therapeutic. The severed nerves were readapted or approximated on the temporalis muscle fascia used to reconstruct the eardrum. During secondary surgery, we tried to detect regenerated CTN. Preoperative and postoperative gustatory function was assessed using electrogustometry. Regenerated CTN was detected during secondary surgery in 58.1% (18/31) of pediatric patients and 31.1% (19/61) of adults (p < 0.05). However, the number of patients with preoperatively elevated electrogustometry threshold was greater in adult patients. When the subjects were limited to those with preoperatively normal taste function, there was no significant difference between the 2 groups. Among patients with CTN regeneration, the incidence of taste function recovery was higher (12/18; 66.7%) in children than that (6/19; 31.6%) in adults (p < 0.05). However, there was no significant difference when the subjects were limited to those with preoperatively normal taste function. Chronic inflammation may not severely affect the CTN in pediatric patients, resulting in higher incidences of CTN regeneration and gustatory function recovery after severing the nerve, compared with those in adult patients.


Transection of radial digital nerve of the thumb during trigger release.
Iatrogenic laceration of the radial digital nerve of the thumb during trigger release occurred in four patients. Histologic cross sections through the thumb in cadaveric specimens at the level of the metacarpophalangeal crease showed the radial digital nerve to be 2.19 mm beneath the dermis and 1.15 mm directly anterior to the radial sesamoid bone. In this position the nerve is vulnerable to transection when it is trapped between the sesamoid and the knife blade.


Efficacy of front-of-pack warning label system versus guideline for daily amount on healthfulness perception, purchase intention and objective understanding of nutrient content of food products in Guatemala: a cross-over cluster randomized controlled experiment.
Front-of-package warning labels (FOPWL) have been adopted in many countries aiming at reducing the consumption of unhealthy food and drink products and have also been considered in Guatemala. The aim of the study is to evaluate the efficacy of FOPWL versus Guidelines for Daily Amount (GDA) on products' healthfulness perception (HP), purchase intention (PI) and the objective understanding of the nutrient content (UNC) in Guatemala. Participants (children and adults) (n = 356) were randomly assigned to evaluate either FOPWL or GDA during a crossover cluster randomized experiment in rural and urban areas across 3 phases of exposure. During phase 1, participants evaluated mock-up images of single products (single task) and compared pairs of products within the same food category (comparison task) without any label. In phase 2, participants evaluated labels only (without any product), and during phase 3, they evaluated the same products and questions from phase 1, now depicting the assigned front-of-package label. We generated indicators for single-task questions and scores for comparison tasks, one for each HP, PI and UNC questions. We used intention-to-treat, difference-in-difference regression analysis to test whether exposure to FOPWL was associated with HP, PI and UNC, compared to GDA. We also tested models for children and adults and by area (rural/urban) separately adjusting for sociodemographic variables. In single tasks, FOPWL significantly decreased the PI (β -18.1, 95%CI -23.3, -12.8; p < 0.001) and the HP (β -13.2, 95%CI -18.4, -7.9; p < 0.001) of unhealthy food products compared to GDA. In the comparison task, FOPWL significantly increased the UNC (β 20.4, 95%CI 17.0, 23.9; p < 0.001), improved PI towards healthier choices (OR 4.5, 95%CI 2.9, 7.0 p < 0.001) and HP (OR 5.6, 95%CI 2.8, 11.1; p < 0.001) compared to GDA. Similar results were found in children and adults and in urban and rural settings. FOPWL reduces products' healthfulness perception and purchase intention, and increases understanding of products' nutrient content compared to GDA.


The Technical Quality of Delivered Care for People with Inflammatory Bowel Disease in Tabriz Gastroenterology Clinics.
The Inflammatory Bowel Disease (IBD) is considered as one of the chronic diseasesre-quiring complicated treatment. This study aimed to assess technical quality of providing care for pa-tients with IBD. This cross-sectional study was conducted on 94 people with IBD using interviews and simple random sampling methods in Gastroenterology, Endoscopy and clinic of Imam Reza Hospital and Golgasht Clinic in Tabriz in 2012. The data collection tool was a researcher-designed questionnaire whose validity and reliability had been confirmed. In order to investigate the statistical relationship between the background variables and compliance with the standards the Chi-square test was applied using SPSS 17 Software. "visit by the physician" and "diet advice by the dietitian" have had the highest and the lowest levels of compliance with the standard respectively, and "the care related to the disease exacerbation" and "the care provided by the other physicians" were not compatible with the standards in 80% of the cases. Data analyses also showed that there was a significant relationship between participant's age, job, education and the smoking status and compliance of some care with the relevant standards (P<0.05). The results indicate a substantial gap between provided care for the people with IBD and the relevant standards. This indicates the areas that need of improvement and requires the serious attention of the authorities.


Penetrating injury to the oral cavity: a case report and review of the literature.
Penetrating injury to the oral cavity, although rare, may cause serious morbidity and mortality in the pediatric population. Impalement injuries are known to cause delayed vascular injury to the internal carotid artery, leading to significant neurologic sequelae. We present an unusual case of impalement injury and make recommendations regarding the successful evaluation and management of such injuries.


Cambrian stem-group ambulacrarians and the nature of the ancestral deuterostome.
Deuterostomes are characterized by some of the most widely divergent body plans in the animal kingdom. These striking morphological differences have hindered efforts to predict ancestral characters, with the origin and earliest evolution of the group remaining ambiguous. Several iconic Cambrian fossils have been suggested to be early deuterostomes and hence could help elucidate ancestral character states. However, their phylogenetic relationships are controversial. Here, we describe new, exceptionally preserved specimens of the discoidal metazoan Rotadiscus grandis from the early Cambrian Chengjiang biota of China. These reveal a previously unknown double spiral structure, which we interpret as a chordate-like covering to a coelomopore, located adjacent to a horseshoe-shaped tentacle complex. The tentacles differ in key aspects from those seen in lophophorates and are instead more similar to the tentacular systems of extant pterobranchs and echinoderms. Thus, Rotadiscus exhibits a chimeric combination of ambulacrarian and chordate characters. Phylogenetic analyses recover Rotadiscus and closely related fossil taxa as stem ambulacrarians, filling a significant morphological gap in the deuterostome tree of life. These results allow us to reconstruct the ancestral body plans of major clades of deuterostomes, revealing that key traits of extant forms, such as a post-anal region, gill bars, and a U-shaped gut, evolved through convergence.


Differentiation and transformation of neural plate cells.
The developmental potential of presumptive neural plate cells of prestreak chick embryos (stage 1) and neural plate cells from definitive streak chick embryos (stage 4) has been examined in cell culture using specific markers that identify the major cell types in the vertebrate central nervous system. The prestreak presumptive neural plate (PSPNP) cells, stage 1, assume an epithelial appearance in vitro and synthesize cellular fibronectin, but do not express markers for the neuronal, astrocytic, melanocytic, or oligodendrocytic lineages. Conversely, definitive-streak neural plate (DSNP) cells contain precursors which express cell-type-specific markers for terminally differentiated neurons, astrocytes, and melanocytes, and synthesize an extracellular matrix of cellular fibronectin. Differentiation of DSNP cells in vitro can be prevented by infection with a temperature-sensitive mutant of Rous sarcoma virus (RSV), tsNY68. Differentiation of DSNP cell transformants can be resumed by a temperature shift to the nonpermissive temperature. The morphological and biochemical changes associated with tsNY68 transformation are accompanied by alterations in pp60src kinase activity in the transformed cells.


[Prevention and therapy of respiratory distress syndrome in premature infants by means of bromhexine metabolite VIII. Animal experimental studies on the therapeutic efficacy of bromhexine metabolite VIII in premature respiratory distress syndrome].
In preparing a clinical study 14C-labelled bromhexine metabolite VIII was applied intraamnially in animal experiments. The distribution was measured in different maternal and fetal organs by thinlayer chromatography and autoradiography. A complete placental passage was found in both directions. An organspecific accumulation in the fetal lungs could not be demonstrated.


Toxicity profile of treatment with PD-1 inhibitors for lung cancer, melanoma and renal cell carcinoma: A real-world Brazilian study.
Immunotherapy revolutionized cancer care in the last decade and, notably among its tools, the programmed cell death protein-1 (PD-1) inhibitors. These drugs are related to increased life expectancy rates. However, they can cause several adverse events that have not been fully characterized, thus challenging clinical practice. To evaluate the toxicity profile, determining its frequency, causality, and severity associated with treatment with PD-1 inhibitors in patients treated at an oncology service in the private health sector in Belo Horizonte. Observational, retrospective, and cross-sectional study, based on the review of electronic medical records. The eligibility criteria included patients over 18 years old with a diagnosis of any cancer and staging, receiving a PD-1 inhibitor from January 2017 to January 2020. The sample consisted of 134 patients with lung cancer (46,3%), melanoma (34,3%), and kidney cancer (19,4%). The most common adverse event (AE) related to treatment were fatigue (51.5%), anorexia (23.1%), hypothyroidism (15.7%), and skin rash (14.9%), being grades 1 and 2 more prevalent. Between 3 and 12 months, there were more cutaneous, nutritional, and metabolic toxicities, and fatigue was present throughout the entire treatment period. Gastrointestinal and pulmonary toxicities were more frequent up to the 9th month. Based on real-world evidence, it was possible to reveal important findings to support the safe practice of PD-1 inhibitors treatment. Fatigue was the most prevalent AE among patients. In addition, the kinetics of AE allowed the identification of major occurrences according to the period o treatment, allowing more precise monitoring and surveillance.


