Antigen-Specificity of T Cell Infiltrates in Biopsies With T Cell-Mediated Rejection and BK Polyomavirus Viremia: Analysis by Next Generation Sequencing.
This study interrogates the antigen-specificity of inflammatory infiltrates in renal biopsies with BK polyomavirus (BKPyV) viremia (BKPyVM) with or without allograft nephropathy (BKPyVN). Peripheral blood mononuclear cells (PBMC) from five healthy HLA-A0101 subjects were stimulated by peptides derived from the BKPYV proteome or polymorphic regions of HLA. Next generation sequencing of the T cell-receptor complementary DNA was performed on peptide-stimulated PBMC and 23 biopsies with T cell-mediated rejection (TCMR) or BKPyVN. Biopsies from patients with BKPyVM or BKVPyVN contained 7.7732 times more alloreactive than virus-reactive clones. Biopsies with TCMR also contained BKPyV-specific clones, presumably a manifestation of heterologous immunity. The mean cumulative T cell clonal frequency was 0.1378 for alloreactive clones and 0.0375 for BKPyV-reactive clones. Samples with BKPyVN and TCMR clustered separately in dendrograms of V-family and J-gene utilization patterns. Dendrograms also revealed that V-gene, J-gene, and D-gene usage patterns were a function of HLA type. In conclusion, biopsies with BKPyVN contain abundant allospecific clones that exceed the number of virus-reactive clones. The T cell component of tissue injury in viral nephropathy appears to be mediated primarily by an "innocent bystander" mechanism in which the principal element is secondary T cell influx triggered by both antiviral and anti-HLA immunity.


Safety and efficacy of early feeding based on clinical assessment at 4 hours after ERCP: a prospective randomized controlled trial.
The optimal timing of refeeding after ERCP is unknown. Some practices keep the patient fasting for 24 hours after ERCP, whereas others resume feeding earlier. We aimed to evaluate the risk of post-ERCP pancreatitis (PEP) in patients who initiate early feeding, based on their clinical assessment, including serum amylase testing performed at 4 hours after ERCP. Patients who were scheduled for ERCP were recruited. Patients without abdominal pain and tenderness and a serum amylase level within 1.5-fold the upper limit of normal at 4 hours after ERCP were randomly assigned to either the 4-hour fasting or 24-hour fasting group. Patients from the 4-hour fasting group started oral intake 4 hours after ERCP, whereas those from the 24-hour fasting group fasted for 24 hours after ERCP. Among the 276 enrolled, PEP was identified in 3 (2.2%) from the 4-hour fasting group and in 5 (3.6%) from the 24-hour fasting group, with a rate difference of -1.4% (1-sided 97.5% confidence interval, -∞ to 2.5%). Four-hour fasting was non-inferior to 24-hour fasting in terms of PEP incidence. The total medical costs for treatment-related ERCP were significantly lower in the 4-hour fasting group than in the 24-hour fasting group (1157.20 ± 311.90 vs 1311.20 ± 410.70 U.S. dollars; P = .032). Early feeding in patients without abdominal pain and tenderness and a serum amylase level <1.5-fold the upper limit of normal at 4 hours after ERCP does not increase the incidence of PEP after ERCP and decreases medical costs. (Clinical trial registration number: KCT0002354.).


Noradrenergic innervation of the substantia innominata: a light and electron microscopic analysis of dopamine beta-hydroxylase immunoreactive elements in the rat.
Noradrenergic input to the rat substantia innominata (SI) was analyzed in this study by immunocytochemical localization of dopamine beta-hydroxylase (DBH), the synthetic enzyme for noradrenaline. DBH immunoreactive (DBH+) axons ramified extensively within the SI and appeared to be contiguous with the DBH+ terminal fields within the bed nucleus of stria terminalis and the amygdaloid complex. DBH+ axons in the SI exhibited many large boutons en passant and boutons terminaux. These DBH+ boutons appeared much larger than those in the cerebral cortex, hippocampus, and thalamus. Electron microscopic analysis revealed that DBH+ boutons formed asymmetrical synapses with mainly dendrites, but also somata and spines of SI neurons. Dendrites which were postsynaptic to DBH+ boutons also formed synapses with many other unlabeled axon terminals. Since previous studies have shown that dendrites of SI cholinergic neurons formed few synapses, the present result suggests that the noradrenergic influence of SI cholinergic neurons may be mediated mainly by polysynaptic pathways.


Preterm Birth in the Context of Increasing Income Inequality.
Preterm birth is a leading cause of infant morbidity and mortality. Little is known about the contextual effect of U.S. income inequality on preterm birth, an issue of increasing concern given that the current economic divide is the largest since 1928. We examined changes in inequality over time in relation to preterm birth among singleton deliveries from an electronic medical record-based cohort (n = 223,512) conducted in 11 U.S. states and the District of Columbia from 2002 to 2008. Increasing income inequality was defined as a positive change in state-level Gini coefficient from the year prior to birth. Multi-level models estimated the independent effect of increasing inequality on preterm birth (>22 and <37 weeks) controlling for maternal demographics, health behaviors, insurance status, chronic medical conditions, and state-level poverty and unemployment during the year of birth. The preterm birth rate was 12.3% where inequality increased and 10.9% where it did not. After adjustment, increasing inequality remained significantly associated with preterm birth (adjusted odds ratio 1.07, 95% confidence interval 1.04, 1.11). We observed no significant interaction by insurance status or race, suggesting that increasing inequality had a broad effect across the population. The contextual effect of increasing income inequality on preterm birth risk merits further study.


[Surgery of hyperthyroidism: introduction (author's transl)].
Of the patients operated upon for goiter (n = 1891) within the last 10 years, 625 had hyperthyroidism. Exophthalmia was present in 22.7% toxic nodular goiter in 26.5%; the remaining patients had autonomous adenoma. The different prognosis and treatment of Graves' disease in contrast to other kinds of hyperthyroidism is discussed. The importance of radioimmunoassays and scintigraphic methods as a basis of differentiated and functional surgical treatment is emphasized. Close cooperation among all medical branches involved in the treatment of goiter is recommended.


Comparison of adolescent- and adult-onset unipolar depression.
The author compared the longitudinal clinical profiles of patients with adolescent-onset (N = 20) and adult-onset (N = 38) unipolar depression. The findings support the validity of subtyping depression by age at onset and comorbid substance abuse.


The new era of prostate-specific membrane antigen-directed immunotherapies and beyond in advanced prostate cancer: a review.
The lack of success in prostate cancer from immune checkpoint inhibitors, which is likely multifactorial, has led to the development and investigation of a number of other novel immunotherapeutic techniques, including antibody-drug conjugates, T-cell redirected bispecific therapies, cancer vaccines and chimeric antigen receptor T-cell therapies. Prostate-specific membrane antigen (PSMA) is a tumour-associated antigen (TAA) that is highly expressed in metastatic prostate cancer and has been validated as an effective target for radionuclide treatment. But while PSMA has thus far been the 'front runner' target for these novel immunotherapeutic techniques, it may not be the ideal target for immunotherapy and there are other potential targetable TAAs that will require further exploration. This review will focus on these various PSMA-directed therapies, as well as other potential targets for immunotherapy beyond PSMA.


Synthesis and pharmacological study of a series of 3(2H)-pyridazinones as analgesic and antiinflammatory agents.
The synthesis and the pharmacological evaluation of some 3(2H)-pyridazinone derivatives are reported. The compounds were screened for analgesic, antiinflammatory and antipyretic activities. All tested derivatives showed a higher analgesic activity than phenylbutazone, while being devoid of ulcerogenic action.


Acute spontaneous tumor lysis in anaplastic large T-cell lymphoma presenting with hyperuricemic acute renal failure.
Acute spontaneous tumor lysis (ASTL) syndrome, an extremely rare disease, requires prompt recognition and aggressive management because it is fulminant at its outset, associated with severe metabolic derangement, and potentially reversible. We describe an unusual case in which spontaneous tumor lysis occurred in anaplastic large T-cell lymphoma associated with acute uric acid nephropathy, persistent oliguria, and shock. This case contrasts markedly with previously reported cases of ASTL syndrome, which developed mainly in the pathologic type of Burkitt lymphoma. To our knowledge, this is the first reported occurrence of ASTL syndrome associated with anaplastic large T-cell type lymphoma. This report also chronicles our successful experience with continuous renal replacement therapy in the presence of compromised hemodynamic status.


Internal Carotid Artery Hypoplasia: Role of Color-Coded Carotid Duplex Sonography.
The purpose of this study was to determine the role of color-coded carotid duplex sonography for diagnosis of internal carotid artery hypoplasia. We retrospectively reviewed 25,000 color-coded carotid duplex sonograms in our neurosonographic database to establish more diagnostic criteria for internal carotid artery hypoplasia. A definitive diagnosis of internal carotid artery hypoplasia was made in 9 patients. Diagnostic findings on color-coded carotid duplex imaging include a long segmental small-caliber lumen (52% diameter) with markedly decreased flow (13% flow volume) in the affected internal carotid artery relative to the contralateral side but without intraluminal lesions. Indirect findings included markedly increased total flow volume (an increase of 133%) in both vertebral arteries, antegrade ipsilateral ophthalmic arterial flow, and a reduced vessel diameter with increased flow resistance in the ipsilateral common carotid artery. Ten patients with distal internal carotid artery dissection showed a similar color-coded duplex pattern, but the reductions in the internal and common carotid artery diameters and increase in collateral flow from the vertebral artery were less prominent than those in hypoplasia. The ipsilateral ophthalmic arterial flow was retrograde in 40% of patients with distal internal carotid artery dissection. In addition, thin-section axial and sagittal computed tomograms of the skull base could show the small diameter of the carotid canal in internal carotid artery hypoplasia and help distinguish hypoplasia from distal internal carotid artery dissection. Color-coded carotid duplex sonography provides important clues for establishing a diagnosis of internal carotid artery hypoplasia. A hypoplastic carotid canal can be shown by thin-section axial and sagittal skull base computed tomography to confirm the final diagnosis.


