Perinatal Thyroid Dysfunction: Prenatal Diagnosis and Treatment.
Thyroid diseases affect up to 10% of women, but most respond well to treatment. During pregnancy, however, normal metabolic changes may obscure pathology, and improper management may harm the fetus. Tests for levels of thyroid stimulating hormone (TSH), free thyroxine, and free triiodothyronine are essential. Generally, high TSH values suggest primary hypothyroidism, while suppressed levels indicate hyperthyroidism. Hyperthyroidism is commonly manifested by goiter, ophthalmopathy, proximal muscle weakness, tachycardia, and weight loss or inability to gain weight. Among women, the most common etiology of thyroid disease is thyroid autoimmunity (Graves' disease or Hashimoto's thyroiditis); affected women are at an increased risk of postpartum thyroid dysfunction. Women who have Graves' disease diagnosed during pregnancy typically have a history of hyperthyroidism symptoms antedating conception, and occasionally thyroid stimulating immunoglobulins may be elevated enough to induce fetal hyperthyroidism. Women with Hashimoto's thyroiditis typically are euthyroid but may be hypothyroid with diffuse goiter; diagnosis is confirmed by elevated levels of antithyroid peroxidase antibodies or antimicrosomal antibodies. Other forms of thyroid dysfunction include benign or malignant nodules and hyperemesis gravidarum. Hypothyroidism typically is treated with levothyroxine. Hyperthyroidism is treated with antithyroid drugs. The goal is to avoid overdosage of medication, which could cause goiter and/or hypothyroidism in the fetus.


Tympanomeatal flap creation in endoscopic stapedotomy: cautery vs. cold instrumentation.
Bleeding is one of the most challenging issues for surgeons performing endoscopic stapedotomy. During creation and elevation of the tympanomeatal flap (TMF) prevention or control of bleeding greatly facilitates the safety and comfort in the next steps of the surgery. The aim of this study was to compare the effects of cautery versus cold instrumentation during creation of TMF at endoscopic stapedotomy surgery. We investigated 15 patients TMF created with cautery and 14 patients with cold instrument, and compared bleeding scores, operation time, postoperative hearing, pain and complications between groups. The mean bleeding score was significantly lower in cautery incised patients compared to cold instrument patients (1.2 ± 0.9 vs. 2.3 ± 1, p = 0.005). Mean duration of surgery was also significantly shorter in cautery used patients (35.3 ± 6.8 vs. 48.8 ± 9.2 min, p < 0.001). There was no significant difference between postoperative pain, complications, wound healing, and auditory outcomes. Cautery may be a better choice for the creation of TMF in endoscopic stapedotomy surgery due to reduced bleeding, shorter operation time and increased comfort without causing any complications.


Soft drug-resistant ovarian cancer cells migrate via two distinct mechanisms utilizing myosin II-based contractility.
The failure of chemotherapeutic drugs in treatment of various cancers is attributed to the acquisition of drug resistance. However, the migration mechanisms of drug-resistant cancer cells remain incompletely understood. Here we address this question from a biophysical perspective by mapping the phenotypic alterations in ovarian cancer cells (OCCs) resistant to cisplatin and paclitaxel. We show that cisplatin-resistant (CisR), paclitaxel-resistant (PacR) and dual drug-resistant (i.e., resistant to both drugs) OCCs are more contractile and softer than drug-sensitive cells. Protease inhibition suppresses invasion of CisR cells but not of PacR cells, indicative of a protease-dependent mode of migration in CisR cells and a protease-independent mode of migration in PacR. Despite these differences, actomyosin contractility, mediated by the RhoA-ROCK2-Myosin II signaling pathway, regulates both modes of migration. Confined migration experiments establish the role of myosin IIA and IIB in mediating nuclear translocation and regulation of proteolytic activity. Collectively, our results highlight the importance of myosin II as a potential therapeutic target for treatment of drug-resistant ovarian cancer cells.


Long-lasting novelty-induced neuronal reverberation during slow-wave sleep in multiple forebrain areas.
The discovery of experience-dependent brain reactivation during both slow-wave (SW) and rapid eye-movement (REM) sleep led to the notion that the consolidation of recently acquired memory traces requires neural replay during sleep. To date, however, several observations continue to undermine this hypothesis. To address some of these objections, we investigated the effects of a transient novel experience on the long-term evolution of ongoing neuronal activity in the rat forebrain. We observed that spatiotemporal patterns of neuronal ensemble activity originally produced by the tactile exploration of novel objects recurred for up to 48 h in the cerebral cortex, hippocampus, putamen, and thalamus. This novelty-induced recurrence was characterized by low but significant correlations values. Nearly identical results were found for neuronal activity sampled when animals were moving between objects without touching them. In contrast, negligible recurrence was observed for neuronal patterns obtained when animals explored a familiar environment. While the reverberation of past patterns of neuronal activity was strongest during SW sleep, waking was correlated with a decrease of neuronal reverberation. REM sleep showed more variable results across animals. In contrast with data from hippocampal place cells, we found no evidence of time compression or expansion of neuronal reverberation in any of the sampled forebrain areas. Our results indicate that persistent experience-dependent neuronal reverberation is a general property of multiple forebrain structures. It does not consist of an exact replay of previous activity, but instead it defines a mild and consistent bias towards salient neural ensemble firing patterns. These results are compatible with a slow and progressive process of memory consolidation, reflecting novelty-related neuronal ensemble relationships that seem to be context- rather than stimulus-specific. Based on our current and previous results, we propose that the two major phases of sleep play distinct and complementary roles in memory consolidation: pretranscriptional recall during SW sleep and transcriptional storage during REM sleep.


Label-Free but Still Constrained: Assessment of Global Proteomic Strategies for the Quantification of Hepatic Enzymes and Transporters.
Building and refining pharmacology models require "system" data derived from tissues and in vitro systems analyzed by quantitative proteomics. Label-free global proteomics offers a wide scope of analysis, allowing simultaneous quantification of thousands of proteins per sample. The data generated from such analysis offer comprehensive protein expression profiles that can address existing gaps in models. In this study, we assessed the performance of three widely used label-free proteomic methods, "high N" ion intensity approach (HiN), intensity-based absolute quantification (iBAQ) and total protein approach (TPA), in relation to the quantification of enzymes and transporters in 27 human liver microsomal samples. Global correlations between the three methods were highly significant (R2 > 0.70, P < 0.001, n = 2232 proteins). Absolute abundances of 57 pharmacokinetic targets measured by standard-based label-free methods (HiN and iBAQ) showed good agreement, whereas the TPA overestimated abundances by two- to threefold. Relative abundance distribution of enzymes was similar for the three methods, while differences were observed with TPA in the case of transporters. Variability (CV) was similar across methods, with consistent between-sample relative quantification. The back-calculated amount of protein in the samples based on each method was compared with the nominal protein amount analyzed in the proteomic workflow, revealing overall agreement with data from the HiN method with bovine serum albumin as standard. The findings herein present a critique of label-free proteomic data relevant to pharmacokinetics and evaluate the possibility of retrospective analysis of historic datasets. SIGNIFICANCE STATEMENT: This study provides useful insights for using label-free methods to generate abundance data applicable for populating pharmacokinetic models. The data demonstrated overall correlation between intensity-based label-free proteomic methods (HiN, iBAQ and TPA), whereas iBAQ and TPA overestimated the total amount of protein in the samples. The extent of overestimation can provide a means of normalization to support absolute quantification. Importantly, between-sample relative quantification was consistent (similar variability) across methods.


Review of transition of care literature: Epidermolysis bullosa-A paradigm for patients with complex dermatologic conditions.
Transition from pediatric to adult care is a critical component of health care for children with long-term needs. The characteristics of epidermolysis bullosa (EB) demand higher than average levels of provider support. There is consensus among health care professionals regarding the importance of transition; however, there is a scarcity of practical information regarding models for patients with EB. To review transition of care programs in varying specialties. Highlight practical considerations to facilitate the development of programs for patients with EB and other complex dermatologic conditions. Articles were identified via MEDLINE and EMBASE health literature databases and screened for relevance to transition of care. Various models for transition exist. A well-executed formal transition program, early introduction, interdisciplinary collaboration, and psychosocial support were themes associated with successful outcomes. Transition of care programs that have not been described in the literature are not reflected in this review. Patients with EB have unique needs that affect transition and span expertise across traditional boundaries, such as dependency on others for daily skin care, failure to thrive, and risk of squamous cell carcinoma. Given the rarity of the disease, patients with EB will benefit from collaborative efforts to develop programs to optimize successful transition.


An online learning course in Ergonomics.
For the past two years, the Department of Occupational Therapy at the University of Haifa has offered an online course to third year occupational therapists on the topic of Ergonomics for Health Care Professionals. The development and implementation of this course was funded by the Israeli Ministry of Education. Unique teaching materials, developed and uploaded to the University's server via "High Learn", included interactive and self-directed documents containing graphics, animations, and video clips. Extensive use was made of the discussion forum and survey tools, and students submitted all assignments online. For the final topic, an expert in ergonomics from Boston University delivered a lecture via two-way videoconferencing. The course site included comprehensive library listings in which all bibliographic materials were made available online. Students accessed course materials at the University in a computer classroom and at home via modem. In an accompanying research study, the frequency of student usage of the various online tools was tracked and extensive data were collected via questionnaires documenting students' demographic background, preferred learning style, prior usage of technology, satisfaction with the course and academic achievement. This paper focuses on the results of the research study that examined how the students responded to and coped with teaching material presented and accessed in this format.


