Assessment of chromium biostabilization in contaminated soils using standard leaching and sequential extraction techniques.
The iron reducing microorganism Desulfuromonas palmitatis was evaluated as potential biostabilization agent for the remediation of chromate contaminated soils. D. palmitatis were used for the treatment of soil samples artificially contaminated with Cr(VI) at two levels, i.e. 200 and 500 mg kg(-1). The efficiency of the treatment was evaluated by applying several standard extraction techniques on the soil samples before and after treatment, such as the EN12457 standard leaching test, the US EPA 3060A alkaline digestion method and the BCR sequential extraction procedure. The water soluble chromium as evaluated with the EN leaching test, was found to decrease after the biostabilization treatment from 13 to less than 0.5 mg kg(-1) and from 120 to 5.6 mg kg(-1) for the soil samples contaminated with 200 and 500 mg Cr(VI) per kg soil respectively. The BCR sequential extraction scheme, although not providing accurate estimates about the initial chromium speciation in contaminated soils, proved to be a useful tool for monitoring the relative changes in element partitioning, as a consequence of the stabilization treatment. After bioreduction, the percentage of chromium retained in the two least soluble BCR fractions, i.e. the "oxidizable" and "residual" fractions, increased from 54 and 73% to more than 96% in both soils.


Effect of 8-anilino-1-naphthalene sulfonic acid (ANS) on the interaction between thyroid hormone and anti-thyroid hormone antibodies.
Effect of 8-anilino-1-naphthalene sulfonic acid (ANS) on the interaction between thyroid hormone and anti-thyroid hormone antibodies was examined. Addition of 5.1 x 10(6) or 6.3 x 10(6) molar excess of ANS, respectively, enhanced the binding of 125I-T3 or 125I-T4 to their respective autoantibodies. However, further increase in ANS concentration resulted in a decrease in binding. These results suggest that the optimum concentration of ANS for the detection of anti-thyroid hormone antibodies is 5 approximately 6 x 10(6) molar excess of ANS to 125I-T3 or 125I-T4. On the other hand, addition of 10(4) molar excess of ANS concentration decreased the binding of 125I-insulin to anti-insulin antibodies. It was therefore suggested that the effect of ANS could be a nonspecific one and likely due to its negative charge.


Are digestive characteristics important contributors to the profitability of prey? : A study of diet selection in the fifteen-spined stickleback, Spinachia spinachia (L.).
In the field, Spinachia fed on four types of prey; copepods, isopods, mysids and amphipods. As fish size increased, mysids gradually succeeded amphipods as the most important food type in the diet. Prey dimensions and morphometry of the fish's mouth most accurately predicted capture efficiency for amphipods, whereas for mysids capture efficiency was determined by the prey's escape response and the fish's fast-start capability. Responses to model prey revealed the ability of fish to differentiate among contrasting prey characteristics, resulting in the adoption of appropriate predatory tactics. Amphipods were associated with a shorter gut evacuation time than mysids, although approximately equal proportions of energy were absorbed from each. Similar rations of mysids and amphipods were required to satiate fish. The lower energy content per unit dry mass of amphipods was off set by their lower water content. From pre-digestive behaviour, we predicted that mysids were more profitable than amphipods, and this was reflected in the fish's choice. Conversely, incorporating the net rate of energy uptake by the gut led us to predict that amphipods were more profitable. Although physiological constraints clearly influence the net rate of energy uptake, it appears that dietary preferences are based on pre-digestive predatory behaviour and hence on time minimisation.


COVID-19 multisystem inflammatory syndrome in three teenagers with confirmed SARS-CoV-2 infection.
Coronavirus disease 2019 (COVID-19) is generally a relatively mild illness in children. An emerging disease entity coined as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) has been reported recently, but is very rare and only affects a very small minority of children. Here we describe the clinical presentations and outcomes of three teenagers with serologically-confirmed SARS-CoV-2 infection admitted to a pediatric intensive care unit for PIMS-TS. Although their initial presentations were very similar, their COVID-19-related disease varied in severity.


A-site compositional effects in Ga-doped hollandite materials of the form BaxCsyGa2x+yTi8-2x-yO16: implications for Cs immobilization in crystalline ceramic waste forms.
The hollandite structure is a promising crystalline host for Cs immobilization. A series of Ga-doped hollandite BaxCsyGa2x+yTi8-2x-yO16 (x = 0, 0.667, 1.04, 1.33; y = 1.33, 0.667, 0.24, 0) was synthesized through a solid oxide reaction method resulting in a tetragonal hollandite structure (space group I4/m). The lattice parameter associated with the tunnel dimension was found to increases as Cs substitution in the tunnel increased. A direct investigation of cation mobility in tunnels using electrochemical impedance spectroscopy was conducted to evaluate the ability of the hollandite structure to immobilize cations over a wide compositional range. Hollandite with the largest tunnel size and highest aspect ratio grain morphology resulting in rod-like microstructural features exhibited the highest ionic conductivity. The results indicate that grain size and optimized Cs stoichiometry control cation motion and by extension, the propensity for Cs release from hollandite.


Family Caregiving: A Vision for the Future.
The authors of this review both served on the National Academy of Science, Engineering, and Medicine Committee that produced the report, "Caring for an Aging America". In this commentary we summarize key findings and recommendations most relevant to clinicians and researchers in geriatric psychiatry and related disciplines. The report notes the growing prevalence of family caregiving in the United States, especially those caring for high-need patients with multiple chronic conditions, disability, and/or cognitive impairment. To support the capacity of family caregivers to perform critical caregiving tasks, the report recommends a major shift in healthcare policy toward collaborative partnerships among patients, their defined family, and providers of care. Optimizing the role of family caregivers will minimally require systematic attention to the identification, assessment, and support of family caregivers throughout the care delivery process. Research is needed to develop the tools and protocols to efficiently assess caregivers, and identify ways in which they can be integrated into existing clinical practices. We also need research to identify how to best implement, maintain, and evaluate caregiver support programs within clinical and community settings. The Centers for Medicare and Medicaid Services should be charged with developing, testing, and implementing provider payment reforms that motivate providers to engage and support family caregivers. Payment reforms should include clearly articulated performance standards that hold providers accountable for caregiver engagement, training, and support by explicitly including caregiver outcomes in quality measures.


Akt-mediated cardiomyocyte survival pathways are compromised by G alpha q-induced phosphoinositide 4,5-bisphosphate depletion.
Expression of the wild type alpha subunit of Gq (GqWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active G alpha q subunit (GqQ209L) induces apoptosis. Akt phosphorylation increases with GqWT expression but is markedly attenuated in cardiomyocytes expressing GqQ209L or in those expressing GqWT and treated with agonist. A membrane-targeted Akt rescues GqQ209L-expressing cardiomyocytes from apoptotic cell death. In contrast, leukemia inhibitory factor fails to activate Akt or promote cell survival in these cells. Association of Akt and PDK-1 with the membrane is also diminished in GqQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the primary regulator of Akt, increases significantly in GqWT-expressing cells but not in cardiomyocytes expressing GqQ209L. Levels of phosphatidylinositol 4,5-bisphosphate (PIP2), the immediate precursor of PIP3, are also markedly lower in GqQ209L-expressing compared to control cells. Expression of a GqQ209L mutant that has diminished capacity to activate phospholipase C does not decrease PIP2 or Akt or induce apoptosis. In transgenic mice with cardiac G alpha q overexpression, heart failure and increased cardiomyocyte apoptosis develop during the peripartal period. Akt phosphorylation and PIP2 levels decrease concomitantly. Our findings suggest that an Akt-mediated cell survival pathway is compromised by the diminished availability of PIP2 elicited by pathological levels of Gq activity.


Degradation of bifenthrin and pirimiphos-methyl residues in stored wheat grains (Triticum aestivum L.) by ozonation.
Pesticide insecticides are used on wheat grains in storage units but their efficiency is hindered by persistent residues in the grains. Therefore, this study aims to evaluate the effectiveness of ozone (O3) gas treatment on the degradation of residual bifenthrin and pirimiphos-methyl insecticides commonly used in storage wheat grains, as well as to evaluate degradation of their by-products. The residues of bifenthrin decreased after 180 min of exposure in a concentration of 60 μmol/mol (a 37.5 ± 7.4% reduction) with 20% moisture content and 0.9 water activity. On the other hand, under the same experimental conditions, the pirimiphos-methyl residues significantly decreased in the wheat grains (71.1 ± 8.6%) after 30 min of exposure. After O3 gas treatment, three by-products of pirimiphos-methyl (m/z=306.1) containing different molecular mass to charge ratios (m/z=278.1, 301.1 and 319.2) were identified by LC-MS. O3 is a strong oxidizer that has shown the potential to reduce pesticide residues in stored grain in order to ensure food quality and safety.


267th ENMC International workshop: psychological interventions for improving quality of life in slowly progressive neuromuscular disorders.
This workshop aimed to develop recommendations for psychological interventions to support people living with slowly progressive neuromuscular disorders (NMD). The workshop comprised clinicians, researchers, people living with NMD and their relatives. First, participants considered the key psychological challenges presented by NMD and the impact of NMD on relationships and mental health. Later, several psychological approaches for enhancing well-being in NMD were described. The results of randomised controlled trials of Cognitive Behaviour Therapy and Acceptance and Commitment Therapy for improving fatigue, quality of life, and mood in adults with NMD were examined. Then the group considered ways to adapt therapies for cognitive impairments or neurodevelopmental differences that occur in some NMD, alongside ways to support children and adolescents with NMD and their family members. Based on the evidence from randomised controlled trials, carefully conducted observational studies, and the coherence of these data with the experience of those living with NMD, the group recommends that psychological interventions should be embedded in the routine clinical care offered to people living with NMD.