Cardiovascular disease in the elderly: current considerations.
Today, elderly patients account for one-third of the total United States health care costs and for one-third of all drug prescriptions. As the United States population grows older, health care costs are expected to grow proportionately unless cost reduction strategies are developed. Cardiovascular disease is ranked as the primary cause of mortality and disability in this age group. It is estimated that 80% of cardiovascular disease in the elderly arises as complications of atherosclerosis. Whereas modern technologic advances--cardiac catheterization, coronary angiography, coronary angioplasty, coronary bypass surgery, pacemaker insertion--can help to treat the effects of atherosclerosis, such advances are costly. The most effective cost reduction strategy lies in prevention of atherosclerosis and its complications. A number of studies have linked reduction of risk factors for atherosclerosis to reduction of coronary disease events. However, it is not certain that these data apply directly to the elderly; more research is necessary to develop effective preventive and management strategies.


Identification of new ABA- and MEJA-activated sugarcane bZIP genes by data mining in the SUCEST database.
Sugarcane is generally propagated by cuttings of the stalk containing one or more lateral buds, which will develop into a new plant. The transition from the dormant into the active stage constitutes a complex phenomenon characterized by changes in accumulation of phytohormones and several other physiological aspects. Abscisic acid (ABA) and methyl-jasmonate (MeJA) are major signaling molecules, which influence plant development and stress responses. These plant regulators modulate gene expression with the participation of many transcriptional factors. Basic leucine zipper proteins (bZIPs) form a large family of transcriptional factors involved in a variety of plant physiological processes, such as development and responses to stress. Query sequences consisting of full-length protein sequence of each of the Arabidopsis bZIP families were utilized to screen the sugarcane EST database (SUCEST) and 86 sugarcane assembled sequences (SAS) coding for bZIPs were identified. cDNA arrays and RNA-gel blots were used to study the expression of these sugarcane bZIP genes during early plantlet development and in response to ABA and MeJA. Six bZIP genes were found to be differentially expressed during development. ABA and MeJA modulated the expression of eight sugarcane bZIP genes. Our findings provide novel insights into the expression of this large protein family of transcriptional factors in sugarcane.


23Na nuclear magnetic resonance study of intracellular sodium in vascular endothelial cells.
23Na(+)-NMR was used to determine the intracellular mobility and cell membrane permeability of Na+ in porcine vascular endothelial cells. The cells were grown as monolayers onto microcarrier beads and perfused with a medium containing Dy(P3O10)2(7-) to shift the extracellular from the intracellular Na+ resonance. Using triple quantum coherence filtered NMR experiments and spin echoes, it was shown that not all intracellular Na+ ions are in the extreme narrowing limit. The triple quantum coherence filtered experiments resulted in an observed R2f = 2022 +/- 302 s-1 and R2s = 200 +/- 28 s-1. From spin-echo experiments we obtained R2f = 2200 +/- 355 s-1 and a R2s = 145 +/- 15 s-1. These values are similar to those found in other cell systems and indicate water-Na(+)-protein interactions. Using single quantum NMR, the Na+ permeability of the endothelial membrane was determined. To obtain the Na+ transcellular permeability coefficient the cells were treated with 50 microM ouabain in the perfusion medium. Ouabain inhibits the Na-K pump and caused the intracellular Na+ concentration to increase in time. The permeability coefficient was obtained from the time dependence of the intracellular Na+ concentration. Assuming a monolayer of rectangularly shaped cells, we obtained a value of P = 0.02.10-5 cm s-1.


Molecular characteristics of pediatric nasopharyngeal carcinoma using whole-exome sequencing.
While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC. pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled. Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with >50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy. Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.


Predicting 30-Day Mortality for Patients With Acute Heart Failure in the Emergency Department: A Cohort Study.
Physicians in the emergency department (ED) need additional tools to stratify patients with acute heart failure (AHF) according to risk. To predict mortality using data that are readily available at ED admission. Prospective cohort study. 34 Spanish EDs. The derivation cohort included 4867 consecutive ED patients admitted during 2009 to 2011. The validation cohort comprised 3229 patients admitted in 2014. 88 candidate risk factors and 30-day mortality. Thirteen independent risk factors were identified in the derivation cohort and were combined into an overall score, the MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score. This score predicted 30-day mortality with excellent discrimination (c-statistic, 0.836) and calibration (Hosmer-Lemeshow P = 0.99) and provided a steep gradient in 30-day mortality across risk groups (<2% for patients in the 2 lowest risk quintiles and 45% in the highest risk decile). These characteristics were confirmed in the validation cohort (c-statistic, 0.828). Multiple sensitivity analyses did not find important amounts of confounding or bias. The study was confined to a single country. Participating EDs were not selected randomly. Many patients had missing data. Measurement of some risk factors was subjective. This tool has excellent discrimination and calibration and was validated in a different cohort from the one that was used to develop it. Physicians can consider using this tool to inform clinical decisions as further studies are done to determine whether the tool enhances physician decision making and improves patient outcomes. Instituto de Salud Carlos III, Spanish Ministry of Health; Fundació La Marató de TV3; and Catalonia Govern.


Measurement properties of mental health literacy tools measuring help-seeking: a systematic review.
Mental health literacy is important to improve help-seeking behaviors. However, the quality of mental health help-seeking tools remains unknown. We conducted a systematic review to appraise the quality of such tools. We searched databases for English publications addressing psychometrics of help-seeking tools. We included help-seeking tools addressing mental health in general and tools on four mental disorders: anxiety, depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. We determined the methodological quality of studies as "excellent", "good", "fair", or "indeterminate". We ranked the level of evidence of each measurement property as "strong", "moderate", "limited", "conflicting" or "unknown". We found 12 help-seeking tools in 24 studies that assessed related psychometrics. The methodological quality of included studies ranged from "poor" to "excellent" with four studies on the content validity, structural validity or internal consistency demonstrating "excellent" quality. Three tools demonstrated overall strong evidence (content or structural validity); eight tools demonstrated moderate evidence (internal consistency, structural or construct validity); and eight tools demonstrated limited evidence (reliability, construct validity or internal consistency). We recommend the application of tools with strong or moderate evidence for their psychometric properties. Future research may focus on the generalizability of the tools across diverse settings.


The Ubiquitin Binding Protein TAX1BP1 Mediates Autophagasome Induction and the Metabolic Transition of Activated T Cells.
During immune responses, naive T cells transition from small quiescent cells to rapidly cycling cells. We have found that T cells lacking TAX1BP1 exhibit delays in growth of cell size and cell cycling. TAX1BP1-deficient T cells exited G0 but stalled in S phase, due to both bioenergetic and biosynthetic defects. These defects were due to deficiencies in mTOR complex formation and activation. These mTOR defects in turn resulted from defective autophagy induction. TAX1BP1 binding of LC3 and GABARAP via its LC3-interacting region (LIR), but not its ubiquitin-binding domain, supported T cell proliferation. Supplementation of TAX1BP1-deficient T cells with metabolically active L-cysteine rescued mTOR activation and proliferation but not autophagy. These studies reveal that TAX1BP1 drives a specialized form of autophagy, providing critical amino acids that activate mTOR and enable the metabolic transition of activated T cells.


Using next generation sequencing to identify yellow fever virus in Uganda.
In October and November 2010, hospitals in northern Uganda reported patients with suspected hemorrhagic fevers. Initial tests for Ebola viruses, Marburg virus, Rift Valley fever virus, and Crimean Congo hemorrhagic fever virus were negative. Unbiased PCR amplification of total RNA extracted directly from patient sera and next generation sequencing resulted in detection of yellow fever virus and generation of 98% of the virus genome sequence. This finding demonstrated the utility of next generation sequencing and a metagenomic approach to identify an etiological agent and direct the response to a disease outbreak.