A Systematic Review of Semantic Feature Analysis Therapy Studies for Aphasia.
The purpose of this study was to review treatment studies of semantic feature analysis (SFA) for persons with aphasia. The review documents how SFA is used, appraises the quality of the included studies, and evaluates the efficacy of SFA. The following electronic databases were systematically searched (last search February 2017): Academic Search Complete, CINAHL Plus, E-journals, Health Policy Reference Centre, MEDLINE, PsycARTICLES, PsycINFO, and SocINDEX. The quality of the included studies was rated. Clinical efficacy was determined by calculating effect sizes (Cohen's d) or percent of nonoverlapping data when d could not be calculated. Twenty-one studies were reviewed reporting on 55 persons with aphasia. SFA was used in 6 different types of studies: confrontation naming of nouns, confrontation naming of verbs, connected speech/discourse, group, multilingual, and studies where SFA was compared with other approaches. The quality of included studies was high (Single Case Experimental Design Scale average [range] = 9.55 [8.0-11]). Naming of trained items improved for 45 participants (81.82%). Effect sizes indicated that there was a small treatment effect. SFA leads to positive outcomes despite the variability of treatment procedures, dosage, duration, and variations to the traditional SFA protocol. Further research is warranted to examine the efficacy of SFA and generalization effects in larger controlled studies.


Plastome phylogenomics and historical biogeography of aquatic plant genus Hydrocharis (Hydrocharitaceae).
Hydrocharis L. and Limnobium Rich. are small aquatic genera, including three and two species, respectively. The taxonomic status, phylogenetic relationships and biogeographical history of these genera have remained unclear, owing to the lack of Central African endemic H. chevalieri from all previous studies. We sequenced and assembled plastomes of all three Hydrocharis species and Limnobium laevigatum to explore the phylogenetic and biogeographical history of these aquatic plants. All four newly generated plastomes were conserved in genome structure, gene content, and gene order. However, they differed in size, the number of repeat sequences, and inverted repeat borders. Our phylogenomic analyses recovered non-monophyletic Hydrocharis. The African species H. chevalieri was fully supported as sister to the rest of the species, and L. laevigatum was nested in Hydrocharis as a sister to H. dubia. Hydrocharis-Limnobium initially diverged from the remaining genera at ca. 53.3 Ma, then began to diversify at ca. 30.9 Ma. The biogeographic analysis suggested that Hydrocharis probably originated in Europe and Central Africa. Based on the phylogenetic results, morphological similarity and small size of the genera, the most reasonable taxonomic solution to the non-monophyly of Hydrocharis is to treat Limnobium as its synonym. The African endemic H. chevalieri is fully supported as a sister to the remaining species. Hydrocharis mainly diversified in the Miocene, during which rapid climate change may have contributed to the speciation and extinctions. The American species of former Limnobium probably dispersed to America through the Bering Land Bridge during the Miocene.


Detection of agglutinins in chickens infected with JM leukosis virus.
Hemagglutinins for sheep red blood cells were detected in sera from JM virus-infected single-comb White Leghorn (susceptible S line) chickens. The agglutinins were not sedimented at 97,000 x g and were not affected by freezing and thawing, possibly indicating a soluble hemagglutinating factor. Agglutination titers were read in a relatively short period, after 4 hr of incubation at 4 C. The usefulness of this test for quick and low-cost screening of a large number of samples is indicated.


[Recovery of the cellular immunity system after sublethal radiation].
Dynamics and recovery of quantitative and qualitative characteristics of lymphoid tissue were studied after sublethal irradiation. The data obtained are indicative of a different dynamics of recovery of cells in central and peripheral lymphoid organs, GFUs and antibody-forming elements. The peculiarities have been revealed in a change of functional capacity of some T-lymphocyte populations.


Aggrecan-like biomimetic proteoglycans (BPGs) composed of natural chondroitin sulfate bristles grafted onto a poly(acrylic acid) core for molecular engineering of the extracellular matrix.
Biomimetic proteoglycans (BPGs) were designed to mimic the three-dimensional (3D) bottlebrush architecture of natural extracellular matrix (ECM) proteoglycans, such as aggrecan. BPGs were synthesized by grafting native chondroitin sulfate bristles onto a synthetic poly(acrylic acid) core to form BPGs at a molecular weight of approximately ∼1.6 MDa. The aggrecan mimics were characterized chemically, physically, and structurally, confirming the 3D bottlebrush architecture as well as a level of water uptake, which is greater than that of the natural proteoglycan, aggrecan. Aggrecan mimics were cytocompatible at physiological concentrations. Fluorescently labeled BPGs were injected into the nucleus pulposus of the intervertebral disc ex vivo and were retained in tissue before and after static loading and equilibrium conditioning. BPGs infiltrated the tissue, distributed and integrated with the ECM on a molecular scale, in the absence of a bolus, thus demonstrating a new molecular approach to tissue repair: molecular matrix engineering. Molecular matrix engineering may compliment or offer an acellular alternative to current regenerative medicine strategies. Aggrecan is a natural biomolecule that is essential for connective tissue hydration and mechanics. Aggrecan is composed of negatively charged chondroitin sulfate bristles attached to a protein core in a bottlebrush configuration. With age and degeneration, enzymatic degradation of aggrecan outpaces cellular synthesis resulting in a loss of this important molecule. We demonstrate a novel biomimetic molecule composed of natural chondroitin sulfate bristles grafted onto an enzymatically-resistant synthetic core. Our molecule mimics a 3D architecture and charge density of the natural aggrecan, can be delivered via a simple injection and is retained in tissue after equilibrium conditioning and loading. This novel material can serve as a platform for molecular repair, drug delivery and tissue engineering in regenerative medicine approaches.


Working in partnership with vulnerable families: the experience of child and family health practitioners.
Family circumstances in infancy are persistent and powerful determinants of children's physical and mental health, influencing inequalities that trace from childhood through to adulthood. While the social factors that perpetuate patterns of inequality are more complex than can be addressed through single interventions, child and family health (CFH) services represent crucial sites where trajectories of inequality can be disrupted. In particular, approaches that foster opportunities for practitioner-parent engagement that challenge traditional hierarchical health care practice, such as the Family Partnership Model (FPM), are recommended as ways of addressing disadvantage. Little is known about how practitioners implement models of working in partnership with families and, consequently, there is a gap in understanding how best to develop and sustain these new CFH practices. This paper reports a research project that investigated the experiences of 25 health professionals working within a FPM framework with vulnerable families. Through discussion of four key themes - redefining expertise, changing practices, establishing new relationships with parents and the complexities of partnership practice - the paper offers first-hand accounts of reframing practices that recognise the needs, skills and expertise of parents and thus contribute to empowerment of families.


A Series of Thiadiazolyl-Benzenesulfonamides Incorporating an Aromatic Tail as Isoform-Selective, Potent Carbonic Anhydrase II/XII Inhibitors.
We describe the synthesis of a series of thiadiazolyl-benzenesulfonamide derivatives carrying an aromatic tail linked by an amide linker (12-34), as human carbonic anhydrase (hCA) inhibitors. These thiadiazol derivatives were evaluated against four physiologically relevant CA isoforms (hCA I, II, IX, and XII), and demonstrated intriguing inhibitory activity against CA II with Ki values in the range of 2.4-31.6 nM. Besides hCA II, also hCA XII activity was potently inhibited by some of the derivatives (Ki =1.5-88.5 nM), producing dual inhibitors of both isoforms. Notably, compound 17 was the most potent dual CA II (Ki =3.1 nM) and XII (Ki =1.5 nM) inhibitor with a significant selectivity ratio over CA I and IX isoforms. In conclusion, although all compounds exhibited preferential activity towards hCA II, the nature of the substituents at the tail part of the main scaffold influenced the activity and selectivity toward other isoforms.


[Changes in NT-proBNP levels in patients with atrial fibrillation related to heart failure].
NT-proBNP, a well-established diagnostic and prognostic marker in clinical practice, is significantly elevated in individuals with atrial fibrillation (AF), even in absence of heart failure or major structural heart disease. The aim of this study was to determine the cut-off value of NT-proBNP for diagnosis of heart failure in individuals with atrial fibrillation. We compared 44 patients (25 male/19 female) with AF and concomitant overt heart failure [age 76 (62-82) years; median (interquartile range - IQR)] versus 29 patients (16 male/13 female) with AF with no signs of heart failure [age 59 (50-67) years; median (IQR)]. We considered the underlying causes of heart failure and its severity, comorbidities, echocardiographic and selected laboratory parameters, the body mass index as well as the treatment at discharge. We determined the cut-off value for heart failure and major structural heart disease using ROC curve analysis. Median NT-proBNP in the group of patients with AF and concomitant heart failure was 3 218 ng/l (IQR 1 758-7 480 ng/l) vs 981 ng/l (IQR 431-1 685 ng/l) in the group of patients with AF with no signs of heart failure; this difference was statistically significant (p < 0.001). The level of NT-proBNP higher than 1 524 ng/l in patients with AF was diagnostic of major structural heart disease and pointed towards a possible heart failure (sensitivity 80%, specificity of 76%, accuracy 78%, positive predictive value 83%, negative predictive value 71%). The NT-proBNP levels significantly correlated with age (p < 0.001), left atrial diameter (p < 0.01) and furosemide dose at discharge (p < 0.05). The NT-proBNP levels significantly negatively correlated with left ventricular ejection fraction (p < 0.001) and body mass index (p < 0.05). We found out that NT-proBNP is significantly elevated in patients with AF with preserved left ventricular function and in absence of heart failure and significantly correlates with age, left ventricular ejection fraction, left atrial diameter, body mass index and the furosemide dose necessary to achieve cardiac compensation. Furthermore, we determined the NT-proBNP cut-offvalue predictive of a possible heart failure in patients with AF.