The development of a Cancer Pain Belief Modification Program for patients with oral cancer in China: a feasibility study.
Acceptance-based pain management interventions have been receiving growing attention in cancer pain care. This study aimed to develop a cancer pain management program based on belief modification to improve the cancer pain experience of Chinese oral cancer survivors and to explore the acceptability and preliminary outcomes of the Cancer Pain Belief Modification Program (CPBMP). A mixed-methods approach was applied to develop and revise the program. The CPBMP was developed and revised using the Delphi technique, and its further improvement was explored with a one-group pre- and post-trial designed with a sample of 16 Chinese oral cancer survivors, and semi-structured interviews. Research instruments included Numeric Rating Scale (NRS), Chinese version of Illness Perception Questionnaire-Revised for Cancer Pain (IPQ-CaCP), and the University of Washington Quality of Life assessment scale (UW-QOL). Descriptive statistics, t-test, and Mann-Whitney U test were used to analyse the data. The semi-structured questions were analysed using content analysis. The six-module CPBMP was endorsed by most experts and patients. The expert authority coefficient value was 0.75 in the first round of the Delphi survey and 0.78 in the second round. The "pain intense", "negative pain beliefs" scores of pre- and post-testing decreased from 5.63 ± 0.48 to 0.81 ± 0.54 (t = -3.746, p < 0.001); from 140.63 ± 9.02 to 52.75 ± 7.27 (Z = 12.406, p < 0.001); and the "positive pain beliefs", "quality of life" scores increased from 55.13 ± 4.54 to 66.00 ± 4.70 (Z = -6.983, p < 0.001); from 66.97 ± 15.01 to 86.69 ± 8.42 (Z = 7.283, p < 0.001). The qualitative data also indicated that CPBMP was well acceptable. Our study showed the acceptability and preliminary outcomes of CPBMP patients. CPBMP improves the pain experience of Chinese oral cancer patients and provides a reference for cancer pain management in the future. The feasibility study has already been registered on the Chinese Clinical Trial Registry (ChiCTR) ( www.chictr.org.cn ) in 11/09/2021. (ChiCTR2100051065).


Efficient electrocatalytic CO2 reduction with a molecular cofacial iron porphyrin dimer.
A cofacial iron tetraphenyl porphyrin dimer, , bio-inspired by the Ni-Fe containing metalloenzyme, carbon monoxide dehydrogenase (CODH), efficiently and selectively catalyses the electrochemical reduction of CO2 to CO in DMF/10% H2O solution at the electro-generated Fe(0)(por) species with high Faradic efficiency (95%) and TOF (4300 s(-1)) at a moderate overpotential, η = 0.66 V.


Diaphragmatic relaxing incisions during laparoscopic paraesophageal hernia repair.
Laparoscopic paraesophageal hernia (PEH) repair is associated with an objective recurrence rate exceeding 50% at 5 years. Minimizing tension is a critical factor in preventing hernia recurrence. This study aimed to evaluate the outcomes of crural relaxing incisions in patients undergoing PEH repair. Records were reviewed to identify patients who received a relaxing incision during laparoscopic PEH repair. The patients were followed by chest X-ray and videoesophagram at 3 months and then annually. From November 2010 to March 2013, 58 patients underwent PEH repair, and 15 patients received a relaxing incision to accomplish crural closure. The median age of the patients was 72 years (range 58-84 years). The relaxing incision was right-sided in 13 patients, left-sided in one patient, and bilateral in one patient. All the procedures were completed laparoscopically and included a fundoplication. Collis gastroplasty for a short esophagus was performed for 40% of the patients. No major complications occurred. During a median follow-up period of 4 months, one patient had an asymptomatic mildly elevated left hemidiaphragm, and one patient had a trivial recurrent hernia, as shown on esophagogastroduodenoscopy (EGD). Crural tension likely contributes to the high recurrence rate noted with laparoscopic PEH repair. Relaxing incisions are safe and allow crural approximation. Advanced laparoscopic surgeons should be aware of this option when faced with a large hiatus in a patient with PEH.


Molecular organization of avian epidermal structures.
1. A number of differences in the phi-keratins have been shown to exist among various avian epidermal structures. 2. There is extensive electrophoretic heterogeneity within tissues and two elemental sizes of monomers. Feathers, natal and definitive down monomers have a weight of 10,500 dalton; scale, break and claw monomers approx 13,500 daltons. 3. Differences in the size of the monomers is due to the presence of an insoluble tryptic peptide high in Gly, Phe, Leu and Tyr. 4. Tissue differences in composition are related to structure and function.


Factors predicting the occurrence of disease-causing variants on next-generation sequencing in children with steroid-resistant nephrotic syndrome - implications for resource-constrained settings.
Enhanced availability of high-throughput sequencing (at progressively reducing costs) has revolutionized the identification of monogenic SRNS. However, in resource-poor settings, it may not be possible to perform next-generation sequencing (NGS) in all children wherein monogenic SRNS is suspected. Besides, the optimal strategy of genetic evaluation (in patients with SRNS) in routine clinical practice in resource-limited settings is unknown. Patients with newly diagnosed SRNS were recruited from our center and followed up prospectively. We analyzed the factor(s) independently predicting the occurrence of disease-causing variants in these patients. In our study, 36 children/adolescents with SRNS were included (initial steroid resistance in 53%). On targeted NGS, pathogenic/likely pathogenic variants were identified in 31% (n = 11). These included homozygous or compound heterozygous variants in the following genes: ALOX12B, COL4A3, CRB2, NPHS1, NPHS2, PLCE1, and heterozygous variant in WT1 gene. Overall, 14 variants were identified of which 5 (36%) were novel. Age of < 1 or < 2 years and presence of family history of nephrotic syndrome independently predicted the occurrence of monogenic SRNS on multivariate analysis. While NGS-based genetic testing in SRNS is increasingly being incorporated in routine clinical practice the world over, the scenario is far from optimal in resource-limited settings. Our study highlights that resources for genetic testing in SRNS should be prioritized for patients with early age at disease onset and presence of family history. Larger studies composed of diverse multi-ethnic cohorts of patients with SRNS are required to further delineate the optimal strategy of genetic evaluation in resource-poor settings. A higher resolution version of the Graphical abstract is available as Supplementary information.


Characteristics of Hearing Loss Among Older Adults in the Korean Genome and Epidemiology Study: A Community-Based Longitudinal Cohort Study With an 8-Year Follow-up.
This study investigated the 8-year incidence and progression of hearing loss (HL) and its types and examined the risk factors for changes in HL. This longitudinal cohort study analyzed data from the Korean Genome and Epidemiology Study (KoGES), an ongoing, prospective, community-based cohort study that has been conducted since 2001. Altogether, 1,890 residents of urban areas in Korea aged 45-75 years at time 1 (baseline) were included in the study. Pure-tone audiometry (PTA) testing was performed twice, at time 1 (2008-2009) and time 2 (2015-2018, follow-up), 8 years apart. HL grades were defined as seven mutually exclusive categories following the revised World Health Organization classification. Incidence was defined as PTA >20 dB HL in the better ear at time 2 among those without HL at time 1. Progression was defined as the progressive deterioration of HL among those with HL at time 1. The three types of HL constituted sensorineural (SNHL), conductive, and mixed HL. At time 1, 36.40% of patients were diagnosed with HL, which increased to 51.64% at time 2. The 8-year incidence of HL was 27.20%, and progressive deterioration of HL occurred in 23.11% of those with HL. SNHL was the most common type of HL, and its prevalence markedly increased at time 2. Multivariate analysis demonstrated that the incidence of HL was significantly associated with increasing age, male sex (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.07-2.81), and diabetes mellitus (OR, 1.43; 95% CI, 1.04-1.96). Alcohol consumption was a risk factor for HL deterioration among those with HL at time 1. The prevalence and deterioration of HL were extremely high among older adults, and age was the strongest risk factor for these changes. Therefore, timely screening and intervention are necessary to prevent HL and delay its deterioration among older adults.


Re-Examining the Relationship Between Avoidance and Post-Traumatic Stress Symptoms in Rape Survivors Enrolled in Self-Defense Training: The Protective Effect of Activities Self-Efficacy.
Although many women do not report sexual victimization as motivation for seeking self-defense training, differences in self-efficacy suggest that self-efficacy deficits may influence survivors' desire to seek training. Lower self-efficacy, thought to negatively influence perceived confidence in one's ability to engage in everyday activities, may relate to avoidance of mundane activities and cause exacerbation of post-traumatic stress symptoms (PTSS). The current study examined a three-way interaction modeling the relationships between history of rape, activities self-efficacy, activities avoidance, and PTSS in a diverse sample of 233 women enrolled in self-defense training. Results suggest that survivors who avoid everyday activities experience increased PTSS, but this effect is mitigated by perceived self-efficacy to engage in these activities. Activities self-efficacy may promote resilience in rape survivors regardless of whether they actually engage in such activities. Training that targets self-efficacy, rather than actual engagement in activities, may be sufficient to reduce PTSS in rape survivors.


Resting-state Functional Connectivity During Controlled Respiratory Cycles Using Functional Magnetic Resonance Imaging.
This study aimed to assess the effect of controlled mouth breathing during the resting state using functional magnetic resonance imaging (fMRI). Eleven subjects participated in this experiment in which the controlled "Nose" and "Mouth" breathings of 6 s respiratory cycle were performed with a visual cue at 3T MRI. Voxel-wise seed-to-voxel maps and whole-brain region of interest (ROI)-to-ROI connectome maps were analyzed in both "Nose>Mouth" and "Mouth>Nose" contrasts. As a result, there were more connection pairs in the "Mouth" breathing condition, i.e., 14 seeds and 14 connecting pairs in the "Mouth>Nose" contrast, compared to 7 seeds and 4 connecting pairs in the "Nose>Mouth" contrast (false discovery rate [FDR] of P<0.05). The present study demonstrated that mouth breathing with controlled respiratory cycles could significantly induce alterations in functional connectivity in the resting-state network, suggesting that it can differently affect resting brain function; in particular, the brain can hardly rest during mouth breathing, as opposed to conventional nasal breathing.