A highly potent PROTAC androgen receptor (AR) degrader ARD-61 effectively inhibits AR-positive breast cancer cell growth in vitro and tumor growth in vivo.
The androgen receptor (AR) has been found to be expressed in the majority of human breast cancer and AR antagonists, such as enzalutamide, have shown promising clinical activity in AR-positive (AR+) breast cancer. We have recently reported the discovery of a highly potent PROTAC AR degrader, ARD-61. In this study, we evaluated ARD-61 for its therapeutic potential and mechanism of action in breast cancer models in vitro and in vivo. ARD-61 potently and effectively induces AR degradation in AR+ breast cancer cell lines and is much more potent than enzalutamide in inhibition of cell growth and induction of cell cycle arrest and/or apoptosis. ARD-61 effectively induces complete AR degradation in xenograft tumor tissue and is more effective than enzalutamide in achieving tumor growth inhibition in the MDA-MB-453 xenograft model in mice. Our study provides strong preclinical rationale to develop AR degraders for the treatment of AR+ human breast cancer.


Corneal edema induced by cold in trigeminal nerve palsy.
We examined a 34-year-old man who complained of decreased visual acuity in the right eye when exposed to cold environmental temperatures. Although examination at room temperature was unremarkable, he developed prominent unilateral corneal edema of the right eye when placed in a cold room at 4 C. Corneal thickness increased from 525 to 789 microns in the affected eye. Further examination disclosed a right-sided trigeminal nerve palsy. He was eventually found to have a 3 X 2-cm tentorial ridge meningioma on the right.


Inflammatory Bowel Disease-Associated Colorectal Cancer Epidemiology and Outcomes: An English Population-Based Study.
Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.


There Is Substantial Variation in Rehabilitation Protocols Following Anterior Cruciate Ligament Reconstruction: A Survey of 46 American Orthopaedic Surgeons.
To identify the clinical practice preferences of orthopaedic surgeons regarding anterior cruciate ligament reconstruction (ACLR) rehabilitation through a survey of members of the Arthroscopy Association of North American (AANA) and the American Orthopaedic Society for Sports Medicine (AOSSM). An online survey was distributed to members of AANA and AOSSM between November 2020 and September 2021. Participants reported on their clinical preferences for ACLR protocol development and patient selection, use of technology in ACLR recovery and rehabilitation, and preferences for advancing through multiple phases of the rehabilitative process. Responses from 46 orthopaedic surgeons were analyzed. Patient-reported outcome measures were not found to be utilized often at various phases of the perioperative period. Thirty-eight (82.6%) participants reported utilization of postoperative bracing. There was no consensus on when participants allow their patients to advance through rehabilitation, but most report waiting 3 to 4 months for advancement to jogging/lateral movement, 6 to 8 months for return to noncontact sport, and 9 months of more for return to unrestricted sport. Many participants utilize functional and strength testing with associated limb symmetry indices to determine patient readiness to return to sport, with 18, 26, and 25 participants reporting use of functional testing and 28, 26, and 27 participants reporting use of strength testing at the return to jogging/lateral movements, noncontact return to sport, and unrestricted return-to-sport phases, respectively. This study provides an insight into the rehabilitative protocols and modalities utilized for ACLR by orthopaedic surgeons in practice across the United States. There is notably substantial variation in rehabilitative patterns and preferences, particularly with regards to what constitutes criteria for progressing patients through the phases of returning to unrestricted sport. Additionally, our findings show that while many surgeons believe that quantitative assessment technology could be beneficial in decision-making for returning patients to sport, there are still many barriers that stand in the way of its implementation into clinical practice. Postoperative rehabilitative protocols after ACLR vary by surgeon.


A hive of activity: the future of public health.
In consultation with primary and secondary care, public health has a crucial role in improving the health of the population through health promotion, advice on appropriateness and effectiveness of services and communicable disease control. The speciality of public health medicine can only achieve this goal if it is allowed a degree of stability after the numerous organisational changes of the last two decades. The 'beehive model' of public health may offer an organisational structure that is adaptable to further health service change, reflects the rise in multidisciplinary working, guarantees freedom of speech and is sustainable within existing manpower numbers.


[Endoscopic needle biopsy in larynx and pharynx. A simple method for the histological diagnosis of tumours (author's transl)].
The needle-biopsy taken in the pharynx and larynx is a simple and reliable procedure for the histological diagnosis of submucosal tumours. It can be performed either in local anaesthesia using the zoom-endoscope by v. Stuckrad or during microlaryngoscopy under general anesthesia. This method however does neither replace the single biopsy of exophytic tumours nor the microlaryngoscopic excision of suspicious, precancerous lesions.


Contrast and electrolyte dynamics of the intravenous pyelogram. I. Urinary pH and volume changes in the canine I. V. P.
Canine peripheral venous or suprarenal aortic injections of sodium or meglumine iothalamate produced a significant swing towards an alkaline urine only in individual dogs injected with meglumine salts. When mean values were compared for the sodium or meglumine groups as a whole, however, no significant differences could be established for pH change or induced diuresis. With both salts, ATPase inhibition could play a role in urinary electrolyte excretion. Carbonic anhydrase inhibition does not seem to play a significant role in urinary pH changes induced by contrast media.


Synergistic androgenic effect of a petroleum product caused by the joint action of at least three different types of compounds.
In a previous study, we found a dose-dependent synergistic effect in recombinant yeast stably transfected with the human androgen receptor (AR), in response to co-exposure to testosterone and a commercially-available lubricant (engine) oil for cars. As there is relatively little knowledge on synergistic toxic effects and causative compounds, particularly for the androgenic system, the objective of the present study was to investigate this oil in more detail. The oil was fractionated into SARA fractions (so-called 'saturates', 'aromatics', 'resins', and 'asphaltenes') by open column chromatography. Surprisingly, when exposing the recombinant AR yeast to testosterone in combination with the separate SARA fractions, the synergistic effect could not be reproduced fully. After pooling the fractions again however, the full synergism returned. From subsequent exposures to combinations of two or three SARA fractions, it appeared that both the 'saturates' and the 'resins' fraction were required for obtaining the synergistic response with testosterone. This clearly demonstrates a synergistic effect related to the androgenic system caused by the joint action of at least three chemically-distinct compounds, or groups of compounds (i.e. testosterone, 'resins' and 'saturates'). Although detailed chemical analyses could not reveal the identity of the causative compounds and the in vivo relevance of the present results remains unclear, the results do add to the growing body of evidence on the potentially extremely complex character of mixture effects.


Which clinical decisions benefit from automation? A task complexity approach.
To describe a model for analysing complex medical decision making tasks and for evaluating their suitability for automation. Assessment of a decision task's complexity in terms of the number of elementary information processes (EIPs) and the potential for cognitive effort reduction through EIP minimisation using an automated decision aid. The model consists of five steps: (1) selection of the domain and relevant tasks; (2) evaluation of the knowledge complexity for tasks selected; (3) identification of cognitively demanding tasks; (4) assessment of unaided and aided effort requirements for this task accomplishment; and (5) selection of computational tools to achieve this complexity reduction. The model is applied to the task of antibiotic prescribing in critical care and the most complex components of the task identified. Decision aids to support these components can provide a significant reduction of cognitive effort suggesting this is a decision task worth automating. We view the role of decision support for complex decision to be one of task complexity reduction, and the model described allows for task automation without lowering decision quality and can assist decision support systems developers.


Priming of group 2 metabotropic glutamate receptors facilitates induction of long-term depression in the dentate gyrus of freely moving rats.
Activation of group 1 metabotropic glutamate receptors (mGluRs) has been shown to facilitate the induction of tetanically evoked long-term potentiation in vivo, whereas group 2 mGluR antagonists inhibit long-term depression (LTD) in the CA1 region. LTD has not been successfully demonstrated to date in the dentate gyrus of freely moving rats. In this study, it was found that 1-Hz low-frequency stimulation (LFS) when applied via a stimulating electrode chronically implanted in the perforant path, evoked short-term depression (STD) of field excitatory post-synaptic potentials and population spikes measured from the dentate gyrus granule cell layer. Application of the group 2 mGluR agonists (S)-4-carboxyphenylglycine (4C3HPG) or (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) prior to LFS facilitated the expression of LTD. Application of the group 2 mGluR antagonist (2S)-alpha-ethylglutamic acid (EGLU) prior to agonist application prevented the facilitating effect of the agonists on LFS-induced depression. EGLU did not influence the expression of LFS-induced STD. Neither 4C3HPG, DCG-IV nor EGLU had an effect on basal synaptic transmission at the concentrations used. The present study demonstrates that priming of group 2 mGluRs leads to induction of persistent LTD in the dentate gyrus in vivo, consistent with a role for group 2 mGluRs in metaplasticity.


Long-term management of chronic constipation in children.
A retrospective clinical study was conducted to determine the success of a strict regimen employing the prolonged use of daily enemas in 203 children with chronic constipation. This study confirmed that the use of long-term daily enemas did eliminate constipation as well as the primary complaint of fecal soiling. The majority of children treated had an excellent to good result (85.8%) over an extended period of time. Patients with a past medical history of imperforate anus or Hirschsprung's disease required longer treatment periods (32.6 and 20.1 months, respectively) than children with other medical problems (rectal prolapse, rectal stricture, malrotation, spina bifida, mental retardation, psychological; 13 months) or patients with functional constipation (5.9 months).


Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study.
We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life. Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years). We examined if lifelong physical activity is important for maintaining bone strength in the elderly. The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly.


"Personal Knowledge" in Medicine and the Epistemic Shortcomings of Scientism.
In this paper, we outline a framework for understanding the different kinds of knowledge required for medical practice and use this framework to show how scientism undermines aspects of this knowledge. The framework is based on Michael Polanyi's claim that knowledge is primarily the product of the contemplations and convictions of persons and yet at the same time carries a sense of universality because it grasps at reality. Building on Polanyi's ideas, we propose that knowledge can be described along two intersecting "dimensions": the tacit-explicit and the particular-general. These dimensions supersede the familiar "objective-subjective" dichotomy, as they more accurately describe the relationship between medical science and medical practice. Scientism, we argue, excludes tacit and particular knowledge and thereby distorts "clinical reality" and impairs medical practice and medical ethics.


Diagnostic fine needle aspiration of soft tissue metastases from cancer of the prostate.
Pathologic confirmation of soft tissue metastases is necessary for staging and followup of patients with cancer of the prostate. Fine needle aspiration with cytologic evaluation is recommended over other biopsy procedures because it is safe, accurate and applicable to deep and superficial lesions. Small metastases, such as lymph nodes or skin nodules, remain in situ as useful markers to follow the course of the disease and response to treatment.


Distribution of genetic variability in populations of two chromosomal races of Dichroplus pratensis (Melanoplinae, Acrididae) and their hybrid zone.
We examined, through allozyme electrophoresis, the genetic structure of populations of the acridid grasshopper Dichroplus pratensis from two chromosomal races (Northern and Southern) and their hybrid zone in Argentina. No fixed alleles for any particular race were found, although genetic differentiation among parental races was significant (0 = 0.044, 95% CI: 0.004-0.068). Hybrid populations are genetically more similar to the Southern race (0 = 0.008, 95% CI: -0.005-0.018) than to Northern ones (0 = 0.018, 95% CI: 0.002-0.030). Differential viability or fertility of hybrids, or asymmetry in mating preferences in favour of one particular cross would cause a higher proportion of matings between hybrid individuals and those from the Southern race. This would explain the high genetic similarity between those groups, in spite of their geographical vicinity with northern race populations.


The implication of morphometrics and growth rate of dipteran flies in forensic entomotoxicology research: a review.
Forensic entomotoxicology integrates toxicology into forensic entomology to estimate minimum postmortem interval (PMImin) and circumstances of death where toxicants and poisonous substances are the suspected cause of death. Forensic entomotoxicology not only confirms the presence of toxicants in insects feeding off a cadaver but also studies its effect on the bio-morphometry and growth rate of insects. This review article highlights the effects of various toxicants on forensically important species of dipteran flies. It also discusses the parameters that may affect accuracy in estimation of time since death. The bio-physical effects of toxicants (excluding the analytical approach for qualitative detection) would help understand the trends in forensic entomotoxicological research worldwide.


Room-temperature synthesis of nitrogen-rich conjugated microporous polymers for solid-phase extraction of trace synthetic musks.
This study synthesized a conjugated microporous polymer (CMP) at room temperature, which has high surface area, large conjugate system, and nitrogen-rich features. The material was explored as a solid-phase extraction (SPE) column, and it showed a higher extraction efficiency for nitro-musks compared to most commercial columns. Under optimal SPE conditions, a sensitive and efficient method for determining five nitro-musks was established based on gas chromatography-mass spectrometry (GC-MS). The method showed excellent linearity (R2 ≥ 0.996), low limits of detection (0.13-0.57 ng·L-1), good repeatability (1.1-4.0 %, n = 6) and was applied to the detection of trace nitro-musks in water and milk samples. The mechanism was further discussed combined with a simulation calculation. The advantages of the proposed method were mainly reflected in the extraction efficiency and sensitivity, which also indicated the potential of CMPs as a sample pretreatment material.


Preliminary experience comparing routine cytology results with the composite results of digital image analysis and fluorescence in situ hybridization in patients undergoing EUS-guided FNA.
Studies indicate enhanced diagnostic accuracy for digital image analysis (DIA) and fluorescence in situ hybridization (FISH) versus routine cytology examination (RC) when biliary strictures are evaluated. These tumor markers have not been applied to EUS-guided FNA. Our purpose was to determine the accuracy of RC versus the composite results of DIA/FISH. Patients enrolled with known or suspected malignancy. The final diagnosis was based on strict cytopathologic and imaging criteria and 12-month follow-up. Tertiary referral center. A total of 39 patients were enrolled in whom each diagnostic test was performed on samples from 42 sites to evaluate lymphadenopathy (n=19), pancreatic mass (n=19), esophageal or gastric wall mass (n=3), and thyroid mass (n=1). EUS-guided FNA with RC, DIA, and FISH. Diagnostic accuracy of RC, DIA, and FISH. Malignancy was diagnosed in 30 of 42 patients, including esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, pancreatic mucinous cystic neoplasia, intraductal papillary mucinous neoplasia, metastatic forearm sarcoma, small cell and non-small cell lung cancer, thyroid carcinoma, malignant GI stromal tumor, melanoma, adenocarcinoma of unknown primary, and lymphoma. The sensitivity, specificity, and accuracy of DIA/FISH versus RC for detecting malignancy were 97%, 100%, and 98% versus 87%, 100%, and 90%, respectively. Single-center pilot study. Our findings suggest that DIA and FISH processing of EUS-guided FNA specimens provides higher diagnostic accuracy than RC does. These data suggest that these tumor markers incorporate generic targets as suggested by the high diagnostic sensitivity in this patient cohort with diverse pathologic conditions.


Identity and role of the non-conserved acid/base catalytic residue in the GH29 fucosidase from the spider Nephilingis cruentata.
α-l-Fucosidases are widely occurring enzymes that remove fucose residues from N- and O-fucosylated glycoproteins. Comparison of amino acid sequences of fucosidases reveals that although the nucleophile is conserved among all α-l-fucosidases, the position of the acid/base residue is quite variable. Although several site-directed mutation studies have previously been performed on bacterial fucosidases, the only eukaryotic fucosidase so studied was the human fucosidase. Recent alignments indicate that human and Arthropoda α-l-fucosidases share at least 50% identity and the acid/base residue seems to be conserved among them suggesting a common acid/base residue in Metazoa. Here we describe the cloning and expression in Pichia pastoris of a very active α-l-fucosidase from the spider Nephilingis cruentata (NcFuc) with a Km value for pNPFuc of 0.4 mM. NcFuc hydrolyzed fucoidan, 2´fucosyllactose and also lacto-N-difucohexaose II. Mutants modified at the conserved residues D214N, E209A, E59A were expressed and characterized. The 500-fold lower kcat of D214N than the wild type was consistent with a role in catalysis, as was the 8000-fold lower kcat value of E59A. This was supported by the 57-fold increase in the kcat of E59A upon addition of azide. A complex pH/rate profile was seen for the wild-type and mutant forms of NcFuc, similar to those measured previously for the Sulfolobus fucosidase. The non-conservative catalytic structure and distinct active site organization reinforce the necessity of structural studies of new fucosidases.


Physical dysfunction and nonorganic signs in patients with chronic neck pain: exploratory study into interobserver reliability and construct validity.
Repeated-measurement design. To explore interobserver reliability of the modified physical dysfunction severity (mPDS) as a measure for impairment of the cervical spine and the modified cervical nonorganic signs (mcNOS) as a measure for behavioral signs, and to explore construct validity of the mPDS and mcNOS. The PDS has been used for evaluation of treatment efficacy in controlled trials in primary care. The cervical nonorganic signs were developed to assess illness behavior in patients with neck pain. Two observers independently assessed the mPDS and mcNOS in 51 patients with chronic neck pain in an outpatient tertiary rehabilitation setting, with a 3-week interval between assessments. Interobserver reliability for total scores of the mPDS and mcNOS was expressed as an intraclass correlation coefficient. Interobserver agreement for individual mcNOS tests was calculated as absolute agreement and Cohen kappa. Construct validity was expressed as Spearman correlation between the mPDS and mcNOS with the Neck Pain and Disability Scale and numeric pain rating scale for pain. The interobserver reliability of the mPDS and mcNOS had intraclass correlation coefficients of 0.72 and 0.78, respectively. Agreement for individual mcNOS tests ranged from 63% to 88%, and kappa values ranged from 0.14 to 0.54. Correlation with the Neck Pain and Disability Scale was 0.26 for the mPDS and 0.49 for the mcNOS, and the correlation with the numeric pain rating scale was 0.32 for the mPDS and 0.37 for the mcNOS. Interobserver reliability of both the mPDS and mcNOS was acceptable. The interobserver agreement for the individual mcNOS tests ranged from poor to acceptable. Construct validity of the mPDS and mcNOS appeared satisfactory.


