Sex differences in GABAergic neurotransmission to rat DMV neurons.
Functional gastrointestinal disorders, including delayed gastric emptying and decreased gastric motility, are more prevalent in women, suggesting a potential role for circulating gonadal hormones, including estrogen. Gastric motility is tuned by the vagal inputs arising from the dorsal motor nucleus of the vagus (DMV), which is itself controlled by tonic GABAergic inputs. Estrogen increases GABA functions in various central nervous system areas; however, the effect of the estrus cycle in modulating GABAergic inputs onto DMV neurons, hence vagal control of gastric motility, has not been investigated. The aim of the present study was to test the hypothesis that GABAergic tone to DMV neurons, hence the vagal output to the stomach, varies according to sex and the estrus cycle. Experiments were performed on age-matched Sprague-Dawley male and virgin female rats; females were subdivided according to the high-estrogen (HE) or low-estrogen (LE) period of their cycle. Whole-cell patch-clamp recordings were made from gastric-projecting DMV neurons, and the response to perfusion with the GABAA receptor antagonist bicuculline was examined. The response of corpus and antrum tone and motility to bicuculline microinjected in the dorsal vagal complex, recorded via strain gauges sewn to the anterior gastric surface, was also assessed. Bicuculline increased the firing rate of DMV neurons, as well as gastric tone and motility, to a larger extent in HE compared with LE or male rats, suggesting a higher GABAergic tone in HE female rats. Taken together, the data support the hypothesis that GABAergic tone to DMV neurons varies according to sex and estrus cycle.NEW & NOTEWORTHY GABAergic neurotransmission to the dorsal motor nucleus of the vagus (DMV) plays a pivotal role in the modulation of gastric tone and motility. Gastric motility is reduced in women and may contribute to the higher incidence of functional gastrointestinal disorders. In the present study, we report that GABAergic tone to rat DMV neurons, hence vagal output to the stomach, varies according to sex and estrus cycle, and the GABAergic tone is increased during the high-estrogen period of the estrus cycle.


Relationship between aggression and individual resilience with the mediating role of spirituality in academic students - A path analysis.
The importance of spirituality and spiritual growth in humans has been increasingly taken to attention by psychologists and mental health professionals. In this study, we aimed to investigate the relationship between the tendency to aggression and individual resilience also considering the role of mediator of spirituality in academic students by path analysis. A cross-sectional study was conducted using structural equation method (SEM). The target population consisted all of undergraduate academic students in Ilam, Iran University of Applied Sciences, in 2018. Participants included 200 people whom were selected by stratified random sampling. Data collection tools were demographic, Buss and Perry aggression, spirituality assessment, and resiliency of Connor and Davidson questionnaire. In this study, bivariate analysis was used to determine the directionality correlation between the study variables. The results showed that there was a significant and positive correlation between spirituality and resilience (r = 154% r = 83%). Furthermore, there was a negative and nonsignificant relationship between aggression with resiliency (r = -122% P = 101). In addition, there was no significant correlation between the aggression and spirituality (r = 0.05%, P = 0.942). The results of SEM showed that spirituality and aggression can predict about 20% of the variations in the degree of resilience in academic students. Accordingly, the results of SEM spirituality in an indirect path reduce the aggression and thus increase the resilience (r = 0.102). The results of this study showed the effect of spirituality on increasing the level of resilience and also positive mediator role of spirituality between aggression and resiliency.


The Predictive Validity of the Beck Depression Inventory Suicide Item.
The current study examines the predictive validity of the Beck Depression Inventory (BDI) suicide item for death by suicide and suicide attempts. The study included 2 samples: (1) 5,200 psychiatric outpatients who were evaluated between 1975 and 1995 and followed prospectively for up to 20 years (all psychiatric diagnoses based on DSM-III and DSM-III-R), and (2) 119 patients who, between 2000 and 2004, participated in a randomized controlled trial of outpatient Cognitive Therapy for Suicide Prevention after a suicide attempt and were followed for 18 months (all psychiatric diagnoses based on DSM-IV-TR). All patients completed structured diagnostic interviews, as well as the BDI and Scale for Suicide Ideation. Cox regression models demonstrated that the BDI suicide item significantly predicted both deaths by suicide (Wald χ(2)1 = 35.67; P < .001 [N = 5,200]) and repeat suicide attempts (Wald χ(2)1 = 8.82; P < .01 [N = 119]), with each successive rating on the item conferring greater risk. Using receiver operating characteristic (ROC) curves, optimal cutoff scores of 1 and above for suicide and 2 and above for suicide attempts were identified as providing the best balance between sensitivity and specificity. The BDI suicide item is associated with both risk of repeat suicide attempts and death by suicide. The use of the item as a brief, efficient screen for suicide risk in routine clinical care is recommended. Clinicians would then conduct a comprehensive suicide risk assessment in response to a positive screen. Future research examining the item's performance in other at-risk groups (ie, older adults, adolescents, inpatients, etc) is encouraged.


Role of NH(2)- and COOH-terminal domains of the P protein of human parainfluenza virus type 3 in transcription and replication.
The phosphoproteins (P proteins) of paramyxoviruses play a central role in transcription and replication of the viruses by forming the RNA polymerase complex L-P and encapsidation complex (N-P) with nucleocapsid protein (N) and binding to N protein-encapsidated genome RNA template (N-RNA template). We have analyzed the human parainfluenza virus type 3 (HPIV3) P protein and deletion mutants thereof in an in vitro transcription and in vivo replication system. The in vitro system utilizes purified N-RNA template and cell extract containing L and P proteins coexpressed via plasmids using a recombinant vaccinia virus expression system. The in vivo system takes advantage of minigenome replication, which measures luciferase reporter gene expression from HPIV3 minigenomes by viral proteins in a recombinant vaccinia virus expression system. These studies revealed that the C-terminal 20-amino-acid region of P is absolutely required for transcription in vitro and luciferase expression in vivo, suggesting its critical role in viral RNA synthesis. The N-terminal 40-amino-acid region, on the other hand, is essential for luciferase expression but dispensable for transcription in vitro. Consistent with these findings, the C-terminal domain is required for binding of P protein to the N-RNA template involved in both transcription and replication, whereas the N-terminal domain is required for the formation of soluble N-P complex involved in encapsidation of nascent RNA chains during replication. Coimmunoprecipitation analysis showed that the P protein forms a stable homooligomer (perhaps a trimer) that is present in L-P and N-P complexes in the higher oligomeric forms (at least a pentamer). Interestingly, coexpression of a large excess of N- or C-terminally deleted P with wild-type P had no effect on minigenome replication in vivo, notwithstanding the formation of heterooligomeric complexes. These data indicate that P protein with a deleted terminal domain can function normally within the P heterooligomeric complex to carry out transcription and replication in vivo.


Differential mesenteric fat deposition in bovines fed on silage or concentrate is independent of glycerol membrane permeability.
In the meat industry, the manipulation of fat deposition in cattle is of pivotal importance to improve production efficiency, carcass composition and ultimately meat quality. There is an increasing interest in the identification of key factors and molecular mechanisms responsible for the development of specific fat depots. This study aimed at elucidating the influence of breed and diet on adipose tissue membrane permeability and fluidity and their interplay on fat deposition in bovines. Two Portuguese autochthonous breeds, Alentejana and Barrosã, recognized as late- and early-maturing breeds, respectively, were chosen to examine the effects of breed and diet on fat deposition and on adipose membrane composition and permeability. Twenty-four male bovines from these breeds were fed on silage-based or concentrate-based diets for 11 months. Animals were slaughtered to determine their live slaughter and hot carcass weights, as well as weights of subcutaneous and visceral adipose depots. Mesenteric fat depots were excised and used to isolate adipocyte membrane vesicles where cholesterol content, fatty acid profile as well as permeability and fluidity were determined. Total accumulation of neither subcutaneous nor visceral fat was influenced by breed. In contrast, mesenteric and omental fat depots weights were higher in concentrate-fed bulls relative to silage-fed animals. Membrane fluidity and permeability to water and glycerol in mesenteric adipose tissue were found to be independent of breed and diet. Moreover, the deposition of cholesterol and unsaturated fatty acids, which may influence membrane properties, were unchanged among experimental groups. Adipose membrane lipids from the mesenteric fat depot of ruminants were rich in saturated fatty acids, and unaffected by polyunsaturated fatty acids dietary levels. Our results provide evidence against the involvement of cellular membrane permeability to glycerol on fat accumulation in mesenteric fat tissue of concentrate-fed bovines, which is consistent with the unchanged membrane lipid profile found among experimental groups.


Colostral and milk antibody titers in cows vaccinated with a modified live-rotavirus-coronavirus vaccine.
Colostral and milk whey rotavirus (RV) and coronavirus (CV) antibody titers stimulated in 15 beef heifers by vaccination with a modified live-RV-CV vaccine were compared with titers in 15 nonvaccinated heifers. Geometric mean antibody titers to RV in colostral and 3-day milk whey from vaccinated heifers were 2,807 and 92, respectively, and in control heifers were 1,613 and 71, respectively. Geometric mean antibody titers to CV in colostral and 3-day milk whey of vaccinated heifers were 877 and 13, respectively, compared with titers were 877 and 13, respectively, compared with titers in nonvaccinated heifers of 731 and 7, respectively. Differences in antibody titers between vaccinated and nonvaccinated heifers were not significantly different.


Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome).
FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. To further define the role of FGD1 in skeletal development, we examined its expression in developing mouse embryos and correlated this pattern with FGDY skeletal defects. In this study, we show that Fgd1, the mouse FGD1 ortholog, is initially expressed during the onset of ossification during embryogenesis. Fgd1 is expressed in regions of active bone formation in the trabeculae and diaphyseal cortices of developing long bones. The onset of Fgd1 expression correlates with the expression of bone sialo-protein, a protein specifically expressed in osteoblasts at the onset of matrix mineralization; an analysis of serial sections shows that Fgd1 is expressed in tissues containing calcified and mineralized extracellular matrix. Fgd1 protein is specifically expressed in cultured osteoblast and osteoblast-like cells including MC3T3-E1 cells and human osteosarcoma cells but not in other mesodermal cells; immunohistochemical studies confirm the presence of Fgd1 protein in mouse calvarial cells. Postnatally, Fgd1 is expressed more broadly in skeletal tissue with expression in the perichondrium, resting chondrocytes, and joint capsule fibroblasts. The data indicate that Fgd1 is expressed in a variety of regions of incipient and active endochondral and intramembranous ossification including the craniofacial bones, vertebrae, ribs, long bones and phalanges. The observed pattern of Fgd1 expression correlates with FGDY skeletal manifestations and provides an embryologic basis for the prevalence of observed skeletal defects. The observation that the induction of Fgd1 expression coincides with the initiation of ossification strongly suggests that FGD1 signaling plays a role in ossification and bone formation; it also suggests that FGD1 signaling does not play a role in the earlier phases of skeletogenesis. With the observation that FGD1 mutations result in the skeletal dysplasia FGDY, accumulated data indicate that FGD1 signaling plays a critical role in ossification and skeletal development.


An updated review of functional properties, debittering methods, and applications of soybean functional peptides.
Soybean functional peptides (SFPs) are obtained via the hydrolysis of soybean protein into polypeptides, oligopeptides, and a small amount of amino acids. They have nutritional value and a variety of functional properties, including regulating blood lipids, lowering blood pressure, anti-diabetes, anti-oxidant, preventing COVID-19, etc. SFPs have potential application prospects in food processing, functional food development, clinical medicine, infant milk powder, special medical formulations, among others. However, bitter peptides containing relatively more hydrophobic amino acids can be formed during the production of SFPs, seriously restricting the application of SFPs. High-quality confirmatory human trials are needed to determine effective doses, potential risks, and mechanisms of action, especially as dietary supplements and special medical formulations. Therefore, the physiological activities and potential risks of soybean polypeptides are summarized, and the existing debitterness technologies and their applicability are reviewed. The technical challenges and research areas to be addressed in optimizing debittering process parameters and improving the applicability of SFPs are discussed, including integrating various technologies to obtain higher quality functional peptides, which will facilitate further exploration of physiological mechanism, metabolic pathway, tolerance, bioavailability, and potential hazards of SFPs. This review can help promote the value of SFPs and the development of the soybean industry.


Specificity of an anti-aluminium monoclonal antibody toward free and protein-bound aluminium.
Anti-aluminium monoclonal antibodies (mAbs) were prepared using aluminium chloride-bovine serum albumin complex (Al-BSA) as immunogen. Competitive enzyme-linked immunosorbant assay (ELISA), using an Al-BSA coated immunoplate, demonstrated that mice immune sera showed stronger reactivity to AlCl3 than to BSA. Supernatants from hybridomas prepared from cloned anti-Al antibody-producing cells reacted in ELISA assays whether the metal was bound to proteins like calmodulin (CaM) and S100b protein or to immunogen BSA. Moreover, addition of citrate, a potent ligand for trivalent cations, resulted in a significant withdrawal in mAb recognition of aluminium which was previously bound to either CaM or S100b proteins. The anti-Al mAbs also reacted with aluminosilicate complexes formed from aluminium chloride and silicic acid. The results indicate that the monoclonal antibodies recognized aluminium alone, aluminium bound to silicate, or aluminium bound to a protein core and thus may be used as an immunologic tool for identifying aluminium in both in vitro and in vivo systems.


Synthesis, Molecular Docking, Dynamics, Quantum-Chemical Computation, and Antimicrobial Activity Studies of Some New Benzimidazole-Thiadiazole Hybrids.
In this study, some new compounds, which are 2-aminothiadiazole derivatives linked by a phenyl bridge to the 2-position of the benzimidazole ring, were designed and synthesized as antimicrobial agents. The structures of the compounds were elucidated by 1H and 13C NMR spectroscopy, high-resolution mass spectrometry, and elemental analysis. The antifungal activities of the synthesized compounds were tested on Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compound 5f is more active against C. albicans and C. glabrata than standard fluconazole and varicanazole. Compounds were also evaluated for their counteracting activity against Gram-positive Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa and Gram-negative Enterococcus faecalis, Bacillus subtilis, and Staphylococcus aureus. Compounds 5c and 5h had minimum inhibitory concentrations against E. faecalis close to that of the standard azithromycin. Molecular docking studies were performed against Candida species' 14-α demethylase enzyme. 5f was the most active compound against Candida species, which gave the highest docking interaction energy. The stabilities of compounds 5c and 5f with CYP51 were tested using 100 ns molecular dynamics simulations. According to the theoretical ADME calculations, the profiles of the compounds are suitable in terms of limiting rules. HOMO-LUMO analysis showed that 5h is chemically more reactive (represented with the lower ΔE = 3.432 eV) than the other molecules, which is compatible with the highest antibacterial activity result.


Mild cognitive impairment is common in Parkinson's disease patients with normal Mini-Mental State Examination (MMSE) scores.
Cognitive impairment occurs in the majority of Parkinson's disease (PD) patients, but little is known about detection of mild cognitive impairment (MCI) in this population. We report on the frequency and characteristics of cognitive deficits in PD patients with intact global cognition based on Mini-Mental State Examination (MMSE) performance. One hundred and six PD patients with normal age- and education-adjusted MMSE scores (mean [SD] score=29.1 [1.1]) were administered standardized neuropsychological tests assessing memory, executive function, and attention. Impairment on a cognitive domain was a low score (i.e., >or=1.5 SD below the published normative mean) on at least two measures or tests (for memory and executive abilities) or a single measure (for attention). Mild cognitive impairment was found in 29.2% of PD patients, with 17.9% demonstrating single domain and 11.3% multiple domain impairment. Memory and attention impairment were most common (15.1% and 17.0%, respectively), followed by executive impairment (8.5%). Depending on the measure of disease severity chosen, increasing age and disease severity, anti-anxiety medication use, and a suggestion for increasing severity of daytime sleepiness were independent predictors of cognitive impairment. Cognitive deficits are common in PD patients with "normal" cognition based on MMSE performance, suggesting that MCI is under-recognized in clinical practice due to routine use of insensitive screening instruments. In contrast with some previous reports, early memory impairment may be as common as either executive or attentional deficits in PD. In addition, psychiatric medication use and daytime sleepiness may be reversible or treatable contributors to cognitive impairment.


Usefulness of a Newly Developed Ultrasonic Microdissector in Neurosurgery: A Preliminary Experimental Study.
Dissection and division of tissues are widely performed in microscopic neurosurgery, especially in brain tumor resection. Dissection maneuvers can be divided into two types: sharp dissection with microscissors and blunt dissection using a dissector. It is essential to use the appropriate method according to the intraoperative situation and conditions. Therefore, specific tools for each type of dissection maneuver are required. We developed an ultrasonic microdissector, a newly designed tool that functions as both microscissors and dissector to further advance brain tumor surgery. This preliminary experimental study was performed to evaluate the usefulness of this new device. Solfy F (J. Morita Mfg. Corp., Kyoto, Japan), a dental ultrasonic instrument, was used to provide power in this study. Two experiments were performed. The first one involved touching the brain parenchyma of a pig cadaver with the tip of the ultrasonic microdissector under various conditions to investigate its side effects. In the second experiment, the rat femoral artery, vein, and nerve were dissected from surrounding structures using a prototype of the ultrasonic microdissector. The effects of this device were then investigated histologically. The amount of tissue damage was greater with the higher ultrasonic power. No irrigation and a long manipulation time also affected tissue degeneration. Dissection using the ultrasonic microdissector was superior to conventional dissection methods in terms of time (p < 0.05) and safety without any additional histologic damages. The newly developed ultrasonic microdissector can dissect soft tissue without damage to the surrounding tissue. Further studies are required to determine the optimal intensity for its clinical use.


Avascular necrosis following bone marrow transplantation: a case-control study.
The role of specific immunosuppressive agents in the development of avascular necrosis (AVN) following hematopoietic stem cell and solid organ transplantation remains unclear. To further explore this question, we conducted a case-control study of patients who underwent bone marrow transplantation (BMT) at the Fred Hutchinson Cancer Research Center. 96 of 1939 long-term survivors transplanted between May 1976 and October 1993 were identified as having AVN. Eight patients were excluded because AVN developed before transplant and one was excluded due to restrictions on reviewing follow-up records. The remaining 87 patients developed AVN a mean of 26.3 +/- 2 months posttransplant and were matched for age, gender, and date of transplant to other BMT recipients. Records were reviewed for corticosteroid and cyclosporine use, pretransplant conditioning with total body irradiation (TBI), and other information including disease for which the transplant was indicated, type of transplant, the occurrence of acute and chronic graft-vs.-host disease, and steroid use prior to transplant. Adjusted odds ratios (ORs) were obtained from conditional logistic regression for 87 matched pairs. Posttransplant steroid use was a risk factor for the occurrence of AVN (adjusted OR, 14.4; 95% CI, 2.8-73.2), with the greatest risk associated with those receiving steroids at the time of diagnosis of AVN (adjusted OR, 31.9; 95% CI, 4.4-248.9). There was no further increasing risk associated with increasing duration of steroid use. Conditioning with TBI was also associated with the occurrence of AVN (adjusted OR, 3.2; 95% CI, 1.1-9.7); however, cyclosporine was not a risk factor for AVN (adjusted OR, 0.5; 95% CI, 0.1-1.9). Our results support the hypothesis that AVN following BMT has a strong association with the administration of corticosteroids. TBI may be an additional risk factor, and cyclosporine does not appear to contribute to an increased incidence of AVN.