Degradation of chlorpyrifos residues in apple under temperate conditions of Kashmir Valley.
The present studies were carried out to observe the dissipation pattern of chlorpyrifos on apple in Kashmir Valley. Persistence of chlorpyrifos in apple was studied following two applications rates of chlorpyrifos (Dursban 20 EC) at 200 g a.i. ha(-1) (single dose T 1) and 400 g a.i. ha(-1) (double dose T 2). The average initial deposit of chlorpyrifos was found to be 1.61 and 1.98 μg g(-1) for T 1 and T 2 application rates respectively on apple. The residues dissipated to 0.09 and 0.06 μg g(-1) after 15- and 30-day post treatment with half-life periods of 3.34 and 5.47 days in T 1 and T 2 application rates, respectively. The residues of chlorpyrifos dissipated to below limit of quantification (LOQ) of 0.04 μg g(-1) after 30 day at T 1 application rate. A waiting period of 6 days must be observed for chlorpyrifos on apple at recommended application rate for the safety of consumers. Theoretical maximum residue contribution (TMRC) values were found to be far less than maximum permissible intake (MPI) at 0 day in both the dosages suggesting chlorpyrifos on apple in Kashmir is unlikely to cause health risks.


Predispositional genome sequencing in healthy adults: design, participant characteristics, and early outcomes of the PeopleSeq Consortium.
Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of predispositional genome sequencing projects, which is examining the medical, behavioral, and economic outcomes of returning genomic sequencing information to healthy individuals. Apparently healthy adults who participated in four of the sequencing projects in the Consortium were included. Web-based surveys were administered before and after genomic results disclosure, or in some cases only after results disclosure. Surveys inquired about sociodemographic characteristics, motivations and concerns, behavioral and medical responses to sequencing results, and perceived utility. Among 1395 eligible individuals, 658 enrolled in the Consortium when contacted and 543 have completed a survey after receiving their genomic results thus far (mean age 53.0 years, 61.4% male, 91.7% white, 95.5% college graduates). Most participants (98.1%) were motivated to undergo sequencing because of curiosity about their genetic make-up. The most commonly reported concerns prior to pursuing sequencing included how well the results would predict future risk (59.2%) and the complexity of genetic variant interpretation (56.8%), while 47.8% of participants were concerned about the privacy of their genetic information. Half of participants reported discussing their genomic results with a healthcare provider during a median of 8.0 months after receiving the results; 13.5% reported making an additional appointment with a healthcare provider specifically because of their results. Few participants (< 10%) reported making changes to their diet, exercise habits, or insurance coverage because of their results. Many participants (39.5%) reported learning something new to improve their health that they did not know before. Reporting regret or harm from the decision to undergo sequencing was rare (< 3.0%). Healthy individuals who underwent predispositional sequencing expressed some concern around privacy prior to pursuing sequencing, but were enthusiastic about their experience and not distressed by their results. While reporting value in their health-related results, few participants reported making medical or lifestyle changes.


Clinical decision making in brain metastases.
Surgery for metastatic cancer of the brain parenchyma has been shown to increase length of survival, especially in patients with primary breast cancer, RCC, and lung cancer. The identification of prognostic variables common to patients with brain metastases has permitted development of therapeutic guidelines.


Spatio-temporal patterns of neuronal activity: analysis of optical imaging data using geometric shape matching.
Optical imaging of neuronal network activity yields information of spatial dynamics which generally is analyzed visually. The transient appearance of spatial activity patterns is difficult to gauge in a quantifiable manner, or may even altogether escape detection. Here, we employ geometric shape matching using Fréchet distances or straight skeletons to search for pre-selected patterns in optical imaging data with adjustable degrees of tolerance. Data were sampled from fluorescence changes of a voltage-sensitive dye recorded with a 464-photodiode array. Fluorescence was monitored in a neuronal network in vitro. Neuronal activity prompting fluorescence fluctuations consisted of spontaneous epileptiform discharges in neocortical slices from patients undergoing epilepsy surgery. The experiments show that: (a) spatial activity patterns can be detected in optical imaging data; (b) shapes such as "mini-foci" appear in close correlation to bioelectric discharges monitored with field potential electrodes in a reproducible manner; (c) Fréchet distances yield more conservative matches regarding rectangular, and less conservative hits with respect to radially symmetric shapes than the straight skeleton approach; and (d) tolerances of 0.03-0.1 are suited to detect faithful images of pre-selected shapes, whereas values >0.8 will report matches with any polygonal pattern. In conclusion, the methods reported here are suited to detect and analyze spatial, geometric dynamics in optical imaging data.


A review of intestinal fatty acid binding protein gene variation and the plasma lipoprotein response to dietary components.
Because there is interindividual variation in the metabolic response to diet, it important to find and evaluate candidate genes, which have common functional variants in the general population, and which may be determinants of interindividual differences in the response to components of the diet, such as dietary fat and fiber. One such candidate gene is FABP2, which encodes the intestinal fatty acid binding protein. This gene has a common variation in the coding sequence, which results in either alanine or threonine to be translated at residue 54. This amino acid variation has an in vitro functional impact. In addition, there have been several published associations with metabolic phenotypes, such as impaired glucose tolerance, obesity, altered plasma lipids and lipoproteins. It is the FABP2 T54 variant that is almost always associated with the more deleterious phenotypic expression. Recent experiments have found that most of the inter-individual variation in the plasma lipoprotein response to dietary fiber could be attributed to the FABP2 A54T polymorphism. However, it is likely that differences in environment, such as the type of fatty acid or fiber consumed, might interact with functional differences in the gene product to produce phenotypic differences. This means that more experimental work, using a variety of study samples and complementary approaches, is necessary before advocating routine testing of FABP2 genotype in people in order to determine their potential responsiveness to various dietary interventions, such as increased dietary soluble fiber.


Human Immunodeficiency Virus-Associated Cerebral Aneurysmal Vasculopathy: A Systematic Review.
Human immunodeficiency virus (HIV)-associated cerebral aneurysmal vasculopathy is a rare complication of HIV affecting pediatric and adult patients and has been the subject of many case reports and case series. We performed a systematic literature search of PubMed, EMBASE, Scopus, Web of Science, Science Direct, and Google Scholar up to April 10, 2015. Our inclusion criteria encompassed all reported original case series and reports of HIV-associated cerebral aneurysms diagnosed radiologically. We analyzed the clinical characteristics and management of the reported cases. We identified 61 patients reported in the literature (45 pediatric and 16 adult patients). The median age was 9.8 years for pediatric patients and 36.5 years for adult patients. Weakness was the most common presenting symptom in adult and pediatric patients. The most common affected artery was the middle cerebral artery. Approximately 87.2% of pediatric patients and 42.9% of adult patients were on antiretroviral therapy (ART) at presentation. The mortality rate was 60% and 35.7% among pediatric and adult patients, respectively. The optimal management is not well established. Variable response to ART was reported with possible survival benefits when ART was initiated early. HIV-associated cerebral aneurysmal arteriopathy is associated with high mortality. The optimal management is not well established, but early initiation of ART may improve the survival rate.


OPATs: Omnibus P-value association tests.
Combining statistical significances (P-values) from a set of single-locus association tests in genome-wide association studies is a proof-of-principle method for identifying disease-associated genomic segments, functional genes and biological pathways. We review P-value combinations for genome-wide association studies and introduce an integrated analysis tool, Omnibus P-value Association Tests (OPATs), which provides popular analysis methods of P-value combinations. The software OPATs programmed in R and R graphical user interface features a user-friendly interface. In addition to analysis modules for data quality control and single-locus association tests, OPATs provides three types of set-based association test: window-, gene- and biopathway-based association tests. P-value combinations with or without threshold and rank truncation are provided. The significance of a set-based association test is evaluated by using resampling procedures. Performance of the set-based association tests in OPATs has been evaluated by simulation studies and real data analyses. These set-based association tests help boost the statistical power, alleviate the multiple-testing problem, reduce the impact of genetic heterogeneity, increase the replication efficiency of association tests and facilitate the interpretation of association signals by streamlining the testing procedures and integrating the genetic effects of multiple variants in genomic regions of biological relevance. In summary, P-value combinations facilitate the identification of marker sets associated with disease susceptibility and uncover missing heritability in association studies, thereby establishing a foundation for the genetic dissection of complex diseases and traits. OPATs provides an easy-to-use and statistically powerful analysis tool for P-value combinations. OPATs, examples, and user guide can be downloaded from http://www.stat.sinica.edu.tw/hsinchou/genetics/association/OPATs.htm.


Biosynthesis of pyrrolopyrimidines.
Pyrrolopyrimidine containing compounds, also known as 7-deazapurines, are a collection of purine-based metabolites that have been isolated from a variety of biological sources and have diverse functions which range from secondary metabolism to RNA modification. To date, nearly 35 compounds with the common 7-deazapurine core structure have been described. This article will illustrate the structural diversity of these compounds and review the current state of knowledge on the biosynthetic pathways that give rise to them.


Carcinoma erysipelatoides originating from stomach adenocarcinoma.
Carcinoma erysipelatoides is an uncommon form of cutaneous metastasis, which is most commonly caused by breast carcinoma, it has rarely been linked to the primary cancers of other organs. We report a 36-year-old woman with carcinoma erysipelatoides originating from a gastric carcinoma. Immunohistochemical and morphologic studies of skin biopsies revealed that the signet ring cells in the dilated lymphatics originated from adenocarcinoma of the stomach.


Synthesis of radioiodinated metyrapone--a potential adrenal imaging agent.
Metyrapone has been labelled with radioiodine selectively in the 4'-position of ring B. The synthesis of 123I-(131)-metyrapone involves four intermediate compounds. 4'-Bromo-metyrapone serves as a stable precursor that is labelled before use. Studies of the biodistribution of [131I]metyrapone in rats indicate the highest concentration in the adrenal gland 10 min after the injection with a fast elimination of the radioactivity. However, the absolute uptake in the normal adrenal is low. When [123I]metyrapone was used in a patient with bilateral hyperplasia, faint adrenal images were obtained.