Bilateral symmetrical lipoma of the buccal fat pad as an incidental finding in a woman with weight gain after tamoxifen: a case report.
Although lipoma is a common benign tumor, it occurs relatively infrequently in the oral and maxillofacial areas, and only 31 cases of lipoma in the buccal fat pad have been reported. Herein, we present an extremely rare case of symmetric lipomas in both buccal fat pads. These masses were incidentally discovered during a facelift procedure in a 50-year-old woman with a 4-year history of tamoxifen use. during which she had gained 10 kg. The patient stated that cheek protrusion had developed concomitantly with weight gain and was exacerbated by an injection lipolysis procedure she had received 1 year previously. This case underscores the importance of paying careful attention to the patient's medication use and surgical history when evaluating suspected cases of lipoma, and sheds light on tamoxifen use and subcutaneous injections of phosphatidylcholine and deoxycholate as potential risk factors for lipoma development.


Efficacy of high zinc biofortified wheat in improvement of micronutrient status, and prevention of morbidity among preschool children and women - a double masked, randomized, controlled trial.
Biofortification of staple food crops with zinc (Zn) can be one of the cost-effective and sustainable strategies to combat zinc deficiency and prevent morbidity among the target population. Agronomic approaches such as application of Zn fertilizers to soil and/or foliar spray seem to be a practical tool for Zn biofortification of wheat. However, there is a need to evaluate its efficacy from randomized controlled trials. This study aimed to evaluate the efficacy of zinc biofortified wheat flour on zinc status and its impact on morbidity among children aged 4-6 years and non-pregnant non lactating woman of child bearing age (WCBA) in Delhi, India. In a community based, double-masked randomized controlled trial, 6005 participants (WCBA and child pairs) were enrolled and randomly allocated to receive either high zinc biofortified wheat flour (HZn, 30 ppm zinc daily) or low zinc biofortified wheat flour (LZn, 20 ppm zinc daily) for 6 months (WCBA @ 360 g/day and children @ 120 g/day). Baseline and endline blood samples were obtained for assessing hematological markers; zinc status and data on compliance and morbidity were collected. Compliance rates were high; ~ 88% of the WCBAs in both the groups consumed 50% or more of recommended amount of biofortfied wheat flour during the follow up. Similarly 86.9% children in HZn and 87.5% in LZn consumed 50% or more of recommended wheat flour intake. There was no significant difference in mean zinc levels between the groups at end study. This observation might be due to a marginal difference in zinc content (10 ppm) between the HZn and LZn wheat flour, and a short intervention period. However a positive impact of bio-fortification on self-reported morbidity was observed. Compared to children in LZn group, children in HZn group had 17% (95% CI: 6 to 31%, p = 0.05) and 40% (95% CI: 16 to 57%; p = 0.0019) reduction in days with pneumonia and vomiting respectively. WCBA in the HZn group also showed a statistically significant 9% fewer days with fever compared to LZn group. Biofortified wheat flour had a good compliance among children and WCBAs. Significant improvement on some of the self-reported morbidity indicators suggests that evaluating longer-term effects of biofortification with higher grain zinc content would be more appropriate. http://ctri.nic.in/Clinicaltrials/ , CTRI/2014/04/004527, Registered April 7, 2014.


Initiation of hamster sperm motility from quiescence: effect of conditions upon flagellation and respiration.
The point within the male reproductive tract where sperm motility originates varies with mammalian species. Premotile sperm from hamster, a species whose sperm are still quiescent in the epididymis, were used here to investigate further the parameters involved in the initiation of sperm motility. Two types of motility were produced: (1) partial, weak flagellation by simple dilution; (2) strong, complete motility by inducers (calcium, cyclic adenosine 3':5'-monophosphate) in the presence of amplifiers (caffeine, spermine). Expansion of initiation conditions to test tube volumes revealed that, at high sperm dilutions, bicarbonate could also induce motility. The respiratory consequences of sperm motility induction were measured. A Large, short-term burst of oxygen consumption occurred at a time paralleling the previously reported shifts in nucleotide levels associated with this event.


Effects of ursolic acid on muscle mass and bone microstructure in rats with casting-induced muscle atrophy.
Recent studies suggest that ursolic acid (UA) is a potential candidate for a resistance exercise mimetic that can increase muscle mass and alleviate the deleterious effect of skeletal muscle atrophy on bone health. However, these studies evaluated the effects of UA on skeletal muscle and bone tissues, and they have not verified whether such effect could occur concurrently on muscle and bone, as is the case with resistance exercise. Thus, the aim of this study was to analyze the effect of UA injection on muscle mass and bone microstructure using an animal model of atrophy to demonstrate the potential of UA as a resistance exercise mimetic. The immobilization (IM) method was used on the left hindlimb of Sprague Dawley (SD) rats for 10 days to induce muscle atrophy, whereas the right hindlimb was used as an internal control (IC). The animal models were divided into two groups, SED (sedentary, n=6) and UA (n=6) to demonstrate the effect of UA on atrophic skeletal muscles. The UA group received a daily intraperitoneal injection of UA (5 mg/kg/day) for 8 weeks. After 10 days of IM, the data collected for the IC were compared with that of IM to determine whether muscle atrophy might occur. Muscle atrophy was induced and bone mineral density (BMD) decreased significantly. The 8-week UA treatment significantly increased the gastrocnemius muscle mass compared to the SED group. In regard to the effect of UA on bones, negative results such as a decrease in BMD, trabecular bone volume fraction, and trabecular number, and an increase in trabecular separation, were observed in the SED group, but no such difference was observed in the UA group. No significant difference was observed in atrophic hindlimbs between SED and UA groups. These results alone are insufficient to suggest that UA is a potential resistance exercise mimetic for atrophic skeletal muscle and weakened bone. However, this study will help determine the potential of UA as a resistance exercise mimetic.


Triterpenes and limonoids of Cedrela: Distribution, biosynthesis, and 1 H and 13 C NMR data.
Cedrela genus, a member of the Meliaceae family, presents both chemical characteristics associated with and those that distinguish it from the rest of its members. The presence of triterpenes and limonoids is the characteristic of the Meliaceae family, but the class and type of these chemical constituents are distinctive for each genus. Cedrela includes cycloartane, ursane, oleanane, tirucallane, butyrospermane, and apotirucallane triterpenes, and its limonoids belongs to six class and nine types, known as class Ia-type havanensines, class Ib-type delevoyin, class II-type gedunin, class IIIb-type andirobin, class IIIg-type mexicanolide, class IVa-type evoludone, class Va-type obacunol, class V-type limonin, and class VIII. Each of these structural arrangements includes specific traits, defined by their biosynthetic origin, which can be established by means of structural elucidation techniques, particularly 1 H and 13 C NMR, which assisted by 2D NMR techniques, allowing to deduce their structures unequivocally. The constant presence of these skeletal arrangements in Cedrela ensures that they are its chemophenetic markers and their recurrence is an important criterion for their identity. This review is a compilation of the occurrence of triterpenes and limonoids in Cedrela genus, detailing their biosynthetic association and collecting and organizing their NMR data, with the purpose of facilitating its location, analysis, and use in the phytochemical study of species from this genus.


Study of the prevalence of the risk of malnutrition in the non-institutionalized population over 65 years old attended in a health center in Barcelona.
To know the prevalence of risk of malnutrition in community-dwelling elderly (defined as aged >65) attended in a Primary Care Center, to find the main factors associated to malnutrition risk and to evaluate the Mini Nutritional Assessment Questionnaire (MNA) MNA Short Form vs. MNA Full Test. Design: Cross-Sectional study. Primary Care Center. 337 participants visited in the Community Care Center. Mini Nutritional Assessment Questionnaire (MNA) was applied; sociodemographic and Health variables were collected as well as functional evaluation tests (Short Portable Mental Status Questionnaire and Lawton & Brody Instrumental Activities of Daily Living Scale). Clinical history information was taken from the Medical Records. Using MNA Full Test (MNA-FT) as the gold standard, sensitivity, specificity and predictive values of MNA Short Form (MNA-SF) were evaluated. prevalence according MNA-FT was 0.6% for malnutrition and 7.7% for malnutrition risk. No gender differences were found. The average age was higher in the population with malnutrition or at risk for malnutrition (p=0.016). Significant association of malnutrition with having carer (p<0.0001) or being more dependent (p<0.0001) was found. MNA-SF showed an acceptable sensitivity (67.9%) and good specificity (92.6%). Compared with other studies this data showed a low prevalence of malnutrition risk in community-living elderly using the MNA test. It is recommended to use the MNA-FT in order to avoid under diagnosing malnutrition with MNA-SF.


Neurogenesis in adult primate neocortex: an evaluation of the evidence.
Reports of continuous genesis and turnover of neurons in the adult primate association neocortex--the site of the highest cognitive functions--have generated great excitement. Here, I review the available evidence, and question the scientific basis of this claim.


Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.
Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αβ subtype (TCRαβ) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.


'Orch OR' is the most complete, and most easily falsifiable theory of consciousness.
The 'Orch OR' theory attributes consciousness to quantum computations in microtubules inside brain neurons. Quantum computers process information as superpositions of multiple possibilities (quantum bits or qubits) which, in Orch OR, are alternative collective dipole oscillations orchestrated ('Orch') by microtubules. These orchestrated oscillations entangle, compute, and terminate ('collapse of the wavefunction') by Penrose objective reduction ('OR'), resulting in sequences of Orch OR moments with orchestrated conscious experience (metaphorically more like music than computation). Each Orch OR event selects microtubule states which govern neuronal functions. Orch OR has broad explanatory power, and is easily falsifiable.


From pharmacogenetics to pharmaco-omics: Milestones and future directions.
The origins of pharmacogenetics date back to the 1950s, when it was established that inter-individual differences in drug response are partially determined by genetic factors. Since then, pharmacogenetics has grown into its own field, motivated by the translation of identified gene-drug interactions into therapeutic applications. Despite numerous challenges ahead, our understanding of the human pharmacogenetic landscape has greatly improved thanks to the integration of tools originating from disciplines as diverse as biochemistry, molecular biology, statistics, and computer sciences. In this review, we discuss past, present, and future developments of pharmacogenetics methodology, focusing on three milestones: how early research established the genetic basis of drug responses, how technological progress made it possible to assess the full extent of pharmacological variants, and how multi-dimensional omics datasets can improve the identification, functional validation, and mechanistic understanding of the interplay between genes and drugs. We outline novel strategies to repurpose and integrate molecular and clinical data originating from biobanks to gain insights analogous to those obtained from randomized controlled trials. Emphasizing the importance of increased diversity, we envision future directions for the field that should pave the way to the clinical implementation of pharmacogenetics.


