Recognition of fibrous dysplasia of bone mimicking skeletal metastasis on 18F-FDG PET/CT imaging.
Fibrous dysplasia of bone (FDB) reveals intense 18F-FDG uptake mimicking metastases on 18F-FDG PET/CT. We reviewed sites of FDB revealed by 18F-FDG PET/CT imaging to allow identification of this abnormality. Eleven patients (7 male, 4 female, aged 16-78 years) were evaluated after 55 MBq (0.15 mCi)/kg 18F-FDG utilizing a 16-slice multiple detector CT (MDCT) whole-body PET scanner, with LOR algorithm 3D reconstruction. One- and 2-h imaging was performed in 9 patients. Standard uptake value (SUV) for each lesion, on early and delayed imaging, was calculated. Lesions were confirmed in 6 patients by biopsy. The PET images correlated with MDCT to establish the imaging characteristics. Solitary lesions were found in 4 patients, two lesions in 1 patient, and in 6 patients there were multiple bone lesions. The SUV(early) ranged from 1.23 to 9.64 with an average of 3.76 ± 2.40. The SUV(delayed) ranged from 1.76 to 11.42 with an average of 4.51 ± 3.07. The SUV(delayed) decreased or increased slightly (-31% to 5%) in 6 of our patients, and increased significantly (11% to 39%) in 3. There was a negative correlation between SUVs and age, as well as the number of affected bones. In our study, FDB had wide skeletal distribution with variability of 18F-FDG uptake and CT appearance. SUV in the delayed stage was seen to either decrease or increase on dual-time 18F-FDG PET scanning. It is very important to recognize the characteristics of this skeletal dysplasia to allow differentiation from skeletal metastasis.


Evolution of RXLR-class effectors in the oomycete plant pathogen Phytophthora ramorum.
Phytophthora plant pathogens contain many hundreds of effectors potentially involved in infection of host plants. Comparative genomic analyses have shown that these effectors evolve rapidly and have been subject to recent expansions. We examined the recent sequence evolution of RXLR-class effector gene families in the sudden oak death pathogen, P. ramorum. We found that P. ramorum RXLR effectors have taken multiple evolutionary paths, including loss or gain of repeated domains, recombination or gene conversion among paralogs, and selection on point mutations. Sequencing of homologs from two subfamilies in P. ramorum's closest known relatives revealed repeated gene duplication and divergence since speciation with P. lateralis. One family showed strong signatures of recombination while the other family has evolved primarily by point mutation. Comparison of a small number of the hundreds of RXLR-class effectors across three clonal lineages of P. ramorum shows striking divergence in alleles among lineages, suggesting the potential for functional differences between lineages. Our results suggest future avenues for examination of rapidly evolving effectors in P. ramorum, including investigation of the functional and coevolutionary significance of the patterns of sequence evolution that we observed.


Dynamics of cell-surface receptors.
The cell-surface receptors that combine with hormones or neurotransmitters to initiate cellular responses are a heterogeneous group of proteins with specific recognition sites for binding particular compounds with a high affinity and specificity. These molecules are relatively mobile in the cell membrane and, when occupied by the appropriate hormone or neurotransmitter, can interact with other effector molecules within the membrane to alter ionic gradients, enzyme activity or phospholipid metabolism, thus initiating a biological response. The relationship between occupancy of the receptor by hormone or neurotransmitter and production of a cellular response is not the same in every tissue and can be altered by various mechanisms when the normal stimulation of the tissue is increased or decreased over a period of time. Such alterations in sensitivity are important in the pathology of a number of disease states and also important in long-term adaptation to chronic drug therapy. For these reasons, an understanding of the molecular basis of drug action and the receptor molecules through which drugs act is important to the rational use of drug therapy.


Electronic cigarette user plasma nicotine concentration, puff topography, heart rate, and subjective effects: Influence of liquid nicotine concentration and user experience.
Electronic cigarette (ECIG) nicotine delivery and other effects may depend on liquid nicotine concentration and user experience. This study is the first to systematically examine the influence of ECIG liquid nicotine concentration and user experience on nicotine delivery, heart rate, puff topography, and subjective effects. Thirty-three ECIG-experienced individuals and 31 ECIG-naïve cigarette smokers completed 4 laboratory conditions consisting of 2, 10-puff bouts (30-sec interpuff interval) with a 3.3-V ECIG battery attached to a 1.5-Ω "cartomizer" (7.3 W) filled with 1 ml ECIG liquid. Conditions differed by liquid nicotine concentration: 0, 8, 18, or 36 mg/ml. Participants' plasma nicotine concentration was directly related to liquid nicotine concentration and dependent on user experience, with significantly higher mean plasma nicotine increases observed in ECIG-experienced individuals relative to ECIG-naïve smokers in each active nicotine condition. When using 36 mg/ml, mean plasma nicotine increase for ECIG-experienced individuals was 17.9 ng/ml (SD = 17.2) and 6.9 (SD = 7.1; p < .05) for ECIG-naïve individuals. Between-group differences were likely due to longer puffs taken by experienced ECIG users: collapsed across condition, mean puff duration was 5.6 sec (SD = 3.0) for ECIG-experienced and 2.9 (SD = 1.5) for ECIG-naïve individuals. ECIG use also suppressed nicotine/tobacco abstinence symptoms in both groups; the magnitude of abstinence symptom suppression depended on liquid nicotine concentration and user experience. These and other recent results suggest that policies intended to limit ECIG nicotine delivery will need to account for factors in addition to liquid nicotine concentration (e.g., device power and user behavior). (PsycINFO Database Record