How do we modulate our emotions? Parametric fMRI reveals cortical midline structures as regions specifically involved in the processing of emotional valences.
One of the major problems in affective neuroscience of healthy subjects as well as of patients with emotional dysfunctions is to disentangle emotional core functions and non-emotional processes. Emotional valence is considered an emotional key process. The present study employed a parametric functional magnetic resonance imaging (fMRI) study to address this question. Thirteen healthy volunteers were scanned during emotional stimulus processing (International Affective Picture System). The presented pictures covered the entire range of emotional valences. The fMRI data were consecutively subjected to a preliminary categorical (valence-independent) and a detailed parametric analysis, the latter using individual valence ratings as regressor. The parametric analysis revealed a linear valence-dependent modulation of the BOLD signal in the orbito- and dorsomedial prefrontal cortex (OMPFC, DMPFC), medial parietal cortex (MPC), and insula. In addition, we observed that emotional valence exerts its effects predominantly via modulation of signal decreases. We conclude that the psychological concept of emotional valence may be related to neural processing in cortical midline regions.


Heterotopic pregnancy of a ruptured ectopic pregnancy coexisting with a twin intra-uterine pregnancy: a case report.
A case of ruptured ectopic and twin intra-uterine pregnancy is presented. The patient had conceived following ovulation induction with clomiphene citrate.


Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease.
Soluble dipeptidyl peptidase-4 (sDPP-4) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance. Sodium-glucose co-transporter-2 (SGLT2) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated the effects of dapagliflozin (an SGLT2 inhibitor) on serum levels of sDPP-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Fifty-seven patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin group (5 mg/d for 24 weeks) (n = 33) or the control group (n = 24). Serum levels of sDPP-4 were measured with a commercial ELISA kit. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by dual bioelectrical impedance analysis. In a total of 57 patients, baseline serum sDPP-4 was positively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT) and HOMA-IR Both VAT and SAT areas decreased significantly in the dapagliflozin group alone. Liver enzymes were decreased at 24 weeks in the dapagliflozin group, but were unchanged in the control group. Although both groups showed significant reduction of serum sDPP-4 after 24 weeks of treatment, the magnitude of decrease was significantly larger in the dapagliflozin group. Changes in liver enzymes during treatment with dapagliflozin were positively correlated with the change in serum sDPP-4, but not with changes in VAT volume or HbA1c. Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum sDPP-4, suggesting that reduction of serum sDPP-4 by SGLT2 inhibitors may be a therapeutic strategy for NAFLD/NASH in patients with type 2 diabetes that is independent of glucose lowering or weight loss.


Molecular signature of hepatitis B virus regulation by interferon-γ in primary human hepatocytes.
A complete cure for chronic hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA; however, this remains to be clinically achieved. Interferon (IFN)-γ, a type II IFN, is produced by intrahepatic cytotoxic T lymphocytes and has non-cytolytic antiviral potential. However, the mechanism by which IFN-γ regulates HBV infection has not been fully elucidated. Thus, we developed an in vitro HBV infection assay system and analyzed the molecular signature of HBV regulation by IFN-γ. The in vitro HBV infection assay system was established in primary human hepatocytes infected with HBV derived from the plasmid containing 1.3-mer HBV genome, and treated with IFN-γ. The antiviral effects and signaling pathways of IFN-γ were examined using microarray, and assessed by siRNA knockdown experiments of the related genes. IFN-γ treatment suppressed both HBV propagation and transcription as efficiently as IFN-α. Microarray analysis showed that IFN-γ stimulation induced the activation of both IFN-γ and IFN-α signaling, regulating HBV covalently closed circular DNA. HBV production was decreased by IFN-γ through Janus kinase/signal transducer and activator of transcription signaling and interferon-stimulated genes, such as 2'-5'-oligoadenylate synthase 2 and apolipoprotein B mRNA editing enzyme catalytic subunit 3G. IFN-γ can suppress HBV propagation and transcription in hepatocytes by activating specific intracellular signaling pathways in hepatocytes, and suggests the future application of these particular signaling pathways or genes for the complete elimination of HBV.


Effect of metoprolol on diet-induced atherosclerosis in rabbits.
The effect of metoprolol, a beta 1-blocker, on atherogenesis was evaluated in rabbits fed a diet supplemented with 0.25% cholesterol and 3% coconut oil for 21 weeks. After 7 weeks on the diet, the rabbits were randomly divided into treated (n = 22) and untreated (n = 22) groups. Treated animals received metoprolol subcutaneously by an osmotic pump for 14 weeks, resulting in a plasma level of 774 +/- 69 nM during the investigation. Plasma concentrations of cholesterol, triglycerides, and phospholipids did not differ between the two groups. Nor were there any significant differences between the two groups in plasma concentrations of apolipoprotein A-I, apolipoprotein B, apolipoprotein C-III, and apolipoprotein E measured by electroimmunoassay. At the end of the study, the aortas were cut into three portions and the extent of atherosclerosis was determined by morphometry. The group that had received metoprolol had significantly (p less than 0.015) less atherosclerosis in the aorta (ascending plus arch 37.8 +/- 6.8%, thoracic 32.9 +/- 6.1%, abdominal 19.8 +/- 6.1% of total intimal area; mean +/- SEM) than the controls (ascending plus arch 54.9 +/- 7.1%, thoracic 48.0 +/- 6.2%, abdominal 25.9 +/- 5.5%).


Mathematical analysis and flux-based radius of influence for radon/VOC vapor intrusion mitigation systems.
Volatile organic compounds (VOCs) and radon progeny pose potential health risks to occupants of certain buildings via subsurface vapor intrusion (VI) to indoor air. VI mitigation is usually performed using systems that extract gas from below the building, and the system performance is typically evaluated by measuring the distribution of applied vacuum below the floor. This article provides a new approach to assessing the radius of influence (ROI) for subslab venting systems based on mass flux instead of static vacuum distribution and includes an analyses of 121 pneumatic tests performed at 65 different suction points in 16 different buildings. The mathematical model represents a two-layer system with horizontal radial flow through transmissive material below the floor slab and vertical flow through discontinuities in the floor slab (which is simplified to approximate an equivalent porous medium). The analysis includes comparisons of the flux-based ROI to values calculated using the two-layer model for 1) vacuum, 2) velocity, and 3) travel time, which may be useful as alternative performance metrics for mitigation systems.


[The clinic of apathy in schizophrenia: a critical review of the issue].
Today the concept of apathy is subject to many questions. This psychological state is present and predominant in different disorders such as neurodegenerative and psychiatric diseases or neurological acquired disorders. Apathy is a part of the clinical vocabulary, however, we can note that in the literature there remains confusion in its definition, and we can find an amalgam with other clinical symptoms. The aim of this review is to provide a clarification of the concept of apathy in clinical practice in schizophrenia as well as to highlight the gaps that exist. Apathy belongs to the negative symptoms of schizophrenia. For its understanding, it is necessary to define apathy as a multidimensional syndrome (cognitive, emotional, and behavioral) manifesting as a quantitative reduction of voluntary behaviors directed toward one or several goals. However, at present, we are witnessing a reductionist and simplistic conception of the syndrome of apathy and this especially in the Anglo-Saxon literature. Several authors reduce apathy to its behavioral component, so in other words, to avolition/amotivation. Avolition refers to a loss of self-initiated and spontaneous behaviors. In this definition only observable behavior is taken into account and not the underlying mechanisms (cognitive and emotional). In order to understand the syndrome of apathy, it is necessary to have a holistic and multidimensional outlook. Some authors have proposed diagnostic criteria for apathy by taking into account the different dimensions of apathy. Moreover not only is apathy confused with avolition, but it is also still difficult to distinguish it from depression. Apathy and depression share common clinical signs (i.e. loss of interest), but they also have distinct clinical signs (lack of motivation for apathy, and suicidal ideation for depression). Authors have shown that the presence of one symptom (apathy or depression) does not predict the presence of the other. An apathetic patient does not have to be necessarily in a depressive state and vice versa. However, to our knowledge, there is no data capable of distinguishing depression from apathy in schizophrenia, and knowing what is the part of one and the other when the patient has both symptoms. In addition, we can see that the confusion that persists between those two symptoms also stems from assessment tools. Indeed, some assessment tools such as the Montgomery and Asberg Depression Rating Scale (MARDS) have an apathy subscale. Therefore, this scale does not only evaluate depression. Regarding the assessment of apathy in schizophrenia, there are specific and nonspecific tools. Nonspecific tools define apathy differently. For this reason, authors have proposed to measure apathy by using analytic factors of negative symptoms. In this case, apathy is going to be assessed by the factor "motivation/pleasure" including anhedonia, asociality and avolition. This factor will provide the possibility of a better assessment of apathy. Concerning specific scales (like AES), there are gaps such as a lack of standardization in the execution and the quotation. Furthermore, no scale takes into account the factors causing apathy. Knowing the reasons for apathy is necessary because this syndrome is frequent in schizophrenia, and it is found in the different phases of this disease (prodromal, first episode psychosis, and chronic). In addition, apathy has significant functional consequences on the patient's quality of life, as well as on his or her global functioning. Indeed, apathy impacts on his or her social and professional life. Patients with schizophrenia have a loss of autonomy, less employment and social withdrawal. Consequently, interest in its drug or treatment it is obvious. However, drug and non-drug treatments are not specific to apathy and therefore little effective on this syndrome. Implications to stimulate future research are presented.


Exceptional increases in fluvial sediment fluxes in a warmer and wetter High Mountain Asia.
Rivers originating in High Mountain Asia are crucial lifelines for one-third of the world's population. These fragile headwaters are now experiencing amplified climate change, glacier melt, and permafrost thaw. Observational data from 28 headwater basins demonstrate substantial increases in both annual runoff and annual sediment fluxes across the past six decades. The increases are accelerating from the mid-1990s in response to a warmer and wetter climate. The total sediment flux from High Mountain Asia is projected to more than double by 2050 under an extreme climate change scenario. These findings have far-reaching implications for the region's hydropower, food, and environmental security.