ECM signalling: orchestrating cell behaviour and misbehaviour.
The extracellular matrix (ECM) provides signalling cues that regulate cell behaviour and orchestrate functions of cells in tissue formation and homeostasis. The composition of the ECM, its three-dimensional organization and proteolytic remodelling are major determinants of the microenvironmental signalling context that controls cell shape, motility, growth, survival and differentiation. In recent years, the importance of ECM signalling has been underscored by the evidence that misregulation of cell-ECM interactions can contribute to many diseases, including developmental, immune, haemostasis, degenerative and malignant disorders. This review discusses recent insights into the regulatory functions of the ECM and their role in disease, focusing on cancer as a paradigm.


AtTHIC, a gene involved in thiamine biosynthesis in Arabidopsis thaliana.
Thiamine (vitamin B(1)) is an essential compound for organisms. It contains a pyrimidine ring structure and a thiazole ring structure. These two moieties of thiamine are synthesized independently and then coupled together. Here we report the molecular characterization of AtTHIC, which is involved in thiamine biosynthesis in Arabidopsis. AtTHIC is similar to Escherichia coli ThiC, which is involved in pyrimidine biosynthesis in prokaryotes. Heterologous expression of AtTHIC could functionally complement the thiC knock-out mutant of E. coli. Downregulation of AtTHIC expression by T-DNA insertion at its promoter region resulted in a drastic reduction of thiamine content in plants and the knock-down mutant thic1 showed albino (white leaves) and lethal phenotypes under the normal culture conditions. The thic1 mutant could be rescued by supplementation of thiamine and its defect functions could be complemented by expression of AtTHIC cDNA. Transient expression analysis revealed that the AtTHIC protein targets plastids and chloroplasts. AtTHIC was strongly expressed in leaves, flowers and siliques and the transcription of AtTHIC was downregulated by extrinsic thiamine. In conclusion, AtTHIC is a gene involved in pyrimidine synthesis in the thiamine biosynthesis pathway of Arabidopsis, and our results provide some new clues for elucidating the pathway of thiamine biosynthesis in plants.


Response to radiotherapy of head and neck tumors in AIDS patients.
Initial manifestations of AIDS in the head and neck area occur frequently. In fact, up to 40 percent of patients may have involvement of the head and neck. The most common malignancies are Kaposi's sarcoma and non-Hodgkin's lymphoma. Since AIDS-related malignancies are a relatively new problem for radiation oncologists, optimal therapy for these neoplasms is unknown. A retrospective review of AIDS patients treated with radiotherapy has been performed. Fourteen patients were identified. Of these, five were treated for head and neck tumors (four for Kaposi's sarcoma and one for non-Hodgkin's lymphoma). Epidemic Kaposi's sarcoma, as well as non-Hodgkin's lymphoma, were seen to be as radioresponsive as the classical forms, but local control was difficult to achieve. Kaposi's sarcoma tended to recur marginally and within the field. Nonetheless, we believe radiotherapy can offer significant palliation for AIDS patients with head and neck tumors. It is of utmost importance that the head and neck surgeon must be acutely aware of the common patterns of presentation of this disease.


Proliferative responses of HT29 and Caco2 human colorectal cancer cells to a panel of lectins.
Altered lectin binding is common in malignant and premalignant epithelia, but its functional significance is unclear. This study examined the proliferative effects of four lectins on HT29 and Caco2 colon cancer cells. Proliferation was assessed in log growth and confluent culture by thymidine incorporation and cell counts. Peanut agglutinin (PNA) binding was characterized by Scatchard analysis and electrophoresis of lectin affinity-purified cell surface-radiolabeled preparations. PNA, 5 micrograms/mL, increased thymidine incorporation in HT29 but had no effect on Caco2. Wheat germ agglutinin and concanavalin A stimulated proliferation slightly at 0.5-1.0 microgram/mL but were inhibitory at higher concentrations. Ulex europaeus 1 had no significant effect. Similar results were obtained when proliferation was assessed by cell counts and with confluent cell cultures. Scatchard analysis with both cell lines showed multisite best fit models with similar binding affinities. Three PNA-binding glycoproteins were identified in both cell lines, but two were of lower molecular weight in HT29 than in Caco2. Membrane preparations from a resected colorectal cancer contained a 30-kilodalton PNA-binding glycoprotein similar to that in HT29 cells. Lectins are plentiful in the normal diet and often escape digestion. This study suggests that altered expression of lectin receptors, particularly the upregulation of PNA receptor seen in colonic malignancy and hyperplasia, may have an important role in growth modulation.


Diastereoselective construction of quaternary carbons directed via macrocyclic ring conformation: formal synthesis of (-)-mesembrine.
In this article, we report a highly diastereoselective new method for the generation of quaternary carbon centers through an anionic oxy-Cope/alkylation sequence where the diastereoselectivity is induced by the conformation of a macrocyclic tetrasubstituted enolate. The use of our methodology culminated in the formal total synthesis of (-)-mesembrine (34) in 11 steps from known starting materials.


Microbicides finally gel, securing spotlight at the International AIDS Conference.
The efficacy of a microbicide candidate was the definitive bright spot at this year's conference, while the lingering economic slowdown and its impact on HIV/AIDS funding were dark clouds on the horizon


Decreased mechanotransduction prevents nuclear collapse in a Caenorhabditis elegans laminopathy.
The function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the nuclear envelope and mediates nuclear mechanotransduction, the process by which mechanical signals and forces are transmitted across the nuclear envelope. In turn, the AAA+ ATPase torsinA is thought to regulate force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia, though the extent to which endogenous mechanical stresses contribute to these pathologies is unclear. Here, we use the Caenorhabditis elegans germline as a model to investigate mechanisms that maintain nuclear integrity as germ cell nuclei progress through meiotic development and migrate for gametogenesis-processes that require LINC complex function. We report that decreasing the function of the C. elegans torsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog. We show that decreasing OOC-5/torsinA activity prevents nuclear collapse in lamin mutants by disrupting the function of the LINC complex. At a mechanistic level, OOC-5/torsinA promotes the assembly or maintenance of the lamin-associated LINC complex and this activity is also important for interphase nuclear pore complex insertion into growing germline nuclei. These results demonstrate that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina. Thus, the torsinA-LINC complex nexus might comprise a therapeutic target for certain laminopathies by preventing damage from endogenous cellular forces.


Variations in gestational length and preterm delivery by race, ethnicity and migration.
Preterm delivery rates within industrialized countries have been reported to vary according to the parents' race, ethnicity and migrant status; however, such disparities are poorly understood. In this paper, the available evidence and potential clinical significance of racial/ethnic and migrant disparities in gestational length and preterm delivery are assessed alongside potential explanatory factors. Although measurement bias in gestational length has the potential to inflate disparities, there is a consistently higher risk of preterm birth among some racial/ethnic groups. These differences most likely reflect lasting socio-economic disadvantage and discrimination rather than genetic mechanisms. The effect of migrant status is less conclusive due to heterogeneity of populations and the healthy migrant effect; however, environmental influences in the receiving country are implicated in driving increases of overall preterm rates. When assessing preterm delivery rates across ethnic and migrant groups, the use of standardized, ultrasound-based pregnancy dating methods is crucial to minimize bias. Current evidence does not justify the provision of a different clinical care approach to minority or immigrant women solely based on their race, ethnicity or country of origin; however, these labels may serve as flags for further inquiry on individual risk factors and a detailed obstetric history.


Effects of CYP-Induced Cystitis on Growth Factors and Associated Receptor Expression in Micturition Pathways in Mice with Chronic Overexpression of NGF in Urothelium.
We have determined if cyclophosphamide (CYP)-induced cystitis produces additional changes in growth factor/receptors expression in the urinary bladder (urothelium, detrusor) and lumbosacral (L6-S1) dorsal root ganglia (DRG) in a transgenic mouse model with chronic urothelial overexpression of NGF (NGF-OE). Functionally, NGF-OE mice treated with CYP exhibit significant increases in voiding frequency above that observed in control NGF-OE mice (no CYP). Quantitative PCR was used to determine NGF, BDNF, VEGF, and receptors (TrkA, TrkB, p75(NTR)) transcripts expression in tissues from NGF-OE and wild-type (WT) mice with CYP-induced cystitis of varying duration (4 h, 48 h, 8 days). In urothelium of control NGF-OE mice, NGF mRNA was significantly (p ≤ 0.001) increased. Urothelial expression of NGF mRNA in NGF-OE mice treated with CYP (4 h, 48 h, 8 days) was not further increased but maintained with all durations of CYP treatment evaluated. In contrast, CYP-induced cystitis (4 h, 48 h, 8 days) in NGF-OE mice demonstrated significant (p ≤ 0.05) regulation in BDNF, VEGF, TrkA, TrkB, and P75(NTR) mRNA in urothelium and detrusor smooth muscle. Similarly, CYP-induced cystitis (4 h, 48 h, 8 days) in NGF-OE mice resulted in significant (p ≤ 0.05), differential changes in transcript expression for NGF, BDNF, and receptors (TrkA, TrkB, p75(NTR)) in S1 DRG that was dependent on the duration-of CYP-induced cystitis. In general, NGF, BDNF, TrkA, and TrkB protein content in the urinary bladder increased in WT and NGF-OE mice with CYP-induced cystitis (4 h). Changes in NGF, TrkA and TrkB expression in the urinary bladder were significantly (p ≤ 0.05) greater in NGF-OE mice with CYP-induced cystitis (4 h) compared to WT mice with cystitis (4 h). However, the magnitude of change between WT and NGF-OE mice was only significantly (p ≤ 0.05) different for TrkB expression in urinary bladder of NGF-OE mice treated with CYP. These studies are consistent with target-derived NGF and other inflammatory mediators affecting neurochemical plasticity with potential contributions to reflex function of micturition pathways.