[Contracting and relaxing action of substance P on the airway muscles in the dog].
In anesthetized and artificially ventilated dogs, trachea and bronchi with low resting tone responded to i.v. bolus injection of the substance P with constriction in a dose-dependent manner. The constriction was partially abolished after cooling of cervical vagi or administration of atropine. If the resting tone had been elevated with continuous administration of 5-HT, the bolus injection of the substance P evoked dilation of the trachea and bronchi, which was augmented by atropine and diminished by propranolol. The constrictor response to the substance P seems to be due to the direct interaction of the peptide with specific receptor and an indirect action through activating of vagal pathways. Dilatory response seems to be entirely indirect and mediated through both beta-adrenergic and unknown non-vagal non-histaminergic mechanisms.


Advances in autoimmune myasthenia gravis management.
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder with no cure and conventional treatments limited by significant adverse effects and variable benefit. In the last decade, therapeutic development has expanded based on improved understanding of autoimmunity and financial incentives for drug development in rare disease. Clinical subtypes exist based on age, gender, thymic pathology, autoantibody profile, and other poorly defined factors, such as genetics, complicate development of specific therapies. Areas covered: Clinical presentation and pathology vary considerably among patients with some having weakness limited to the ocular muscles and others having profound generalized weakness leading to respiratory insufficiency. MG is an antibody-mediated disorder dependent on autoreactive B cells which require T-cell support. Treatments focus on elimination of circulating autoantibodies or inhibition of effector mechanisms by a broad spectrum of approaches from plasmapheresis to B-cell elimination to complement inhibition. Expert commentary: Standard therapies and those under development are disease modifying and not curative. As a rare disease, clinical trials are challenged in patient recruitment. The great interest in development of treatments specific for MG is welcome, but decisions will need to be made to focus on those that offer significant benefits to patients.


A qualitative study: Barriers and support for participation for children with disabilities.
This qualitative-exploratory study examined the barriers to participation amongst children with disabilities in Lusaka, Zambia, from the mothers' perspective. The objectives of this study were to understand how mothers of children with physical and cognitive disabilities who engaged their children in community-based rehabilitation (CBR) services in Lusaka, Zambia, perceived and described (1) the level of support they received and the barriers they encountered in terms of their child's meaningful social participation; (2) the use and awareness of these barriers to identify and pursue advocacy strategies; and (3) hopes for their child's future. Data were collected through semi-structured interviews with each mother in her home. Results: Findings revealed both support and barriers to the child's social participation in relationship to their family, friends and community. Support also came from the CBR programme and mothers' personal resourcefulness. Mothers identified their child's school, their immediate environment and financial burdens as barriers to participation as well as their own personal insecurities and fears. Strategies to overcome barriers included internal and external actions. The mothers involved in the study hope their child's abilities will improve with continued CBR services. Some mothers described a bleak future for their child due to a lack of acceptance and access to education. The findings of this study suggest the significant role the mother of a child with a disability plays in her child's social participation. Recommendations include enhancing CBR programming for families, especially for mothers, and advocating on behalf of children with disabilities and their families to attract the attention of policy makers.


Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis.
Multiple myeloma (MM) is a plasma cell malignancy without effective therapeutics. Thromboxane A2 (TxA2)/TxA2 receptor (T prostanoid receptor (TP)) modulates the progression of some carcinomas; however, its effects on MM cell proliferation remain unclear. In this study, we evaluated cyclooxygenase (COX) enzymes and downstream prostaglandin profiles in human myeloma cell lines RPMI-8226 and U-266 and analyzed the effects of COX-1/-2 inhibitors SC-560 and NS-398 on MM cell proliferation. Our observations implicate COX-2 as being involved in modulating cell proliferation. We further incubated MM cells with prostaglandin receptor antagonists or agonists and found that only the TP antagonist, SQ29548, suppressed MM cell proliferation. TP silencing and the TP agonist, U46619, further confirmed this finding. Moreover, SQ29548 and TP silencing promoted MM cell G2/M phase delay accompanied by reducing cyclin B1/cyclin-dependent kinase-1 (CDK1) mRNA and protein expression. Notably, cyclin B1 overexpression rescued MM cells from G2/M arrest. We also found that the TP agonist activated JNK and p38 MAPK phosphorylation, and inhibitors of JNK and p38 MAPK depressed U46619-induced proliferation and cyclin B1/CDK1 protein expression. In addition, SQ29548 and TP silencing led to the MM cell apoptotic rate increasing with improving caspase 3 activity. The knockdown of caspase 3 reversed the apoptotic rate. Taken together, our results suggest that TxA2/TP promotes MM cell proliferation by reducing cell delay at G2/M phase via elevating p38 MAPK/JNK-mediated cyclin B1/CDK1 expression and hindering cell apoptosis. The TP inhibitor has potential as a novel agent to target kinase cascades for MM therapy.


Pediatric Osteopathic Manipulative Medicine: A Scoping Review.
A common reproach precluding the use of osteopathic manipulative medicine (OMM) in pediatrics is a lack of evidence regarding its safety, feasibility, and effectiveness. We conducted a systematic, scoping review of pediatric osteopathic medicine to identify gaps in the literature and make recommendations for future research. We searched 10 databases using 6 key words and medical subject heading terms for any primary articles reporting OMM use in children published from database inception until initiation of the study. Articles were selected if they reported primary data on OMM conducted in the United States on patient(s) 0 to 18 years old. Baseline study characteristics were collected from each article and the Grading of Recommendations, Assessment, Development, and Evaluations system was used to critically appraise each study. Database search yielded 315 unique articles with 30 studies fulfilling inclusion and exclusion criteria. Of these, 13 reported the data required to demonstrate statistically significant results, and no significant adverse events were reported. The majority of studies were graded as providing weak clinical evidence because of significant methodologic flaws and biases. The review was limited to US-based studies and reports. Minimal discrepancies between reviewers were resolved via an objective third reviewer. There is little strong, scientific, evidence-based literature demonstrating the therapeutic benefit of OMM for pediatric care. No strong clinical recommendations can be made, but it can be medically tolerated given its low risk profile. High-quality, scientifically rigorous OMM research is required to evaluate safety, feasibility, and efficacy in pediatrics.


Survival of corneal grafts from donors supported by mechanical ventilation.
Eighty-five patients undergoing penetrating keratoplasty with tissue from donors supported by mechanical ventilation (Ventilator group) were compared to a surgeon- and diagnosis-matched group (Control group). Age at surgery, duration of follow-up, and sex of recipient patients were similar in the two groups. The mean donor age in the Ventilator group (26.4 years) was significantly less than in the Control group (45.8 years, P less than 0.0001). Mean time on the ventilator was 99.4 hours (range, 4 hours to 21 days). Overall graft survival rates in the Ventilator and Control groups were similar (P greater than or equal to 0.72). Time on the ventilator did not affect graft survival. Cultures of corneoscleral donor rims were positive more often in the Ventilator group than in Controls (39.7 versus 23.1%), but the difference was not significant (P = 0.09). Prolonged ventilator time was not associated with a higher rate of positive corneoscleral rim cultures, nor did positive cultures affect graft survival. The most common cause of graft failure in both groups was allograft rejection. In no case could postoperative bacterial infection be attributed to contamination of the donor material. One case of primary donor failure occurred in the Ventilator group, but the incidence (1.2%) is similar to that of previously reported studies. The data indicate that corneal tissue from ventilator-supported donors should be considered for use in penetrating keratoplasty.


The challenges in creating reference maps for verification of ultrasound images.
In the development of new medical imaging techniques, references to which the images can be compared are necessary if one wants to assess how precise the images are. This is especially interesting in diagnostic ultrasound where a number of artefacts influence the image. The reference can either be derived from a phantom with precisely known properties and geometry, from the specifications of a computer phantom (simulated images) or from evaluation of biological tissue. The third approach can be conducted with other medical imaging modalities (CT, MRI, etc.) or "destructive testing" involving histology. In this paper, aspects of the latter method is considered in detail. Formalin fixed tissue is moulded into an agar block containing at set of fiducial markers. The block is scanned with ultrasound. Both tissue and fiducial markers are imaged. The block is afterwards sliced at the location of the fiducial markers. The slices are then photographed and analyzed histologically. From this data, reference maps with similar geometry as the ultrasound images can be created. Ideally, for each pixel in the ultrasound image, these reference maps indicate tissue type, such as collagen poor tissue, collagen rich tissue, etc. Many of the sources of error as well as the challenges with such a method are discussed.


Association of μ-Opioid Activation in the Prefrontal Cortex with Spontaneous Migraine Attacks - Brief Report I.
We evaluated in vivo the μ-opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using Positron Emission Tomography with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. In the ictal phase, there was μOR activation in the medial prefrontal cortex, which was strongly associated with the μOR availability level during the interictal phase. Furthermore, μ-opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high μOR activation in the migraineurs' brains during headache attacks in response to their pain.


[No quetiapine for sleeping disorders].
The prescribing of low doses of quetiapine for the treatment of sleeping disorders appears to be widespread. Recently, in a systematic literature review on low-dose quetiapine use for the treatment of sleeping disorders, it was concluded that evidence for its efficacy is currently lacking. Furthermore, quetiapine is probably associated with potentially severe adverse effects, also at low doses. In conclusion, sufficient scientific evidence that justifies the current practice of off-label prescribing of low-dose quetiapine for the treatment of sleeping disorders is insufficient; further research into its efficacy and safety is needed.