Spatial reconstruction of single-cell gene expression data.
Spatial localization is a key determinant of cellular fate and behavior, but methods for spatially resolved, transcriptome-wide gene expression profiling across complex tissues are lacking. RNA staining methods assay only a small number of transcripts, whereas single-cell RNA-seq, which measures global gene expression, separates cells from their native spatial context. Here we present Seurat, a computational strategy to infer cellular localization by integrating single-cell RNA-seq data with in situ RNA patterns. We applied Seurat to spatially map 851 single cells from dissociated zebrafish (Danio rerio) embryos and generated a transcriptome-wide map of spatial patterning. We confirmed Seurat's accuracy using several experimental approaches, then used the strategy to identify a set of archetypal expression patterns and spatial markers. Seurat correctly localizes rare subpopulations, accurately mapping both spatially restricted and scattered groups. Seurat will be applicable to mapping cellular localization within complex patterned tissues in diverse systems.


Patients Access to Medicines - A Critical Review of the Healthcare System in Kenya.
Access to affordable, safe, effective, and quality-assured medicines by a patient is important for good health outcomes. Unfortunately, there is sparse literature published on the pharmaceutical enablers that may increase the sale of a substandard and falsified (SF) medicine to a patient in Kenya. The review highlights some of the factors that may facilitate the entry of SF medicines into the legitimate pharmaceutical supply chain and discusses their impact on patient access to medicines. Lack of essential medicines in public health facilities is an important factor that may contribute to increased demand for medicine-related out-of-pocket expenses from private health facilities, thus a likelihood for a patient purchasing SF medicine from unlicensed and illegal medicine outlets or unregulated websites. The need to increase medicine availability in the public sector by the Ministry of Health (MOH) is emphasized in addition to the strengthening of public procurement to cushion it from corruption and mismanagement. In addition, the MOH should promote local pharmaceutical manufacturing and implement a medicine pricing containment policy to avoid abuse and prevent overexploitation of patients, increase medicine price transparency, and reduce pharmaceutical supply chain distortion. Recommended regulatory reviews include accreditation of unlicensed illegal medicine outlets to facilitate accountability, regulatory oversight, and active surveillance. The national post-market surveillance regulatory capacity should be strengthened to improve rational medicine use. A 3-year diploma course should be replaced with a shorter 1- or 2-year pharmaceutical support staff training not eligible to superintend a pharmacy. The recommended legislative review includes a mandatory clause to enforce generic prescribing and the implementation of generic substitution by health workers. Unethical manipulative pharmaceutical marketing practices should carry stiffer penalties to deter malpractice. Future research areas include investigation of medicine prescribing and dispensing practices, medicine consumption studies, medicine price differences within different health sub-sectors, and between licensed pharmacies and unlicensed illegal medicine outlets.


Salmonella septic arthritis in Zambian children.
Thirty-four children under the age of 3 years with septic arthritis presented to Mukinge Hospital between 1 January 1992 and 31 March 1993. Twenty-six of these cultured Salmonella spp. The salmonella group comprised 17 males and 9 females with an average age of 10 months. Most patients were anaemic and all were under 50th centile for weight. The commonest presentation was swelling, pyrexia and non-use of the limb. The mean white cell count (WBC) was 14,000/mm3 and the mean erythrocyte sedimentation rate (ESR) was 15.8 mm/h, but in many cases both the WBC and ESR were normal. All patients were treated with drainage and antibiotics. All made a good recovery and were discharged pain free, apyrexial and using the affected joint. One patient was readmitted because of recurrent infection. Nine patients reviewed after 1 month had continued good function. We consider that malnutrition and local trauma are predisposing factors to the development of salmonella septic arthritis in a population where salmonella is endemic.


The reliability and minimal detectable change of the cardiovascular response and self-selected exercise intensity during forward and backward treadmill exercise in individuals with Parkinson disease.
This study examined test-retest relative (intraclass correlation coefficient) and absolute (minimum detectable change) reliabilities for heart rate, blood pressure, rate of perceived exertion, and the cerebral oxygen response during both forward and backward treadmill walking in clients with Parkinson disease. In addition, the intensity of exercise based on the individual's heart rate response during forward and backward walking treadmill work was assessed. Test-retest reliability study. A total of 22 clients with Parkinson disease (Hoehn and Yahr stages 1-3). Outcome measures of heart rate, blood pressure, and cerebral oxygen response were assessed during forward and backward walking on a treadmill for a total of 20 minutes up to an intensity based on the clients' prior treadmill work and their rate of perceived exertion. Good to excellent 6-8 day test-retest findings for both forward (intraclass correlation coefficient(2,1), 0.89-0.99) and backward (intraclass correlation coefficient(2,1), 0.82-0.99) treadmill walking were found for heart rate, blood pressure, cerebral oxygen response, and the participants' rate of perceived exertion. Low minimum detectable change (MDC)95 values were found for heart rate (4.9 and 4.8), rate of perceived exertion (1.0 and 1.6), and cerebral oxygen response (1.2 and 0.92), during forward and backward walking, respectively. All treadmill exercise heart rates attained by participants were within an intensity of 54%-87% of the client's predicted maximal heart rate. Treadmill exercise training can be included in Parkinson disease exercise programs with relative confidence in test-retest reliability of cardiovascular response. It was also demonstrated that individuals with Parkinson disease previously involved with exercise consistently self-select walking speeds which induce heart rates within recommended guidelines for positive cardiovascular adaptation.


Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients.
Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the US, 61.4% patients with an acute rejection episode received steroids, 20.4% received an antibody preparation and 18.2% received both. To determine the benefits and harms of mono- or polyclonal antibodies (Ab) used to treat acute rejection in kidney transplant recipients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), and the specialised register of the Cochrane Renal Group (June 2005). Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of acute graft rejection, when compared to any other treatment for acute rejection. Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) with 95% confidence intervals (CI). Twenty one trials (49 reports, 1387 patients) were identified. Trials were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. Fourteen trials (965 patients) compared therapies for first rejection episodes. Ab was better than steroid in reversing rejection (RR 0.57, 95% CI 0.38 to 0.87) and preventing graft loss (death censored RR 0.74, CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection or death at one year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection. There was no benefit of muromonab-CD3 over ATG or ALG in either reversing rejection, preventing subsequent rejection, preventing graft loss or death. In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed.


Degree centrality for semantic abstraction summarization of therapeutic studies.
Automatic summarization has been proposed to help manage the results of biomedical information retrieval systems. Semantic MEDLINE, for example, summarizes semantic predications representing assertions in MEDLINE citations. Results are presented as a graph which maintains links to the original citations. Graphs summarizing more than 500 citations are hard to read and navigate, however. We exploit graph theory for focusing these large graphs. The method is based on degree centrality, which measures connectedness in a graph. Four categories of clinical concepts related to treatment of disease were identified and presented as a summary of input text. A baseline was created using term frequency of occurrence. The system was evaluated on summaries for treatment of five diseases compared to a reference standard produced manually by two physicians. The results showed that recall for system results was 72%, precision was 73%, and F-score was 0.72. The system F-score was considerably higher than that for the baseline (0.47).


Protective effect of Prunella vulgaris var. L extract against blue light induced damages in ARPE-19 cells and mouse retina.
Age-related macular degeneration (AMD) is one of leading causes that induce severe visual impairment and loss in the elderly. Previous studies have suggested that blue light (BL) could induce retinal degeneration, which is a major cause of the onset and development of severe AMD. In the retinal pigment epithelium (RPE) cells, A2E, a lipofuscin fluorophore, is accumulated with aging. When A2E is exposed to BL, it is easily oxidized to A2E-epoxides, leading to oxidative stress and inflammatory response in retina. The aim of this study was to investigate protective effect of Prunella vulagris (P.V) extract against oxidative stress and inflammation caused by BL, and to elucidate the underlying mechanisms in the cultured RPE cells and balb-c mice. In both model studies, P.V extract activated NF-E2 related factor 2 (Nrf-2)/hemeoxygenase-1 (HO-1) signaling pathway, followed by inhibition of ROS/MDA production, GSH depletion and reduction in SOD activity. Furthermore, P.V extract inhibited upregulation of inflammatory related genes (interlukin (IL)-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor A (VEGF A)) and BL induced RPE cell death, determined by cell viability and histological analyses. The mechanism of protection against inflammation by P.V extract involves inhibition of nuclear translocation of nuclear factor kappa beta (NF-kB) along with degradation of NF-kB inhibitor alpha (IkB alpha). The results suggest that P.V extract could be a potential intervention to prevent the onset and development of severe AMD.


Noninvasive Voice Biomarker Is Associated With Incident Coronary Artery Disease Events at Follow-up.
To evaluate the association between a preidentified voice biomarker and incident coronary artery disease (CAD) events. Patients referred for clinically indicated coronary angiography underwent a total of three 30-second voice recordings using the Vocalis Health smartphone application between January 1, 2015, and February 28, 2017. A pre-established voice biomarker was derived from each individual recording, and the mean biomarker value was calculated for each patient. Individuals were clinically observed through December 31, 2019. The prespecified primary outcome was a composite of presenting to the emergency department with chest pain, being admitted to the hospital with chest pain, or having an acute coronary syndrome; the prespecified secondary outcome was a composite of a positive stress test result at follow-up or the presence of CAD at follow-up coronary angiography. In the final analysis, 108 patients were included (mean age, 59.47±11.44 years; male, 59 [54.6%]). The median follow-up time was 24 months (range, 1 to 60 months). In multivariable Cox proportional hazards models adjusting for CAD grade on baseline angiography, a high baseline mean voice biomarker was significantly associated with both the primary (hazard ratio, 2.61; 95% CI, 1.42 to 4.80; P=.002) and secondary (hazard ratio, 3.13; 95% CI, 1.13 to 8.68; P=.03) composite outcomes. This study found a significant association between a noninvasive voice biomarker and incident CAD events at follow-up. These results may have important clinical implications for the remote and noninvasive screening of patients to identify those at risk of coronary disease and its complications.