Coherent two-dimensional terahertz-terahertz-Raman spectroscopy.
We present 2D terahertz-terahertz-Raman (2D TTR) spectroscopy, the first technique, to our knowledge, to interrogate a liquid with multiple pulses of terahertz (THz) light. This hybrid approach isolates nonlinear signatures in isotropic media, and is sensitive to the coupling and anharmonicity of thermally activated THz modes that play a central role in liquid-phase chemistry. Specifically, by varying the timing between two intense THz pulses, we control the orientational alignment of molecules in a liquid, and nonlinearly excite vibrational coherences. A comparison of experimental and simulated 2D TTR spectra of bromoform (CHBr3), carbon tetrachloride (CCl4), and dibromodichloromethane (CBr2Cl2) shows previously unobserved off-diagonal anharmonic coupling between thermally populated vibrational modes.


Mitogenic activity of influenza virus and haemagglutinin.
Influenza A viruses behave as T cell-independent B cell mitogens in vitro. The magnitude of the proliferation induced varies with the haemagglutinin subtype of the virus, the order being H2 greater than H6 greater than H3 greater than H1 for Balb/c mice. H3 viruses are equally mitogenic for all strains of mice tested. In contrast, the mitogenic response to H2 and H6 viruses is controlled by the I-E subregion of the major histocompatibility complex. These viruses are mitogenic only for strains of mice that express surface I-E antigen (haplotypes a, d, k, p, r), and not for haplotypes b, f, q, s, which fail to synthesize a normal E alpha chain and do not express surface I-E antigen. Mitogenesis by H2 and H6 viruses may involve direct interaction of virus with I-E molecules on the B lymphocyte or an accessory cell, whereas mitogenesis by H3 viruses does not appear to involve I-E.


TNF-α increases αvβ3 integrin expression and migration in human chondrosarcoma cells.
Chondrosarcoma is a type of highly malignant tumour with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Tumour necrosis factor (TNF)-α is a key cytokine involved in inflammation, immunity, cellular homeostasis and tumour progression. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. However, the effects of TNF-α in migration and integrin expression in chondrosarcoma cells are largely unknown. In this study, we found that TNF-α increased the migration and the expression of αvβ3 integrin in human chondrosarcoma cells. Activations of MAPK kinase (MEK), extracellular signal-regulating kinase (ERK) and nuclear factor-κB (NF-κB) pathways after TNF-α treatment were demonstrated, and TNF-α-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK and NF-κB cascades. Taken together, our results indicated that TNF-α enhances the migration of chondrosarcoma cells by increasing αvβ3 integrin expression through the MEK/ERK/NF-κB signal transduction pathway.


Heterogeneity of purified cholera toxin.
The heterogeneity of Vibrio cholerae toxin, obtained from culture filtrates in homogeneous form by gel filtration and preparative disc gel electrophoresis has been studied. By means of disc electrophoresis on polyacrylamide gel cholera toxin was separated into three forms designated I (5%), II (15%) and III (80%). The toxic activity, amino acid content and molecular weight of the three forms were similar. The difference so far observed between the various electrophoretic fractions is a difference in net charge. Incubation of either cholera toxin II or cholera toxin III at relatively high pH leads to the formation of the more acidic forms. These forms, generated in vitro by deamidation of asparagine and/or glutamine residues, are indistinguishable from the toxins of similar electrophoretic mobilities isolated from crude culture filtrates.


Stability and Hopf bifurcation for a prey-predator model with prey-stage structure and diffusion.
In this paper, we first propose a prey-predator model with prey-stage structure and diffusion. Then we discuss the following three problems: (1) stability of non-negative constant steady states for the reduced ODE system and the corresponding reaction diffusion system with homogeneous Neumann boundary conditions; (2) Hopf bifurcation for the ODE system; (3) Hopf bifurcation created by diffusion.


Objectively measured physical activity and sedentary time in young adults born preterm-The ESTER study.
Young adults born preterm have higher levels of cardio metabolic risk factors and they report less physical activity than their peers born at term. Physical activity provides important cardio metabolic health benefits. We hypothesized that objectively measured physical activity levels are lower and time spent sedentary is higher among preterm-born individuals compared with controls. We studied unimpaired participants of the ESTER birth cohort study at age 23.3 y (SD: 1.2): 60 born early preterm (<34 wk), 108 late preterm (34-36 wk), and 178 at term (controls). Physical activity and sedentary time were measured by hip-worn accelerometer (ActiGraph). As compared with controls' (mean physical activity, 303 counts per minute (cpm; SD 129)), physical activity was similar among adults born early preterm (mean difference = 21 cpm, 95% CI -61, 19) or late preterm (5 cpm, -27, 38). Time spent sedentary was also similar. Adjustments for early life confounders or current mediating characteristics did not change the results. In contrast to our hypothesis, we found no difference in objectively measured physical activity or time spent sedentary between adults born preterm and at term. The previously reported differences may be limited to physical activity captured by self-report.


Specificity of neuronal factors which aggregate acetylcholine receptors on cultured myotubes.
Neuronal factors from conditioned medium of neuroblastoma X glioma hybrid cells or isolated from embryonic pig brain aggregate acetylcholine receptors (AChR) on cultured chicken and rat myotubes. A membrane surface protein labelled with a fluorescent monospecific antibody was not aggregated with the same treatment. Antibodies against AChR block the action of the aggregating factors but do not produce large aggregates themselves. These findings indicate that the factors specifically react with the AChR on developing myotubes.


Environmental, economic, and energy analysis of municipal solid waste incineration under anoxic environment in Tibet Plateau.
The first Municipal solid waste incineration (MSWI) plant in Lhasa, Tibet, the plateau region of China, started its operation in 2018. Considering the elevation and extreme climate (low pressure and low oxygen content) in Tibet, noticeable differences may be envisaged compared to MSWI elsewhere. The aim of this study is to evaluate the environmental impacts, economic benefits, and energy efficiency of this MSWI project with three representative MSWI case in plain region using Life cycle assessment (LCA), Cost-benefit analysis (CBA), and energy analysis methods. The result showed that enhancing blast volume and cross-sectional area of the boiler help adapt to the oxygen-deficient environment. GaBi model was employed based on the CML 2001 methodology to perform LCA. LCA shows that the Lhasa MSWI project has lower positive environment impacts than the projects in plain region. More attention is needed for the deficiencies in flue gas emissions of MSWI in the plateau region. CBA shows that the payback period is 11.97 years and the internal rate of return is 8.75%. The energy analysis indicates that the boiler energy efficiency is up to 81.92%. MSWI subject to minor changes seems suitable to Tibetan plateau, and can be deployed further.


Effect of methotrexate on folate binding to a folate binding protein in cow's milk.
Folate in cow's milk was strongly bound to a minor whey protein. Methotrexate inhibited the folate binding in a log dosis dependent manner, but was a rather weak inhibitor. The binding mechanism of folate changed from a cooperative to a non-cooperative type in the presence of methotrexate. This model system could be used in investigations on human body fluids and tissues.


[Complications of the irradiation therapy with beta applicators in malign melanomas (author's transl)].
Depending on prominence and localization of malign melanomas of the choroid, there are - besides enucleation - other clinical treatments possible. Irradiation therapy with beta applicators (106Ru/106Rh) gives also radiogenous complications. But contrarily to a treatment with cobalt-60 applicators, these complications are less important.


Evolutionary analysis of Babesia vulpes and Babesia microti-like parasites.
The Babesia microti-like parasite is an emerging tick-borne piroplasm that has been detected in a range of hosts worldwide. Babesia vulpes, which is found in dogs and foxes, has been reclassified from B. microti-like parasites. The relationships among these B. microti-like parasites and B. vulpes with respect to host range and geographical origin have not been elucidated. Blood samples were collected from 27 raccoon dogs in South Korea and used to screen for B. microti-like parasites based on a PCR assay targeting the 18S rRNA gene of Babesia. For comparative purposes, in addition to 18S rRNA sequences from nine raccoon dogs, we also analyzed 18S rRNA sequences from B. microti-like parasites infecting hosts in different geographical regions worldwide obtained from the GenBank database, giving 123 sequences in total. The genetic variation and evolutionary relationships among these sequences were examined based on analyses using DnaSP, MEGA, Arlequine, and BEAST software. Babesia microti-like parasites were identified in nine raccoon dogs and found to be related to B. vulpes obtained from Spanish dogs. Among the 123 sequences from 14 countries and various hosts, we identified 43 haplotypes with high genetic variance. Based on the genetic variance and phylogenetic analyses, we established that the B. microti-like parasites isolated in different geographical regions and from hosts belonging to five orders showed higher among-population variation than within-population variation. Babesia vulpes parasites infecting carnivore hosts, including raccoon dogs, foxes, skunks and dogs, appear to be genetically distinct from B. microti-like parasites infecting hosts belonging to the other orders. Our study demonstrated the genetic variation and evolutionary relationships among 18S rRNA sequences obtained from blood samples collected from various hosts and different geographical regions. Babesia vulpes was identified from raccoon dogs in South Korea. In addition, higher genetic variations were observed among populations of different hosts and geographical origins and, in particular, low connectivity was observed among host populations in the order Carnivora and those in other orders. These results suggest the B. vulpes, a piroplasmid species pathogenic in domestic dogs and wild canines, is genetically and evolutionarily different from B. microti-like parasites.