[Systemic scleroderma associated to a glomerulonephritis with anti-MPO antibodies: a case report and literature review].
Besides the classic "renal crisis", a well known form of acute renal failure sometimes complicating scleroderma, another type of acute renal injury, even rarer and not well recognized, does exist: a crescentic glomerulonephritis associated with ANCA, and more seldom with anti-GBM antibodies, which is often (but not always) secondary to the use of D-penicillamine. We report the case of a 70 years-old female who presented with a severe acute renal failure accompanied by positive anti-MPO ANCA as well as anti-GBM antibodies. She had a long history of systemic scleroderma which had been treated with D-penicillamine for many years. The clinical picture was typical of an ANCA-positive vasculitis of the microscopic form of polyangeitis, with a crescentic glomerulonephritis on renal biopsy. Unfortunately, the patient died despite therapy with plasma exchanges and immunosuppressive drugs. Some forty cases of crescentic glomerulonephritis associated with scleroderma have been reported. They were initially considered as always associated with D-penicillamine use, but more recently some observations have been made outside this drug context. As will be shown through a literature review, it can be concluded that there are two (or even three according to some authors) forms of acute renal involvement associated to scleroderma, which should be distinguished as soon as possible, given the quite differing therapeutic and prognostic consequences of this distinction.


The effect of dexmedetomidine on perioperative hemodynamics in patients undergoing craniotomy.
The perioperative course of patients undergoing intracranial surgery is frequently complicated by hypertensive episodes. Dexmedetomidine (DEX), an alpha-2 adrenoreceptor agonist, is gaining popularity in neuroanesthesia, because its sympatholytic and antinociceptive properties may improve hemodynamic stability at critical moments of surgery. We designed this study to assess the efficacy of DEX in controlling hypertensive responses in patients undergoing intracranial surgery. Patients scheduled for elective craniotomy were randomly assigned to receive either sevoflurane-opioid or sevoflurane-opioid-DEX anesthesia. Bispectral index was used to maintain a similar level of hypnosis in both groups (40-50). Opioids, sevoflurane, and vasoactive medications were titrated in a routine manner, at the discretion of the blinded anesthesiologist managing the case, to maintain systolic blood pressure (SBP) targeted within 90-130 mm Hg and heart rate (HR) between 50 and 90 bpm. Hemodynamic variables were continuously recorded and stored on a computer for analysis. Efficacy of the anesthetic technique in controlling SBP or HR is inversely proportional to the area under the curve (AUC) outside the targeted range. Areas under the curves above and below targeted ranges for SBP-time (AUCsbp mm Hg*min/h) and HR-time (bpm*min/h) were compared. Coefficient of variation was used to assess hemodynamic stability. Seventy-two patients were recruited for the study. Computerized records of 56 patients only were analyzed because of technical problems with data collection in 14 cases. AUCsbp for above the targeted range was significantly lower for patients in the DEX group (P=0.044). The coefficient of variation for SBP or HR did not differ between groups. A significantly smaller proportion of patients in the DEX group required treatment with antihypertensive medications (12 of 28, 42% vs 24 of 28, 86%, P=0.0008). The DEX group required fewer opioids in the intraoperative period, but there were no differences in the use of sevoflurane. In the postanesthesia care unit, patients in the DEX group had fewer hypertensive episodes (1.25+/-1.55 vs 2.50+/-2.00, P=0.0114) and were discharged earlier (91+/-17 vs 130+/-27 min, P<0.0001). There were no differences in the requirement for postoperative opioids or antiemetics. By using indices, which assess a global hemodynamic stability of the anesthetic, we determined that intraoperative DEX infusion was effective for blunting the increases in SBP perioperatively. The use of DEX did not increase the incidence of hypotension or bradycardia, common side effects of the drug.


[Comparison of dynamic contour tonometry, Goldmann applanation Tonometry and tonopen for measuring intraocular pressure in normal tension glaucoma].
Normal tension glaucoma (NTG) is a chronic progressive optic neuropathy, characterized by relatively normal intraocular pressure (IOP) measurements. This study utilized three modalities in the measurement of lOP: dynamic contour tonometry (Pascal-DCT), Goldmann applanation tonometry (GAT) and Tonopen XL. To compare the lOP measurements of the three devices in eyes with NTG. This retrospective study of thirty-three NTG patients (66 eyes) who underwent lOP measurements using the three devices was approved by a local ethics committee. The lOP measurements were stratified according to central corneal thickness (CCT) and corneal curvature (CC). The mean DCT IOP was higher (16.22 +/- 3.04 mmHg) than the mean GAT IOP (13.14 +/- 2.83 mmHg, P < 0.0042). The mean Tonopen XL lOP was lower than the mean GAT IOP (12.76 +/- 3.11 mmHg, P < 0.001). GAT and DCT measurements were significantly infLuenced by corneal curvature (P = 0.004 and P < 0.0001, respectiveLy). lOPs measured by GAT or Tonopen XL were consistently lower than by DCT. CC significantly influenced GAT and DCT results.


The effect of weak π-π interactions on single-molecule electron transport properties of the tetraphenylethene molecule and its derivatives: a first-principles study.
Intramolecular π-π interactions are a significant research focus in fields such as chemistry, biology, and materials science. Different configurations of benzene-benzene moieties within a molecule can affect the magnitude of their π-π interactions, consequently influencing the electronic transport capabilities of the molecule. In this study, we designed three π-conjugated molecules, TPEM, TPEEM, and TEEPM, based on tetraphenylethene (TPE). These three molecules exhibit three distinct π-conjugated structures: linear cis-π-conjugation, linear trans-π-conjugation, and cross-π-conjugation. Thereinto, TPEM and TPEEM molecules share the same TPE core, with identical π-π interaction distances, while the TEEPM molecule has acetylene groups between the TPE units, thereby increasing the π-π interaction distances between the benzene moieties. Using density functional theory calculations combined with non-equilibrium Green's function (DFT+NEGF), our results reveal that the conductance order of different π-conjugated structures in TPEM and TPEEM molecules is as follows: cis > cross ≈ trans. Through analysis of transmission spectra, transmission pathways, and the innermost π orbitals, we find that in TPEM and TPEEM molecules, the cis- and cross-π-conjugated structures exhibit π-π interactions between benzene moieties and provide special through-space electron transport pathways, enhancing their electronic transport capabilities in coordination with the bonded molecular framework, whereas their trans-conjugated structures only allow electron transport along the molecular backbone. In contrast, in TEEPM molecule, due to the absence of π-π interactions, the conductance of different π-conjugated structures is primarily determined by the molecular backbone and follows the order: trans > cis > cross. These findings provide a theoretical basis for designing single-molecule electronic devices with multiple electron channels based on intramolecular π-π interactions.


Antagonism between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B.
A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA-entry and HBe-SC in the natural history of CHB. To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n=102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. Ruminococcus gnavus was the most abundant species in CHB patients in the IT-phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with ALT-flares, HBeAg loss and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients, since R. gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A. muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A. muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R. gnavus to allow HBV elimination. R. gnavus and A. muciniphila play opposite roles in HBV infection. A. muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.


Prevalence of Subclinical Systemic Lymphedema in Patients Following Treatment for Breast Cancer and Association with Body Mass Index.
The aim of the present study is to evaluate the prevalence of subclinical systemic lymphedema in patients with lymphedema following treatment for breast cancer and the association with the body mass index (BMI). A cross-sectional study was conducted to determine the prevalence of subclinical systemic lymphedema using bioelectrical impedance analysis in patients with lymphedema following treatment for breast cancer. One hundred women with lymphedema of the upper limbs resulting from treatment for breast cancer were evaluated at the Godoy Clinic in 2019. Fisher's exact test demonstrated a significant association between BMI higher than 30 kg/m2 and subclinical systemic lymphedema (p=0.01). The prevalence of subclinical systemic lymphedema is high among patients with lymphedema following treatment for breast cancer and is associated with the increase in BMI.


Copeptin - a new diagnostic and prognostic biomarker in neurological and cardiovascular diseases.
Copeptin, arginine vasopressin (AVP)-associated 39 aminoacid glycopeptide, is a C-terminal part of pro-AVP. AVP acts through V1a, V1b, and V2 receptors. The effect on V1a receptors is connected with arterial vasoconstriction, on V2 with antidiuretic action, and on V1b with the secretion of ACTH, insulin, glucagon. Copeptin is found in the circulation in equimolar amounts with AVP. It is a very stable peptide and easy to estimate. Copeptin is a good diagnostic marker in many disorders in which vasopressinergic dysfunction plays a role in pathogenesis such as a polyuria-polydipsia syndrome, neurological disease (ischemic stroke, nontraumatic, intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage and neurodegenerative disease (multiple sclerosis). Copeptin is a diagnostic and prognostic marker in cardiovascular diseases like heart failure (HF) and acute myocardial infarct (AMI). Copeptin is a sensitive diagnostic marker in the early stage of AMI especially in patients with non-ST segment elevation and post AMI complications. Copeptin is also an important diagnostic and prognostic marker in metabolic diseases (diabetes mellitus, metabolic syndrome, insulin resistance), connected with some neurological and cardiovascular diseases. In the future, these findings may have also therapeutic applications in conditions where the AVP receptor antagonist therapy is appropriate.