Treatment of stroke with liposomal neuroprotective agents under cerebral ischemia conditions.
Since the proportion of patients given thrombolytic therapy with tissue plasminogen activator (t-PA) is very limited because of the narrow therapeutic window, the development of new therapies for ischemic stroke has been desired. We previously reported that liposomes injected intravenously accumulate in the ischemic region of the brain via disruption of the blood-brain barrier that occurs under cerebral ischemia. In the present study, we investigated the efficacy of a liposomal neuroprotective agent in middle cerebral artery occlusion (MCAO) rats to develop ischemic stroke therapy prior to the recovery of cerebral blood flow. For this purpose, PEGylated liposomes encapsulating FK506 (FK506-liposomes) were prepared and injected intravenously into MCAO rats after a 1-h occlusion. This treatment significantly suppressed the expansion of oxidative stress and brain cell damage. In addition, administration of FK506-liposomes before reperfusion significantly ameliorated motor function deficits of the rats caused by ischemia/reperfusion injury. These findings suggest that FK506-liposomes effectively exerted a neuroprotective effect during ischemic conditions, and that combination therapy with a liposomal neuroprotectant plus t-PA could be a promising therapeutic strategy for ischemic stroke.


Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans.
Wnt proteins regulate axonal outgrowth along the anterior-posterior axis, but the intracellular mechanisms that modulate the strength of Wnt signaling in axon guidance are largely unknown. Using the Caenorhabditis elegans mechanosensory PLM neurons, we found that posteriorly enriched LIN-44/Wnt acts as a repellent to promote anteriorly directed neurite outgrowth through the LIN-17/Frizzled receptor, instead of controlling neuronal polarity as previously thought. Dishevelled (Dsh) proteins DSH-1 and MIG-5 redundantly mediate the repulsive activity of the Wnt signals to induce anterior outgrowth, whereas DSH-1 also provides feedback inhibition to attenuate the signaling to allow posterior outgrowth against the Wnt gradient. This inhibitory function of DSH-1, which requires its dishevelled, Egl-10, and pleckstrin (DEP) domain, acts by promoting LIN-17 phosphorylation and is antagonized by planar cell polarity signaling components Van Gogh (VANG-1) and Prickle (PRKL-1). Our results suggest that Dsh proteins both respond to Wnt signals to shape neuronal projections and moderate its activity to fine-tune neuronal morphology.


Reproducibility of regional DEXA examinations of abdominal fat and lean tissue.
The aim of this study was to develop and test the validity of a new repeatable method to delimit abdominal areas for follow-up of fat mass (FM) and lean tissue mass (LM) in DEXA examinations. 37 male volunteers underwent two DEXA examinations. Total body FM and LM measurements and corresponding abdominal measurements in a carefully defined region were calculated from the first scan. After repositioning of the subjects and a second scan, the delimited region was copied and the abdominal tissues re-calculated. The mean LM of the abdominal area was 2.804 kg (SD 0.556), and the mean FM was 1.026 kg (SD 0.537). The intra-class correlation coefficient for the repeated abdominal LM, FM, and LM/FM ratio measurements was 0.99. The mean difference (bias) for the repeated abdominal LM measurements was -13 g (95% confidence interval (CI) -193.0 to 166.8), and for the repeated abdominal FM measurements it was -35 g (95% CI -178.9 to 108.5). The results indicate that regional DEXA is a sensitive method with excellent reproducibility in the measurements of the abdominal fat and lean tissues. The method may serve as a useful tool for evaluation and follow-up of various dietary and training programmes.


[Influence of leukocytes on coronary flow reserve, left ventricular systolic function, and in-hospital events, in patients with acute anterior myocardial infarction treated by primary angioplasty].
To assess the relationship between leukocyte count, non invasive coronary flow reserve (CFR), left ventricular systolic function, and in-hospital adverse events in acute anterior myocardial infarction (AMI) treated by primary angioplasty. Leukocyte count at admission and within 24h after angioplasty, and differential count at admission were obtained in 72 consecutive patients with a first AMI (mean age 56±12 years) successfully treated by primary angioplasty. Transthoracic Doppler echocardiography was performed within 24h after angioplasty and 3 months later to assess the CFR (using intravenous adenosine), in the left anterior descending artery (LAD), left ventricular ejection fraction (LVEF) and the wall motion score index using the nine segments assigned to the LAD territory (WMSi-lad). In hospital events were defined as death, heart failure (Killip≥2) and reinfarction. Leukocyte count was higher before and after angioplasty in patients with impaired acute CFR (<1.7), when compared to patients without such impairment (P≤0.01), and a significant correlation was found between CFR and leukocyte, neutrophil and monocyte count (P<0.05). Leukocyte (before and after angioplasty), and neutrophil count, were lower in patients with recovery of global and regional LV function (P<0.05). A significant correlation was found between leukocyte count before and after angioplasty, and, initial and follow-up LVEF, and WMSi-lad (all, P≤0.01). Leukocyte (before and after angioplasty) and monocyte count were higher in patients with in-hospital events (n=14), by comparison to patients without events (all, P<0.01). In multivariate analysis, leukocyte count after angioplasty was an independent predictor of CFR, and in-hospital events, and neutrophil count of WMSi-lad at follow-up (all, P<0.05). In the first AMI treated successfully by primary angioplasty, leukocyte count is inversely correlated to CFR, and global and regional LV systolic function at follow-up. These links are higher after than before reperfusion. And, leukocyte count after angioplasty is an independent predictor of in-hospital adverse events.


How do health care services help and hinder recovery after a suicide attempt? A qualitative analysis of Finnish service user perspectives.
Suicide attempt survivors are at high risk of re-attempts and suicide death. Previous research has shown that service users' experiences of post-attempt care are related to future treatment engagement and re-attempts. In-depth understanding of how current services meet service users' needs in the period immediately following a suicide attempt is thus imperative for the development of more effective tertiary prevention practices in real-life health care systems. In this qualitative study, Finnish suicide attempt survivors' experiences of and perspectives on mental health services were explored through a semi-structured interview. Participants were seven female and seven male service users interviewed 3-6 months after the index suicide attempt. A conventional content analysis of these service user interviews is presented. Participants' experiences of care ranged from helping to hindering recovery. Seven key aspects of services were described as helpful when present and hindering when absent. These included (1) meeting the service user as worthy of help, (2) supporting the exploration of personal meanings, (3) supporting the exploration of suicidality, (4) psychological continuity and predictability, (5) offering a responsive partnership in navigating recovery, (6) inviting service user involvement in medication decisions, and (7) accounting for service users' relational context. Current health care services are inconsistent in meeting suicide attempt survivors' subjective needs, leaving clear room for improvement in tertiary suicide prevention. To be perceived as meaningful by service users, services should strive to offer opportunities for both biomedical, psychological, and social interventions, with responsivity to individual needs and preferences. A focus on the social aspects of recovery (e.g., offering support to loved ones affected by the suicidal incident; facilitating peer support and social belonging) was most often found to be lacking in current services.


Assessment of computational methods for the analysis of single-cell ATAC-seq data.
Recent innovations in single-cell Assay for Transposase Accessible Chromatin using sequencing (scATAC-seq) enable profiling of the epigenetic landscape of thousands of individual cells. scATAC-seq data analysis presents unique methodological challenges. scATAC-seq experiments sample DNA, which, due to low copy numbers (diploid in humans), lead to inherent data sparsity (1-10% of peaks detected per cell) compared to transcriptomic (scRNA-seq) data (10-45% of expressed genes detected per cell). Such challenges in data generation emphasize the need for informative features to assess cell heterogeneity at the chromatin level. We present a benchmarking framework that is applied to 10 computational methods for scATAC-seq on 13 synthetic and real datasets from different assays, profiling cell types from diverse tissues and organisms. Methods for processing and featurizing scATAC-seq data were compared by their ability to discriminate cell types when combined with common unsupervised clustering approaches. We rank evaluated methods and discuss computational challenges associated with scATAC-seq analysis including inherently sparse data, determination of features, peak calling, the effects of sequencing coverage and noise, and clustering performance. Running times and memory requirements are also discussed. This reference summary of scATAC-seq methods offers recommendations for best practices with consideration for both the non-expert user and the methods developer. Despite variation across methods and datasets, SnapATAC, Cusanovich2018, and cisTopic outperform other methods in separating cell populations of different coverages and noise levels in both synthetic and real datasets. Notably, SnapATAC is the only method able to analyze a large dataset (> 80,000 cells).


Achieving best outcomes for patients with cardiovascular disease in China by enhancing the quality of medical care and establishing a learning health-care system.
China has an immediate need to address the rapidly growing population with cardiovascular disease events and the increasing number of people living with this illness. Despite progress in increasing access to services, China faces the dual challenge of addressing gaps in quality of care and producing more evidence to support clinical practice. In this Review, we address opportunities to strengthen performance measurement, programmes to improve quality of care, and national capacity to produce high-impact knowledge for clinical practice. Moreover, we propose recommendations, with implications for other diseases, for how China can immediately make use of its Hospital Quality-Monitoring System and other existing national platforms to assess and improve performance of medical care, and to generate new knowledge to inform clinical decisions and national policies.


The effect of metiamide in in vitro and in vivo canine models of type I hypersensitivity reactions.
The histamine H2-receptor antagonist metiamide was evaluated in in vitro and in vivo canine models of immediate-type hypersensitivity reactions. At concentrations of 2 and 4 X 10(-4) M, the antagonist significantly increased the amount of histamine present in the medium surrounding passively sensitized canine lung fragments which had been challenged with ascaris antigen. In contrast, the compound was without effect on the release of a slow reacting substance of anaphylaxis. On the basis of these observations metiamide was investigated in an in vivo canine model of allergic asthma. At doses of 10, 30 and 50 mu moles/kg, the antagonist did not enhance the ascaris antigen-induced pulmonary pathophysiology. Similarly, at 10 and 50 mu moles/kg metiamide did not alter histamine-induced increases in pulmonary resistance or decreases in dynamic lung compliance. Insofar as the canine model of allergic asthma may be predictive of the human disease, it could be anticipated that the use of histamine H2-receptor antagonists may not be deleterious to allergic asthmatics.