A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy.
The aim of this study was to determine the safety and efficacy of recombinant human thrombopoietin (rhTPO) for the management of immune thrombocytopenia (ITP) during pregnancy. Pregnant patients with ITP were enrolled in the study if they had a platelet count less than 30 × 109/L, were experiencing bleeding manifestations, had failed to respond to corticosteroids and/or intravenous immunoglobulin (IVIG), and had developed refractoriness to platelet transfusion. Thirty-one patients received rhTPO at an initial dose of 300 U/kg once daily for 14 days. Twenty-three patients responded (74.2%), including 10 complete responders (>100 × 109/L) and 13 responders (30-100 × 109/L). It appears that rhTPO ameliorated the bleeding symptoms remarkably, even in the nonresponders. rhTPO was well tolerated. Dizziness, fatigue, and pain at an injection site were reported in 1 patient each. No congenital disease or developmental delays were observed in the infants in a median follow-up of 53 (range, 39-68) weeks. In conclusion, rhTPO is a potentially safe and effective treatment choice for patients with ITP during pregnancy. Our work has paved the way for further study on the clinical application of rhTPO and other thrombopoietic agents for the management of ITP during pregnancy. This study is registered at www.clinicaltrials.gov as NCT02391272.


Post-traumatic growth and optimism as outcomes of an internet-based intervention for complicated grief.
This explorative study examines the effects of an internet-based cognitive-behavioural therapy for complicated grief on post-traumatic growth and optimism. The study is part of a larger randomized controlled trial described in Wagner, Knaevelsrud, and Maercker (2006). The patients were randomly assigned to either a treatment group (n = 26) or a waiting list control condition (n = 25). The internet-based intervention consisted of exposure to bereavement cues, cognitive reappraisal exercises, and a module on integration and restoration. A short form of the Post-traumatic Growth Inventory (PTGI), the Life Orientation Test-Revised (LOT-R), and measures of complicated grief and psychopathological outcomes were administered. Results indicate that post-traumatic growth increased in the treatment group. No treatment effect was found for optimism. These findings contribute to the growing literature on personal growth in psychotherapy.


Identification and characterization of TLR7, TLR8a2, TLR8b1 and TLR8b2 genes in Atlantic salmon (Salmo salar).
Mammalian Toll-like receptor (TLR) 7 and 8 are responsible for recognizing viral single-stranded RNA (ssRNA) and are activated by anti-viral imidazoquinoline compounds, leading to a series of defensive mechanisms being launched to protect the host against viruses. In this study, we identified two TLR7 (with one probably a pseudogene) and three TLR8 genes, namely TLR8a2, TLR8b1 and TLR8b2 from Atlantic salmon (Salmo salar) whole-genome shotgun (WGS) contigs. Bioinformatics analysis showed that salmon TLR7 and TLR8a2 are closely related to the corresponding trout orthologs, however, salmon TLR8b1 and TLR8b2 share the highest amino acid sequence similarity to zebrafish TLR8b and formed a subfamily of the piscine TLR8 molecules in phylogenetic tree analysis. A conserved gene synteny was found with the salmon TLR7/8a members as seen in other vertebrate loci. Deduced domain organisation of salmon TLR7 and TLR8 molecules showed similar structural features, with equal numbers of leucine-rich repeats (LRRs) and insertion motifs. Individual TLR molecules were expressed in a similar pattern between parr and post-smolts, with a high expression level in immune tissues. Promoter analysis predicted several transcription factor binding sites in the TLR8a1/2 and TLR8b1 5' flanking regions, namely C/EBP, AP-1, STAT, NFκB, and IRF family, suggesting cytokine regulation of the genes. Hence, three recombinant cytokines, type I IFN, IFNγ and IL-1β were used to study the regulation of the salmon TLR gene expression levels in primary head kidney cells and the Salmon Head Kidney-1 (SHK-1) cell line. Salmon TLR7 and TLR8a1 gene expression was more sensitive to type I IFN and IFNγ treatment in primary head kidney cells and SHK-1 cells respectively, with no significant up-regulation of TLR8a2 and TLR8b2 by any of the treatments. On the other hand, salmon TLR8a1 and TLR8b1 were most sensitive to IL-1β treatment in SHK-1 cells and primary head kidney cells, respectively. TLR8b2 was undetectable in SHK-1 cells under these same conditions.


NCAM-dependent neurite outgrowth is inhibited in neurons from Fyn-minus mice.
Src-related nonreceptor protein tyrosine kinases in nerve growth cones (p59fyn, pp60c-src, and pp62c-yes) are potential intracellular signaling molecules for cell adhesion molecule-directed axonal growth. To determine whether src-related tyrosine kinases mediate NCAM-dependent neurite outgrowth, cultures of cerebellar and sensory neurons from fyn-, src-, and yes- minus mice were analyzed for neurite outgrowth on monolayers of NCAM140-transfected L fibroblasts. NCAM-dependent neurite outgrowth was selectively inhibited in cultures of cerebellar and dorsal root ganglion neurons from fyn-, but not src- or yes- mice. Neurite outgrowth by fyn-, src-, or yes- neurons on untransfected fibroblast monolayers was unaffected, indicating that these kinases do not contribute significantly to axon growth on at least some integrins or other adhesive substrates present on fibroblasts. This study demonstrates that p59fyn is an essential component of the NCAM signaling pathway leading to axonal growth.


Fast-computed tomography evaluation of age-related changes in upper airway structure and function in normal men.
The reasons for the increase prevalence of snoring and sleep-disordered breathing in elderly adults are not clear. We hypothesized that age-related reductions in upper airway (UA) size, increased UA collapsibility, and/or inadequate compensatory action of the UA dilator muscles were contributory factors. Fast-computed tomography (CT) was used to examine UA size at FRC and atmospheric pressure, as well as its collapsibility and distensibility in response to negative and positive UA pressures actively generated by the subjects at FRC. The electromyographic activity of the genlogiossal muscle group (EMGgg) was recorded to assess UA dilator muscle response. Thirty adult men with normal overnight polysomnography (mean AHI = 4 +/- 1/h) were studied, and three subgroups of 10 subjects each, young (20-39), middle-age (40-59), and old (60-79), were compared. Unexpectedly, minimal UA cross-sectional area (Amin) at FRC and atmospheric pressure was larger in the old group than in the young group (73 +/- 9 versus 49 +/- 7 mm2, p = 0.04). In response to negative UA pressures of -10 and -50 cm H2O, there were no significant age group differences in Amin, indicating that no age-related increase in UA collapsibility was present. Although no significant difference in tonic EMGgg activity at FRC and atmospheric pressure was detected between groups, the old group demonstrated greater EMGgg activity than did the younger age groups in response to negative UA pressure loading (p less than 0.05). This finding indicated increased compensatory UA dilator muscle activity in response to negative pressures in the older subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


[The EEG characteristics of patients with Huntington's chorea and their clinically healthy relatives].
Clinical and electroencephalographic examination has involved 170 persons (93 patients with Huntington's chorea and their 77 clinically normal relatives). The overwhelming majority of patients and 37% of their clinically healthy relatives have varying degrees of alpha-activity diminution (in 51% of the patients alpha-activity was totally absent). The degree of alpha-activity significantly correlated with severity of the disease. The above EEG changes, in combination with the findings of other methods of examination, may be also employed in the diagnosis of initial and subclinical manifestations of the disease.


Barriers to healthy food access: Associations with household income and cooking behavior.
To examine how barriers to healthy food access and household income are associated with cooking and eating behaviors we fielded a nationally representative survey among 1112 adults in the United States in 2015. The survey included measures of barriers to accessing healthy food, household income, and frequency of cooking and eating meals, cooking practices, and other eating behaviors. We used multivariable poisson regression to examine the association of household income and barriers to healthy food access with cooking and eating behavior outcomes. We find that low income was associated with higher barriers to accessing healthy food (barriers) and that both income and barriers were associated with differences in cooking frequency/practices, and consumption behaviors. In interaction models, cooking and eating behaviors did not vary based on barriers for the lowest income level (<$25,000). In the middle income level ($25,000-$59,000), barriers were associated with cooking breakfast (3.35 vs. 2.64 times/week, p = 0.03) and lunch (3.32 vs. 2.56 times/week, p = 0.02) more frequently compared to those who never/rarely encountered barriers. At the highest income level (≥$60,000), barriers were associated with less frequently eating breakfast (4.29 vs. 5.11 times/week, p < 0.001) and lunch (4.77 vs. 5.56, times/week, p < 0.001) compared to those who never/rarely encountered barriers. Barriers to healthy food access are related to both household income and cooking and eating behaviors important for diet quality and healthy eating. Targeted interventions to address time available to shop, and the price, selection and quality of healthy foods, are necessary.


Comparison between two mobile applications measuring shoulder elevation angle-A validity and feasibility study.
Pain in the shoulder complex affects the working population where work with elevated arms is a risk factor. The aim of the present study was to compare a mobile application for measurements of arm elevation, ErgoExposure, against an existing mobile application, ErgoArmMeter, in a laboratory setting and to test the feasibility in a field trial. Eleven persons performed three tasks in the laboratory setting: static, dynamic, and simulated work tasks, where the applications were validated against an optical tracking system (OTS). Also, ErgoExposure was tested by a teacher in a real-world situation. Limits of agreement for the static task varied between -6.1° to 4.2° (ErgoExposure) and between -7.6° to 5.2° (ErgoArmMeter). The average root mean square difference for dynamic and simulated work tasks was 3.4° (ErgoExposure) and 7.7° (ErgoArmMeter). From the field trial, different work tasks produced distinct exposure variation analysis patterns. Both apps showed similar results compared to OTS, but ErgoExposure was more accurate than ErgoArmMeter.