Assessment of the feasibility and clinical value of further research to evaluate the management options for children with Down syndrome and otitis media with effusion: a feasibility study.
There is clinical uncertainty of the benefits and costs of different treatment options for children with Down syndrome who have glue ear. This study was designed to assess the extent of this lack of knowledge and determine if pursuing further information would be practical, beneficial and cost-effective. To assess the level and practical effect of current uncertainty around treatment options for children with Down syndrome and glue ear. To assess the feasibility of studying the options for management of glue ear in children with Down syndrome via a randomised controlled trial (RCT) or multicentre prospective cohort study by evaluating the willingness of (1) parents to agree to randomisation for their children and (2) clinicians to recruit participants to a definitive study. To undertake value of information analyses to demonstrate the potential economic benefit from undertaking further research. A feasibility study exploring the views of parents of children with Down syndrome and professionals who have responsibility for the health and education of children with Down syndrome, on the participation in, and value of, future research into interventions for glue ear. Data were collected from parents via self-completed questionnaires, face-to-face interviews and focus groups and from professionals via online questionnaires and a Delphi review exercise. Development of economic models to represent clinical pathways of care and a RCT informed a value of information (VOI) analysis. UK (professionals); East Midlands region of the UK (parents). Parents of children aged 1-11 years with Down syndrome (n = 156). Professionals including audiologists, ear, nose and throat surgeons, audiological physicians, speech and language therapists, and teachers of the deaf (n = 128). Quantitative and qualitative data on parental views and experiences of glue ear and its effects; interventions and treatment received; taking part in research and factors that would encourage or discourage participation; and the importance of various outcome domains to them and for their children. For professionals: information on caseloads; approaches to clinical management; opinions on frequency and significance of the consequences of glue ear for this population; importance of different outcome measures; opinions of interventions and their role in future research; views on health research; facilitators and barriers to recruitment, and participation in research involving RCTs. The complexity of the experience and individual characteristics of children with Down syndrome poses challenges for the design of any future research but these challenges were not considered by professionals to raise sufficient barriers to prevent it being undertaken. Parents were generally supportive of the need for, and value of, research but identified practical and emotional issues that would need addressing. Glue ear was considered to impact more on speech, language and communication than on hearing. Outcome measures for future research would need to evaluate these elements but measures should be designed specifically for the population. Parents and professionals identified randomisation as a significant barrier to participation. The VOI analyses identified lack of data as problematic but concluded that a future trial involving surgical intervention would be feasible at costs of < £650,000. Future research into the benefits of interventions for glue ear in children with Down syndrome would be feasible and could be cost-effective but should be carefully designed to facilitate and maximise participation from parents and professionals responsible for recruitment. The National Institute for Health Research Health Technology Assessment programme.


Fetal Kidney Cells Can Ameliorate Ischemic Acute Renal Failure in Rats through Their Anti-Inflammatory, Anti-Apoptotic and Anti-Oxidative Effects.
Fetal kidney cells may contain multiple populations of kidney stem cells and thus appear to be a suitable cellular therapy for the treatment of acute renal failure (ARF) but their biological characteristics and therapeutic potential have not been adequately explored. We have culture expanded fetal kidney cells derived from rat fetal kidneys, characterized them and evaluated their therapeutic effect in an ischemia reperfusion (IR) induced rat model of ARF. The fetal kidney cells grew in culture as adherent spindle shaped/polygonal cells and expressed CD29, CD44, CD73, CD90, CD105, CD24 and CD133 markers. Administration of PKH26 labeled fetal kidney cells in ARF rats resulted in a significant decrease in the levels of blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin and decreased tubular necrosis in the kidney tissues (p<0.05 for all). The injected fetal kidney cells were observed to engraft around injured tubular cells, and there was increased proliferation and decreased apoptosis of tubular cells in the kidneys (p<0.05 for both). In addition, the kidney tissues of ARF rats treated with fetal kidney cells had a higher gene expression of renotropic growth factors (VEGF-A, IGF-1, BMP-7 and bFGF) and anti-inflammatory cytokine (IL10); up regulation of anti-oxidative markers (HO-1 and NQO-1); and a lower Bax/Bcl2 ratio as compared to saline treated rats (p<0.05 for all). Our data shows that culture expanded fetal kidney cells express mesenchymal and renal progenitor markers, and ameliorate ischemic ARF predominantly by their anti-apoptotic, anti-inflammatory and anti-oxidative effects.