Sensing Responses Based on Transfer Characteristics of InAs Nanowire Field-Effect Transistors.
Nanowire-based field-effect transistors (FETs) have demonstrated considerable promise for a new generation of chemical and biological sensors. Indium arsenide (InAs), by virtue of its high electron mobility and intrinsic surface accumulation layer of electrons, holds properties beneficial for creating high performance sensors that can be used in applications such as point-of-care testing for patients diagnosed with chronic diseases. Here, we propose devices based on a parallel configuration of InAs nanowires and investigate sensor responses from measurements of conductance over time and FET characteristics. The devices were tested in controlled concentrations of vapour containing acetic acid, 2-butanone and methanol. After adsorption of analyte molecules, trends in the transient current and transfer curves are correlated with the nature of the surface interaction. Specifically, we observed proportionality between acetic acid concentration and relative conductance change, off current and surface charge density extracted from subthreshold behaviour. We suggest the origin of the sensing response to acetic acid as a two-part, reversible acid-base and redox reaction between acetic acid, InAs and its native oxide that forms slow, donor-like states at the nanowire surface. We further describe a simple model that is able to distinguish the occurrence of physical versus chemical adsorption by comparing the values of the extracted surface charge density. These studies demonstrate that InAs nanowires can produce a multitude of sensor responses for the purpose of developing next generation, multi-dimensional sensor applications.


Broad influenza-specific CD8+ T-cell responses in humanized mice vaccinated with influenza virus vaccines.
The development of novel human vaccines would be greatly facilitated by the development of in vivo models that permit preclinical analysis of human immune responses. Here, we show that nonobese diabetic severe combined immunodeficiency (NOD/SCID) beta(2) microglobulin(-/-) mice, engrafted with human CD34+ hematopoietic progenitors and further reconstituted with T cells, can mount specific immune responses against influenza virus vaccines. Live attenuated trivalent influenza virus vaccine induces expansion of CD8+ T cells specific to influenza matrix protein (FluM1) and nonstructural protein 1 in blood, spleen, and lungs. On ex vivo exposure to influenza antigens, antigen-specific CD8+ T cells produce IFN-gamma and express cell-surface CD107a. FluM1-specific CD8+ T cells can be also expanded in mice vaccinated with inactivated trivalent influenza virus vaccine. Expansion of antigen-specific CD8+ T cells is dependent on reconstitution of the human myeloid compartment. Thus, this humanized mouse model permits preclinical testing of vaccines designed to induce cellular immunity, including those against influenza virus. Furthermore, this work sets the stage for systematic analysis of the in vivo functions of human DCs. This, in turn, will allow a new approach to the rational design and preclinical testing of vaccines that cannot be tested in human volunteers.


An observational study of hand hygiene adherence following the introduction of an education intervention.
Hand hygiene adherence needs to be increased and sustained in order to prevent and reduce healthcare associated infections. We implemented an educational intervention and observed the adherence of healthcare workers, patients and visitors over 24 hour periods at four observation points. For healthcare workers a total of 2,294 opportunities were observed and for patients and visitors, a total of 597 opportunities were observed. Healthcare worker adherence increased following the introduction of the educational intervention, with 53.0% (282/532) adherence at baseline (observation point 1), and was sustained varying between 67.7% and 70.8% in the post-intervention points (p=0.0007). The greatest increase in adherence was observed between baseline and the observation point 2. Adherence varied according to type of opportunity (p<0.0001) with the lowest level of adherence observed after contact with patient surroundings, however there was no obvious trend across the observation points. There was an interaction between point of study and ward (p=0.0001). For patients and visitors, adherence did differ according to the point of study (p=0.0074) with adherence prior to the intervention being 49.1% and then ranging from 43.5-61.8%. We suggest that future educational interventions should be implemented as this study implies that there is potential for increased and sustained adherence to hand hygiene protocols.


Androgen pathway resistance in prostate cancer and therapeutic implications.
Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance. This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer. Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.


Hyperactivation of Oncogenic JAK3 Mutants Depend on ATP Binding to the Pseudokinase Domain.
Janus kinase 3 (JAK3) tyrosine kinase has a central role in the control of lymphopoiesis, and mutations in JAK3 can lead to either severe combined immunodeficiency or leukemia and lymphomas. JAK3 associates with the common gamma chain (γc) receptor and functions in a heteromeric signaling pair with JAK1. In IL-2 signaling JAK1 is the effector kinase for STAT5 phosphorylation but the precise molecular regulatory mechanisms of JAK1 and JAK3 and their individual domains are not known. The pseudokinase domain (JAK homology 2, JH2) of JAK3 is of particular interest as approximately half of clinical JAK3 mutations cluster into it. In this study, we investigated the role of JH2s of JAK1 and JAK3 in IL-2R signaling and show that STAT5 activation requires both JH1 and JH2 of JAK1, while both JH1 and JH2 in JAK3 are specifically required for the cytokine-induction of cellular signaling. Characterization of recombinant JAK3 JH2 in thermal shift assay shows an unstable protein domain, which is strongly stabilized by ATP binding. Unexpectedly, nucleotide binding to JAK3 JH2 was found to be cation-independent. JAK3 JH2 showed higher nucleotide binding affinity in MANT-ATP and fluorescent polarization competition assays compared to the other JAK JH2s. Analysis of the functional role of ATP binding in JAK3 JH2 in cells and in zebrafish showed that disruption of ATP binding suppresses ligand-independent activation of clinical JAK3 gain-of-function mutations residing in either JH2 or JH1 but does not inhibit constitutive activation of oncogenic JAK1. ATP-binding site mutations in JAK3 JH2 do not, however, abrogate normal IL-2 signaling making them distinct from JH2 deletion or kinase-deficient JAK3. These findings underline the importance of JAK3 JH2 for cellular signaling in both ligand-dependent and in gain-of-function mutation-induced activation. Furthermore, they identify the JH2 ATP-binding site as a key regulatory region for oncogenic JAK3 signaling, and thus a potential target for therapeutic modulation.


A Randomized Study of the Single-Dose Safety, Pharmacokinetics, and Food Effect of Chinfloxacin and Its Effect on Thorough QT/QTc Interval in Healthy Chinese Volunteers.
Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single-ascending-dose study to assess safety and tolerability of chinfloxacin. The single-dose pharmacokinetic study, a food effect study, and a multiple-dose pharmacokinetics study were conducted in parts B, C, and D, respectively. Part E was a randomized, placebo-controlled and positive-control single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/corrected QT (QTc) interval. The results suggest that single and multiple oral administrations of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis, and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to peak plasma concentration (Tmax and Cmax, respectively) was about 2 h, and the half-life was 14 to 16 h. Food slightly affected the drug's rate and extent of absorption, increasing the Tmax from 1.60 to 2.59 h and reducing the Cmax by 13.6% and area under the concentration-time curve by 8.95%. Chinfloxacin at 400 mg had no effect on prolongation of QT/QTc intervals. Although 600 mg chinfloxacin had a mild effect on the prolongation of the QT/QTc interval, the effect was less pronounced than that of the positive control, 400 mg moxifloxacin. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at www.ChiCTR.org.cn under identifiers ChiCTR-TRC-10001619 for parts A to D and ChiCTR1800015906 for part E.).


Recent progress on transition metal diselenides from formation and modification to applications.
The development of graphene promotes the research of similar two-dimensional (2D) materials, especially 2D transition metal dichalcogenides (TMDCs) with semiconductor properties. Monolayer or few-layer TMDCs have several advantages, such as direct band gap, weak interlayer van der Waals force, large interlayer spacing, and abundant marginal active sites, which make them widely used in catalysis, optoelectronics, as well as energy conversion and storage devices. In addition, transition metal diselenides (TMDSs) also possess many intriguing characteristics. For instance, transition metal diselenides (e.g., MoSe2) have a more stable 1T phase, larger interlayer spacing, smaller band gap, and more obvious metallic property of Se than TMDCs (e.g., MoS2). Thus, it has become one of the most attractive research topics branching out from TMDCs. Herein, this review unveils the structures, synthesis, properties, modifications, applications, and perspectives for TMDSs.


Mucosal immunization with recombinant adenoviruses: induction of immunity and protection of cotton rats against respiratory bovine herpesvirus type 1 infection.
To facilitate the evaluation of vaccines against bovine herpesvirus type 1 (BHV-1), a cotton rat model of intranasal (i.n.) BHV-1 infection was established. Cotton rat lung cells were similar to bovine cells in their ability to support BHV-1 replication in vitro. Furthermore, i.n. inoculation of cotton rats with BHV-1 resulted in pulmonary lesions comparable to BHV-1 infection in cattle. Using this model, the potential of i.n. and gastrointestinal (g.i.) immunization was examined with recombinant human adenoviruses expressing glycoprotein D (gD) of BHV-1 to induce protective immunity against BHV-1. The replication-competent virus (gD-dE3) was more efficient than the replication-defective virus (gD-dE1E3) in inducing gD-specific antibody in the serum and in the respiratory tract. Furthermore, i.n. immunization with gD-dE3 stimulated antigen-specific antibody-secreting cells in the lung 12 weeks following immunization. Protection against BHV-1 challenge correlated with gD-specific antibody levels such that i.n. immunization with gD-dE3 conferred complete protection, while g.i. immunization conferred only partial protection of the lungs of most animals against BHV-1 challenge. In comparison, immunization with gD-dE1E3 by either route resulted in only a partial reduction of BHV-1 titre in the respiratory tract. The results obtained demonstrate that mucosal immunization with replication-competent recombinant adenovirus expressing gD of BHV-1 can induce immunity and protection against BHV-1 challenge.


Intrahospital transport of the critically ill adult: a research review and implications.
Transporting the critically ill adult from the relative stability of the critical care environment to a testing site or new area is a nursing responsibility. Yet current research about the risks and benefits of intrahospital transport is at times conflicting. This article provides an analysis of available research on the critical elements involved in intrahospital transport and suggests recommendations for clinical practice.


Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer.
In recent studies, we showed that TP53 gene mutation or high levels of cytosolic vascular endothelial growth factor (VEGF) in estrogen receptor (ER)-alpha-positive primary breast tumors predict a poor disease outcome for patients treated with first-line tamoxifen for advanced disease. Mutant TP53 may up-regulate VEGF, whereas, on the other hand, wild-type TP53 may decrease VEGF production. In the present study, we aimed to assess the combined predictive value of TP53 gene mutation and VEGF status of 160 advanced breast cancer patients with ER-positive tumors who were treated with tamoxifen (median follow-up from start of tamoxifen treatment, 64 months). To assess TP53 gene mutation status, the entire open reading frame was sequenced; for VEGF status, an ELISA was used. In univariate analysis, both TP53 gene mutation (28% of the tumors) and a VEGF level above the median value were significantly associated with a short progression-free survival, post-relapse overall survival, and a poor rate of response to tamoxifen. In Cox multivariate regression analysis including the traditional predictive factors, the addition of TP53 gene mutation and VEGF status, alone or in combination, significantly predicted a poor efficacy of tamoxifen treatment. When the two factors were combined, a significantly decreased odds ratio was seen for the rate of response (odds ratio, 0.27). Similarly, an increased hazard ratio (HR) was seen for progression-free survival (HR, 2.32) and post-relapse overall survival (HR, 1.68) in the group with mutant TP53 and high VEGF compared with the group with both risk factors absent. Combined TP53 gene mutation status and high VEGF levels of ER-positive primary breast tumors independently predict a poor course of the disease of patients with advanced breast cancer treated with tamoxifen. These patients, having unfavorable tumor characteristics, might benefit more from other types of (individualized) treatment protocols.


Promotion of enzyme flexibility by dephosphorylation and coupling to the catalytic mechanism of a phosphohexomutase.
The enzyme phosphomannomutase/phosphoglucomutase (PMM/PGM) from Pseudomonas aeruginosa catalyzes an intramolecular phosphoryl transfer across its phosphosugar substrates, which are precursors in the synthesis of exoproducts involved in bacterial virulence. Previous structural studies of PMM/PGM have established a key role for conformational change in its multistep reaction, which requires a dramatic 180° reorientation of the intermediate within the active site. Here hydrogen-deuterium exchange by mass spectrometry and small angle x-ray scattering were used to probe the conformational flexibility of different forms of PMM/PGM in solution, including its active, phosphorylated state and the unphosphorylated state that occurs transiently during the catalytic cycle. In addition, the effects of ligand binding were assessed through use of a substrate analog. We found that both phosphorylation and binding of ligand produce significant effects on deuterium incorporation. Phosphorylation of the conserved catalytic serine has broad effects on residues in multiple domains and is supported by small angle x-ray scattering data showing that the unphosphorylated enzyme is less compact in solution. The effects of ligand binding are generally manifested near the active site cleft and at a domain interface that is a site of conformational change. These results suggest that dephosphorylation of the enzyme may play two critical functional roles: a direct role in the chemical step of phosphoryl transfer and secondly through propagation of structural flexibility. We propose a model whereby increased enzyme flexibility facilitates the reorientation of the reaction intermediate, coupling changes in structural dynamics with the unique catalytic mechanism of this enzyme.


A nanoscale characterization with electron microscopy of multilayered CrAlYN coatings: a singular functional nanostructure.
A combination of transmission electron microscopy techniques and spatially resolved microanalysis is used to investigate the nanostructure, constituting phases, and chemical elemental distribution in CrAlYN multilayered coatings. The location of the metallic elements and their chemical state are needed to understand their functional properties. Samples were prepared with variable Al (4-12 at%) and Y (2-5 at%) contents by direct current reactive magnetron sputtering on silicon substrates using metallic targets and Ar/N2 mixtures under different deposition parameters (power applied to the target and rotation speed of the sample holder). The changes produced in the nanostructure and chemical distribution were investigated. Nanoscale resolution electron microscopy analysis has shown that these coatings present a singular nanostructure formed by multilayers containing at a certain periodicity nanovoids filled with molecular nitrogen. Spatially resolved energy dispersive spectroscopy and electron energy loss elemental mappings and profiles showed that the chromium, aluminum, and yttrium atoms are distributed in a sequential way following the position of the targets inside the deposition chamber. Analysis of the different atomic distribution and phases formed at the nanoscale is discussed depending on the deposition parameters.


Etiology of pruritic papular eruption with HIV infection in Uganda.
A frequent cause of human immunodeficiency virus (HIV)-related morbidity in sub-Saharan Africa is a commonly occurring, intensely pruritic skin rash. The resulting scars are disfiguring and stigmatizing. Despite the substantial prevalence of pruritic papular eruption (PPE) among HIV-infected Africans, the cause has been elusive. To determine the etiology of PPE occurring in HIV-infected individuals. Cross-sectional study of HIV-infected patients with active PPE from clinics in Uganda conducted from May 19 through June 6, 2003. Enrollment occurred in the month preceding May 19. Each participant was clinically examined by 2 dermatologists, had laboratory studies performed, was administered an epidemiologic questionnaire, and had a skin biopsy of a new lesion evaluated by a dermatopathologist. Histological characteristics of new pruritic lesions. Other assessments included CD4 cell count, eosinophil count, and physician-assessed rash severity. Of 109 patients meeting inclusion criteria, 102 (93.6%) completed the study. The CD4 cell counts in this study population were generally low (median, 46/microL) and inversely related to increasing rash severity (median CD4 cell counts: 122 for mild, 41 for moderate, and 9 for severe; P<.001 for trend). Eighty-six patients (84%; 95% confidence interval, 77%-91%) had biopsy findings characteristic of arthropod bites. Patients with arthropod bites on biopsy had significantly higher peripheral eosinophil counts (median, 330 vs 180/microL; P = .02) and had a trend toward lower CD4 cell counts (median, 40 vs 99/microL; P = .07) than those without histological evidence of arthropod bites. Pruritic papular eruption occurring in HIV-infected individuals may be a reaction to arthropod bites. We hypothesize that this condition reflects an altered and exaggerated immune response to arthropod antigens in a subset of susceptible HIV-infected patients.


The criteria of "inoperability".
In the literature, the term "inoperable" mainly refers to two specific clinical aspects: cancer staging and technical difficulty/impossibility in performing. In light of this clarification, the statement "the patient cannot be anesthetized" has no medical foundation. On the contrary, the physicians have to carefully stratify the perioperative risk and optimize the patients' preoperative clinical status. In order to perform a precise risk stratification, the European Society of Cardiology and the European Society of Anaesthesiology have joined and published the guidelines for the perioperative cardiovascular management of patients scheduled to undergo non-cardiac surgery. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) represents the most complete and accurate prediction tool so far. It includes 21 preoperative factors relating to demographics, comorbidities and procedures able to predict outcomes based on preoperative risk factors such as death, cardiac complications, pneumonia, and acute kidney injury. The present article will address aspects related to common aspects concerning modifiable and non-modifiable that should be addressed in every patient to whom elective surgery has been scheduled.


Metatranscriptomic characterization of six types of forensic samples and its potential application to body fluid/tissue identification: A pilot study.
Microorganisms are potential markers for identifying body fluids (venous and menstrual blood, semen, saliva, and vaginal secretion) and skin tissue in forensic genetics. Existing published studies have mainly focused on investigating microbial DNA by 16 S rRNA gene sequencing or metagenome shotgun sequencing. We rarely find microbial RNA level investigations on common forensic body fluid/tissue. Therefore, the use of metatranscriptomics to characterize common forensic body fluids/tissue has not been explored in detail, and the potential application of metatranscriptomics in forensic science remains unknown. Here, we performed 30 metatranscriptome analyses on six types of common forensic sample from healthy volunteers by massively parallel sequencing. After quality control and host RNA filtering, a total of 345,300 unigenes were assembled from clean reads. Four kingdoms, 137 phyla, 267 classes, 488 orders, 985 families, 2052 genera, and 4690 species were annotated across all samples. Alpha- and beta-diversity and differential analysis were also performed. As a result, the saliva and skin groups demonstrated high alpha diversity (Simpson index), while the venous blood group exhibited the lowest diversity despite a high Chao1 index. Specifically, we discussed potential microorganism contamination and the "core microbiome," which may be of special interest to forensic researchers. In addition, we implemented and evaluated artificial neural network (ANN), random forest (RF), and support vector machine (SVM) models for forensic body fluid/tissue identification (BFID) using genus- and species-level metatranscriptome profiles. The ANN and RF prediction models discriminated six forensic body fluids/tissue, demonstrating that the microbial RNA-based method could be applied to BFID. Unlike metagenomic research, metatranscriptomic analysis can provide information about active microbial communities; thus, it may have greater potential to become a powerful tool in forensic science for microbial-based individual identification. This study represents the first attempt to explore the application potential of metatranscriptome profiles in forensic science. Our findings help deepen our understanding of the microorganism community structure at the RNA level and are beneficial for other forensic applications of metatranscriptomics.


Surgical resection versus liver transplant for patients with hepatocellular carcinoma.
Hepatocellular carcinoma is a major worldwide health problem, involving more than half a million new patients yearly, with a different incidence in different parts of the world. Hepatocellular carcinoma develops in about 80% of cirrhotic patients, and cirrhosis is considered the strongest predisposing factor for it. Surgical resection and liver transplantation are conventional treatment modalities that can offer long-term survival for patients with hepatocellular carcinoma. To assess the benefits and harms of surgical resection compared with those of liver transplantation in patients with hepatocellular carcinoma. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (SCI-EXPANDED) at ISI Web of Science (last search February 2013). We also searched the abstracts from annual meetings of the American Society of Clinical Oncology, the American Association for the Study of Liver Diseases (AASLD), and the European Association for the Study of the Liver (EASL), provided through The Cochrane Hepato-Biliary Group until February 2013. Randomised clinical trials comparing surgical resection and hepatic transplantation. The search strategies were run and two authors individually evaluated whether the retrieved studies fulfilled the inclusion criteria. No randomised clinical trials comparing surgical resection and liver transplantation as the major methods of treating hepatocellular carcinoma were found. There are no randomised clinical trials comparing surgical resection and liver transplantation for hepatocellular carcinoma treatment.