[Analysis of the changes in the electrophysical and morphometric parameters in the growth and sporulation periods of Bacillus thuringiensis].
Changes in the electrophysical and morphometrical parameters of Bacillus thuringiensis cells were studied during their growth and differentiation using the electrophysical procedure with the frequency of an alternating electric field varying within a wide range. The appearing variations were interpreted on the basis of the data about changes in the concentration of vegetative cells and spores, the optical density and pH of the cultural broth, and the assimilation of glucose by the culture. The changes found in the electrophysical and morphometrical parameters were shown to accompany the main physiological processes in the cells. In principle, they can be used to control the process of cultivation.


Smartband Use During Enhanced Recovery After Surgery Facilitates Inpatient Recuperation Following Minimally Invasive Colorectal Surgery.
Background: Enhanced recovery after surgery (ERAS) is valuable in perioperative care for its ability to improve short-term surgical outcomes and facilitate patient recuperation after major surgery. Early postoperative mobilization is a vital component of the integrated care pathway and is a factor strongly associated with successful outcomes. However, early mobilization still has various definitions and lacks specific strategies. Methods: Patients who underwent minimally invasive surgery for colorectal cancer followed our perioperative ERAS program, including mobilization from the first postoperative day. After perioperative care skills were improved in our well-established program, compliance, inpatient surgical outcomes, and complications associated with adding smartband use were evaluated and compared with the outcomes for standard protocol. Quality of recovery was evaluated using patient-rated QoR-40 questionnaires the day before surgery, on postoperative days 1 and 3, and on the day of discharge. Results: Smartband use after minimally invasive colorectal surgery failed to increase compliance with early mobilization or reduce the occurrence of postoperative complications significantly compared with standard ERAS protocol. However, when smartbands were utilized, quality of recovery was optimized and patients returned to their preoperative status earlier, at postoperative day 3. The length of hospital stay, as defined by discharge criteria, and hospital stay of patients without complications was reduced by 1.1 and 0.9 days, respectively (P = 0.009 and 0.049, respectively). Conclusions: Smartbands enable enhanced communication between patients and surgical teams and strengthen self-management in patients undergoing minimally invasive colorectal resection surgery. Accelerated recovery to preoperative functional status can be facilitated by integrating smartbands into the process of early mobilization during ERAS.


Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans.
Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.


Vascular malformation of the sphenoid sinus.
Isolated sphenoid sinus lesions are usually inflammatory lesions or mucoceles. We report an unusual case of a thrombosed arteriovenous malformation presenting as a unilateral primary vascular malformation of the sphenoid sinus. To the best of our knowledge, no one has ever reported such an entity in the medical literature. Differential diagnosis of sphenoid sinus lesions and possible etiologies for this case will be detailed.


In-treatment 4D cone-beam CT with image-based respiratory phase recognition.
The use of respiration-correlated cone-beam computed tomography (4D-CBCT) appears to be crucial for implementing precise radiation therapy of lung cancer patients. The reconstruction of 4D-CBCT images requires a respiratory phase. In this paper, we propose a novel method based on an image-based phase recognition technique using normalized cross correlation (NCC). We constructed the respiratory phase by searching for a region in an adjacent projection that achieves the maximum correlation with a region in a reference projection along the cranio-caudal direction. The data on 12 lung cancer patients acquired just prior to treatment and on 3 lung cancer patients acquired during volumetric modulated arc therapy treatment were analyzed in the search for the effective area of cone-beam projection images for performing NCC with 12 combinations of registration area and segment size. The evaluation was done by a "recognition rate" defined as the ratio of the number of peak inhales detected with our method to that detected by eye (manual tracking). The average recognition rate of peak inhale with the most efficient area in the present method was 96.4%. The present method was feasible even when the diaphragm was outside the field of view. With the most efficient area, we reconstructed in-treatment 4D-CBCT by dividing the breathing signal into four phase bins; peak exhale, peak inhale, and two intermediate phases. With in-treatment 4D-CBCT images, it was possible to identify the tumor position and the tumor size in moments of inspiration and expiration, in contrast to in-treatment CBCT reconstructed with all projections.


Thermal behavior of beta-1 subunits in lignin: pyrolysis of 1,2-diarylpropane-1,3-diol-type lignin model compounds.
1,2-Diarylpropane-1,3-diol-type lignin model compounds, 1,2-bis(4-hydroxy-3-methoxyphenyl)propane-1,3-diol (1) and 1-(3,4-diethoxyphenyl)-2-(4-methoxyphenyl)propane-1,3-diol (2), were pyrolyzed at 500 degrees C for 4 s to clarify the thermal behavior of beta-1 subunits in lignin. Products were monitored by gas chromatography/mass spectrometry. The cleavage of the Calpha-Cbeta bond to produce benzaldehydes such as 4-hydroxy-3-methoxybenzaldehyde (9) and phenylethanals as the counterparts such as 4-hydroxy-3-methoxyphenylethanal (10) occurred in pyrolyses of both 1 and 2. In pyrolysis of 1, an oxetane pathway leading to the formation of Z/E-stilbenes without the gamma-CH2OH group such as Z/E-4,4'-dihydroxy-3,3'-dimethoxystilbene (3) was predominant. In pyrolysis of 2, the oxetane pathway was minor, while pathways producing a dimer with a =CgammaH2 group by loss of water and a dimer with an alpha-carbonyl group were predominant. Pyrolysis of Japanese cedar wood provided 3 and 10 in approximately 0.8% and 0.6% yields, respectively, based on the Klason lignin content, while pyrolysis of a guaiacyl bulk dehydrogenation polymer gave them in a very small amount.


[Lipid peroxidation as an indicator of the effectiveness of treating patients with chronic ischemic heart disease using a helium-neon laser].
A therapeutic response to clinical application of Helium-Neon laser irradiation in combination with antianginal drugs was evaluated for chronic sufferers with coronary heart disease (CHD). The largest scope of information on the efficacy of the laser therapy has been provided by the parameters of lipid peroxidation. Individually adjusted doses of the irradiation allowed achievement of the best treatment results.


UV Light and Gas Sensing Properties of Hybrid Sensor Based on Indium-Tin-Oxide Nanocrystals.
We proposed a hybrid sensor which is able to detect both UV light and gas species. The sensor was fabricated by screen printing using indium-tin-oxide (ITO) nanocrystals. To improve the UV sensitivity, high temperature annealing (600 degrees C) under an external pressure (0.2 MPa) was applied. We could observe room temperature operation of the sensor under the simultaneous stimulation of UV light and CH4 gas. This is indicating that an improved fire warning is possible by using the proposed hybrid sensor.


Endonuclease FEN1 Coregulates ERα Activity and Provides a Novel Drug Interface in Tamoxifen-Resistant Breast Cancer.
Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex vivo-cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof of principle for FEN1 blockade in tamoxifen-resistant breast cancer. SIGNIFICANCE: These findings show that pharmacologic inhibition of FEN1, which is predictive of outcome in tamoxifen-treated patients, effectively blocks ERα function and inhibits proliferation of tamoxifen-resistant tumor cells.


Structural and chemical characterization of TiO2 memristive devices by spatially-resolved NEXAFS.
We used spatially-resolved NEXAFS (near-edge x-ray absorption fine structure) spectroscopy coupled with microscopy to characterize the electronic, structural and chemical properties of bipolar resistive switching devices. Metal/TiO2/metal devices were electroformed with both bias polarities and then physically opened to study the resulting material changes within the device. Soft x-ray absorption techniques allowed isolated study of the different materials present in the device with 100 nm spatial resolution. The resulting morphology and structural changes reveal a picture of localized polarity-independent heating occurring within these devices initiated by and subsequently accelerating polarity-dependent electrochemical reduction/oxidation processes.


Engineered vascular-targeting antibody-interferon-gamma fusion protein for cancer therapy.
A number of cytokines are either approved drugs or are in advanced clinical trials, yet these biopharmaceuticals do not typically localize efficiently in solid tumors and manifest their therapeutic potential at the expense of severe side effects. The targeted delivery of cytokines to solid tumors is a promising avenue for increasing the therapeutic index of these biopharmaceuticals. We engineered a fusion protein between scFv(L19), a human antibody fragment specific to the EDB domain of fibronectin, and a cysteine-free mutant of murine interferon-gamma. The resulting fusion protein was capable of targeting new blood vessels in solid tumors, and the targeting efficiency was strikingly increased in tumor-bearing knockout mice lacking the interferon-gamma receptor. ScFv(L19)-interferon-gamma displayed a strong antitumor effect in both subcutaneous and metastatic murine F9 teratocarcinomas, but was not efficacious as single agent when used to treat C51 and CT26 tumors. The potency of this fusion protein could be substantially enhanced by combination with doxorubicin and other immunocytokines. These findings are of clinical relevance, as the EDB domain is a marker of angiogenesis, with identical sequence in mouse and man, which is abundantly expressed in a variety of aggressive solid tumors but is undetectable in most normal tissues.


High-speed spectroradiometer for remote sensing.
A high-speed spectroradiometer designed for spectral reflectance measurement in remote sensing is described. This instrument uses a monochromatic grating and a photomultiplier system for light detection and sweeps over the 400-850-nm wavelength spectral range with the spectral resolution of 2 nm within 1 s. The instrument has the inherent advantage of portability and speed of operation which make it particularly suitable for field work in the area of fast moving surfaces, e.g., water with wave motion. Some applications of its use in laboratory and field experiments also have been presented. The instrument would seem to be an appropriate instrument for ground data collection in remote sensing.