Oocyte numbers in the mouse increase after treatment with 5-aminoisoquinolinone: a potent inhibitor of poly(ADP-ribosyl)ation.
Poly(ADP-ribosyl)ation is a posttranslational protein modification carried out by a family of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). It has been proposed that the broad nuclear distribution of PARPs may allow them to modulate gene expression in addition to their more accepted role as DNA repair mediators. The role of poly(ADP-ribosyl)ation during oogenesis and folliculogenesis is unknown. Here we found that when 3- to 4-wk-old mice were injected with 5-amninoisoquinolinone, a water soluble inhibitor of poly(ADP-ribosyl)ation, it leads to considerably increased oocyte numbers and a dramatic increase in primordial follicle numbers. Furthermore, we show that inhibition of poly(ADP-ribosyl)ation leads to an increased expression of specific genes and pathways in mouse ovaries, in particular, transforming growth factor superfamily members. Our results demonstrate that poly(ADP-ribosyl)ation, is important in oogenesis and folliculogenesis, and it may have a differential role in regulating gene expression, DNA repair, and apoptosis. The novel function of poly(ADP-ribosyl)ation in oogenesis and folliculogenesis sheds light on the alternative role that DNA repair mediators may play in cellular development and differentiation.


Dynamic alignment using external socket reaction moments in trans-tibial amputees.
Prosthetic alignment is used to optimize prosthetic functioning and comfort. Spatio-temporal and kinematic gait parameters are generally observed to guide this process. However, they have been shown to be influenced by compensations, which reduces their sensitivity to changes in alignment. Alternatively, the use of moments working at the base of the prosthetic socket, external socket reaction moments (ESRM), has been proposed to quantify prosthetic alignment. To investigate if a predetermined kinetic alignment criterion, 0Nm averaged over the stance phase, can be used to fine-tune prosthetic alignment. 10 transtibial amputees were included in this intervention study. Firstly, their prostheses were aligned using conventional alignment procedures. Kinetic parameters and Socket Comfort Score (SCS) were measured in this initial alignment (IA) condition. Subsequently, the coronal plane ESRM during gait was presented to the prosthetist in real time using a Gait Real-time Analysis Interactive Lab. The prosthetist iteratively adapted the prosthetic alignment towards a predetermined average ESRM during the stance phase of 0 Nm. At the Final Alignment (FA), kinetic parameters and SCS were measured again and a paired sample t-test was performed to compare ESRMs and SCSs between alignments. A significant (p < 0.001) change was found in the absolute coronal plane ESRM (mean ± SD) from IA (|0.104| ± 0.058 Nm/kg) to FA (|0.012| ± 0.015 Nm/kg). In addition a significant (p < 0.001) change of the external coronal adduction knee moments was observed from IA (-0,127 ± 0.079 Nm/kg) to FA (-0.055 ± 0.089 Nm/kg), however this change was more variable among participants. On average, no significant (p = 0.37) change in the SCS was observed. While this study shows the potential of quantifying and guiding alignment with the assistance of kinetic criteria, it also suggests that a sole reliance on the ESRM as a single alignment criterion might be too simple.


Primary meningioma of the nasopharynx: case report and review of ectopic meningioma.
Meningiomas not uncommonly spread outside the central nervous system, but primary extracranial meningiomas are much less common, the sites described including the orbit, the calvarium, the neck, the temporal bone and the paranasal sinuses. Reported here is the first instance of extracranial meningioma of the nasopharynx. The histological appearance of meningiomas is diverse, and in ectopic sites can be mistaken for malignant epithelial tumors, as happened here initially. The tumor was excised via a transpalatal flap using an intracapsular debulking approach borrowed from the armamentarium of the intracranial surgeon. Prolonged follow-up with interval CT scans are recommended in patients with apparent ectopic meningioma, in case undemonstrable intracranial disease later becomes manifest.