Smartphone-Aided Fluorescence Detection of Cardiac Biomarker Myoglobin by a Ratiometric Fluorescent AuNCs-QDs Nanohybrids Probe with High Sensitivity.
Simple and sensitive detection of cardiac biomarkers is of great significance for early diagnosis and prevention of acute myocardial infarction (AMI). Here, a ratiometric fluorescent nanohybrids probe (AuNCs-QDs) was synthesized through the coupling of bovine serum albumin-functionalized gold nanoclusters (AuNCs) with CdSe/ZnS quantum dots (QDs) to realize simple and sensitive detection of cardiac biomarker myoglobin (Mb). The AuNCs-QDs probe shows pink fluorescence under UV light, with two emission peaks at 468 nm and 630 nm belonging to QDs and AuNCs, respectively. Importantly, the presence of Mb caused fluorescence quenching of the blue-emitting QDs, thereby inhibiting the fluorescence resonance energy transfer (FRET) process between QDs and AuNCs, and reducing the fluorescence intensity ratio (F468/F630) of AuNCs-QDs probe effectively. As the concentration of Mb increases, the ratiometric fluorescent probe also exhibits a visible fluorescence color change. The detection limit was as low as 4.99 μg/mL, and the response of the probe to Mb showed a good linear relationship up to 0.52 mg/mL. Moreover, the probe has excellent specificity for Mb. Besides, the AuNCs-QDs has been applied to detect Mb of urine samples. More importantly, we also developed an AuNCs-QDs probe modified smartphone-aided paper-based strip for on-site monitoring of Mb. As far as we know, this is the first report of a smartphone-aided paper-based strip for on-site quick monitoring of Mb, which provides a useful approach for AMI biomarker monitoring and may can be extended to other medical diagnostics.


Urinary catecholamine excretion and blood sugar response during acute poisonings with dinitrobenzenes.
Rats were injected intraperitoneally with 0.015 mmol of p-dinitrobenzene/kg, 0.15 mmol of m-dinitrobenzene/kg and 0.45 mmol of o-dinitrobenzene/kg body wt. The dinitrobenzenes induced methaemoglobin concentrations of 86%, 60% and 49%, respectively, as well as increases of urinary catecholamine excretion and blood sugar concentration. Due to hyperglycaemia the glycolysis may be stimulated as mechanism for energy production in methaemoglobin-induced oxygen deficiency and as mechanism for reduction of methaemoglobin, that means as responses favouring survival after poisoning.


Transcriptional regulation of the resistin gene.
Resistin, which is a protein that is secreted exclusively by adipocytes, plays an important role in insulin resistance and adipocyte differentiation. Adipocytes express significant amounts of resistin mRNA, while preadipocytes express low levels of resistin mRNA. The mechanism that causes this difference is unclear. Therefore, we studied the mechanism regulating resistin expression and the roles of different transcriptional factors in this process. The results from fluorescent photography and semi-quantitative RT-PCR showed that sterol regulatory element-binding protein 1c (SREBP1c) and cyclic AMP response-element-binding protein (CREB) had no effect on resistin expression. By contrast, CCAAT/enhancer-binding protein-alpha (C/EBPalpha) increased resistin mRNA levels both in 3T3-L1 preadipocytes and in 293T cells. The relative increase in the amount of resistin mRNA in the 293T cells was much larger than that in the 3T3-L1 preadipocytes. Moreover, while C/EBPalpha was necessary for resistin expression, we found that up-regulating C/EBPalpha levels alone was not sufficient to induce a similar level of resistin in preadipocytes to that in adipocytes.


The association of ankle dorsiflexion and dynamic knee valgus: A systematic review and meta-analysis.
The objective of this systematic review was to evaluate the association between ankle dorsiflexion (ADF) and dynamic knee valgus (DKV). Electronic searches were conducted in MEDLINE, EMBASE, CINAHL and SPORTDiscus. A modified Downs and Black checklist was used for quality assessment and meta-analysis was performed to compare standardised mean differences (SMD) of ADF. Seventeen studies met the inclusion criteria. Meta-analysis showed that reduced ADF is associated with participants presenting with DKV compared to controls (SMD -0.65, 95% CI -0.88 to -0.41). Subgroup analysis showed consistent results regarding different forms of ADF measurement; restriction in ADF measured in weight-bearing position (SMD -1.25, 95% CI -2.24 to -0.25), non-weight-bearing with knee flexed (SMD -0.56, 95% CI -0.97 to -0.16) or non-weight-bearing with knee extended (SMD -0.54, 95% CI -0.80 to -0.28) was significantly associated with DKV. The meta-analysis results provide evidence that reduced ADF is correlated with DKV. The assessment of ADF in the clinical setting is important, as it may be related to harmful movement patterns of the lower limbs.


Proposed guidelines for maximum acceptable air-borne microorganism levels in dairy processing and packaging plants.
From the total number of air-borne microorganisms present per m3 of air, 1.5% were found to contaminate a dairy product while being packed into a container with an opening of 100 cm2 if it was exposed for 60 s. This value was used to compile a proposed guideline of maximum acceptable number of air-borne microorganisms per m3 which, if complied with, could ensure that no significant air-borne contamination of the product being packaged would take place.


Reaction of fluorogenic reagents with proteins II: capillary electrophoresis and laser-induced fluorescence properties of proteins labeled with Chromeo P465.
The fluorogenic reagent Chromeo P465 is considered for the analysis of proteins by capillary electrophoresis with laser-induced fluorescence detection. The reagent was first used to label alpha-lactalbumin; the product was analyzed by capillary zone electrophoresis in a sub-micellar sodium dodecyl sulfate (SDS) buffer. The product generated a set of equally spaced but poorly resolved peaks that formed a broad envelope with a net mobility of 4 x 10(-4)cm(2) V(-1) s(-1). The components of the envelope were presumably protein that had reacted with different numbers of labels. The mobility of these components decreased by roughly 1% with the addition of each label. The signal increased linearly from 1.0 nM to 100 nM alpha-lactalbumin (r(2)=0.99), with a 3sigma detection limit of 70 pM. We then considered the separation of a mixture of ovalbumin, alpha-chymotrypsinogen A, and alpha-lactalbumin labeled with Chromeo P465; unfortunately, baseline resolution was not achieved with a borax/SDS buffer. Better resolution was achieved with N-cyclohexyl-2-aminoethanesulfonic acid/Tris/SDS/dextran capillary sieving electrophoresis; however, dye interactions with this buffer system produced a less than ideal blank.


Direct absorption of atmospheric lead by rapeseed siliques is the leading cause of seed lead pollution.
Rapeseed cultivation is a novel approach to safely utilizing lead (Pb) contaminated farmland. However, the mechanism of Pb absorption in seeds remains uncertain. A field experiment was conducted to explore this mechanism with two contrasting treatments: rapeseed exposed to atmospheric deposition and non-exposed treatment. Non-exposed treatment ultimately decreased Pb content in leaf, silique, and seed by 46.7%, 53.7%, and 53.6%, respectively. Sub-microstructure analysis further confirmed that rapeseed leaves and siliques could directly absorb atmospheric Pb. In addition, Pb isotope analysis indicates that atmospheric deposition is the primary source of silique and seed Pb. The root and silique organs had relative Pb contributions of 28.0% and 72.0%, respectively, to seed. Thus, the direct absorption of atmospheric Pb by siliques during the filling stage was found to be the leading cause of seed Pb pollution.


Outcomes of Total Knee Arthroplasty with a Prior Contralateral Above-Knee Amputation: A Report of 10 Cases.
Total knee arthroplasty (TKA) in the setting of a prior contralateral above-knee amputation (AKA) represents a rare scenario with limited reported outcomes. As such, it is difficult for surgeons to effectively counsel these patients relative to risks and expected outcomes after TKA. We report outcomes for a series of 10 such patients. We retrospectively reviewed all patients at our institution from 2005 to 2018 who underwent a primary TKA and prior contralateral AKA and had a minimum 12-month follow-up. Data regarding complications, ambulatory status, reported pain, patient demographics, length of follow-up, and comorbidities were obtained. Ten patients met criteria. Follow-up ranged from 1 to 8 years. Six reported no pain or improved pain with weight-bearing. Ambulatory status worsened for 5 patients, remained unchanged for 3, and improved for 2. Five patients had significant postoperative complications: infection requiring repeat surgery (3), quadriceps tendon rupture (1), and revision for implant failure and instability (1). Patients in this cohort had a median of 3 medical comorbidities known to affect postoperative outcomes and complication rates. While a contralateral AKA is not an absolute contraindication to TKA, these results should influence patient counseling. Most of our cohort benefited from improved pain, but only 2 of 10 had improved ambulation and half had significant complications. Medical comorbidities may have contributed to these complications. Surgeons contemplating TKA in this situation might consider modified postoperative recovery protocols and aggressive preoperative optimization of medical comorbidities to lower the risk of complication in this high-risk population.


Two-dimensional correlation and codistribution spectroscopy (2DCOS and 2DCDS) analyses of time-dependent ATR IR spectra of d-glucose anomers undergoing mutarotation process in water.
Two cyclic diastereoisomeric structures, known as α- and β-anomers of d-glucose with different configurations around C1 with OH groups in axial or equitroial positions, undergo the mutarotation conversion to each other in water. Two-dimensional correlation and codistribution spectroscopy (2DCOS and 2DCDS) analyses were applied to the time-dependent ATR IR spectra of aqueous solutions of α- and β-d-glucose undergoing such mutarotation conversion. 2DCOS analysis reveals that the increase and decrease in the IR intensities after the dissolution of α- or β-d-glucose are not fully synchronized, suggesting the mutarotation of d-glucose in water is not a simple binary conversion process but a multi-step reaction involving an intermediate species with a finite and observable concentration level and lifetime. 2DCDS analysis of the time-dependent ATR IR spectra clearly demonstrated the presence of intermediate species contributing to the band positions overlapped close to bands for α- and β-d-glucose. The fact that band positions identified for the intermediate species for α- to β-d-glucose conversion are the same for the reverse reaction suggests that they arise from the same species, most likely the open-ring structure produced by the hydrolysis.