On the detection of peaks and valleys using the local descriptors method.
In this correspondence it is demonstrated that the derivative of the angle with respect to an arbitrary independent parameter cannot in general be used to find peaks and valleys of a shape. It is then shown, using concepts from differential geometry, that curvature corresponds to the derivative of the angle with respect to an independent variable if and only if the angle is deflned as a single variable. It is further shown that peaks and valleys detected using curvature as a criterion are insufficient to completely describe a shape.


Biphasic translocation of Bax to mitochondria.
Using green fluorescent protein-tagged Bax, we demonstrate that Bax is sequestered from the cytosol of cardiomyocytes in two distinct phases following the induction of apoptosis with staurosporine. In the first phase, lasting several hours, Bax removal from the cytosol was relatively small. In the second phase, Bax was very largely removed from the cytosol and sequestered into large aggregates associated with the mitochondria. To test which of the phases involved cytochrome c release, cells were transfected with a red fluorescent protein-cytochrome c fusion. The cytochrome c fusion protein was accumulated by mitochondria of healthy cells and was released by staurosporine in phase 1. When green fluorescent protein-Bax was immunoprecipitated from extracts of cells in phase 1 and phase 2, the voltage-dependent anion channel (mitochondrial outer membrane) and the adenine nucleotide translocase (mitochondrial inner membrane) were also precipitated. These data support a two-phase model of Bax translocation in which Bax targets the mitochondrial intermembrane contact sites and releases cytochrome c in the first phase, and is then packaged into large aggregates on mitochondria in the second.


RNAi analysis of Deformed, proboscipedia and Sex combs reduced in the milkweed bug Oncopeltus fasciatus: novel roles for Hox genes in the hemipteran head.
Insects have evolved a large variety of specialized feeding strategies, with a corresponding variability in mouthpart morphology. We have, however, little understanding of the developmental mechanisms that underlie this diversity. Until recently it was difficult to perform any analysis of gene function outside of the genetic model insects Drosophila melanogaster and Tribolium castaneum. In this paper, we report the use of dsRNA-mediated interference (RNAi) to dissect gene function in the development of the milkweed bug Oncopeltus fasciatus, which has specialized suctorial mouthparts. The Hox genes Deformed (Dfd), proboscipedia (pb) and Sex combs reduced (Scr) have previously been shown to be expressed in the gnathal appendages of this species. Strikingly, the milkweed bug was found to have an unusual expression pattern of pb. Here, by analyzing single and combination RNAi depletions, we find that Dfd, pb and Scr are used in the milkweed bug to specify the identity of the mouthparts. The exact roles of the genes, however, are different from what is known in the two genetic model insects. The maxillary appendages in the bug are determined by the activities of the genes Dfd and Scr, rather than Dfd and pb as in the fly and beetle. The mandibular appendages are specified by Dfd, but their unique morphology in Oncopeltus suggests that Dfd's target genes are different. As in flies and beetles, the labium is specified by the combined activities of pb and Scr, but again, the function of pb appears to be different. Additionally, the regulatory control of pb by the other two genes seems to be different in the bug than in either of the other species. These novelties in Hox function, expression pattern and regulatory relationships may have been important for the evolution of the unique Hemipteran head.


Investigational drugs in early phase development for primary biliary cholangitis.
Introduction: With a large percentage of patients having an incomplete response or intolerance to current FDA approved medications, new therapies for the treatment of primary biliary cholangitis are in great demand. Areas covered: In this review, we assess currently available drugs as well as promising new therapies for the treatment of primary biliary cholangitis. A literature search was performed with the following search terms: 'PBC treatment,' 'PBC therapeutics,' 'PBC clinical trials,' and included original articles, meta-analyses, and systematic reviews from 1 January 1981, to 1 January 2020. ClinicalTrials.gov was accessed for data from ongoing trials. Expert opinion: Targeted drug therapies offer an alternative for patients who are unable to meet their therapeutic goals with either of the two currently approved treatment options. Specifically, new drugs targeting bile-acid regulation, immune-modulation, and fibrogenic pathways are currently in development with multiple agents showing encouraging early results with the ultimate goal of developing therapies that will achieve high rates of biochemical remission, will be well tolerated, and improve symptoms and quality of life in patients with primary biliary cholangitis. Based on a review of the current literature, PPAR agonists appear to be promising agents, along with FGF19 analogs and FXR agonists.


Prooxidant-initiated lipid peroxidation in isolated rat hepatocytes: detection of 4-hydroxynonenal- and malondialdehyde-protein adducts.
Toxicity associated with prooxidant-mediated hepatic lipid peroxidation is postulated to originate from the interaction of the aldehydic end products of lipid peroxidation with cellular constituents. The principal alpha,beta-unsaturated aldehydic products of lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA), are known to modify proteins through covalent alkylation of lysine, histidine, and cysteine amino acid residues. To detect and characterize the formation of 4-HNE- and MDA-adducted proteins during prooxidant-initiated lipid peroxidation, rabbit polyclonal antibodies were raised to 4-HNE-sulfhydryl, dinitrophenylhydrazine (DNPH)-4-HNE-sulfhydryl, and MDA-amine conjugates of keyhole limpet hemocyanin (KLH). Each antiserum displayed high antibody titers to either 4-HNE-metallothionein, DNPH-albumin, or MDA-albumin adducts when measured by ELISA. To study the formation of 4-HNE- and MDA-protein adducts during prooxidant-initiated cellular injury, isolated hepatocytes were exposed to either carbon tetrachloride or iron/ascorbate for 2 h. Indices of hepatocellular oxidative stress (i.e., cell viability and glutathione status) and lipid peroxidation (i.e., formation of 4-HNE, protein carbonyls, and MDA) were monitored continuously. Hepatocellular viability was affected moderately by carbon tetrachloride, while cellular reduced glutathione status was moderately affected by both iron/ascorbate and carbon tetrachloride. Levels of MDA and protein carbonyls increased dramatically with both prooxidants, whereas 4-HNE levels did not change significantly over the time course studied. In addition, hepatocellular proteins were immunoprecipitated with each antiserum, and aldehyde-modified immunopositive proteins were detected by immunoblotting. Prooxidant-induced increases in MDA corresponded with increases in intensity and number of MDA-adducted proteins over the time course studied. A total of 13 MDA-modified proteins (20, 25, 28, 30, 33, 38, 41, 45, 80, 82, 85, 130, and 150 kDa) were detected with the MDA-amine antiserum. Additionally, both iron/ascorbate- and carbon tetrachloride-induced formation of DNPH-derivatizable protein carbonyls corresponded quantitatively with the ability to detect specific proteins (80, 100, 130, and 150 kDa) with the DNPH-4-HNE-cysteine antiserum. Neither CCl4 nor iron/ascorbate elicited changes in 4-HNE or induced the formation of 4-HNE-modified proteins when assessed by immunoprecipitation-immunoblot analysis with the 4-HNE-sulfhydryl antiserum. In all instances detection of aldehyde-modified proteins was not associated with cell death and may be related to the function of these proteins as aldehyde-binding proteins which sequester electrophilic molecules during oxidative liver injury.


Direct reprogramming of urine-derived cells with inducible MyoD for modeling human muscle disease.
Cellular models of muscle disease are taking on increasing importance with the large number of genes and mutations implicated in causing myopathies and the concomitant need to test personalized therapies. Developing cell models relies on having an easily obtained source of cells, and if the cells are not derived from muscle itself, a robust reprogramming process is needed. Fibroblasts are a human cell source that works well for the generation of induced pluripotent stem cells, which can then be differentiated into cardiomyocyte lineages, and with less efficiency, skeletal muscle-like lineages. Alternatively, direct reprogramming with the transcription factor MyoD has been used to generate myotubes from cultured human fibroblasts. Although useful, fibroblasts require a skin biopsy to obtain and this can limit their access, especially from pediatric populations. We now demonstrate that direct reprogramming of urine-derived cells is a highly efficient and reproducible process that can be used to establish human myogenic cells. We show that this method can be applied to urine cells derived from normal individuals as well as those with muscle diseases. Furthermore, we show that urine-derived cells can be edited using CRISPR/Cas9 technology. With progress in understanding the molecular etiology of human muscle diseases, having a readily available, noninvasive source of cells from which to generate muscle-like cells is highly useful.


2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.
The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.


[Post-exposure prophylaxis following exposure to HIV: adaptation to the situation may be indicated].
A woman aged 36 injured herself on a needle that had been used to take an iliac-crest biopsy from an HIV-positive patient and a man aged 34 and a woman aged 35 had sexual contact with their HIV-positive partners during which the condom tore. They were given post-exposure prophylaxis (PEP) which was formulated using medication and virus resistance data from the HIV-positive individual. At 3 and 6 months the patients were all still HIV-negative. After occupational or non-occupational exposure to HIV, PEP is initiated if there is a reasonable risk of transmission of HIV. In The Netherlands a combination of 3 antiretroviral drugs is advised based on demonstrated antiviral effectiveness in the regular treatment of HIV-infections. Frequently a standard PEP-regimen is prescribed. If the source patient has a history of antiretroviral therapy, the virus might be resistant to standard PEP-regimens. In these cases the choice of drugs in the PEP-regimen can be individualised based on the antiretroviral medication history of the source patient and known resistance patterns of the source virus.