Backbone and Ile, Leu, Val methyl group resonance assignment of CoV-Y domain of SARS-CoV-2 non-structural protein 3.
The worldwide COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonstructural protein 3 (nsp3) has 1945 residues and is the largest protein encoded by SARS-CoV-2. It comprises more than a dozen independent domains with various functions. Many of these domains were studied in the closely-related virus SARS-CoV following an earlier outbreak. Nonetheless structural and functional information on the C-terminal region of nsp3 containing two transmembrane and three extra-membrane domains remains incomplete. This part of the protein appears to be involved in initiation of double membrane vesicle (DMV) formation, membranous organelles the virus builds to hide its replication-transcription complex from host immune defenses. Here we present the near-complete backbone and Ile, Leu, and Val methyl group chemical shift assignments of the most C-terminal domain of nsp3, CoV-Y. As the exact function and binding partners of CoV-Y remain unknown, our data provide a basis for future NMR studies of protein-protein interactions to elucidate the molecular mechanism of DMV formation.


The Role of Flies as Pollinators of Horticultural Crops: An Australian Case Study with Worldwide Relevance.
Australian horticulture relies heavily on the introduced managed honey bee, Apis mellifera Linnaeus 1758 (Hymenoptera: Apidae), to pollinate crops. Given the risks associated with reliance upon a single species, it would be prudent to identify other taxa that could be managed to provide crop pollination services. We reviewed the literature relating to the distribution, efficiency and management potential of a number of flies (Diptera) known to visit pollinator-dependent crops in Australia and worldwide. Applying this information, we identified the taxa most suitable to play a greater role as managed pollinators in Australian crops. Of the taxa reviewed, flower visitation by representatives from the dipteran families Calliphoridae, Rhiniidae and Syrphidae was frequently reported in the literature. While data available are limited, there was clear evidence of pollination by these flies in a range of crops. A review of fly morphology, foraging behaviour and physiology revealed considerable potential for their development as managed pollinators, either alone or to augment honey bee services. Considering existing pollination evidence, along with the distribution, morphology, behaviour and life history traits of introduced and endemic species, 11 calliphorid, two rhiniid and seven syrphid species were identified as candidates with high potential for use in Australian managed pollination services. Research directions for the comprehensive assessment of the pollination abilities of the identified taxa to facilitate their development as a pollination service are described. This triage approach to identifying species with high potential to become significant managed pollinators at local or regional levels is clearly widely applicable to other countries and taxa.


Borderline personality disorder and emotional intelligence.
The present study investigated emotional intelligence (EI) in borderline personality disorder (BPD). It was hypothesized that patients with BPD (n = 61) compared with patients with other personality disorders (PDs; n = 69) and nonpatients (n = 248) would show higher scores on the ability to perceive emotions and impairments in the ability to regulate emotions. EI was assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test (Mayer, Salovey, and Caruso [New York: MHS, 2002]). As compared with the PD group and the nonpatient group, the patients with BPD displayed the anticipated deficits in their ability to understand, whereas no differences emerged with respect to their ability to perceive, use, and regulate emotions. In addition, a negative relationship was found between the severity of BPD and total EI score. However, this relationship disappeared when intelligence quotient was partialled out. These results suggest that BPD is associated with emotion understanding deficits, whereas temporary severity of BPD is associated with emotion regulation deficits.


Split-protein systems: beyond binary protein-protein interactions.
It has been estimated that 650,000 protein-protein interactions exist in the human interactome (Stumpf et al., 2008), a subset of all possible macromolecular partnerships that dictate life. Thus there is a continued need for the development of sensitive and user-friendly methods for cataloguing biomacromolecules in complex environments and for detecting their interactions, modifications, and cellular location. Such methods also allow for establishing differences in the interactome between a normal and diseased cellular state and for quantifying the outcome of therapeutic intervention. A promising approach for deconvoluting the role of macromolecular partnerships is split-protein reassembly, also called protein fragment complementation. This approach relies on the appropriate fragmentation of protein reporters, such as the green fluorescent protein or firefly luciferase, which when attached to possible interacting partners can reassemble and regain function, thereby confirming the partnership. Split-protein methods have been effectively utilized for detecting protein-protein interactions in cell-free systems, Escherichia coli, yeast, mammalian cells, plants, and live animals. Herein, we present recent advances in engineering split-protein systems that allow for the rapid detection of ternary protein complexes, small molecule inhibitors, as well as a variety of macromolecules including nucleic acids, poly(ADP) ribose, and iron sulfur clusters. We also present advances that combine split-protein systems with chemical inducers of dimerization strategies that allow for regulating the activity of orthogonal split-proteases as well as aid in identifying enzyme inhibitors. Finally, we discuss autoinhibition strategies leading to turn-on sensors as well as future directions in split-protein methodology including possible therapeutic approaches.