Ease of donning surgical gloves: an important consideration in glove selection.
It is a commonly held belief among physicians that powder free surgical gloves are more difficult to don than cornstarch powdered gloves. This difficulty is supposedly enhanced when the physician's hands are wet, a situation commonly encountered when regloving during surgical procedures. This investigation dispels these beliefs by demonstrating that the forces required to don powder free gloves do not differ significantly from those required to don gloves coated in cornstarch lubricant. Moreover, Biogel, a new powder free glove with an inner hydrogel lining, is shown to don easily and safely without ripping, even with wet hands, a circumstance not encountered with other gloves.


Interference of serum with lipoplex-cell interaction: modulation of intracellular processing.
We have investigated the mechanism of lipoplex-mediated transfection, employing a dialkyl pyridinium surfactant (SAINT-2), and using serum as a modulator of complex stability and processing. Particle size and stability determine lipoplex internalization, the kinetics of intracellular processing, and transfection efficiency. Clustered SAINT-2 lipoplexes are obtained in the absence of serum (-FBS lipoplexes), but not in its presence (+FBS lipoplexes), or when serum was present during lipoplex formation [FBS], conditions that mimic potential penetration of serum proteins. The topology of DNA in [FBS] lipoplexes shifts from a supercoiled, as in -FBS lipoplexes, to a predominantly open-circular conformation, and is more prone to digestion by DNase. Consistently, atomic force microscopy revealed complexes with tubular extensions, reflecting DNA that protrudes from the lipoplex surface. Interestingly, the internalization of [FBS] lipoplexes is approximately three-fold higher than that of -FBS and +FBS lipoplexes, yet their transfection efficiency is approximately five-fold lower. Moreover, in contrast to -FBS and +FBS complexes, [FBS] complexes were rapidly processed into the late endosomal/lysosomal degradation pathway. Intriguingly, transfection by [FBS] complexes is greatly improved by osmotic rupture of endocytic compartments. Our data imply that constraints in size and morphology govern the complex' ability to interact with and perturb cellular membranes, required for gene release. By extrapolation, we propose that serum may regulate these parameters in an amphiphile-dependent manner, by complex 'penetration' and modulation of DNA conformation.


The MUC1 mucin specifically inhibits activation of the NLRP3 inflammasome.
MUC1 is a cell membrane-associated mucin, expressed ubiquitously on the mucosal epithelia as well as by immune cells, that limits the inflammatory response to multiple pathogens. We have recently shown that MUC1 controls inflammation resulting from Helicobacter pylori infection by suppressing interleukin-1β (IL-1β) produced via the NLRP3 inflammasome. Here, we demonstrate that MUC1 also regulates IL-1β secretion induced by the NLRP3-activating bacteria Haemophilus influenzae but not bacteria that activate other inflammasomes. Using purified ligands, we further demonstrate that MUC1 regulation of NLRP3 is specific, as it has no effect on the NLRP1b, NLRC4 and AIM2 inflammasomes. This indicates a unique role for MUC1 in the regulation of NLRP3-activating bacterial infections.


Predictive value of the APACHE II score in cardiogenic shock patients treated with a percutaneous left ventricular assist device.
The APACHE II score assesses patient prognosis in intensive care units. Different disease entities are predictable by using a specific factor called Diagnostic Category Weight (DCW). We aimed to validate the prognostic value of the APACHE II score in patients treated with a percutaneous left ventricular assist device because of refractory cardiogenic shock (CS). From the Dresden Impella Registry, we analyzed 180 patients receiving an Impella CP®. The main outcome was the observed intrahospital mortality ( S ^ ( t h o s p ) ), which was compared to the predicted mortality estimated by the APACHE II score. The APACHE II score, which was 33.5 ± 0.6, significantly overestimated intrahospital mortality ( S ^ ( t h o s p ) 54.4 ± 3.7% vs. APACHE II 74.6 ± 1.6%; p < 0.001). Nevertheless, the APACHE II score showed an acceptable accuracy to predict intrahospital mortality (ROC AUC 0.70; 95% CI 0.62-0.78). Thus, we adapted the formula for calculation of predicted mortality by adjusting DCW. The total registry cohort was randomly divided into derivation group for calculation of adjusted DCW and validation group for testing. Intrahospital mortality was much more precisely predicted using the adjusted DCW compared to the conventional DCW (difference of predicted and observed mortality: -4.7 ± 2.4% vs. -23.2 ± 2.3%; p < 0.001). The new calculated DCW was -1.183 for the total cohort. The APACHE II score has an acceptable accuracy for the prediction of intrahospital mortality but overestimates its total amount in CS patients. Adjustment of the DCW can lead to a much more precise prediction of prognosis.


Regulation of cell cycle transcription factor Swi5 by karyopherin Msn5.
Inactivation of S. cerevisiae β-karyopherin Msn5 causes hypersensitivity to the overexpression of mitotic cyclin Clb2 and aggravates growth defects of many mutant strains in mitotic exit, suggesting a connection between Msn5 and mitotic exit. We determined that Msn5 controlled subcellular localization of the mitotic exit transcription factor Swi5, since it was required for Swi5 nuclear export. Msn5 physically interacted with the N-terminal end of Swi5. Inactivation of Msn5 caused a severe reduction in cellular levels of Swi5 protein. This effect occurred by a post-transcriptional mechanism, since SWI5 mRNA levels were not affected. The reduced amount of Swi5 in msn5 mutant cells was not due to an increased protein degradation rate, but to a defect in Swi5 synthesis. Despite the change in localization and protein level, Swi5-regulated transcription was not defective in the msn5 mutant strain. However, a high level of Swi5 was toxic in the absence of Msn5. This deleterious effect was eliminated when Swi5 nuclear import was abrogated, suggesting that nuclear export by Msn5 is important for cell physiology, because it prevents toxic Swi5 nuclear accumulation.


Early recognition and treatment of the patient suffering from acute myocardial infarction. A description of the Myocardial Infarction Triage and Intervention Project.
Involving emergency medical personnel in the evaluation and treatment of the AMI patients is feasible. A standard, organized approach saves time. Obtaining an ECG in the prehospital setting is also feasible and decreases the delay to diagnosis and subsequent treatment for patients after hospital arrival. Early findings from the MITI registry suggests that only 20% to 30% of patients with AMI are currently eligible to receive thrombolytic medications. This seems to indicate that either current treatment guidelines need to be broadened or that thrombolytic therapy is not appropriate for all AMI patients and, therefore, alternative acute treatment approaches need to be investigated further.


The Relationship and Clinical Significance of Hepc-20, LpPLA2, PTX3, and Acute Myocardial Infarction in Patients with Varying Degrees of Coronary Artery Disease.
This study aimed to investigate the association between hepcidin-20 (Hepc-20), lipoprotein-associated phospholipase A2 (LpPLA2), pentraxin 3 (PTX3), acute myocardial infarction (AMI) occurrence, the severity of coronary artery lesions, and their predictive effectiveness. A total of 100 patients diagnosed and treated for AMI at our hospital between January 2021 and January 2022 were included in the AMI group. Based on the severity of coronary artery lesions determined by the Gensini score, patients were divided into the mild group and the moderate-to-severe group. Additionally, 100 healthy individuals were selected as control samples and included in the normal group. Serum levels of Hepc-20, LpPLA2, and PTX3 were compared, and receiver operating characteristic curves (ROC curves) were constructed to analyze the predictive efficacy of these biomarkers for AMI occurrence and the degree of coronary artery disease. Compared to the normal group, the AMI group exhibited significantly increased serum levels of Hepc-20, LpPLA2, and PTX3 (P < .05). The sensitivity and specificity of serum Hepc-20, LpPLA2, and PTX3 in predicting AMI occurrence and the severity of coronary artery lesions were >60.00%, and the Area Under Curve (AUC) was >0.70. Moreover, compared to the mild group, the moderate-to-severe group showed significantly higher serum levels of Hepc-20, LpPLA2, and PTX3 (P < .05). Hepc-20, LpPLA2, and PTX3 demonstrated positive correlations with the severity of coronary artery lesions (P < .05). The levels of Hepc-20, LpPLA2, and PTX3 are elevated abnormally in AMI patients and positively associated with the degree of coronary artery disease. Hepc-20, LpPLA2, and PTX3 have the potential to serve as sensitive and accurate predictors of AMI occurrence and the severity of coronary artery disease, thereby warranting their clinical application.