Prevalence of xerophthalmia in relation to nutrition and general health in preschool-age children in three regions of Tanzania.
Integrated nutrition/health surveys were carried out in Mbeya, Iringa and Kagera Regions in Tanzania in which a total of 12,880 children were examined for the presence of xerophthalmia. Xerophthalmia was found to be a problem of public health significance in two of the three regions surveyed where the prevalence of active corneal xerophthalmic lesions was above the criteria set by WHO. Because of clustering of the children with Bitot's spots, corneal xerosis/ulceration and corneal scarring, only certain villages or groups of villages could be regarded as areas where xerophthalmia is a problem. The results of the ophthalmological examinations are discussed in relation to the nutritional status of the children as measured by anthropometric indices, serum levels of retinol-binding protein and prealbumin, haematological parameters, and vaccination status.


Comparative phylotranscriptomics reveals putative sex differentiating genes across eight diverse bivalve species.
Mollusks, especially bivalves, exhibit a great diversity of sex determining mechanisms, including both genetic and environmental sex determination. Some bivalve species can be gonochoristic (separate sexes), while others are hermaphroditic (sequential or simultaneous). Several models have been proposed for specific bivalve species, utilizing information gained from gene expression data, as well as limited RAD-seq data (e.g., from Crassostrea gigas). However, these mechanisms are not as well studied as those in model organisms (e.g., Mus musculus, Drosophila melanogaster, Caenorhabditis elegans) and many genes involved in sex differentiation are not well characterized. We used phylotranscriptomics to better understand which possible sex differentiating genes are in bivalves and how these genes relate to similar genes in diverse phyla. We collected RNAseq data from eight phylogenetically diverse bivalve species: Argopecten irradians, Ensis directus, Geukensia demissa, Macoma tenta, Mercenaria mercenaria, Mya arenaria, Mytilus edulis, and Solemya velum. Using these data, we assembled representative transcriptomes for each species. We then searched for candidate sex differentiating genes using BLAST and confirmed the identity of nine genes using phylogenetics analyses from nine phyla. To increase the confidence of identification, we included ten bivalve genomes in our analyses. From the analysis of doublesex and mab-3 related transcription factor (DMRT) genes, we confirmed the identify of a Mollusk-specific sex determining DMRT gene: DMRT1L. Based on gene expression data from M. edulis and previous research, DMRT1L and FoxL2 are key genes for male and female development, respectively.


Taxonomic and genomic characterization of Sporosarcina cyprini sp. nov., moderately tolerant of Cr+6 and Cd+2 isolated from the gut of invasive fish Cyprinus carpio var. communis (Linn., 1758).
A Gram-stain-positive, motile, and rod-shaped bacterium, designated as strain MB25T, was isolated from the gut of Cyprinus carpio from the highly polluted river Yamuna, India. Phylogenetic analysis based on 16S rRNA gene sequence revealed that strain MB25T belonged to the genus Sporosarcina, sharing the highest sequence similarity with S. luteola Y1T (98.98%) and S. koreensis S-K12T (98.91%). Digital DNA-DNA hybridization and average nucleotide identity values of strain MB25T with strain Y1T and S-K12T were 18.9, 77.69, and 18.2, 76.80 respectively. Genome analysis of strain MB25T revealed its biotechnological properties such as tolerance to potent heavy metals, genes for the production of carbohydrate-active enzymes, antimicrobial compounds, and also degradation of aromatic compounds. The G + C content of strain MB25T genome was 45%. Growth observed at 10-40 °C (optimum, 28-30 °C), pH 6.0-8.5 (optimum pH 7.5-8.0); NaCl concentrations up to 6.0% (w/v). The dominant respiratory quinone was MK-7, cell wall peptidoglycan is of the A-4 type containing amino acids Lys-Glu and the major fatty acids are anteiso-C11:0 and iso-C15: 0. The major polar lipids of strain MB25T are diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. On the basis of phenotypic, chemotaxonomic, phylogenetic, and phylogenomic data, strain MB25T represents a novel species of the genus Sporosarcina, for which the name Sporosarcina cyprini sp. nov. is proposed. The type strain is MB25T (= MCC 4366 T = JCM 34521 T = CCM 9113 T).


Loss of glucocorticoid receptors in B16BL6 murine melanoma associated with serial transplantation, metastatic selection and altered growth properties.
Glucocorticoid cytosolic receptors (GR) have been studied in both a primary and in a lung selected (metastatic) series of a B16BL6 murine melanoma. In the primary series tumour there was an initial increase in GR content from 40 to 95.6 fM mg-1 protein. GR levels then fell over the next 11 transplant generations to 10 fM mg-1 protein. In the metastatic series, in the course of six transplant generations, GR content of 73 fM mg-1 protein fell to below detectable levels, i.e. less than 5 fM mg-1 protein. Both the metastatic and primary series tumours showed a significant decrease in doubling times with increasing transplant generation. We therefore suggest that in the primary series tumours, after an initial phase of adaptation from tissue culture to in vivo conditions, the increased growth of the tumours is independent of the loss of hormonal control caused by a reduction in the glucocorticoid receptor content associated with serial transplantation. In the metastatically selected series of tumours, there appears to be a selective growth pressure brought about by the cyclic transplantation procedure which was also accompanied by an increase in metastatic ability.


Tumor-derived proliferative CTCs and CTC clusters predict aggressiveness and early recurrence in hepatocellular carcinoma patients.
Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC). We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors. Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha-fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P < 0.0001, P = 0.0017, and P = 0.0157). A nomogram model based on these risk factors showed a considerable prediction ability for HCC recurrence (area under the curve = 0.947). PCP (training: log-rank P < 0.0001; hazard ratio [HR] 30.13, 95% confidence interval [CI] = 11.12-81.62; validation: log-rank P < 0.0001; HR 25.73, 95% CI = 5.28-106.60) and CTC clusters (training: log-rank P < 0.0001; HR 17.34, 95% CI = 7.46-40.30; validation: log-rank P < 0.0001; HR 9.92, 95% CI = 2.55-38.58) were more significantly correlated with worse recurrence-free survival than CTC number (training: log-rank P < 0.0001; HR 14.93, 95% CI = 4.48-49.78; validation: log-rank P = 0.0007; HR 9.03, 95% CI = 2.53-32.24). PCP and CTC clusters may predict HCC recurrence and improve the performance of the serum biomarker AFP.


Characterization of preferential flow in soils near Zarqa river (Jordan) using in situ tension infiltrometer measurements.
The Zarqa River (ZR) is located in the northern part of Jordan and supplies King Talal Dam (KTD). The streamflow that discharges into KTD is composed of treated wastewater from the Khirbat Es-Samra water treatment plant (KTP) and runoff generated during the winter season. Thus, during the summer, the streamflow of the ZR is dominated by effluent from the KTP. Due to the severe scarcity of water in Jordan, a portion of the streamflow is utilized for irrigated agriculture in the ZR valley, located between the KTP and KTD. The groundwater in the vicinity of the ZR is vulnerable to contamination-a risk that may be exacerbated by the potential occurrence of preferential flow (PF). Therefore, the PF in the soils near the ZR should be carefully considered. The macropore flux fraction (Q macro) and macroscopic capillary length (λ c ) were determined from in situ measurements using a tension infiltrometer equipped with an infiltration disc with a diameter of 20 cm. The macropore was defined as the pore size that drains at a tension of less than --3- cm. The λ c less than 80 mm was considered to be an indication of PF. The measurements were taken at 69 sites along the ZR between the KTP and KTD. At each measurement site, the soil organic matter content (OM) and soil texture were determined using a composite soil sample obtained by excavating the soil beneath the infiltration disc to a depth of 10 cm. The data was split into two groups: the matrix flow group (MF), which includes data associated with λ c > 80 mm, and the PF group, which includes data associated with λ c < 80 mm. The Q macro values of 0.67 and 0.57, respectively, for PF and MF were significantly different at p < 0.01 (t-test). The flow rates at h=0 were generally well associated with λ c , as attested to by a significant difference between the averages of PF (57.8 mm/hr) and MF (21.0 mm/hr) at p < 0.01 (t-test). The OM was positively associated with PF. This was statistically confirmed by a t-test at p < 0.01. The average sand and clay contents of PF and MF were not statistically different. Analysis of the ratio of Soil Organic Carbon (SOC) to clay showed that the average SOC/clay of the PF (14%) was larger than that of the MF (13.3%). After the exclusion of soils with clay content less than 8%, the differences between the SOC/clay averages of PF (9.8%) and MF (7.5%) were significant at p < 0.05, as shown by a WM-test. The OM was positively associated with PF. Soil texture-and clay content in particular-influenced the λ c values. However, the association of clay content with PF was not statistically significant. Consideration of the SOC/clay ratio showed that the tendency toward PF increases as the complexation of the clay content increases. This was most obvious in soils with a clay content of greater than 8% and SOC/clay of approximately 10%. The OM either influences or is inter-correlated with the processes responsible for the formation of macropores.


Biological function of Extracellular Vesicles (EVs): a review of the field.
Extracellular vesicles (EVs) theranostic potential is under intense investigation. There is a wealth of information highlighting the role that EVs and the secretome play in disease and how these are being utilized for clinical trials and novel therapeutic possibilities. However, understanding of the physiological and pathological roles of EVs remain incomplete. The challenge lies in reaching a consensus concerning standardized quality-controlled isolation, storage, and sample preparation parameters. Interest in circulating EV cargo as diagnostic and prognostic biomarkers is steadily growing. Though promising, various limitations need to be addressed before there can be successful, full-scale therapeutic use of approved EVs. These limitations include obtaining or manufacturing from the appropriate medium (e.g., from bodily fluid or cell culture), loading and isolating EVs, stability, and storage, standardization of processing, and determining potency. This review highlights specific topics, including circulation of abnormal EVs contribute to human disease and the theranostic potential of EVs. Theranostics is defined as a combination of the word's therapeutics and diagnostics and describes how a specific medicine or technique can function as both. Key findings include, (1) EVs and the secretome are future theranostics which will be utilized as both biomarkers for diagnosis and as therapeutics, (2) basic and translational research supports clinical trials utilizing EVs/secretome, and (3) additional investigation is required to fully unmask the theranostic potential of EVs/secretome in specific diseases and injuries.