Predictive value of tissue inhibitor of metalloproteinases-1 and carcinoembryonic antigen plasma levels in response to chemotherapy in patients with metastatic colorectal cancer.
Colorectal cancer is one of the most important causes of morbidity and mortality in the world. It has been suggested that tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a particular role in cancer promotion. The objective of the present study was to compare the effect of repeated measurement of carcinoembryonic antigen (CEA) and TIMP-1 plasma levels in a follow-up response to chemotherapy treatment in patients with unresectable metastatic colorectal cancer by surgery. All consecutive patients between 18 and 75 years old in both genders with rectal adenocarcinoma who referred to Sayed Al-Shohada Medical Center, during 6 months of study period enrolled in the study. Level of CEA and TIMP-1 were assessed before and after two cycles of chemotherapy. Furthermore, patients underwent computed tomography scan to assess response to chemotherapy. The sensitivity, specificity, and areas under the receiver operating characteristic curves (AUC) calculated for baseline level of CEA and TIMP. The mean age of the studied patients was 52.7 ± 7.5 years, 12 patients (48%) were male. Response to chemotherapy after two cycles was 80%. In patients who responded to chemotherapy level of TIMP after treatment was significantly decreased compared to before treatment (P < 0.0001). Before and after treatment in patients who responded to chemotherapy the level of TIMP was significantly lower than who did not response to chemotherapy (P < 0.05). The critical values for the prediction response to chemotherapy for CEA was >63 (AUC: 0.54) and for TIMP was ≤8823 (AUC: 0.68). The present study has identified a strong significant association between high plasma TIMP-1 levels and short survival in patients with colorectal cancer. In addition, results demonstrated that the TIMP-1 provides stronger prognostic information than CEA.


Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study.
Patients with cancer are at increased risk of venous thromboembolism (VTE). Laboratory tests measuring the overall thrombophilic tendency might be useful to assess VTE risk. The aim of this study was to investigate thrombin generation, a key process in hemostasis, as predictor of cancer-associated VTE. The Vienna Cancer and Thrombosis Study (CATS) is a prospective observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. The study end point is occurrence of objectively confirmed symptomatic or fatal VTE within a follow-up period of 2 years. Thrombin generation was measured with a commercially available assay. One thousand thirty-three patients with malignancies of the breast (n = 151), lung (n = 148), upper (n = 44) and lower gastrointestinal tract (n = 125), pancreas (n = 67), kidney (n = 34), prostate (n = 122), and brain (n = 134) or lymphoma (n = 126), multiple myeloma (n = 26), and other tumor types (n = 56) were observed for a median observation period of 517 days. VTE occurred in 77 patients (7.5%). Patients with elevated peak thrombin (defined as values ≥ 611 nM thrombin, representing the 75th percentile of the total study population) had an increased risk of VTE with a hazard ratio of 2.1 (95% CI, 1.3 to 3.3, P = .002) in multivariable analysis including age, sex, surgery, chemotherapy, and radiotherapy. The cumulative probability of developing VTE after 6 months was significantly higher in patients with elevated peak thrombin than in those with lower peak thrombin (11% v 4%; log-rank test: P = .002). Measurement of thrombin generation may help identify patients with cancer at high risk of VTE.


Multilocus sequence analysis of biocontrol fluorescent Pseudomonas spp. producing the antifungal compound 2,4-diacetylphloroglucinol.
The genetic and evolutionary relationship among 2,4-diacetylphloroglucinol (Phl)-producing pseudomonads that protect plants from soil-borne pathogens were investigated by multilocus sequence typing. A total of 65 pseudomonads consisting of 58 Phl-positive biocontrol strains of worldwide origin and seven Phl-negative representatives of characterized Pseudomonas species were compared using 10 housekeeping genes (i.e. rrs, dsbA, gyrB, rpoD, fdxA, recA, rpoB, fusA, rpsL and rpsG). Multilocus sequence typing differentiated 51 strains among 58 Phl-positive pseudomonads and proved to be as discriminative as enterobacterial repetitive intergenic consensus polymerase chain reaction profiling. As phylogenetic trees inferred from each locus were rather incongruent with one another, we derived the topology from all concatenated loci, which led to the identification of six main groups of Phl-producing Pseudomonas spp. Taxonomically, these groups could correspond to at least six different species. Linkage disequilibrium analysis pointed to a rather clonal structure, even when the analysis was restricted to Phl-producing pseudomonads from a same geographic location or a same phylogenetic group. Intragenic recombination was evidenced for gyrB, rpoD and fdxA, but was shown to be a weaker force than mutation in the origin of intragenetic diversity. This is the first multilocus assessment of the phylogeny and population structure of an ecologically important bacterial group involved in plant disease suppression.