Distinct binding of cetirizine enantiomers to human serum albumin and the human histamine receptor H1.
Cetirizine, a major metabolite of hydroxyzine, became a marketed second-generation H1 antihistamine that is orally active and has a rapid onset of action, long duration of effects and a very good safety record at recommended doses. The approved drug is a racemic mixture of (S)-cetirizine and (R)-cetirizine, the latter being the levorotary enantiomer that also exists in the market as a third-generation, non-sedating and highly selective antihistamine. Both enantiomers bind tightly to the human histamine H1 receptor (hH1R) and behave as inverse agonists but the affinity and residence time of (R)-cetirizine are greater than those of (S)-cetirizine. In blood plasma, cetirizine exists in the zwitterionic form and more than 90% of the circulating drug is bound to human serum albumin (HSA), which acts as an inactive reservoir. Independent X-ray crystallographic work has solved the structure of the hH1R:doxepin complex and has identified two drug-binding sites for cetirizine on equine serum albumin (ESA). Given this background, we decided to model a membrane-embedded hH1R in complex with either (R)- or (S)-cetirizine and also the complexes of both ESA and HSA with these two enantiomeric drugs to analyze possible differences in binding modes between enantiomers and also among targets. The ensuing molecular dynamics simulations in explicit solvent and additional computational chemistry calculations provided structural and energetic information about all of these complexes that is normally beyond current experimental possibilities. Overall, we found very good agreement between our binding energy estimates and extant biochemical and pharmacological evidence. A much higher degree of solvent exposure in the cetirizine-binding site(s) of HSA and ESA relative to the more occluded orthosteric binding site in hH1R is translated into larger positional fluctuations and considerably lower affinities for these two nonspecific targets. Whereas it is demonstrated that the two known pockets in ESA provide enough stability for cetirizine binding, only one such site does so in HSA due to a number of amino acid replacements. At the histamine-binding site in hH1R, the distinct interactions established between the phenyl and chlorophenyl moieties of the two enantiomers with the amino acids lining up the pocket and between their free carboxylates and Lys179 in the second extracellular loop account for the improved pharmacological profile of (R)-cetirizine.


The association between nutritional status and cognitive impairment in brazilian community-dwelling older adults assessed using a range of anthropometric measures - the Bambui study.
In most studies, body mass index (BMI) has been used as the main measurement of nutritional status. However, BMI does not differentiate between body fat and muscle mass. To investigate the association between nutritional status and cognitive impairment in a population of Brazilian elderly. Participants (n=1,496) from the Bambuí Cohort Study of Aging were selected based on the results for the two variables nutritional status and cognitive impairment (MMSE score). Gender, age, education, lifestyle, ApoE, chronic diseases, depressive symptoms, current use of hypnotic or sedative medication and functional disability were used as confounding factors for adjusting the logistic regression. Cognitive impairment was associated with lower BMI (OR: 0.91; CI: 0.86-0.95), waist circumference (OR: 0.97; CI: 0.95-0.99), triceps skinfold thickness (OR: 0.92; CI: 0.89-0.96) among the younger participants (60-69 years), while lower arm muscle circumference (OR: 0.88; CI: 0.80-0.98) and corrected arm muscle area (OR: 0.96; CI: 0.93-0.99) were associated with cognitive impairment among the older participants (70 years and over). There was a difference of association between anthropometric measures and cognitive impairment after stratifying by age group. In the group aged between 60 and 69, cognitive impairment was associated with measures related to fat mass, while in the group aged over 70, cognitive impairment was associated with measures related to muscle mass. This finding suggests that investigation of nutritional status in the elderly using anthropometric measures should not be restricted only to the use of BMI, and should also, differ according to age.


Measuring Type 2 diabetes mellitus knowledge and perceptions of risk in middle-class African Americans.
There is a paucity in the literature examining the African American middle-class. Most studies of African Americans and Type 2 Diabetes Mellitus (T2DM) have concentrated on lower-SES individuals, or make no distinction between African Americans of varying socio-economic positions. Middle-class African Americans are vulnerable in ways often overlooked by researchers. This study quantitatively examines specific T2DM knowledge and perceptions of risk in middle-class African Americans (N = 121). The majority of respondents, 70.2%, were unable to correctly identify all the warning signs of T2DM development. Only 3.3% of respondents correctly identified all risk factors provided as 'possible causes' of T2DM development. The difference between those participants who considered themselves to be at risk for T2DM development and their level of risk, according to the American Diabetes Associations' risk assessment, was not statistically significant (P = 0.397). However, there were statistically significant differences between participants' perceptions of their weight and clinical definitions of overweight, a major risk factor in T2DM development, based on BMI (P = 0.000). Middle-class African Americans are not inherently protected or exempt from developing T2DM. This study demonstrates gaps in knowledge and overall incongruent levels of perceived susceptibility, suggesting a need for additional research and health education in this segment of the population.


PIM-1 kinase interacts with the DNA binding domain of the vitamin D receptor: a further kinase implicated in 1,25-(OH)2D3 signaling.
The vitamin D3 receptor (VDR) is responsible for mediating the pleiotropic and, in part, cell-type-specific effects of 1,25-dihydroxyvitamin D3 (calcitriol) on the cardiovascular and the muscle system, on the bone development and maintenance, mineral homeostasis, cell proliferation, cell differentiation, vitamin D metabolism, and immune response modulation. Based on data obtained from genome-wide yeast two-hybrid screenings, domain mapping studies, intracellular co-localization approaches as well as reporter transcription assay measurements, we show here that the C-terminus of human PIM-1 kinase isoform2 (amino acid residues 135-313), a serine/threonine kinase of the calcium/calmodulin-regulated kinase family, directly interacts with VDR through the receptor's DNA-binding domain. We further demonstrate that PIM-1 modulates calcitriol signaling in HaCaT keratinocytes by enhancing both endogenous calcitriol response gene transcription (osteopontin) and an extrachromosomal DR3 reporter response. These results, taken together with previous reports of involvement of kinase pathways in VDR transactivation, underscore the biological relevance of this novel protein-protein interaction.


Complications of HIPEC for ovarian cancer surgery: evaluation over two time periods.
Cytoreductive surgery in conjunction with hyperthermic intraperitoneal chemotherapy (HIPEC) is being explored in the upfront, interval, and recurrent setting in patients with ovarian cancer. The objective of this systematic review was to assess the rate of complications associated with HIPEC in epithelial ovarian cancer surgery over two time periods. This study was registered in PROSPERO (CRD42022328928). A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Ovid/Medline, Ovid/Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials were searched from January 2004 to April 2022. We included studies reporting on patients with advanced primary or recurrent epithelial ovarian cancer who underwent cytoreductive surgery and HIPEC. We evaluated two different time periods: 2004-2013 and 2014-2022. A random-effects meta-analysis was used to produce an overall summary. Subgroup analyses were planned according to recruited period for each specific complication type. Heterogeneity was assessed using the I2 statistic. A total of 4928 patients were included from 69 studies for this systematic review; 19 published from 2004-2013, and 50 published from 2014-2022. No significant differences were found between the two time periods in terms of blood transfusions (33% vs 51%; p=0.46; I2=95%) overall gastrointestinal complications (15% vs 21%; p=0.36; I2=98%), infectious diseases (16% vs 13%; p=0.62; I2=93%), overall respiratory complications (12% vs 12%; p=0.88; I2=91%), overall urinary complications (6% vs 12%; p=0.06; I2=94%), or thromboembolic events (5% vs 3%; p=0.25; I2=63%). Also, no differences were found in intensive care unit (ICU) admissions (89% vs 28%; p=0.06; I2=99%), reoperations (8% vs 7%; p=0.50; I2=37%), or deaths (3% vs 3%; p=0.77; I2=57%). Our review showed that overall complications have not changed over time for patients undergoing HIPEC in the setting of primary or recurrent ovarian cancer. There was no decrease in the rates of ICU admissions, reoperations, or deaths.


Effects of Therapeutic Intervention on Parentally Bereaved Children's Emotion Reactivity and Regulation 15 Years Later.
The Family Bereavement Program (FBP) is a family-based intervention for parentally bereaved children and surviving caregivers. Results are reported of a randomized controlled trial, examining intervention effects on emotional reactivity and regulation of young adults who participated in the program 15 years earlier. Participants (N = 152) completed four emotion challenge tasks: reactivity to negative images, detached reappraisal while viewing negative images, positive reappraisal while viewing negative images, and reengagement with positive images. Outcomes included cardiac interbeat interval (IBI), pre-ejection period (PEP), and respiratory sinus arrhythmia (RSA) as well as self-reported emotional experience and regulation effectiveness. Direct intervention effects and effects mediated through improved parenting were estimated. Several significant effects were observed in primary analyses; however, none remained significant after correction for familywise Type I error. Parenting mediated FBP effects on IBI during negative reactivity (b = 15.04), and on RSA during positive reengagement (b = 0.35); the latter effect was accounted for by changes in breathing. Intervention condition was a direct predictor of self-reported detached reappraisal effectiveness (b = 1.00). Intervention and gender interacted in predicting self-reported negative emotion during the negative reactivity (b = 1.04) and positive reappraisal tasks (b = 1.31) such that intervention-condition men reported more negative emotions during those tasks. Although these findings should be considered preliminary given the limited power of the corrected statistical tests, they suggest long-term effects of family intervention following the death of a parent on offspring's emotional reactivity and regulation ability that should be pursued further in future research.


A Novel Multi-Ingredient Supplement Activates a Browning Program in White Adipose Tissue and Mitigates Weight Gain in High-Fat Diet-Fed Mice.
We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocation into experimentalgroups for 4 weeks: HFD control, HFD + ME10 (10 components), HFD + ME7 (7 components), HFD + ME10 + EX, HFD + EX (where '+EX' animals exercised 3 days/week), and chow-fed control. After the intervention, HFD control animals had significantly greater body weight and fat mass. Despite the continuation of HFD, animals supplemented with multi-ingredient ME or who performed exercise training showed an attenuation of fat mass and preservation of lean body mass, which was further enhanced when combined (ME+EX). ME supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.