Human SP-A and a pharmacy-grade porcine lung surfactant extract can be reconstituted into tubular myelin--a comparative structural study of alveolar surfactants using cryo-transmission electron microscopy.
Cryo-transmission electron microscopy (cryo-TEM) is a rather artefact-free method, well suited to study the alveolar surfactant system. A pharmacy grade porcine lung surfactant extract (HL-10) was mixed with human SP-A and Ringer's solution (for calcium ions), and it was shown by cryo-TEM that the tubular myelin (TM) type of structure was reconstituted. These aggregates were associated to liposomal aggregates, and resulted in macroscopic phase-separation. This phase showed a weak birefringence in the polarising microscope, which is characteristic for a liquid-crystalline type of structure. TM from rabbit lung lavage was also examined, and showed the same periodic arrangement of bilayers as alveolar surface layer from freshly cut rabbit lungs deposited directly on the cryo-TEM grids. The distance between the bilayers of TM was 40-50 nm, and an electron dense material, assumed to be SP-A, was sometimes seen to occur periodically along the bilayers, oriented perpendicularly to the tubuli. The results are consistent with the surface-phase model of the alveolar lining.


Association of Regulatory Genetic Variants for Protein Kinase Cα with Mortality and Drug Efficacy in Patients with Heart Failure.
Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown. Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n = 951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models. The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR = 0.81 (95% CI = 0.67-0.98), p = 0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p > 0.1 for all). A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.


Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss.
Osteoprotegerin (OPG) is a key regulator of bone remodeling. Mutations and variations in the OPG gene cause many human diseases that are characterized by not only skeletal abnormalities but also poorly understood hearing loss: Paget's disease, osteoporosis, and celiac disease. To gain insight into the mechanisms of hearing loss in OPG deficiency, we studied OPG knockout (Opg(-/-)) mice. We show that they develop sensorineural hearing loss, in addition to conductive hearing loss due to abnormal middle-ear bones. OPG deficiency caused demyelination and degeneration of the cochlear nerve in vivo. It also activated ERK, sensitized spiral ganglion cells (SGC) to apoptosis, and inhibited proliferation and survival of cochlear stem cells in vitro, which could be rescued by treatment with exogenous OPG, an ERK inhibitor, or bisphosphonate. Our results demonstrate a novel role for OPG in the regulation of SGC survival, and suggest a mechanism for sensorineural hearing loss in OPG deficiency.


Clinical features of bilateral temporal bone xanthoma with LDLR gene mutation.
Here we presented a rare case of bilateral temporal bone xanthoma associated with type II hyperlipidemia. The lesion caused osteolytic destruction in mastoid air cells, auditory ossicles and bony labyrinth. The patient was operated on the symptomatic side and the lesion was totally removed. The type of LDLR gene mutation had been clarified for the members of the patient's family. This case was the first one regarding bilateral temporal bone leading to retroauricular swelling. The patient need life-long follow-up by either CT or MR imaging.


Conversion disorder (DSM-III 300.11): symptomatology and course in childhood and adolescence.
The incidence, age and sex distribution, symptomatology, psychosocial stress factors and course of conversion symptoms in a child and adolescent psychiatric patient sample were studied. Under the age of 10 conversion symptoms are comparatively rare and consequently require careful diagnosis, particularly regarding visual and hearing defects. Predominant conversion symptoms are seizures, gait problems and paralysis.


Genetic analysis of rDNA-ITS2 and RAPD loci in field populations of the malaria vector, Anopheles stephensi (Diptera: Culicidae): implications for the control program in Iran.
Anopheles stephensi is one of the most important malaria vectors in the Middle-East, the Indian subcontinent, the Far-East and is the main malaria vector in south of Iran. This vector is thought to be a single but polytypic species, despite its enormous geographical range. To examine this hypothesis, we analyzed the rDNA-ITS2 and RAPD loci in different populations of An. stephensi from Iran. rDNA-ITS2 region in all sequenced specimens of An. stephensi contained a (CA)7 microsatellite sequence. Construction of phylogenetic tree based on rDNA-ITS2 sequences revealed that there only is a minor polymorphism between the different populations, despite their vast geographical distances. RAPD-PCR could differentiate rural and urban populations of An. stephensi, but it is unclear whether these two samples represent mysorensis and the type form. Further characterization of interested RAPD fragments by cloning; have shown the nature of inverted repeats and the presence of microsatellite region (GT) in both ends near to inverted repeat sequences of primers. These results showed that An. stephensi in Iran could be considered a single species with different biological and ecological forms in different zoogeographical zones. Further studies are needed to demonstrate the relation between RAPD and microsatellite sequences and the differences seen in the field for this species. This data will serve as first report on the sequence of rDNA-ITS2 and a microsatellite-containing RAPD region, which could be used for species-specific diagnosis and differentiation of urban and rural populations in An. stephensi.


Artificial scholarship: LLMs in health professions education research.
This editorial examines the implications of artificial intelligence (AI), specifically large language models (LLMs) such as ChatGPT, on the authorship and authority of academic papers, and the potential ethical concerns and challenges in health professions education (HPE).


Distinct Structures and Dynamics of Chromatosomes with Different Human Linker Histone Isoforms.
The repeating structural unit of metazoan chromatin is the chromatosome, a nucleosome bound to a linker histone, H1. There are 11 human H1 isoforms with diverse cellular functions, but how they interact with the nucleosome remains elusive. Here, we determined the cryoelectron microscopy (cryo-EM) structures of chromatosomes containing 197 bp DNA and three different human H1 isoforms, respectively. The globular domains of all three H1 isoforms bound to the nucleosome dyad. However, the flanking/linker DNAs displayed substantial distinct dynamic conformations. Nuclear magnetic resonance (NMR) and H1 tail-swapping cryo-EM experiments revealed that the C-terminal tails of the H1 isoforms mainly controlled the flanking DNA orientations. We also observed partial ordering of the core histone H2A C-terminal and H3 N-terminal tails in the chromatosomes. Our results provide insights into the structures and dynamics of the chromatosomes and have implications for the structure and function of chromatin.


Defects associated with mitochondrial DNA damage can be mitigated by increased vacuolar pH in Saccharomyces cerevisiae.
While searching for mutations that alleviate detrimental effects of mitochondrial DNA (mtDNA) damage, we found that disrupting vacuolar biogenesis permitted survival of a sensitized yeast background after mitochondrial genome loss. Furthermore, elevating vacuolar pH increases proliferation after mtDNA deletion and reverses the protein import defect of mitochondria lacking DNA.


Structure of two rat genes coding for closely related rolipram-sensitive cAMP phosphodiesterases. Multiple mRNA variants originate from alternative splicing and multiple start sites.
The products of two phosphodiesterase (PDE) genes (ratPDE3/IVd and ratPDE4/IVb) are present in the rat Sertoli cell in culture, and their expression is under the control of the gonadotropin follicle-stimulating hormone (Swinnen, J.V., Tsikalas, K.E., and Conti, M. (1991) J. Biol. Chem. 266, 18370-18377). To understand the basis of the sequence heterogeneity found in the 5'-region of the different cDNAs thus far characterized, the structure of the coding region of these two cAMP PDE genes was investigated. Analysis of five ratPDE3/IVd and ratPDE4/IVb genomic clones showed that the coding region of these genes expressed in the Sertoli cell is divided into 11 exons distributed over 35-45 kilobases of genomic DNA. The intron/exon boundaries agreed, with some exceptions, with the established consensus sequences and were located in the same position in the coding region of the two genes. Also present were similarities to the exon composition of the Drosophila melanogaster "dunce" gene, the ancestor of these mammalian cAMP PDEs. Multiple AUG codons and short open reading frames were present at the 5'-untranslated end of the ratPDE4/IVb mRNA, but not in the ratPDE3 mRNA. By using polymerase chain reaction amplification or Northern analysis, it was determined that at least two forms of ratPDE3/IVd mRNA are present in rat Sertoli and FRTL-5 thyroid cells, but not in the brain. These mRNA variants are generated by inclusion or removal of an intron sequence that produces a frameshift affecting the position of the initiation AUG codon. Both mRNA species were efficiently translated into cAMP PDE proteins with different molecular masses in a transient transfection assay in COS cells. Polymerase chain reaction amplification demonstrated that heterogeneity of ratPDE4/IVb mRNAs was present in the same location as in the ratPDE3/IVd mRNA. Two ratPDE4/IVb mRNAs with different 5'-ends were expressed in Sertoli and FRTL-5 cells and in the brain. This heterogeneity is caused by the presence of an intron promoter that controls the transcription of this mRNA in Sertoli and FRTL-5 cells, but not in the brain. Upstream exons and additional promoters are probably present and necessary to generate the brain-specific mRNAs. These findings demonstrate that the cAMP-specific PDE genes have complex structure and that cAMP PDE proteins with different amino termini are derived from these genes.


Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.
Postprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved. Glucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients. All three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass. These findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.


Construction of replicative and integrative plasmids for setting up the in vivo expression technology in Helicobacter pylori.
Some pathogenic factors of Helicobacter pylori, a bacterium involved in peptic ulcer and gastric cancer, have already been identified using either global or particular approach, but there are still some orphan genes and unidentified pathogenic factors. One of the methods used successfully for the identification of virulence genes of many pathogens is the in vivo expression technology. We describe here the construction and sequences of three different plasmids, one integrative and two replicatives, for the identification of virulence genes by using in vivo expression technology in H. pylori, and of potential use in other bacteria such as Campylobacter spp. Moreover, the use of the green fluorescent protein could allow to classify the genes according to the strength of their expression and to identify those which are repressed upon interaction with gastric mucosa.