An intergated serum and urinary metabonomic research based on UPLC-MS and therapeutic effects of Gushudan on prednisolone-induced osteoporosis rats.
Gushudan, a Chinese compound formulation based on the theory of traditional Chinese medicine and desgined to treat osteoporosis. However, its intergated intervention effective mechanism in vivo is not well understood. In this study, an intergated serum and urinary metabonomic strategy based on UPLC-MS technique have been developed to increase the understanding of the metabolism characters of osteoporosis and to investigate the holistic therapeutic efficacy of Gushudan on prednisolone-induced osteoporosis rat model. Principle component analysis (PCA) was utilized to identify differences in metabolic profiles of rats in the control group, prednisolone-induced osteoporosis model group and Gushudan-treatment group and clear separation was achieved among three groups. Furthermore, 17 potential biomarkers from urine and 10 potential biomarkers from serum were identified, primiarily related to amino acid metabolism, energy metabolism, lipid metabolism, intestinal flora metabolism and kidney damage. Gushudan has therapeutic effects on rat with osteoporosis via the regulation of multiple metabolic pathways. It's worth mentioning that some new biomarkers associated with osteoporosis such as 3-methoxydopa, 2,8-digydroxyadenine have been discovered in this study for the first time. This study provides a useful approach to get insight into the intergated metabonomic mechanism of prednisolone-induced osteoporosis and to assess the efficacy of Gushudan on osteoporotic rats. The work also shows that the metabonomics method is a promising tool in the efficacy and mechanism research of traditional Chinese compound medicines.


The effect of contrast adaptation on briefly presented stimuli.
Wilson and Humanski (1993) have recently reported evidence that adapting to low temporal frequency sinewave gratings yields little threshold elevation for briefly presented test stimuli. We postulated that brief stimuli may be detected by a transient channel which would be minimally affected by a low temporal frequency adapting pattern. We therefore measured the effect of adaptation on briefly presented test stimuli for a wider range of adapting temporal frequencies. The results indicate that adaptation may yield threshold elevation for briefly presented stimuli and that threshold elevation is greater for high than low temporal frequency adapting patterns. These results are consistent with the hypothesis that briefly presented stimuli are detected by a transient channel.


Initial study of anaemia profile for primary care centres with automated laboratory algorithms reduces the demand for ferritin, iron, transferrin, vitamin B12 and folate tests.
To evaluate the influence of an algorithm designed to incorporate reflex testing according to haemogram results for analytical tests ordered to investigate anaemia. In 2020, a new request for 'initial study of anaemia' was created in three primary care pilot centres for suspected anaemia or new anaemias. A haemogram was ordered and the remainder of the tests were created in a reflex manner according to an algorithm integrated in the laboratory information system that also generates a comment that is completed and validated by a haematologist. The demand for tests was evaluated over three time periods. Of 396 requests, anaemia was detected in 80 (20.2%), with 26 microcytic anaemias (6.57%), 20 iron deficiency anaemias, 41 (10.3%) normocytic anaemias and 13 macrocytic anaemias (3.28%); 4 with folate deficiency; and 1 haemolytic anaemia. No haematological diseases were detected. Twenty-four (6.06%) cases exhibited microcytosis/hypochromia without anaemia, 12 of which exhibited iron deficiency. Four young women exhibiting within-limit haemoglobin levels had iron deficiency. There were 56 (14.1%) cases of macrocytosis without anaemia.With the new profile of 'initial study of anaemia', the demand for tests was reduced and was significantly lower than in the remainder of primary centres for iron, transferrin, ferritin, vitamin B12 and folate. A new profile of 'initial study of anaemia' in the request form with algorithms integrated in the laboratory information system enabled submission of orders and decreased the demand for unnecessary iron, transferrin, ferritin, vitamin B12 and folate tests.


Structural analysis and binding sites of inhibitors targeting the CD47/SIRPα interaction in anticancer therapy.
Cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) is a negative innate immune checkpoint signaling pathway that restrains immunosurveillance and immune clearance, and thus has aroused wide interest in cancer immunotherapy. Blockade of the CD47/SIRPα signaling pathway shows remarkable antitumor effects in clinical trials. Currently, all inhibitors targeting CD47/SIRPα in clinical trials are biomacromolecules. The poor permeability and undesirable oral bioavailability of biomacromolecules have caused researchers to develop small-molecule CD47/SIRPα pathway inhibitors. This review will summarize the recent advances in CD47/SIRPα interactions, including crystal structures, peptides and small molecule inhibitors. In particular, we have employed computer-aided drug discovery (CADD) approaches to analyze all the published crystal structures and docking results of small molecule inhibitors of CD47/SIRPα, providing insight into the key interaction information to facilitate future development of small molecule CD47/SIRPα inhibitors.


Raising concerns on questionable ethics approvals - a case study of 456 trials from the Institut Hospitalo-Universitaire Méditerranée Infection.
The practice of clinical research is strictly regulated by law. During submission and review processes, compliance of such research with the laws enforced in the country where it was conducted is not always correctly filled in by the authors or verified by the editors. Here, we report a case of a single institution for which one may find hundreds of publications with seemingly relevant ethical concerns, along with 10 months of follow-up through contacts with the editors of these articles. We thus argue for a stricter control of ethical authorization by scientific editors and we call on publishers to cooperate to this end. We present an investigation of the ethics and legal aspects of 456 studies published by the IHU-MI (Institut Hospitalo-Universitaire Méditerranée Infection) in Marseille, France. We identified a wide range of issues with the stated research authorization and ethics of the published studies with respect to the Institutional Review Board and the approval presented. Among the studies investigated, 248 were conducted with the same ethics approval number, even though the subjects, samples, and countries of investigation were different. Thirty-nine (39) did not even contain a reference to the ethics approval number while they present research on human beings. We thus contacted the journals that published these articles and provide their responses to our concerns. It should be noted that, since our investigation and reporting to journals, PLOS has issued expressions of concerns for several publications we analyze here. This case presents an investigation of the veracity of ethical approval, and more than 10 months of follow-up by independent researchers. We call for stricter control and cooperation in handling of these cases, including editorial requirement to upload ethical approval documents, guidelines from COPE to address such ethical concerns, and transparent editorial policies and timelines to answer such concerns. All supplementary materials are available.


Pain Paroxysms With Coronal Radiation: Case Series and Proposal of a New Variant of Epicrania Fugax.
We aim to report 4 patients with brief pain paroxysms whose clinical features remind of typical epicrania fugax (EF), except for the direction along a transverse trajectory. EF has been defined as a brief paroxysmal head pain, with stabbing quality, describing a linear or zig-zag trajectory across the surface of one hemicranium. We considered all patients attending the headache outpatient office at 3 tertiary hospitals from March 2008 to December 2015. We identified a total of 4 cases with dynamic pain paroxysms moving in coronal direction. The mean age at onset was 49 years (range 34-75). All the patients suffered a dynamic pain from parietal or temporal areas to the contralateral ones, crossing the midline in a linear or zig zag trajectory, the entire sequence lasting 2-3 seconds. No triggers were identified. One patient noticed mild interictal tenderness at the stemming point. The frequency of the attacks varied from 2 per week to 1 every 2 months. No underlying disorders were identified by physical and neurological exams and neuroimaging and laboratory tests. Our patients presented with a paroxysmal head pain that might correspond to a transverse variant of EF. These observations may not only expand the EF phenotype but also reinforce the distinction between EF and pericranial neuralgias.


Occurrence and temporal variation of antibiotics and antibiotic resistance genes in hospital inpatient department wastewater: Impacts of daily schedule of inpatients and wastewater treatment process.
The temporal variation of antibiotics and ARGs as well as the impact of daily schedule of inpatients on their regular occurrence in hospital wastewater (HWW) were previously obscure. In this study, the wastewater of the inpatient department pre- and posttreatment (hydraulic retention time = 8 h) was collected intraday and intraweek. The absolute concentrations of antibiotics/metabolites and ARGs in HWW were analyzed to investigate the temporal variations of their occurrence levels. Fluoroquinolones were the predominant drugs used in the inpatient department (681.30-881.66 ng/mL in the effluent) and the main contaminant in the outlet of the disinfection pond (538.29-671.47 ng/mL). Diurnal variations peaked at 19:00 for most antibiotics and ARGs, while the maximum of them occurred on weekends. Aminoglycoside resistance genes (AMRGs, 21.6-23000 copies/mL) and β-lactam resistance genes (BLGRs, 1.24-8500 copies/mL) were the dominant ARGs before and after treatment processing, respectively (p < 0.05). The significant removal rates (>50%) of most antibiotics and ARGs, as well as the integrase gene intI1 and 16S rRNA gene, were found to be subjected solely to the chloride disinfection process, suggesting the necessity of the self-contained wastewater treatment process. Meanwhile, the statistically significant correlation among antibiotics, ARGs, intI1, and 16S rRNA (p < 0.05) demonstrated that the risk of selective pressure, horizontal transfer and vertical propagation of ARGs in the effluent of the hospital was warranted. Principal component analysis (PCA) showed that the daily schedule of inpatients and wastewater treatment processes could markedly induce fluctuations in antibiotic and ARG levels in HWW, indicating that they should be considered an impact factor for environmental monitoring. This study demonstrated for the first time the temporal variations in the abundance and dissemination of antibiotics and ARGs in a semiclosed zone and provided new insight into the development of assessments of the associated ecological risk and human health.


Analysis of operational methane emissions from pressure relief valves from biogas storages of biogas plants.
The study presents the development of a method for the long term monitoring of methane emissions from pressure relief valves (PRV(1)) of biogas storages, which has been verified during test series at two PRVs of two agricultural biogas plants located in Germany. The determined methane emission factors are 0.12gCH4kWhel(-1) (0.06% CH4-loss, within 106days, 161 triggering events, winter season) from biogas plant A and 6.80/7.44gCH4kWhel(-1) (3.60/3.88% CH4-loss, within 66days, 452 triggering events, summer season) from biogas plant B. Besides the operational state of the biogas plant (e.g. malfunction of the combined heat and power unit), the mode of operation of the biogas flare, which can be manually or automatically operated as well as the atmospheric conditions (e.g. drop of the atmospheric pressure) can also affect the biogas emission from PRVs.


Exploration of the validity of the two-dimensional sagittal plane assumption in modeling the standing long jump.
Most previous standing long jump studies have been based on the assumption of two-dimensional sagittal plane motion with bilateral symmetry. The purpose of this study was to investigate the validity of this assumption. Standing long jump trials were collected using six adult male participants. Each participant stood with a foot on each of two force plates and performed eight standing long jumps for maximal distance. Inverse dynamics analyses were performed for two-dimensional (2D) and three-dimensional (3D) models, and joint moments, powers, and work values were compared. The differences between these models with respect to the validity of the common planar jumping assumption were analyzed. Good agreement was observed between 2D and 3D methods for the lower body, with minimal differences in sagittal plane moments, power, and work for the ankle, knee, and lower back. There were significant, but relatively small differences in the sagittal plane kinematics and kinetics at the hip. For the upper body, the results contradicted the sagittal plane assumption in that significant moments and power were generated about the abduction/adduction axis of the shoulder and a similar amount of work was performed about both abduction/adduction and flexion/extension axes of the shoulder. The elbow also showed significant differences in power and work. These results indicate that an assumption of planar motion should be sufficient for many studies of the standing long jump that only examine lower body movement. However, for studies that include upper body motion, diagnosing injury risk, or investigating gender differences, a 3D model may be more appropriate.