Antiproliferative effects and mechanism of action of ICI 195,739, a novel bis-triazole derivative, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi.
The in vitro antiproliferative effects of ICI 195,739, a recently developed bis-triazole derivative (T. Boyle, D. J. Gilman, M. B. Gravestock, and J. M. Wardleworth, Ann. N.Y. Acad. Sci. 544:86-100, 1988; J. F. Ryley, S. McGregor, and R. G. Wilson, Ann. N.Y. Acad. Sci. 544:310-328, 1988), on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi and some aspects of its mechanism of action are described. Despite previous claims that triazole compounds act on susceptible organisms by essentially the same mechanism demonstrated for the imidazole compounds, i.e., by interfering with the synthesis of ergosterol at the level of the cytochrome P-450-dependent C-14 demethylation of lanosterol, our results indicate that ICI 195,739 acts on T. cruzi epimastigotes by a dual mechanism which involves blockade of ergosterol byosynthesis and a second, still-unidentified target whose alteration leads to immediate growth arrest. Although ICI 195,739 blocks ergosterol biosynthesis at the level of C-14 lanosterol demethylation, as shown by gas-liquid and thin-layer chromatography, growth arrest in ICI 195,739-treated cells is not related to the depletion of the endogenous ergosterol pool, contrary to what was previously found for ketoconazole, the reference compound among antifungal and antiprotozoal azole derivatives. Consistent with this observation is the fact that the concentration of ICI 195,739 required to inhibit de novo synthesis of ergosterol in epimastigotes by 50% is 60 nM, which is essentially identical to that previously found for ketoconazole under identical conditions, while the minimum concentration required to produce complete growth inhibition is 0.1 microM, which is 300 times lower than that of ketoconazole. With respect to the intracellular amastigote form proliferating inside vertebrate (Vero) cells, 10 nM is sufficient to eradicate the parasite completely in 96 h, with no effects on the host cells; this concentration is identical to that previously found for ketoconazole. Growth inhibition and morphological alterations induced by ketoconazole can be reserved by exogenously added ergosterol but not by cholesterol; for ICI 195, 739, neither sterol is capable of reserving the drug effects. Contrary to what was observed for ketoconazole, the in vitro antiproliferative effects of ICI 195, 739 on both forms of the parasite are not potentiated by the simultaneous presence of terbinafine, an allylamine which blocks ergosterol production by the parasite at a different level of the sterol biosynthetic pathway. These results, together with those of an accompanying study of the ultrastructural alterations induced by the drug, strongly support the notion that ICI 195, 739 acts on T. cruzi by a novel combination of biochemical and cellular effects, which could explain its extraordinary potency in vivo against the parasite.


[Marine algae of Baja California Sur, Mexico: nutritional value].
The Baja California Peninsula is one of the richest regions of seaweed resources in México. The objective of this study was to determine the chemical composition of some marine algae species of Baja California Sur, with an economical potential due to their abundance and distribution, and to promote their use as food for human consumption and animal feeding. The algae studied were Green (Ulva spp., Enteromorpha intestinalis, Caulerpa sertularoides, Bryopsis hypnoides), Red (Laurencia johnstonii, Spyridia filamentosa, Hypnea valentiae) and Brown (Sargassum herporizum, S. sinicola, Padina durvillaei, Hydroclathrus clathrathus, Colpomenia sinuosa). The algae were dried and ground before analysis. In general, the results showed that algae had a protein level less than 11%, except L. johnstonii with 18% and low energy content. The ether extract content was lower than 1%. However, the algae were a good source of carbohydrates and inorganic matter.


Theta oscillations by synaptic excitation in a neocortical circuit model.
Neocortical theta-band oscillatory activity is associated with cognitive tasks involving learning and memory. This oscillatory activity is proposed to originate from the synchronization of interconnected layer V intrinsic bursting (IB) neurons by recurrent excitation. To test this hypothesis, a sparsely connected spiking circuit model based on empirical data was simulated using Hodgkin-Huxley-type bursting neurons and use-dependent depressing synaptic connections. In response to a heterogeneous tonic current stimulus, the model generated coherent and robust oscillatory activity throughout the theta-band (4-12 Hz). These oscillations were not, however, self-sustaining without a driving current, and not dependent on N-methyl-D-aspartate receptor synaptic currents. At realistic connection strengths, synaptic depression was necessary to avoid instability and expanded the basin of attraction for theta oscillations by controlling the gain of recurrent excitation. These results support the hypothesis that IB neuron networks can generate robust and coherent theta-band oscillations in neocortex.