Hoechst 33258: a fluorescent nuclear counterstain suitable for double-labelling immunofluorescence.
Counterstaining with the chromosomal dye Hoechst 33258 is a simple procedure that provides an excellent general purpose nuclear counterstain for immunofluorescent work. Benefits from its use include the ready identification and orientation of structures, differentiation of lymphoid and non-lymphoid cells and easy assessment of frequency in specifically labelled cellular subpopulations. It can be used at the same time as FITC and TRITC double-labelling immunofluorescence.


A combined HNCA/HNCO experiment for 15N labeled proteins with 13C at natural abundance.
A triple resonance NMR experiment is presented for the simultaneous recording of HNCA and HNCO data sets on (15)N, natural abundance (13)C samples. The experiment exploits the fact that transfers of magnetization from (15)N to (13)CO and from (15)N to (13)C(alpha) (and back) proceed independently for samples that are not enriched in (13)C. A factor of 2 in measuring time is gained by recording the two data sets simultaneously with no compromise in spectral quality. An application to a 0.5 mM (15)N labeled sample of protein-L is presented with all expected correlations observed in spectra recorded with a cryogenic probe at 500 MHz.


CircCDK1 blocking IGF2BP2-mediated m6A modification of CPPED1 promotes laryngeal squamous cell carcinoma metastasis via the PI3K/AKT signal pathway.
Circular RNA (circRNA) is a novel noncoding RNA (ncRNA) that plays a critical role in various cancers. However, the clinical significance, biological function, and molecular mechanisms of circRNAs in laryngeal squamous cell carcinoma (LSCC) remain unclear. A circRNA array was performed to identify the differentially expressed circRNAs. In vitro and in vivo assays were proceeded to verify the biological function of circCDK1 in LSCC. RNA pulldown assays and RNA immunoprecipitation (RIP) were used to confirm the binding between circCDK1 and insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2). The MeRIP assay was then used to identified the N6-methyladenisine (m6A) methylation of calcineurin like phosphatase domain containing1 (CPPED1). Hsa_circ_0005774 (circCDK1) was found upregulated in LSCC tissues compared to adjacent normal tissues. The level of circCDK1 was positively correlated with poor prognosisof LSCC patients. In vitro and in vivo, circCDK1 promoted migration and invasion of LSCC cells. Mechanistically, eukaryotic translation initiation factor4A3(EIF4A3) induced biogenesis of circCDK1 by binding to its flanking. By competitively binding to IGF2BP2, circCDK1 blocked the m6A modification of CPPED1 in IGF2BP2-dependent manner. Moreover, the circCDK1-mediated decrease of CPPED1 activated the PI3K/AKT signal pathway to facilitate progression of LSCC. Our findings demonstrated that EIF4A3-induced upregulation of circCDK1 promoted LSCC metastasis via EIF4A3-circCDK1-IGF2BP2-CPPED1 to activate PI3K-AKT signal pathway. CircCDK1 might serve as a new diagnostic and prognostic marker or potential therapeutic target for LSCC.


Safe start at home: what parents of newborns need after early discharge from hospital - a focus group study.
The length of postpartum hospital stay is decreasing internationally. Earlier hospital discharge of mothers and newborns decreases postnatal care or transfers it to the outpatient setting. This study aimed to investigate the experiences of new parents and examine their views on care following early hospital discharge. Six focus group discussions with new parents (n = 24) were conducted. A stratified sampling scheme of German and Turkish-speaking groups was employed. A 'playful design' method was used to facilitate participants communication wherein they used blocks and figurines to visualize their perspectives on care models The visualized constructions of care models were photographed and discussions were audio-recorded and transcribed verbatim. Text and visual data was thematically analyzed by a multi-professional group and findings were validated by the focus group participants. Following discharge, mothers reported feeling physically strained during recuperating from birth and initiating breastfeeding. The combined requirements of infant and self-care needs resulted in a significant need for practical and medical support. Families reported challenges in accessing postnatal care services and lacking inter-professional coordination. The visualized models of ideal care comprised access to a package of postnatal care including monitoring, treating and caring for the health of the mother and newborn. This included home visits from qualified midwives, access to a 24-h helpline, and domestic support for household tasks. Participants suggested that improving inter-professional networks, implementing supervisors or a centralized coordinating center could help to remedy the current fragmented care. After hospital discharge, new parents need practical support, monitoring and care. Such support is important for the health and wellbeing of the mother and child. Integrated care services including professional home visits and a 24-hour help line may help meet the needs of new families.


The use of nerve growth factor as a reverse transforming agent for the treatment of neurogenic tumors: in vivo results.
The rationale behind the evaluation of natural differentiating agents, such as nerve growth factor (NGF), for reverse transforming potential is based on the theory that such compounds may represent a nontoxic means of controlling tumor growth. Previous in vitro experiments have shown that NGF is capable of retarding growth and of inducing persistent differentiation of neurogenic tumor cell lines. In vivo, NGF is capable of causing a persistent reduction in the number of ethylnitrosourea-induced neurinomas and of increasing survival time following intracerebral implantation of F98 anaplastic glioma cells. In this study, anaplastic glioma and neurinoma implants were treated with NGF to evaluate the reverse transforming potential of NGF in vivo. Results indicate that NGF is capable of causing a significant decrease in the growth rate of subcutaneous T9 (anaplastic glioma) and clone 16 (anaplastic neurinoma) implants. Significantly, NGF treatment was accompanied by adverse effects that were minimal and transient. Continued tumor growth (although greatly retarded) following NGF treatment is an aspect that requires further investigation. However, the results of this study suggest that NGF may prove useful, alone or in combination with other types of therapy, for the treatment of tumors of neurogenic origin.


Evaluation of the efficacy of doramectin against an artificial infection of Dictyocaulus viviparus in calves.
Three groups of eight Friesian calves, reared parasite-free, were experimentally infected with 1000 infective larvae of Dictyocaulus viviparus. Two groups were injected subcutaneously with 1% doramectin at 0.2 mg/kg body weight, one group 5 days after infection and the other 25 days after infection. A third group served as untreated controls. Faecal samples were examined for lungworm larvae on days 28, 32, 33, 34 and 35 after infection; the calves were killed and necropsied 39 or 40 days after infection and any lungworms present recovered and counted. Doramectin proved 100% effective against both 5-day-old and mature D. viviparus infections.


Enzymatic assays for NAD-dependent deacetylase activities.
The NAD-dependent deacetylases are a new class of enzymes responsible for the removal of acetyl groups from lysines on proteins. Instead of water, the NAD-dependent deacetylases use a highly reactive ADP-ribose intermediate as a recipient for the acetyl group. The products of the reaction are nicotinamide, acetyl-ADP-ribose, and a deacetylated substrate. Many assays have been developed for the measurement of NAD-dependent deacetylase activity. In this review we present assays based on each of the two reactions catalyzed by these enzymes, deacetylation and NAD hydrolysis. First we describe methods for the production of acetylated protein and peptide substrates for use in deacetylation reactions. Then we describe four methods for assaying deacetylation, three of which directly measure the loss of acetyl groups from a protein or peptide substrate, and one that measures acetate production. We also describe two indirect methods for following enzyme activity, NAD hydrolysis and a novel NAD-nicotinamide exchange reaction. Finally, a quantitative method using a monoacetylated peptide as a substrate and HPLC to measure products is described.


Ten years on: a review of medical terminations of pregnancy performed in a sexual health clinic.
Background Access to medical termination of pregnancy (MToP) services in regional Queensland remains inadequate and it is still possible for women and providers to be criminally prosecuted for accessing or providing abortion. Cairns Sexual Health Service (CSHS) has been providing medical terminations of pregnancy for 10 years, demonstrating that this service can be safely and successfully integrated into a primary healthcare setting. A retrospective audit of MToPs performed between 2011 and 2015 was conducted to follow on from our previously reported audit covering 2006-09. In total, 1859 MToPs have been performed by CHSH since 2006, with 1712 within the 5-year period of 2011-15. Changes in clinical practice over this time have streamlined the service and reduced unsuccessful outcomes from 12.2% between 2006 and 2009 to 0.9% between 2011 and 2015. The initial provision of MToP through CSHS was anticipated to be a short-term arrangement; however, 10 years on, this service continues with strong community demand. Provision of MToP services through primary healthcare settings can help improve access for women living outside of major metropolitan areas. If moves to decriminalise abortion in Queensland are successful, there is potential for even greater access.


Renal cell carcinoma in the pediatric population: A case report and review of the literature.
Renal cell carcinoma is a cancer thought to originate from renal epithelial cells. Commonly seen in patients older than 60 years of age, renal cell carcinoma presents as rare pathological entity seen in urological cancers among the pediatric population. A 17-year-old female patient presented with complaints of intermittency, dysuria, and gross hematuria. Radiological imaging was in favor of a left renal mass. Under general anesthesia, the left kidney was completely laparoscopically resected and sent to pathology, which along with correlating the age group of the patient and the morphology on pathological analysis, was suggestive of microphthalmia family translocation renal cell carcinoma.


Craniofacial osteotomies for skull base access.
During a five year period 150 craniofacial access osteotomies for skull base access have been performed allowing direct exposure of pathology in difficult anatomical acreas with minimal complications. These approaches have been developed by considering the craniofacial skeleton as a single osteoplastic structure. Bone segments are mobilised and replaced using rigid fixation. In this way osteotomies can be planned which significantly improve access and preserve form and function in the complex region of the skull base.