Dopamine inhibits voltage-activated calcium channel currents in rat pars intermedia pituitary cells.
Several lines of evidence suggest that dopamine acts as a neurotransmitter that inhibits both hormone secretion and electrical activity in pituitary intermediate cells (melanotrophs). In this study we examined the effects of exogenously applied dopamine on voltage activated calcium currents recorded with the whole-cell mode of the patch-clamp technique from short-term primary cultures of melanotrophs. Two types of calcium currents were distinguished by their voltage dependence and kinetics of inactivation similar to the low voltage-activated currents (LVA; or T-type) and high voltage-activated currents (HVA; N&L-types) of calcium currents. Exogenously applied dopamine (2-20 microM) reversibly reduced both LVA and HVA types of calcium currents. Evidence for these results came from experiments in which LVA and HVA calcium currents were separated by stepping to different membrane potentials from a fixed holding potential (Vh) or by changing Vh. These results suggest that dopamine can regulate the entry of calcium into melanotrophs by acting on at least two different populations of calcium channels thereby affecting hormone secretion and electrical activity.


[Laparoscopic surgery. Preliminary experience].
The first 23 cases of surgical laparoscopy carried out in the Obstetrics and Gynecology Department of the Valdivia Hospital are presented. The advantages of this surgical technique and its indication, in anexal pathology, specially in young women who wish to preserve their fertility is emphasized.


Recombinant multimeric dog allergen prevents airway hyperresponsiveness in a model of asthma marked by vigorous TH 2 and TH 17 cell responses.
Allergy to dogs affects around 10% of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit. We established a mouse model of dog allergy by repeatedly administering dog dander and epithelium extracts via the intranasal route. We also assessed the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts. Repeated inhalation of dog extracts induced infiltration of the airways by TH 2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted TH 17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA-Seq analysis of T helper cells in the airways pinpointed a unique gene signature for TH 17 cells. Analysis of T-cell receptors depicted a high frequency of clones that were shared between TH 17, TH 2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1-2-4-6 protein prior to sensitization reduced airway hyperresponsiveness and type 2-mediated inflammation in this model. Dog allergen extracts induce robust TH 2 and TH 17 cell-mediated responses in mice. Recombinant Can f 1-2-4-6 can induce tolerance to complex dog allergen extracts.


[TEG-guided treatment of a dabigatran overdose in a patient with acute kidney failure].
This article presents the case of a multimorbid male patient with an accidental dabigatran overdose caused by kidney failure in the context of an acute intestinal disorder. After effective initial antagonizing of the dabigatran effect using idarucizumab a dabigatran rebound was detected caused by a single hemodialysis leading to a severe intrapulmonary hemorrhage. As dabigatran plasma level testing was not available and conventional coagulation analysis was out of interpretable range due to the impact of dabigatran, continuous thrombelastography (TEG) was used to detect the effect of dabigatran and monitor the treatment results. The most significant parameter used in the kaolin activated clotting time was the R‑time parameter, which was massively prolonged by the interrupted coagulation cascade.


[Correlation Between Index Components and Climatic Factors of Pseudostellariae Radix].
To analyze the correlation between index components and climatic factors of Pseudostellariae Radix. Correlation analysis ( CA), partial least square (PLS) and PCA ordination were applied to analyze the correlation of index components in Pseudostellariae Radix and climatic factors, and to explore the main climatic factors affecting the accumulation of index components in Pseudostellariae Radix. The origin and harvest time had influence on index components. The monthly minimum temperature, monthly average humidity, monthly precipitation and the annual precipitation were the dominant factors influencing the content of index components. Through the positive and negative correlation between climatic factors and index components, it could explain the rationality of traditional harvest time and the reason of high content of heterophyllin B in Pseudostellariae Radix from Jiangsu Jurong.


Extraction of a weak climatic signal by an ecosystem.
The complexity of ecosystems can cause subtle and chaotic responses to changes in external forcing. Although ecosystems may not normally behave chaotically, sensitivity to external influences associated with nonlinearity can lead to amplification of climatic signals. Strong correlations between an El Niño index and rainfall and maize yield in Zimbabwe have been demonstrated; the correlation with maize yield was stronger than that with rainfall. A second example is the 100,000-year ice-age cycle, which may arise from a weak cycle in radiation through its influence on the concentration of atmospheric CO2 (ref. 5). Such integration of a weak climatic signal has yet to be demonstrated in a realistic theoretical system. Here we use a particular climatic phenomenon-the observed association between plankton populations around the UK and the position of the Gulf Stream-as a probe to demonstrate how a detailed marine ecosystem model extracts a weak signal that is spread across different meteorological variables. Biological systems may therefore respond to climatic signals other than those that dominate the driving variables.


Use of a Y-tube conduit after facial nerve injury reduces collateral axonal branching at the lesion site but neither reduces polyinnervation of motor endplates nor improves functional recovery.
Despite increased understanding of peripheral nerve regeneration, functional recovery after surgical repair remains disappointing. A major contributing factor is the extensive collateral branching at the lesion site, which leads to inaccurate axonal navigation and aberrant reinnervation of targets. To determine whether the Y tube reconstruction improved axonal regrowth and whether this was associated with improved function. We used a Y-tube conduit with the aim of improving navigation of regenerating axons after facial nerve transection in rats. Retrograde labeling from the zygomatic and buccal branches showed a halving in the number of double-labeled facial motor neurons (15% vs 8%; P < .05) after Y tube reconstruction compared with facial-facial anastomosis coaptation. However, in both surgical groups, the proportion of polyinnervated motor endplates was similar (≈ 30%; P > .05), and video-based motion analysis of whisking revealed similarly poor function. Although Y-tube reconstruction decreases axonal branching at the lesion site and improves axonal navigation compared with facial-facial anastomosis coaptation, it fails to promote monoinnervation of motor endplates and confers no functional benefit.


Cannabis legalization and driving under the influence of cannabis in a national U.S. Sample.
The relationship between cannabis legalization and traffic safety remains unclear. Physiological measures of cannabis impairment remain imperfect. This analysis used self-report data to examine the relationship between cannabis legalization and driving under the influence of cannabis (DUIC). Using a cross-sectional national sample (2016-2017) of 1,249 past-30-day cannabis users, we regressed self-reported DUIC (driving within three hours of "getting high") on cannabis legalization (recreational and medical (recreational), medical only (medical), or no legal cannabis), adjusting for demographics, days of use (past 30 days), days of use*legal status, calibration weights, and geographic clustering. The risk of DUIC in recreational (risk ratio [RR] = 0.41, 95% confidence interval (CI):0.23-0.72) and medical (RR = 0.39, 95% CI:0.20-0.79) states was lower than in states without legal cannabis, with one exception. Among frequent cannabis users (≥20 days per month), there was a significantly lower risk of DUIC for those living in recreational states (RR = 0.70, 95% CI: 0.49-0.99), but not for those living in medical states (RR = 0.87, 95% CI: 0.60-1.24), compared to users living in states without legal cannabis. The risk of self-reported DUIC was lower in recreational and medical cannabis states compared to states without legal cannabis. The only exception was for frequent users in medical states, for whom there was no difference in risk compared to frequent users living in states without legal cannabis.


HIV-related research in correctional populations: now is the time.
The incarcerated population has increased to unprecedented levels following the 1970 US declaration of war on illicit drug use. A substantial proportion of people with or at risk for HIV infection, including those with substance use and mental health disorders, have become incarcerated. The overlapping epidemics of incarceration and HIV present a need for academic medical centers to collaborate with the criminal justice system to improve the health of incarcerated populations. With coordinated collaboration and new programmatic initiatives it is possible to reduce HIV-associated risk behaviors and the likelihood of acquisition and transmission of HIV. Centers for AIDS Research (CFAR), funded by the National Institutes of Health, have proactively responded to this need through Collaboration on HIV in Corrections (CHIC) to improve the diagnosis, treatment, linkage to care, and prevention of HIV. This collaboration serves as a model for aligning academic expertise with criminal justice to confront this challenge to individual and public health. This is especially relevant given recent evidence of the effectiveness of antiretroviral therapy in reducing HIV transmission.


The relationship between adolescent reading habits and older adult social engagement - A longitudinal cohort analysis.
To investigate an access point during youth with the potential to have a positive impact on social engagement in later-life. Our social selves begin long before older adulthood, a life-stage during which people face extensive changes to their social milieu. Adolescence is a sensitive period for sociocultural processing and adolescent activities have the potential to impact social engagement in older adulthood. We examine reading since, in adolescence, it promotes social-cognitive skills which facilitate social engagement. Our main goal was to study the relationship between adolescent reading and older adult social engagement. We used longitudinal cohort data from Project Talent and ordered logistic regression as well as two-wave, cross-lagged panel model to analyze this relationship. Ancillary analyses examined recognized relationships between reading and social-cognition and between social-cognition and social engagement in both adolescence and older adulthood. Adolescent reading was related to more frequent older adult social engagement with both family and friends. This relationship was independent of reading during older adulthood, social engagement during adolescence, and social-cognition at both life-stages. Adolescent social engagement was not associated with older adult reading in the two-wave, cross-lagged model. Reading was positively related to social-cognition in adolescence, but was insignificant in older adulthood. And, social-cognition was positively related to social engagement in both adolescence and older adulthood. Reading is declining for both young and older Americans. Young Americans are also socializing less than in previous decades. These trends could have a detrimental influence on social engagement and social isolation in future cohorts of older adults. We recommend continuing to look for activities and experiences during youth, especially the sensitive period of adolescence, that could stimulate social engagement over the life-course and into older adulthood.