Planning phase III multi-site clinical trials in palliative care: the role of consecutive cohort audits to identify potential participant populations.
Multiple sites enable more successful completion of adequately powered phase III studies in palliative care. Audits of the frequency and distribution of the symptoms of interest can better inform research planning by determining realistic recruitment goals for each site. The proposed studies are to improve the evidence-base for registration and subsidy applications for frequently encountered symptoms where current pharmacological interventions are being used 'off-licence'. Six services participated in a standardised, retrospective, consecutive cohort audit of five symptoms of their inpatient populations to inform the design of double blind randomised controlled phase III studies to which each site would recruit simultaneously. The audit covered all deaths in a 3-month period for people who were referred to a specialist palliative care service who had at least one inpatient admission between referral and death, regardless of when the person was referred to the service. The audits were based around inclusion and exclusion criteria for the proposed studies. Of the 468 people whose medical records were reviewed, potential study participant rates varied by symptom having accounted for general and specific inclusion and exclusion criteria: pain 17.7%; delirium 5.8%; anorexia 5.1%; bowel obstruction 2.8% and cholestatic itch 0%. For those people with a symptom of interest, it was noted at the beginning of the inpatient admission more than half the time. Of all inpatients, fewer than one third would be eligible to participate in at least one study. These data provide a baseline estimate of potential people to approach about clinical trials in supportive care but do not account for clinician 'gate-keeping', lack of interest in participating nor withdrawal from the study once initiated. The data are retrospective and therefore, limited by clinical documentation. The audit directly informed an increase in the number of participating sites.


Apoptosis-dependent subversion of the T-lymphocyte epitope hierarchy in lymphoma cells.
Tumor cells undergoing programmed death are an attractive source of tumor-associated antigens, and evidences are available for their therapeutic efficacy in vivo when used either alone or in association with dendritic cells. However, little is known about the specificity of the immune response induced by such antigen formulation. Indeed, activation of specific proteases during apoptosis may influence the cytoplasmic degradation of proteins and the generation of CTL epitopes. We show here that on injection of C57BL/6 mice either with RMA lymphoma cells induced to apoptosis or bone marrow-derived dendritic cells pulsed with apoptotic RMA cells, a specific and protective CTL response is induced, which, however, is not directed against the immunodominant CTL epitope gag(85-93). Lack of in vivo expansion of gag(85-93)-specific CTL in vaccinated mice is attributable to the apoptosis-dependent loss of gag(85-93) in dying tumor cells. Indeed, we found loss of gag(85-93) in RMA, MBL-2, and EL-4G+ lymphoma cells, which share gag(85-93) as an immunodominant CTL epitope, induced to apoptosis by UV irradiation, mitomycin C, doxorubicin, or daunorubicin. This phenomenon appears to be caspase-dependent, because caspase inhibition by N-benzyloxycarbonyl-Val-Ala-asp-fluoromethylketone prevents apoptosis of lymphoma cells and loss of gag(85-93). Therefore, subversion of the epitope hierarchy in apoptotic tumor cells might be relevant in the induction of tumor-specific T-lymphocyte responses.


An experimental study of the anticonvulsant effect of amlodipine in mice.
The need for the rational development of newer and adjuvant drugs to treat epilepsy has prompted this study of the potential anticonvulsant effect of amlodipine. The acute effect was studied in mice in single doses of 1 mg/kg, 2 mg/kg and 4 mg/kg of amlodipine and the chronic effect was studied in doses of 1 mg/kg and 4 mg/kg (administered daily for 21 days) using the maximal electroshock seizure and pentylenetetrazole-induced seizure models of epilepsy. Sodium valproate and normal saline were used as the standard and control, respectively. For the acute study, in the maximal electroshock seizure model, the administration of 1 mg/kg of amlodipine resulted in the complete abolition of seizures in 33 percent of the mice, and this was increased to 67 percent with the administration of 4 mg/kg. In the pentylenetetrazole-induced seizure model, the administration of 1 mg/kg and 2 mg/kg amlodipine protected 33 percent of the animals from mortality, and 67 percent were protected with the administration of 4 mg/kg. For the chronic study, in the maximal electroshock seizure model, the administration of 1 mg/kg amlodipine resulted in the complete abolition of seizures in 40 percent of the mice and in 60 percent, with the administration of 4 mg/kg. In the pentylenetetrazole-induced seizure model, 50 percent of the mice were protected from mortality with 1 mg/kg amlodipine and 60 percent, with 4 mg/kg amlodipine. These findings indicate that amlodipine may be a good candidate as an add-on therapy for epilepsy.


Edge type affects leaf-level water relations and estimated transpiration of Eucalyptus arenacea.
While edge effects on tree water relations are well described for closed forests, they remain under-examined in more open forest types. Similarly, there has been minimal evaluation of the effects of contrasting land uses on the water relations of open forest types in highly fragmented landscapes. We examined edge effects on the water relations and gas exchange of a dominant tree (Eucalyptus arenacea Marginson & Ladiges) in an open forest type (temperate woodland) of south-eastern Australia. Edge effects in replicate woodlands adjoined by cleared agricultural land (pasture edges) were compared with those adjoined by 7- to 9-year-old eucalypt plantation with a 25m fire break (plantation edges). Consistent with studies in closed forest types, edge effects were pronounced at pasture edges where photosynthesis, transpiration and stomatal conductance were greater for edge trees than interior trees (75m into woodlands), and were related to greater light availability and significantly higher branch water potentials at woodland edges than interiors. Nonetheless, gas exchange values were only ∼50% greater for edge than interior trees, compared with ∼200% previously found in closed forest types. In contrast to woodlands adjoined by pasture, gas exchange in winter was significantly lower for edge than interior trees in woodlands adjoined by plantations, consistent with shading and buffering effects of plantations on edge microclimate. Plantation edge effects were less pronounced in summer, although higher water use efficiency of edge than interior woodland trees indicated possible competition for water between plantation trees and woodland edge trees in the drier months (an effect that might have been more pronounced were there no firebreak between the two land uses). Scaling up of leaf-level water relations to stand transpiration using a Jarvis-type phenomenological model indicated similar differences between edge types. That is, transpiration was greater at pasture than plantation edges in summer months (most likely due to greater water availability at pasture edges), resulting in significantly greater estimates of annual transpiration at pasture than plantation edges (430 vs. 343lm(-2)year(-1), respectively). Our study highlights the need for landscape-level water flux models to account for edge effects on stand transpiration, particularly in highly fragmented landscapes.


Cost-utility of metal-on-metal hip resurfacing compared to conventional total hip replacement in young active patients with osteoarthritis.
Metal-on-metal hip resurfacing arthroplasty (MoM HRA) has emerged as an alternative to total hip arthroplasty (THA) for younger active patients with osteoarthritis (OA). Birmingham hip resurfacing is the most common MoM HRA in Alberta, and is therefore compared with conventional THA. The objective of this study was to estimate the expected cost-utility of MoM HRA versus THA, in younger patients with OA, using a decision analytic model with a 15-year time horizon. A probabilistic Markov decision analytic model was constructed to estimate the expected cost per quality-adjusted life-year (QALY) of MoM HRA versus THA from a health care payer perspective. The base case considered patients with OA aged 50 years; men comprised 65.9% of the cohort. Sensitivity analyses evaluated cohort age, utility values, failure probabilities, and treatment costs. Data were derived from the Hip Improvement Project and the Hip and Knee Replacement Pilot databases in Alberta, the 2010 National Joint Replacement Registry of the Australian Orthopaedic Association, and the literature. In the base case, THA was dominated by MoM HRA (incremental mean costs of -$583 and incremental mean QALYs of 0.079). In subgroup analyses, THA remained dominated when cohort age was 40 years instead of 50 years or when only men were assessed. THA dominated when the cohort age was 60 years or when only women were assessed. Results were sensitive to utilities, surgery costs, and MoM HRA revision and conversion probabilities. At a willingness-to-pay of Can $50,000/QALY, there was a 58% probability that MoM HRA is cost-effective. The results show that, on average, MoM HRA was preferred to THA for younger and male patients, but THA is still a reasonable option if the patient or clinician prefers given the small absolute differences between the options and the confidence ellipses around the cost-effectiveness estimates.


Amoxicillin and Clavulanate Form Chemically and Immunologically Distinct Multiple Haptenic Structures in Patients.
Amoxicillin-clavulanate (AC) is one of the most common causes of drug induced liver injury (DILI). The association between AC-DILI and HLA alleles and the detection of drug-specific T cells in patients with AC-DILI indicate that the adaptive immune system is involved in the disease pathogenesis. In this study, mass spectrometric methods were employed to characterize the antigen formed by AC in exposed patients and the antigenic determinants that stimulate T cells. Amoxicillin formed penicilloyl adducts with lysine residues on human serum albumin (HSA) in vitro, with K190 and K199 being the most reactive sites. Amoxicillin-modified K190 and K199 have also been detected in all patients, and more extensive modification was observed in patients exposed to higher doses of amoxicillin. In contrast, the binding of clavulanic acid to HSA was more complicated. Multiple adducts were identified at high concentrations in vitro, including those formed by direct binding of clavulanic acid to lysine residues, novel pyrazine adducts derived from binding to the degradation products of clavulanic acid, and a cross-linking adduct. Stable adducts derived from formylacetic acid were detected in all patients exposed to the drug. Importantly, analysis of hapten-protein adducts formed in the cell culture medium revealed that the highly drug-specific T-cell responses were likely driven by the markedly different haptenic structures formed by these two drugs. In this study, the unique haptenic structures on albumin in patients formed by amoxicillin and clavulanic acid have been characterized and shown to function as chemically distinct antigens which can stimulate separate, specific T-cell clones.