Lithium attenuates bupivacaine-induced neurotoxicity in vitro through phosphatidylinositol-3-kinase/threonine-serine protein kinase B- and extracellular signal-regulated kinase-dependent mechanisms.
Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. Lithium is a mood stabilizer for the treatment of bipolar disorder and may exert neuroprotective effects. In this study, we evaluated the effects of lithium on bupivacaine (a frequently used LAs)-induced injury in mouse neuroblastoma neuro 2a (N2a) cells. N2a cells were treated with bupivacaine in the presence or absence of lithium. After treatment, the cell injury was evaluated by examination of viability, morphology changes, and nuclear condensation. The levels of mitochondrial transmembrane potential (ΔΨm) and activation of phosphatidylinositol-3-kinase (PI3K)/ threonine-serine protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also examined. In a separate experiment, we investigated the effect of Akt and ERK inhibition on cell injury after bupivacaine and lithium treatment. Pretreatment of N2a cells with lithium significantly attenuated bupivacaine-induced cell injury. Lithium pretreatment completely reversed the suppression of PI3K/Akt and ERK signalings and significantly prevented the decline of ΔΨm in N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERK diminished the protective effect of lithium against bupivacaine-induced neuronal death. Our data suggest that lithium pretreatment provides a protective effect on bupivacaine-induced neuronal cell injury. This action of lithium is mediated through, at least in part, the activating of PI3K/Akt- and ERK-dependent mechanisms. Because lithium is a clinically proved safety drug for neurons, it is worthwhile to identify whether coadministration of LAs with lithium will decrease the risks of LAs-induced postoperative neurological complications in clinic practice.


[Value of the assay of cholinesterase activity in superficial biopsies of the rectum in the diagnosis of Hirschsprung's disease].
Cholinesterase activity have been estimated in rectal biopsies of 19 children with Hirschsprung's disease and 80 normal children. A high level of acetyl-cholinesterase is a strong argument for the diagnosis of aganglionosis. However the ratio acetylcholinesterase over butyrylcholinesterase seems to be a better sign allowing a right diagnosis in 99% of the cases.


How consultants, hospitals, trusts and deaneries affect pre-registration house officer posts: a multilevel model.
To examine variation in reported quality and working conditions of pre-registration house officer (PRHO) posts. To use multilevel modelling to determine how much of the variation was due to the effects of consultant firms, hospitals, trusts and deaneries, as well as variation at the level of the individual doctor. Questionnaire survey of national sample of PRHOs at the end of the pre-registration year. Multilevel modelling was carried out using MLwiN. PRHOs working in UK approved medical and surgical posts in NHS hospitals from August 1996 to January 1999. One thousand, four-hundred and thirty-five PRHOs who had previously been part of an extended cohort study of medical student selection and training. They reported on a total of 4926 posts, on 2721 identifiable consultant firms, in 336 hospitals, in 264 trusts and in 17 deaneries. PRHOs' perceptions of the overall quality of all PRHO posts they had worked in, and working conditions in the current post. Twenty percent of PRHO posts were described as excellent and 34% as very good, through to 6% reported as not very good, poor or bad. The overall rating of the post showed highly significant variation at the level of hospital/trust, and consultant firm. Other aspects of posts, such as working conditions showed variation at the level of deanery, trust, hospital and firms, with different patterns for the different measures. Assessments of stress in PRHOs (GHQ, burnout, response to uncertainty), and a desire to leave medicine, showed no variation at the level of deanery, trust, hospital or firm. Some aspects of a PRHO post, in particular overall rated quality, but also many aspects of working conditions, show substantial variation at the level of hospital, trust and consultant firm, suggesting that differences reflect local variation in working practices and treatment of PRHOs, with the possibility of change and improvement. The lack of any variation at the level of deanery, trust, hospital or firm in stress of PRHOs suggests that these responses are idiosyncratic, individual responses by doctors themselves, rather than a general characteristic of posts, hospitals, trusts or deaneries.


Evaluation of HMG-CoA reductase inhibitors for multiple sclerosis: opportunities and obstacles.
The disease-modifying agents currently used in the treatment of multiple sclerosis (MS) are not completely effective and are associated with adverse effects and high costs. Thus, alternative treatment options are highly desirable. HMG-CoA reductase inhibitors (statins), widely prescribed as cholesterol-lowering agents, may be a future treatment option for MS--either in an add-on therapy regimen or alone--as they have been shown to exhibit potent immunomodulatory effects. Several recent reports have demonstrated that HMG-CoA reductase inhibitors prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory mode of action of HMG-CoA reductase inhibitors that is comparable to that of interferon-beta, an established treatment for MS. An open-label clinical trial assessing simvastatin treatment in patients with MS revealed a significant decrease in the number and volume of new lesions, as assessed using magnetic resonance imaging, and a favourable safety profile. A large multicentre, placebo-controlled phase II clinical trial assessing atorvastatin in patients with a clinically isolated syndrome (i.e. a single clinical event that is indicative of demyelination, and that predisposes to the development MS) has recently been initiated. However, prospective placebo-controlled trials of HMG-CoA reductase inhibitors in definite MS are difficult to perform because of ethical and financial issues. Furthermore, overly optimistic reports in the popular media, as well as the often uncontrolled access to HMG-CoA reductase inhibitors by patients with MS, complicate the evaluation of HMG-CoA reductase inhibitors as a realistic future treatment option for MS.


A novel bridge between oxidative stress and immunity: the interaction between hydrogen peroxide and human leukocyte antigen G in placental trophoblasts during preeclampsia.
The aim of this study was to investigate a possible association between hydrogen peroxide and human leukocyte antigen G (HLA-G) in preeclampsia. We explored the correlation between HLA-G and hydrogen peroxide in preeclamptic (n = 30) and normotensive (n = 30) placentas, which was confirmed by in vitro experiments. Furthermore, RNA interference was used to explore the influence of HLA-G on the proliferation, apoptosis and invasion of HTR-8/SVneo cells when exposed to hydrogen peroxide. We found an inverse correlation between hydrogen peroxide and HLA-G expression in preeclamptic placentas. High levels of hydrogen peroxide could down-regulate HLA-G expression in HTR-8/SVneo. Compared with HLA-G knockdown HTR-8/SVneo, increased proliferation inhibition, higher apoptosis, and decreased cell invasion were found in the cell expressing HLA-G when exposed to hydrogen peroxide. Our findings highlight that high levels of hydrogen peroxide can down-regulate HLA-G expression in trophoblasts during preeclampsia and trophoblasts expressing HLA-G are vulnerable to oxidative stress.


Bacterial infectibility of chronically implanted endothelial cell-seeded expanded polytetrafluoroethylene vascular grafts.
Vascular prosthetic grafts become more resistant to infection as the interval between implantation and bacteremic challenge increases. Endothelial cell (EC) seeding of such grafts has been shown to improve measurably their ability to resist a bacteremic challenge several weeks after implantation, presumably by reducing the amount of thrombus-free area (TFA) on their luminal surface. However, no investigators have reported the impact of EC seeding on the ability of chronically implanted vascular prostheses to resist a late bacteremic challenge. Bilateral common carotid interposition grafts were placed in 15 adult mongrel dogs with a 4 mm internal diameter, experimental, expanded polytetrafluoroethylene (ePTFE) prosthesis. One animal died shortly after operation and the grafts in two dogs thrombosed, thereby leaving 12 animals with at least one patent graft for subsequent study. At a mean interval of 45 weeks after implantation, five dogs (seven patent grafts) were challenged with an intravenous infusion of 3 X 10(8) radiolabeled Staphylococcus aureus; bacterial adherence and the TFA of the graft's luminal surface were determined for each of the patent grafts. There was no statistically significant difference in bacterial adherence or TFA between EC-seeded and control grafts. At a mean interval of 53 weeks after implantation, the remaining seven dogs (14 patent grafts) received a similar bacterial infusion and the animals were allowed to recover. Five days later, the grafts were harvested and cultured. Once again, there was no significant difference in the infectibility of EC-seeded vs. control grafts.(ABSTRACT TRUNCATED AT 250 WORDS)


Corrigendum: The Generation of Mouse and Human Huntington Disease iPS Cells Suitable for In vitro Studies on Huntingtin Function.
[This corrects the article on p. 253 in vol. 10, PMID: 28848389.].