Diagnosis and assessment of trachoma.
Trachoma is caused by Chlamydia trachomatis. Clinical grading with the WHO simplified system can be highly repeatable provided graders are adequately trained and standardized. At the community level, rapid assessments are useful for confirming the absence of trachoma but do not determine the magnitude of the problem in communities where trachoma is present. New rapid assessment protocols incorporating techniques for obtaining representative population samples (without census preparation) may give better estimates of the prevalence of clinical trachoma. Clinical findings do not necessarily indicate the presence or absence of C. trachomatis infection, particularly as disease prevalence falls. The prevalence of ocular C. trachomatis infection (at the community level) is important because it is infection that is targeted when antibiotics are distributed in trachoma control campaigns. Methods to estimate infection prevalence are required. While culture is a sensitive test for the presence of viable organisms and nucleic acid amplification tests are sensitive and specific tools for the presence of chlamydial nucleic acids, the commercial assays presently available are all too expensive, too complex, or too unreliable for use in national programs. There is an urgent need for a rapid, reliable test for C. trachomatis to assist in measuring progress towards the elimination of trachoma.


A case of yellow fever in a brown howler (Alouatta fusca) in Southern Brazil.
Many brown howlers (Alouatta fusca) have died in a 3-month period in a subtropical forest in Southern Brazil. One was examined after a systemic illness. According to clinical signs, and necropsy and histopathology findings, yellow fever virus (YFV) infection was suspected. Tissue sections from liver, kidney, and lymphoid organs were screened by immunohistochemistry for YFV antigens. Cells within those tissues stained positively with a polyclonal antibody against YFV antigens (1:1,600 dilution), and yellow fever was diagnosed for the first time in the brown howler in the area.


Carbon dioxide negatively modulates N-methyl-D-aspartate receptors.
Carbon dioxide (CO2) dose-dependently decreases minimum alveolar concentration (MAC) of anaesthetics in rats. CO2 also dose-dependently decreases cerebrospinal fluid pH. N-methyl-D-aspartate (NMDA) channels exhibit pH sensitivity and are putative targets for inhaled anaesthetics. We hypothesized that CO2 dose-dependently decreases rat NMDA channel current via an acidifying effect at concentrations relevant to CO2 MAC. To test this hypothesis, we studied rat NR1/NR2A glutamate receptors expressed in voltage-clamped Xenopus oocytes. To measure pH effects, we used perfusates adjusted between 7.3 and 5.3 with HCl. To measure CO2 effects, we used equimolar sodium perfusates containing either 0 or 24 mM NaHCO3 and CO2 between 0% and 87% atm. Solution compositions were measured using a blood gas analyser with values corrected using a calibrated pH meter and gas chromatograph with solutions at 37 degrees C. We found that decreasing pH decreased NMDA current. Moreover, pH effects produced by adding CO2 to NaHCO3-containing perfusates were identical to those produced by adding HCl to normal perfusates. The pH inhibiting 50% of NMDA current was 6.52. The CO2 concentration inhibiting 50% of rat NMDA current was 63% for solutions with 24 mM NaHCO3. CO2 exhibited a linear dose-dependent NMDA response analogous to that observed for in vivo CO2 anaesthetic potency in rats. CO2 and hydrogen ions act via the same mechanism to inhibit NMDA receptors. Moreover, CO2 inhibits rat NMDA receptors in a manner that is consistent with CO2 MAC-sparing effects in rats.


Cannabis and COVID-19: Reasons for Concern.
The lockdown measures implemented to curb the spread of SARS-CoV-2 may affect (illicit) drug consumption patterns. This rapid response study investigated changes in cannabis use in a non-probability sample of cannabis users in the Netherlands during the early lockdown period. We fielded an online cross-sectional survey 4-6 weeks after implementation of lockdown measures in the Netherlands on March 15, 2020. We measured self-reported \motives for changes in use, and assessed cannabis use frequency (use days), number of joints per typical use day, and route of administration in the periods before and after lockdown implementation. 1,563 cannabis users were recruited. Mean age was 32.7 ± 12.0 years; 66.3% were male and 67.9% used cannabis (almost) daily. In total, 41.3% of all respondents indicated that they had increased their cannabis use since the lockdown measures, 49.4% used as often as before, 6.6% used less often, and 2.8% stopped (temporarily). One-third of those who were not daily users before the lockdown became (almost) daily users. Before the lockdown, most respondents (91.4%) used cannabis in a joint mixed with tobacco and 87.6% still did so. Among users of joints, 39.4% reported an increase in the average number consumed per use day; 54.2% stayed the same and 6.4% used fewer joints. This rapid response study found evidence that during the lockdown more users increased rather than decreased cannabis consumption according to both frequency and quantity. These data highlight the need to invest more resources in supporting cessation, harm reduction, and monitoring longer term trends in cannabis use.