Microtubule-associated protein 2 and the organization of cellular microtubules.
Microtubule-associated proteins (MAPs) are prominent components of the neuronal cytoskeleton that can promote microtubule formation and whose expression is under strong developmental regulation. They are thought to be involved in organizing the structure of microtubule fascicles in axons and dendrites, although whether they form active cross-links between microtubules or serve as strut-like spacer elements has yet to be resolved. In the experiments reported here we explored their influence on microtubules by expressing them in non-neuronal cells using DNA transfection techniques. We confirm earlier reports that microtubule-associated proteins of the MAP2/tau class can induce bundling of microtubules. In addition we find that MAP2 causes the rearrangement of microtubules in the cytoplasm in a manner that is dependent on the length of the microtubule bundles. Short bundles are straight and run across the cytoplasm whereas long bundles form a marginal band-like array at the periphery. We suggest that the latter arrangement is produced when microtubule bundles that are too long to fit inside the diameter of the cell bend under the restraining influence of the cortical cytoskeleton. In confirmation of this, we show that when the cortical actin network is depolymerized by cytochalasin B the MAP2-containing microtubule bundles push out cylindrical extensions from the cell surface. These results suggest that the induction of stiff microtubules bundles by MAP2, coupled with a breach in the cortical actin network, can confer two of the properties characteristic of neuronal processes; their cylindrical form and the presence of fasciculated microtubules.


The Continuum of Disclosure: Exploring Factors Predicting Tentative Disclosure of Child Sexual Abuse Allegations During Forensic Interviews and the Implications for Practice, Policy, and Future Research.
When a child sexual abuse investigation ensues, many children do not disclose readily to professionals. Defining disclosure beyond the disclosure versus nondisclosure dichotomy is essential, yet little research exists on factors associated with a continuum of disclosure, including active and tentative disclosure. Through the coding of 196 forensic interviews using content analysis and subsequent regression analysis, findings suggest that children of color, children abused by adults, unintentional initial disclosure, and those lacking family support were more likely to tentatively disclose in this study. Implications include a need to understand tentative disclosure as part of a normal continuum of disclosure within court proceedings and investigations of abuse allegations.


1912-2012: a century of research on Plasmodium vivax in vitro culture.
The development of a continuous Plasmodium vivax blood cycle in vitro was first attempted 100 years ago. Since then, and despite the use of different methods, only short-term cultures have been achieved so far. The available literature has been reviewed in order to provide a critical overview of the currently available knowledge on P. vivax blood cycle culture systems and identify some unexplored ways forward. Results show that data accumulated over the past century remain fragmented and often contradictory, making it difficult to draw conclusions. There is the need for an international consortium on P. vivax culture able to collect, update, and share new evidence, including negative results, and thus better coordinate current efforts towards the establishment of a continuous P. vivax culture.


Performance of high-sensitivity cardiac troponin T in predicting major cardiovascular events in patients admitted to the emergency department for syncope with normal ECG: An observational prospective study.
History of syncope, clinical examination and electrocardiographic (ECG) findings are fundamental to assess the risk of major cardiovascular events (MACE) in patients attending the emergency department (ED) for syncope. However, in the absence of abnormal clinical examination findings or an abnormal ECG in the ED, transient rhythm or conduction disorders may not be safely excluded, hence predicting MACE remains challenging. High-sensitivity cardiac troponin T (hs-cTnT) may be a useful tool in this context. The primary objective was to evaluate the performance of hs-cTnT in the diagnosis of MACE at 30 days in patients attending the ED for syncope with a normal initial ECG. This was a prospective observational cohort study that took place in the ED of a French university hospital between June 2018 and June 2019. Patients≥18 years admitted to the ED for syncope with a normal ECG were eligible. After receiving verbal consent from patients, the ED physician collected clinical and ECG data and all patients had a blood sample taken that included hs-cTnT measurement. The primary outcome was MACE within 30 days after the ED visit. MACE were evaluated by consulting the patient's medical records and telephoning patients or their general practitioners. Sensitivity, specificity, positive and negative predictive values were calculated with their 95% confidence intervals (CI) for different hs-cTnT thresholds. Data from 246 patients were analysed, including 21 (9%) with MACE. Hs-cTnT had an area under the curve of 0.917 (CI: 0.872-0.962). Hs-cTnT with a threshold of 19ng/L had a sensitivity of 86% (CI: 64-97) and a specificity of 86% (CI: 81-90) for predicting MACE. Hs-cTnT may be a relevant tool for assessing MACE risk in patients with syncope and normal ECG results.


Thirty years of supplying the missing link. History of gamma globulin therapy for immunodeficient states.
Man has been injecting himself with gamma globulin for almost 100 years. As a result, both the benefits and the hazards of such therapy have been convincingly demonstrated. For 30 years physicians have realized that one group of patients must receive regular injections of this material to avoid death from overwhelming bacterial infections. The health of subjects with congenital or acquired hypogammaglobulinemia is directly related to the successful administration of adequate amounts of immunoglobulin G (IgG). Three phases are easily recognizable when examining the history of how physicians have accomplished such replacement therapy. Initially, therapy was limited to frequent and painful intramuscular injections of concentrated immune serum globulin. In some patients, the administration of monthly infusions of fresh plasma from "buddies" supplied a better approach. Now, the elusive goal of having a concentrated form of gamma globulin suitable for intravenous administration has been reached. Such preparations are revolutionizing the treatment of human immune deficiencies and expanding the therapeutic potential of gamma globulin itself.


Coordinative Alignment in the Pores of MOFs for the Structural Determination of N-, S-, and P-Containing Organic Compounds Including Complex Chiral Molecules.
Coordinative alignment of target small molecules onto a chiral metal-organic framework (MOF-520)provides a powerful method to determine the structures of small molecules through single-crystal X-ray diffraction (SXRD). In this work, the structures of 17 molecules with eight new coordinating functionalities and varying size have been determined by this method, four of which are complex molecules being crystallized for the first time. The chirality of the MOF backbone not only enables enantioselective crystallization of chiral small molecules from a racemic mixture but also imposes diastereoselective incorporation upon achiral molecules. Crystallographic studies assisted by density functional theory (DFT) calculations indicate that the stereoselectivity of MOF-520 not exclusively comes from the steric confinement of the chiral pore environment but also from asymmetric chemical bonding of the target molecules with the framework that is able to provide sufficient energy difference between possible coordination configurations.


A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. II. Biochemical findings.
In a comparative evaluation of zimelidine, a potent serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, 65 hospitalized patients with endogenous depression were evaluated for the following biochemical variables: 5-HT uptake in platelets, 5-HT concentration in whole blood, inhibition of the 5-HT and NA accumulation in rat hypothalamic synaptosomes incubated in the patients' plasma, the excretion of 4-hydroxy-3-methoxyphenyl glycol (HMPG) in urine and the pretreatment levels of the amine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and HMPG in cerebrospinal fluid (CSF). results of the biochemical studies confirmed that zimelidine and desipramine have different profiles with respect to monoamine uptake. Thus zimelidine caused more marked inhibition of 5-HT uptake than desipramine, especially in rat brain synaptosomes incubated in the patient's plasma. Desipramine plasma was much more effective than zimelidine plasma in inhibiting NA uptake in the same preparation. The urinary excretion of HMPG decreased significantly during desipramine treatment but remained unchanged during zimelidine treatment. The combined clinical and biochemical results indicated that patients with low pretreatment levels of 5-HIAA and HVA in CSF responded significantly better to zimelidine than patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of HMPG in CSF tended to respond better to desipramine than those with low levels of this NA metabolite.


Prenatal DNA diagnosis of Noonan syndrome in a fetus with massive hygroma colli, pleural effusion and ascites.
Prenatal molecular genetic diagnosis for Noonan syndrome I is reported. Noonan syndrome was suspected because of large cystic hygroma colli, massive pleural effusion and ascites at 23 weeks of gestation and normal karyotype (46,XX). DNA was prepared from amnion cells and screened for mutations in the PTPN11 gene. In exon 8, a missense mutation (S285F) was found. Delivery was induced at 33 weeks of gestation because of silent cardiotocography (CTG). Despite immediate drainage of the hydrothorax, mechanical ventilation was insufficient and the child died 9 h after birth due to severe pulmonary hypoplasia. Pleural punctate was enriched for small lymphocytes and thus was characterized as chylus. Prenatal ultrasound findings in Noonan syndrome usually are unspecific and rarely lead to a diagnosis. However, with the combination of cystic hygroma, pleural effusion, ascites and normal karyotype Noonan syndrome should be considered and DNA testing for PTPN11 mutations may be appropriate. Malformations of lymphatic vessels and/or chylothorax in Noonan syndrome seem to be more frequent than usually anticipated.


The Impact of a Health IT Changeover on Medical Imaging Department Work Processes and Turnaround Times: A mixed method study.
To assess the impact of introducing a new Picture Archiving and Communication System (PACS) and Radiology Information System (RIS) on: (i) Medical Imaging work processes; and (ii) turnaround times (TATs) for x-ray and CT scan orders initiated in the Emergency Department (ED). We employed a mixed method study design comprising: (i) semi-structured interviews with Medical Imaging Department staff; and (ii) retrospectively extracted ED data before (March/April 2010) and after (March/April 2011 and 2012) the introduction of a new PACS/RIS. TATs were calculated as: processing TAT (median time from image ordering to examination) and reporting TAT (median time from examination to final report). Reporting TAT for x-rays decreased significantly after introduction of the new PACS/RIS; from a median of 76 hours to 38 hours per order (p<.0001) for patients discharged from the ED, and from 84 hours to 35 hours (p<.0001) for patients admitted to hospital. Medical Imaging staff reported that the changeover to the new PACS/RIS led to gains in efficiency, particularly regarding the accessibility of images and patient-related information. Nevertheless, assimilation of the new PACS/RIS with existing Departmental work processes was considered inadequate and in some instances unsafe. Issues highlighted related to the synchronization of work tasks (e.g., porter arrangements) and the material set up of the work place (e.g., the number and location of computers). The introduction of new health IT can be a "double-edged sword" providing improved efficiency but at the same time introducing potential hazards affecting the effectiveness of the Medical Imaging Department.