Potential Role of Zinc Finger 365 rs10822013 and rs10995190 in Mammographic Density, Sporadic Breast Cancer Risk, and Prognosis.
Despite suggesting many genetic risk markers as the outcome of Genome-wide association studies (GWAS) for breast cancer, replicating the results in different populations has remained the main issue. In this regard, this study assessed the association of two variations in Zinc Finger 365 (ZNF365) in an Iranian population. In a case-control study conducted at Mashhad University of Medical Sciences, Mashhad, Iran, between 2017 and 2020, ZNF365-rs10822013 and rs10995190 were genotyped using Allele-Specific PCR (AS-PCR). Breast density was assessed using mammography images. PHASE software module version 2 and SPSS version 16.0 were used for haplotype and statistical analyses. Quantitative and qualitative variables were compared between groups using independent t tests and Chi square tests, respectively. Binary logistic regression analysis was performed to calculate odds ratios. Multivariate analysis was then undertaken for the baseline variables, with a P<0.05 in the univariate analysis. The survival analysis was performed using the Kaplan-Meier method and the log-rank test. In this survey, 732 females, including 342 breast cancer patients and 390 healthy subjects, were enrolled. rs10822013-T allele (P=0.014), rs10995190-G allele (P=0.003), and TG haplotype (P=0.002) were significantly associated with the increased risk of breast cancer. Moreover, rs10995190-GG genotype (P=0.042) and C-G haplotype (P=0.019) revealed a significant association with better overall survival. However, considered polymorphisms and their haplotypes indicated no association with breast density and clinical features of breast cancer. ZNF365 variants might be a potential risk marker of breast cancer in the Iranian population. The interaction between alleles in haplotypes may modulate the amount of the risk conferred by these variants. Further studies on different ethnic groups can validate these results.


Lymphocyte differentiation and major histocompatibility complex antigen expression in the embryonic thymus.
During embryogenesis, stem cells migrate from the bloodstream into the thymic rudiment where they proliferate and differentiate into T lymphocytes. The epithelial cells of the thymic stroma may influence these processes by providing hormonal and/or contact stimuli to the developing lymphoblasts. Recently, it has been shown that T cells 'learn' to recognise the major histocompatability complex (MHC) antigens during thymic lymphopoiesis and become MHC-restricted. Their subsequent response to other antigens can only occur in the context of MHC antigens of the haplotype encountered in the thymus. Little is known, however, of antigen expression on the thymic stroma which may provide the reference framework on which this MHC restriction is based. In this study we use monoclonal antibodies to show that antigens of the K and I regions of the MHC are detectable on cells of the embryonic mouse thymic stroma from around the 14th day of gestation, just when lymphocyte differentiation is commencing. Furthermore, I-region antigen (Ia antigen) expression is probably limited to thymic epithelium at this stage of gestation and we have not detected Ia on other epithelial tissues of the pharyngeal complex. This pattern of expression is consistent with a role for the thymic stroma in MHC restriction, perhaps by the selection of lymphoid cells for survival on the basis of their recognition of stromal MHC determinants.


Adult sex ratio and social status predict mating and parenting strategies in Northern Ireland.
Evidence from animal species indicates that a male-biased adult sex ratio (ASR) can lead to higher levels of male parental investment and that there is heterogeneity in behavioural responses to mate scarcity depending on mate value. In humans, however, there is little consistent evidence of the effect of the ASR on pair-bond stability and parental investment and even less of how it varies by an individual's mate value. In this paper we use detailed census data from Northern Ireland to test the association between the ASR and pair-bond stability and parental investment by social status (education and social class) as a proxy for mate value. We find evidence that female, but not male, cohabitation is associated with the ASR. In female-biased areas women with low education are less likely to be in a stable pair-bond than highly educated women, but in male-biased areas women with the lowest education are as likely to be in a stable pair-bond as their most highly educated peers. For both sexes risk of separation is greater at female-biased sex ratios. Lastly, our data show a weak relationship between parental investment and the ASR that depends on social class. We discuss these results in the light of recent reformulations of parental investment theory.This article is part of the themed issue 'Adult sex ratios and reproductive decisions: a critical re-examination of sex differences in human and animal societies'.


Saccharomyces cerevisiae additions normalized hemocyte differential genes expression and regulated crayfish (Procambarus clarkii) oxidative damage under cadmium stress.
Because China produces the most crayfish in the world, safe solutions must be improved to mitigate the risks of ongoing heavy metal stressors accumulation. This study aimed to use Saccharomyces cerevisiae as a bioremediation agent to counteract the harmful effect of cadmium (Cd) on crayfish (Procambarus clarkia). Our study used three concentrations of S. cerevisiae on crayfish feed to assess their Cd toxicity remediation effect by measuring total antioxidant capacity (TAC) and the biomarkers related to oxidative stress like malondialdehyde (MDA), protein carbonyl derivates (PCO), and DNA-protein crosslink (DPC). A graphite furnace atomic absorption spectroscopy device was used to determine Cd contents in crayfish. Furthermore, the mRNA expression levels of lysozyme (LSZ), metallothionein (MT), and prophenoloxidase (proPO) were evaluated before and following the addition of S. cerevisiae. The results indicated that S. cerevisae at 5% supplemented in fundamental feed exhibited the best removal effect, and Cd removal rates at days 4th, 8th, 12th, and 21st were 12, 19, 29.7, and 66.45%, respectively, which were significantly higher than the basal diet of crayfish. The addition of S. cerevisiae increased TAC levels. On the other hand, it decreased MDA, PCO, and DPC, which had risen due to Cd exposure. Furthermore, it increased the expression of proPO, which was reduced by Cd exposure, and decreased the expression of LSZ and MT, acting in the opposite direction of Cd exposure alone. These findings demonstrated that feeding S. cerevisiae effectively reduces the Cd from crayfish and could be used to develop Cd-free crayfish-based foods.


Early B-cell development and B-cell maturation are impaired in patients with active hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and multiorgan dysfunction. Infections, including the reactivation of viruses, contribute to significant disease mortality in HLH. Although T-cell and natural killer cell-driven immune activation and dysregulation are well described, limited data exist on the status of B-cell compartment and humoral immune function in HLH. We noted marked suppression of early B-cell development in patients with active HLH. In vitro B-cell differentiation studies after exposure to HLH-defining cytokines, such as interferon gamma (IFN-γ) and tumor necrosis factor, recapitulated B-cell development arrest. Messenger RNA sequencing of human CD34+ cells exposed to IFN-γ demonstrated changes in genes and pathways affecting B-cell development and maturation. In addition, patients with active HLH exhibited a marked decrease in class-switched memory B (CSMB) cells and a decrease in bone marrow plasmablast/plasma cell compartments. The decrease in CSMB cells was associated with a decrease in circulating T follicular helper (cTfh) cells. Finally, lymph node and spleen evaluation in a patient with HLH revealed absent germinal center formation and hemophagocytosis with associated lymphopenia. Reassuringly, the frequency of CSMB and cTfh improved with the control of T-cell activation. Taken together, in patients with active HLH, these changes in B cells may affect the humoral immune response; however, further immune studies are needed to determine its clinical significance.


Moral distress and professional freedom of speech among doctors.
Previous studies indicate that Norwegian doctors experience distress in their encounter with differing and partly contradictory ideals, such as the obligation to criticise unethical and inappropriate practices. The objective of this study was to investigate the perception of moral distress and professional freedom of speech among Norwegian doctors as of today, as well as identify changes that have occurred since the previous study undertaken in 2004. A total of 1,522 economically active doctors received a questionnaire listing various statements describing the perception of moral distress and professional freedom of speech. The responses were compared to responses to the 2004 study. Altogether 67% of the doctors responded to the questionnaire. The proportion who reported «fairly strong» or «strong» moral distress varied from 24% to 70% among the different statements. On the whole, the «rank and file» hospital doctors reported the highest degree of moral distress. Nevertheless, a decrease in the scores for moral distress could be observed from 2004 to 2010. During the same period, the perception of professional freedom of speech increased slightly. A reduced level of distress associated with ethical conflicts in working life may be due to improved methods for handling distressing situations, or because the consequences of the health services reorganisations are perceived as less threatening now than in 2004, immediately after the introduction of the hospital reform. However, the perceived lower distress level may also be due to professional and ethical resignation. These findings should be followed up by a qualitative study.


Calcium regulation of the contractile state of isolated mammalian fibroblast cytoplasm.
Calcium-dependent contractions have been induced in fresh, naked cytoplasm of L-929 fibroblasts using physiological solutions (rigor, relaxing and contracting) similar to those designed to control the contractile state of vertebrate striated muscle. Free access of solutions to the cytoplasm was achieved by popping and stripping the plasma membrane from cells using 7-10 strokes of a Dounce homogenizer. Contracting solution (free Ca2+ 7 X 10(-5) M; with added MgATP) applied locally from a micropipette to cells popped in rigor (free Ca2+ less than 10(-8) M) or relaxing (free Ca2+ less than 10(-8) M; with added MgATP) solutions induced symmetrical contractions of unstretched cytoplasm and directional shortening of stretched cytoplasm. The contractions produced 12-18% shortenings and were complete in 1-3 s. The cytoplasm could be cycled repeatedly through the contracted state from the relaxed state. Exogenous MgATP was required for the Ca2+-dependent contractions. At low free Ca2+ concentrations (less than 10(-8) M), MgATP had a marked plasticizing effect on the cytoplasm. Thus cytoplasm prepared in relaxing solution was less cohesive and more easily deformed than cytoplasm prepared in rigor solution. When induced to contract, relaxed cytoplasm showed a loss of plasticity. Using this criterion, the threshold concentration of free Ca2+ for contraction was determined to lie between 7 X 10(-8) M and 5 X 10(-7) M.