Early appraisal of China's huge and complex health-care reforms.
China's 3 year, CN¥850 billion (US$125 billion) reform plan, launched in 2009, marked the first phase towards achieving comprehensive universal health coverage by 2020. The government's undertaking of systemic reform and its affirmation of its role in financing health care together with priorities for prevention, primary care, and redistribution of finance and human resources to poor regions are positive developments. Accomplishing nearly universal insurance coverage in such a short time is commendable. However, transformation of money and insurance coverage into cost-effective services is difficult when delivery of health care is hindered by waste, inefficiencies, poor quality of services, and scarcity and maldistribution of the qualified workforce. China must reform its incentive structures for providers, improve governance of public hospitals, and institute a stronger regulatory system, but these changes have been slowed by opposition from stakeholders and lack of implementation capacity. The pace of reform should be moderated to allow service providers to develop absorptive capacity. Independent, outcome-based monitoring and evaluation by a third-party are essential for mid-course correction of the plans and to make officials and providers accountable.


Detection, enumeration, and characterization of immune cells infiltrating melanoma tumors.
Tumor-infiltrating immune cells have long been thought to affect tumor growth. In recent years, large retrospective studies have shown that the nature and polarization of the immune cells found within the tumor microenvironment impact not only the growth of the primary tumor, but also disease progression and patient survival. This has triggered considerable interest for an in depth analysis of the tumoral immune microenvironment and has created a need for standardized methods to characterize tumor-infiltrating immune cells. Here, we describe three approaches that can be used in mouse and human melanoma tumors.


Intra-pancreatic tissue-derived mesenchymal stromal cells: a promising therapeutic potential with anti-inflammatory and pro-angiogenic profiles.
Human pancreata contain many types of cells, such as endocrine islets, acinar, ductal, fat, and mesenchymal stromal cells (MSCs). MSCs are important and shown to have a promising therapeutic potential to treat various disease conditions. We investigated intra-pancreatic tissue-derived (IPTD) MSCs isolated from tissue fractions that are routinely discarded during pancreatic islet isolation of human cadaveric donors. Furthermore, whether pro-angiogenic and anti-inflammatory properties of these cells could be enhanced was investigated. IPTD-MSCs were expanded in GMP-compatible CMRL-1066 medium supplemented with 5% human platelet lysate (hPL). IPTD-MSCs were found to be highly pure, with > 95% positive for CD90, CD105, and CD73, and negative for CD45, CD34, CD14, and HLA-DR. Immunofluorescence staining of pancreas tissue demonstrated the presence of CD105+ cells in the vicinity of islets. IPTD-MSCs were capable of differentiation into adipocytes, chondrocytes, and osteoblasts in vitro, underscoring their multipotent features. When these cells were cultured in the presence of a low dose of TNF-α, gene expression of tumor necrosis factor alpha-stimulated gene-6 (TSG-6) was significantly increased, compared to control. In contrast, treating cells with dimethyloxallyl glycine (DMOG) (a prolyl 4-hydroxylase inhibitor) enhanced mRNA levels of nuclear factor erythroid 2-related factor 2 (NRF2) and vascular endothelial growth factor (VEGF). Interestingly, a combination of TNF-α and DMOG stimulated the optimal expression of all three genes in IPTD-MSCs. Conditioned medium of IPTD-MSCs treated with a combination of DMOG and TNF-α contained higher levels of pro-angiogenic (VEGF, IL-6, and IL-8) compared to controls, promoting angiogenesis of human endothelial cells in vitro. In contrast, levels of MCP-1, a pro-inflammatory cytokine, were reduced in the conditioned medium of IPTD-MSCs treated with a combination of DMOG and TNF-α. The results demonstrate that IPTD-MSCs reside within the pancreas and can be separated as part of a standard islet-isolation protocol. These IPTD-MSCs can be expanded and potentiated ex vivo to enhance their anti-inflammatory and pro-angiogenic profiles. The fact that IPTD-MSCs are generated in a GMP-compatible procedure implicates a direct clinical application.


Synthesis of Dibenzo[d,f][1,3]Diazepines via Elemental Sulfur-Mediated Cyclocondensation of 2,2'-Biphenyldiamines with 2-Chloroacetic Acid Derivatives.
The three-component reaction of 2,2'-biphenyldiamines with 2-chloroacetic acid derivatives and elemental sulfur was developed for the practical synthesis of unknown 2-carboxamide-substituted dibenzo[d,f][1,3]diazepines. This protocol is distinguished by efficiency in water and good tolerance to functional groups and can be adapted to a large-scale synthesis. The chemoselective preparation of a variety of 2-S,N,O-substituted dibenzo[d,f][1,3]diazepines was accomplished using the developed method.


Matrix Producing Cells Induce the Morphological Difference in the Bacillus subtilis Biofilm.
There is a 'coffee ring' in the Bacillus subtilis biofilm center, and the colony biofilm morphologies are distinct inside and outside the 'coffee ring'. In this paper, we study this morphological difference and explain the reasons of the 'coffee ring' formation and further the causes to the morphological variation. We developed a quantitative method to characterize the surface morphology, the outer area is thicker than the inner area of the 'coffee ring', and the thickness amplitude in outer area is larger than inner area of the 'coffee ring'. We adopt a logistic growth model to obtain how the environmental resistance influence the colony biofilm thickness. Dead cells provide gaps for stress release and make folds formation in colony biofilm. we developed a technique for optical imaging and matching cells with the BRISK algorithm to capture the distribution and movement of motile cells and matrix producing cells in the colony biofilm. Matrix producing cells are mainly distribute in the outside of the 'coffee ring', and the extracellular matrix (ECM) prevents the motile cells moving outward from center. Motile cells mainly locate inside the ring, a small amount of dead motile cells outside the 'coffee ring' give rise to radial folds formation. There are no ECM blocking cell movements inside the ring, which result in uniform folds formation. The distribution of ECM and different phenotypes lead to the formation of the 'coffee ring', which is verified by using eps and flagellar mutants.


Right ventricular infarction: frequency, size and topography in coronary heart disease: a prospective study comprising 107 consecutive autopsies from a coronary care unit.
During a 14 month period autopsies were performed on 107 patients with coronary heart disease and the results were evaluated prospectively with special reference to right ventricular infarction. A total of 214 regional infarcts were found, 107 (50%) of which involved the right ventricle. Right ventricular infarction was found in 90 hearts (84%), but only three isolated right ventricular infarcts were seen. Right ventricular involvement was found with equal frequency in anterior and posterior infarction (64 versus 66%), but posterior right ventricular infarcts were much larger (15% of the right ventricle was infarcted versus 1%). Proximal right coronary artery occlusion caused larger right ventricular infarction than did distal occlusion (15 versus 5 g). Right ventricular infarct size was not influenced by coronary artery disease (evaluated angiographically) in noninfarct-related vessels. Anterior right ventricular infarcts were predominantly located near the apex of the heart (to the left of the sternum), whereas posterior right ventricular infarcts were located near the atrioventricular groove (along the right sternal border). Infarct size was equal in patients who died from a first acute anterior or posterior infarct. However, posterior infarcts had more right ventricular involvement (28% of total infarct size versus 7% in anterior infarcts) leaving more of the left ventricular myocardium intact (79 versus 64%). These differences in infarct topography may explain why right ventricular involvement seldom is diagnosed clinically in patients with anterior infarction, and why left ventricular function and prognosis usually are better after posterior compared with anterior infarcts of enzymatically equal size.


Inclusion of premenopausal women in breast cancer clinical trials.
Patients with premenopausal breast cancer (PMBC) have been historically excluded from some clinical trials because of the limitations of using endocrine therapy (ET) in this population. We analyzed breast cancer randomized clinical trials (RCTs) to determine the rates of and factors associated with inclusion of PMBC patients to provide a benchmark for PMBC inclusion in RCTs moving forward. Using ClinicalTrials.Gov, we identified breast cancer phase III RCTs and extracted inclusion criteria and patient enrollment information. Multiple binary logistic regression modeling was used to assess trial-related factors that were associated with PMBC patient inclusion. Of 170 breast cancer RCTs identified, 131 (77.1%) included PMBC patients. Sixty-five (38.2%) trials analyzed patients with hormone-receptor-positive (HR+) and HER2-negative (HER2-) breast cancer, of which 31 (47.7%) allowed for enrollment of PMBC patients. Lower rates of PMBC inclusion were seen in trials that studied HR+/HER2-patients (47.7% PMBC inclusion in HR+/HER2-trials vs. 94.3% in non-HR+/HER2-trials, aOR 0.07 [95% CI: 0.02-0.19], p < 0.001) and in trials that randomized or mandated ET (44.4% in ET trials vs. 83.2% in non-ET trials, aOR 0.21 [95% CI: 0.10-0.83], p = 0.02). Trials studying chemotherapy (CT) were associated with inclusion of PMBC patients (100% in CT trials vs. 70.5% in non-CT trials, a OR 14.02 [95% CI: 1.54-127.91], p = 0.01). All surgical and radiation therapy clinical trials allowed for the inclusion of PMBC patients in their eligibility criteria. Breast cancer clinical trials should carefully select their enrollment criteria and consider inclusion of premenopausal patients when appropriate.