Radiographic and histologic evaluation of platelet-rich plasma and bovine-derived xenograft combination in bilateral sinus augmentation procedure.
There is currently a great interest regarding the use of platelet-rich plasma (PRP) in combination with various bone graft materials in sinus lift procedures. The purpose of this study was to assess and compare the radiographic and histological results of sinus augmentation procedures following treatment with PRP/bovine-derived xenograft (BDX) vs. BDX/collagen membrane. Using a split mouth design, 10 patients, with ≤5 mm of residual alveolar bone in the vertical direction, were treated with PRP/BDX or BDX/collagen membrane. At 8 months after surgery, both graft materials led to a satisfactory increase in vertical dimensions of bone. Bone biopsies were taken from the augmented sites during the implant placement. Histological analysis demonstrated that majority of the trabecula contained orderly layered lamellar bone in the PRP/BDX group, whereas mainly woven bone with a haphazard arrangement of collagen fibers were noticed in the BDX /collagen membrane group. It can be concluded that both combinations resulted with a satisfactory bone height, but more prominent and mature bone formation was observed at sites treated with PRP/BDX.


A risk-factor model for anterior cruciate ligament injury.
The incidence of non-contact anterior cruciate ligament (ACL) injury is reported to be 6-8 times greater in females than males competing in the same activities. Injury to the ACL occurs as a result of insufficient stability of the tibiofemoral joint, which fails to prevent posterior dislocation of the femur on the tibia. The stability of the tibiofemoral joint is maintained by passive (non-contractile) and dynamic (contractile) mechanisms. The passive mechanisms include the shape of the articular surfaces, the menisci, the ligaments and the joint capsule. The dynamic mechanisms consist of the muscle-tendon units that cross the joint, in particular, the quadriceps and hamstrings. The relative significance of the various passive and dynamic mechanisms in maintaining the stability of the tibiofemoral joint is not clear. A number of intrinsic and extrinsic risk factors have been proposed to account for the sex difference in the incidence of ACL injuries. However, most of the proposed risk factors have arisen from univariate correlation studies based on relatively small samples.


[Transrectal echography in tuberculous prostatitis].
Tuberculous prostatitis is diagnosed incidentally, when the pathologist is studying a specimen of transurethral resection of the prostate or a prostatic biopsy. There is scant literature on the role of transrectal ultrasound in the diagnosis of this pathology. A case of tuberculous prostatitis is presented, with special reference to the transrectal ultrasound pattern. A complete review of the references on the imaging techniques in this pathology is done.


Voltage-dependent calcium channels in plant vacuoles.
Free calcium (Ca(2+)) in the cytoplasm of plant cells is important for the regulation of many cellular processes and the transduction of stimuli. Control of cytoplasmic Ca(2+) involves the activity of pumps, carriers, and possibly ion channels. The patch-clamp technique was used to study Ca(2+) channels in the vacuole of sugar beet cells. Vacuolar currents showed inward rectification at negative potentials, with a single-channel conductance of 40 picosiemens and an open probability dependent on potential. Channels were inhibited by verapamil and lanthanum. These channels could participate in the regulation of cytoplasmic Ca(2+) by sequestering Ca(2+) inside the vacuole.


A case of flax seed induced rhabdomyolysis.
Rhabdomyolysis is a clinical and a biochemical syndrome that occurs due to a skeletal muscle injury. The main cause of rhabdomyolysis is a muscle crush injury, toxins, ischaemia and metabolic disorders. Rare cases of rhabdomyolysis have been reported which had been caused by drugs and after insect stings. The breakdown products of the damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful for the kidneys and they may lead to kidney failure. The symptoms of rhabdomyolysis depend on the severity of the condition. The milder forms of rhabdomyolysis may not cause any muscle symptoms, and the diagnosis is based on abnormal blood tests. The most reliable test in the diagnosis of rhabdomyolysis is the blood level of Creatine Kinase (CK) which is released by the damaged muscles. Here in, we report an unusual case of flax seed induced rhabdomyolysis to alert the medical community about this rare complication.


The hyperresponsiveness of W/W(v) mice to oral sensitization is associated with a decrease in TCRgammadelta-T cells.
We have already reported that WBB6F1-W/W(v) (W/W(v)) mice, which have mutations in the c-kit gene, are highly susceptible to oral sensitization, and that the proportion of TCRgammadelta-T cells among the intraepithelial lymphocytes (IELs) (gammadelta-IELs) of W/W(v) is much lower than in congenic wild-type (+/+) mice. In this study we examined an inhibitory role of gammadelta-IELs in oral sensitization using two different methods. First, wild-type (+/+) mice were sensitized by oral administration of 1.0 mg ovalbumin (OVA) by gavage every day for 9 weeks after anti-TCRgammadelta antibody treatment 4 times. The treatment resulted in an enhanced OVA-specific IgG1 antibody production, active systemic anaphylaxis (ASA), and Th2-dominant cytokine production. Next, W/W(v) mice whose bone marrow cells were reconstituted from C57BL/6J mice for 5 months were sensitized by oral administration of OVA. The OVA-specific IgG1 antibody titer in the bone marrow-reconstituted W/W(v) mice was neither significantly enhanced, nor ASA was induced. The proportion of gammadelta-IELs in the reconstituted mice was much higher than that in the untreated W/W(v) mice. The above findings suggest that the decrease or increase in number of gammadelta-IELs enhances or decreases oral sensitization respectively. These results show that gammadelta-IELs have an important role in the oral tolerance to food antigens.


Epidemiological characteristics and genetic diversity of Bartonella species in rodents from southeastern China.
Rodents are the primary hosts of Bartonella species and carry more than 22 Bartonella species. However, the information on epidemiological characteristics and genetic diversity of Bartonella species in rodents in southeastern China is limited. From 2015 to 2020, 1,137 rodents were captured. Bartonella-positive DNA was detected in 14.9% (169/1,137) of rodents by PCR for both the ssrA and gltA genes. A highest Bartonella prevalence was detected in Apodemus agrarius (33.5%) and lowest in B. indica (1.8%). The probability of Bartonella infection in summer (20.1%) was higher than in spring (14.6%; p = .011, OR = 1.756). Sequencing and phylogenetic analysis revealed that nine known Bartonella species were identified in rodents, including B. tribocorum, B. grahamii, B. rattimassiliensis, B. queenslandensis, B. elizabethae, B. phoceensis, B. coopersplainsensis, B. japonica and B. rochalimae. In our study, Bartonella species exhibited a strong association with their hosts. Zoonotic B. tribocorum, B. grahamii, B. elizabethae and B. rochalimae were found in synanthropic rodent species in southeastern China, which pose a potential threat to the public health. To prevent the spread of zoonotic Bartonella species to humans, preventive and control measures should be implemented, and more research is needed to confirm the pathogen's association with human disease.


A universal protein tag for delivery of SiRNA-aptamer chimeras.
siRNA-aptamer chimeras have emerged as one of the most promising approaches for targeted delivery of siRNA due to the modularity of their diblock RNA structure, relatively lower cost over other targeted delivery approaches, and, most importantly, the outstanding potential for clinical translation. However, additional challenges must be addressed for efficient RNA interference (RNAi), in particular, endosomal escape. Currently, vast majority of siRNA delivery vehicles are based on cationic materials, which form complexes with negatively charged siRNA. Unfortunately, these approaches complicate the formulations again by forming large complexes with heterogeneous sizes, unfavorable surface charges, colloidal instability, and poor targeting ligand orientation. Here, we report the development of a small and simple protein tag that complements the therapeutic and targeting functionalities of chimera with two functional domains: a dsRNA binding domain (dsRBD) for siRNA docking and a pH-dependent polyhistidine to disrupt endosomal membrane. The protein selectively tags along the siRNA block of individual chimera, rendering the overall size of the complex small, desirable for deep tissue penetration, and the aptamer block accessible for target recognition. More interestingly, we found that extending the c-terminal polyhistidine segment in the protein tag to 18 amino acids completely abolishes the RNA binding function of dsRBD.


Constructing and enacting kinship in sister-to-sister egg donation families: a multi-family member interview study.
Although intra-familial egg donation has been practiced for more than 15 years in several countries, little is known about family relationships in this family type. Framed within the new kinship studies, this article focuses on the experiential dimension of kinship in sister-to-sister egg donation families: how is kinship 'unpacked' and 'reconstructed' in this specific family constellation? Qualitative data analysis of interviews with receiving parents, their donating sisters and the donor children revealed six themes: (1) being connected as an extended family; (2) disambiguating motherhood; (3) giving and receiving as structuring processes; (4) acknowledging and managing the 'special' link between donor and child; (5) making sense of the union between father and donor; and (6) kinship constructions being challenged. This study showed the complex and continuous balancing of meanings related to the mother-child dyad, the donor-child dyad and the donor-father dyad. What stood out was the complexity of, on the one hand cherishing the genetic link with the child allowed by the sisters' egg donation, while, on the other, managing the meanings related to this link, by, for instance, acknowledging, downsizing, symbolising, and differentiating it from the mother-child bond. (A Virtual Abstract of this paper can be accessed at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA).


The Current State of Research Regarding the Role of Non-Coding RNAs in Cutaneous Squamous Cell Carcinoma.
Skin cancers, including those of both both melanoma and non-melanoma subtypes, remain among the most common forms of human cancer. Non-melanoma skin cancers are typically further differentiated into the basal cell carcinoma and cutaneous squamous cell carcinoma (cSCC) categories. Current approaches to diagnosing and treating cSCC remain unsatisfactory, and the prognosis for patients with this disease is relatively poor. Recent advances in high-throughput sequencing have led to an increasingly robust understanding of the diversity of non-coding RNAs (ncRNAs) expressed in both physiological and pathological contexts. These ncRNAs include microRNAs, long ncRNAs, and circular RNAs, all of which have been found to play key functional roles and/or to have value as diagnostic biomarkers or therapeutic targets in a range of different disease contexts. The number of ncRNAs associated with cSCC continues to rise, and as such, there is clear value in comprehensively reviewing the functional roles of these molecules in this form of cancer in order to highlight future avenues for research and clinical development.