Time to treatment patterns of head and neck cancer patients before and during the Covid-19 pandemic.
The delivery of healthcare has changed significantly over the past decades. This study analyzes the clinicodemographic factors and treatment patterns of head and neck squamous cell carcinoma (HNSCC) patients between 2004 and 2020. Retrospective cohort analysis of HNSCC patients from the National Cancer Data Base from 2004 to 2020. A total of 164,290 patients were included. Increased times from diagnosis to definitive surgery (TTS) were seen across all facility types (academic centers, AC; non-academic centers, NAC) between 2004 and 2019, with NAC affected more. TTS < 15 days (RR = 1.05, 95%CI:1.05-1.09) and > 75 days (1.07, 95%CI:1.05-1.09) were associated with increased mortality risk. This association was more prominent among HPV + HNSCC (RR = 1.45; 95%CI:1.18-1.78). Treatment in AC was associated with a decreased mortality risk (RR = 0.94, 95%CI:0.93-0.95). Despite the universal increase in wait times from 2004 to 2019, short-term mortality was significantly decreased from 2016 to 2019, relative to 2004-2007 (3-month mortality: RR = 0.77, 95%CI:0.70-0.85; 12-month mortality: RR = 0.80, 95%CI:0.77-0.84). Wait times decreased in 2020. TTS increased between 2004 and 2019, with NAC affected more. However, despite longer wait times, short-term survival increased significantly. Very short (<15 days) and very long (>75 days) TTS were associated with increased mortality risk. Patients with HPV + HNSCC have the highest increase among those treated > 75 days from diagnosis. Treatment at AC was associated with improved survival, which could be explained by the presence of multidisciplinary teams and subspecialists that may be less available at NAC. The 2021 NCDB data are required for a comprehensive analysis of wait times in 2020.


Clinical characteristics and outcomes of robot-assisted laparoscopic radical prostatectomy in HIV-positive patients: a nationwide population-based analysis.
To compare differences in clinical characteristics and outcomes between patients with and without human immunodeficiency virus (HIV) infection in light of robot-assisted laparoscopic radical prostatectomy (RALRP) as the most common surgical technique for prostate cancer. Previous data on perioperative complication rates of RALRP in HIV(+) patients are limited by small sample size. The National Inpatient Sample database from 2008 to 2014 was used to query prostate cancer patients who underwent RALRP. HIV(+) patients were identified through ICD9 codes 042, 043, 044, V08 and 079.53. Intraoperative and postoperative complications, rate of blood transfusion, in-hospital mortality, prolonged length of stay and total cost were compared by univariate, multivariate regression and 1:4 propensity score matched analyses. Overall, 270,319 weighted patients undergoing RALRP were identified, among whom 546 (0.20%) patients were diagnosed with HIV. Patients with HIV were younger, less likely to be white and had more comorbidities. Multivariable regression analysis revealed that HIV(+) patients had significantly increased genitourinary complications (odds ratio [OR]: 3.31; 95% confidence interval [CI]: 1.03-10.68) and miscellaneous surgical events (OR 3.19; 95% CI 1.26-8.08). There were no differences in potentially life-threatening cardiac, respiratory and vascular events between patients with and without HIV after RALRP. Propensity score matched analysis yielded similar results. Our findings suggest that patients who underwent RALRP with HIV did not experience higher risk of potentially life-threatening postoperative complications. RALRP could be safely considered as a surgical treatment for HIV(+) patients with prostate cancer.


A myocardial extraction method using deep learning for 99mTc myocardial perfusion SPECT images: A basic study to reduce the effects of extra-myocardial activity.
The purpose of this study was to automatically extract myocardial regions from transaxial single-photon emission computed tomography (SPECT) images using deep learning to reduce the effects of extracardiac activity, which has been problematic in cardiac nuclear imaging. Myocardial region extraction was performed using two deep neural network architectures, U-Net and U-Net ++, and 694 myocardial SPECT images manually labeled with myocardial regions were used as the training data. In addition, a multi-slice input method was introduced during the learning session while taking the relationships to adjacent slices into account. Accuracy was assessed using Dice coefficients at both the slice and pixel levels, and the most effective number of input slices was determined. The Dice coefficient was 0.918 at the pixel level, and there were no false positives at the slice level using U-Net++ with 9 input slices. The proposed system based on U-Net++ with multi-slice input provided highly accurate myocardial region extraction and reduced the effects of extracardiac activity in myocardial SPECT images.


Human genetics uncovers MAP3K15 as an obesity-independent therapeutic target for diabetes.
We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10-10) and had lower glycosylated hemoglobin (β = -0.14 SD units, P = 1.1 × 10-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10-4). Separately, we identified a Finnish-enriched MAP3K15 protein-truncating variant associated with decreased odds of both type 1 and type 2 diabetes (P < 0.05) in FinnGen. No adverse phenotypes were associated with protein-truncating MAP3K15 variants in the UKB, supporting this gene as a therapeutic target for diabetes.


Equine Herpesvirus-1 Outbreak During a Show-Jumping Competition: A Clinical and Epidemiological Study.
A total of 752 horses were involved in the CES Valencia Spring Tour 2021. Due to an equine herpesvirus-1 (EHV-1) outbreak, the competition was cancelled and the site was locked down. The objective of this study was to describe epidemiological, clinical, diagnostic, and outcome data of the 160 horses remaining in Valencia. Clinical and quantitative polymerase chain reaction (qPCR) data were analysed for 60 horses in a retrospective case-control observational study. The risk of developing clinical manifestations was explored using a logistic regression approach. EHV-1 was detected by qPCR, genotyped as A2254 (ORF30) and isolated on cell culture. From the 60 horses, 50 (83.3%) showed fever, 30 horses (50%) showed no further signs and 20 (40%) showed neurological signs, with eight horses (16%) hospitalised, of which two died (3%). Stallions and geldings were six times more likely to develop EHV-1 infection compared to mares. Horses older than 9 years, or housed in the middle of the tent were more likely to develop EHV-1 myeloencephalopathy (EHM). These data show that for EHV-1 infection, the risk factor was male sex. For EHM the risk factors were age > 9-year old and location in the middle of the tent. These data highlight the crucial role of stable design, position, and ventilation in EHV-outbreaks. It also showed that PCR testing of the horses was important to manage the quarantine.


Direct chronotropic and inotropic responses to guanosine and five different guanine nucleotides in isolated perfused dog atria.
The effects of guanosine and of five guanine nucleotides on sinus rate and contractile force were investigated using the isolated, blood-perfused dog atrium preparation. Guanosine consistently induced a positive chronotropic and inotropic effect which was not suppressed by treatment with a potent beta-adrenoceptor blocking agent, carteolol. GMP, GDP and CTP induced a biphasic chronotropic and inotropic effect. The potencies for inducing the positive effects of GMP, GDP and GTP were almost the same. However, their rank order of potency for inducing negative effects was GTP greater than or equal to GDP greater than GMP. The negative responses to GTP were not inhibited by atropine. Cyclic GMP and dibutyryl cyclic GMP produced only slight negative chronotropic and inotropic effects but not consistently even at larger doses. The positive chronotropic and inotropic responses to norepinephrine were not modified by treatment with dibutyryl cyclic GMP.


Slope of the power spectral density flattens at low frequencies (<150 Hz) with healthy aging but also steepens at higher frequency (>200 Hz) in human electroencephalogram.
The power spectral density (PSD) of the brain signals is characterized by two distinct features: oscillations, which are represented as distinct "bumps," and broadband aperiodic activity, that reduces in power with increasing frequency and is characterized by the slope of the power falloff. Recent studies have shown a change in the slope of the aperiodic activity with healthy aging and mental disorders. However, these studies analyzed slopes over a limited frequency range (<100 Hz). To test whether the PSD slope is affected over a wider frequency range with aging and mental disorder, we analyzed the slope till 800 Hz in electroencephalogram data recorded from elderly subjects (>49 years) who were healthy (n = 217) or had mild cognitive impairment (MCI; n = 11) or Alzheimer's Disease (AD; n = 5). Although the slope reduced up to ~ 150 Hz with healthy aging (as shown previously), surprisingly, at higher frequencies (>200 Hz), it increased with age. These results were observed in all electrodes, for both eyes open and eyes closed conditions, and for different reference schemes. However, slopes were not significantly different in MCI/AD subjects compared with healthy controls. Overall, our results constrain the biophysical mechanisms that are reflected in the PSD slopes in healthy and pathological aging.


Gut barrier dysfunction as detected by intestinal luminal microdialysis.
To evaluate the use of gut luminal microdialysis as a tool for monitoring ischaemic metabolites, particularly glycerol, as markers of intestinal dysfunction during and after intestinal ischaemia. A randomised, controlled animal experiment. National laboratory animal centre. In seven pigs the thoracic aorta was cross-clamped for 60 min followed by 2 h of reperfusion, while five pigs served as controls. Glycerol, lactate and glucose in the intestinal lumen and mucosa were measured by microdialysis. Intestinal tissue blood flow was determined by means of colour-labelled microspheres. To assess intestinal permeability, (14)C-polyethylene glycol 4000 (PEG-4000) was instilled in a jejunal segment and then measured in venous blood. Intestinal blood flow was reduced to 10% of baseline by aortic cross-clamping ( p=0.001) and returned to baseline during reperfusion. Intestinal luminal lactate increased during ischaemia and further increased during reperfusion. The increase was paralleled by augmented intestinal permeability; there was a significant correlation between luminal lactate and venous PEG-4000 ( r=0.89, p<0.01). Aortic cross-clamping caused a marked increase in intestinal mucosal glycerol concentrations, which correlated with luminal glycerol during both ischaemia and reperfusion ( r=0.85, p<0.01). Microdialysis of lactate may be useful for monitoring intestinal ischaemia and reperfusion. Release of lactate into the intestinal lumen appears to be related to increased permeability. Intestinal luminal glycerol closely mirrored glycerol concentrations in the intestinal wall.