Defining the mechanisms by which the reactive oxygen species by-product, 4-hydroxynonenal, affects human sperm cell function.
Lipid peroxidation products such as the naturally occurring aldehyde 4-hydroxynonenal (4-HNE) are known to be cytotoxic toward different cell types, including spermatozoa. In order to understand this at the molecular level, we have employed a proteomic approach to characterize direct 4-HNE adducts on human spermatozoa. Several proteins were identified to be of particular interest, including aldehyde labeling of histone methyltransferase and dynein heavy chain. In addition, we found that 4-HNE bound to part of the activation segment, cysteine residue 199, of protein kinase A (PKA). Interestingly, at low levels, addition of 4-HNE had a stimulatory effect on PKA. However, this did not correlate to increased phosphotyrosine levels during capacitation. This data explains the link between reactive oxygen species and sperm toxicity. Given that epigenetic regulation is likely affected in oxidative-stressed spermatozoa, this data show that spermatozoa appear to shut down under these conditions before reaching the egg.


Differential distribution of low-density lipoprotein-receptor-related protein (LRP) and megalin in polarized epithelial cells is determined by their cytoplasmic domains.
Megalin and the low-density lipoprotein (LDL) receptor-related protein (LRP) are two large members of the LDL receptor family that bind and endocytose multiple ligands. The molecular and cellular determinants that dictate the sorting behavior of these receptors in polarized epithelial cells are largely unknown. Megalin is found apically distributed, whereas the limited information on LRP indicates its polarity. We show here that in Madin-Darby canine kidney cells, both endogenous LRP and a minireceptor containing the fourth ligand-binding, transmembrane and LRP cytosolic domains were basolaterally sorted. In contrast, minireceptors that either lacked the cytoplasmic domain or had the tyrosine in the NPTY motif mutated to alanine showed a preferential apical distribution. In LLC-PK1 cells, endogenous megalin was found exclusively in the apical membrane. Studies were also done using chimeric proteins harboring the cytosolic tail of megalin, one with the fourth ligand-binding domain of LRP and the other two containing the green fluorescent protein as the ectodomain and transmembrane domains of either megalin or LRP. Findings from these experiments showed that the cytosolic domain of megalin is sufficient for apical sorting, and that the megalin transmembrane domain promotes association with lipid rafts. In conclusion, we show that LRP and megalin both contain sorting information in their cytosolic domains that directs opposite polarity, basolateral for LRP and apical for megalin. Additionally, we show that the NPTY motif in LRP is important for basolateral sorting and the megalin transmembrane domain directs association with lipid rafts.


Interventional radiology of synovial chondromatosis in the temporomandibular joint using a thin arthroscope.
This case report describes, for the first time, the use of interventional radiology following arthroscopy with a thin arthroscope for the diagnosis and treatment of synovial chondromatosis (SC) of the temporomandibular joint (TMJ). Therapeutic joint irrigation concomitant with arthroscopic observation of the superior joint compartment (SJC) was performed in a patient with functional TMJ pain caused by SC. The thin arthroscope was inserted with the aid of an X-ray fluoroscope. Arthroscopy confirmed that the SC was at disease stage II and that synovitis existed throughout the SJC. The initial maximal interincisor opening (MIO) was 30 mm, while after the joint-irrigation procedure the MIO was 40 mm. In addition, the TMJ pain was greatly reduced after joint irrigation. Our findings demonstrate that interventional radiology with a thin arthroscope is clinically useful for the diagnosis and primary treatment of patients with painful SC in the TMJ.


Albumin therapy enhances collateral perfusion after laser-induced middle cerebral artery branch occlusion: a laser speckle contrast flow study.
Laser speckle contrast (LSC) was used to compare the extent of cortical ischemia in two inbred mouse strains that differed in their degree of collateral circulation, after laser occlusion of the distal middle cerebral artery, and after treatment with 25% albumin (ALB) or saline (control). Sequential LSC images acquired over ∼90 minutes were coaligned, converted to relative flow, and normalized to baseline. After 3-day survival, infarction was quantified by triphenyl tetrazolium chloride or magnetic resonance imaging. In the sparsely collateralized BALB/c strain, mean flow fell to 13% to 14% and 33% to 34% of baseline in central (core) and peripheral (penumbral) regions of interest, and ALB treatment at 30 minutes enhanced perfusion in both regions by ∼2-fold relative to saline, restoring flow to the benign-oligemic range centrally, and to the hyperemic range peripherally. The ALB-induced increment in parenchymal perfusion was disproportionate to the subtle flow increase in the occluded artery itself, suggesting that ALB improved collateral circulation. Cortical infarction in BALB/c mice was reduced 45% by ALB treatment. In contrast to BALB/c mice, the better-collateralized CD-1 strain developed milder ischemia, had smaller infarcts, and showed no differential benefit of ALB. We conclude that where native collateralization is insufficient (BALB/c strain), ALB treatment exerts a significant therapeutic effect after ischemia by augmenting collateral perfusion.


[A case of mononeuropathy multiplex associated with idiopathic thrombocytopenic purpura].
We report a case of mononeuropathy multiplex with idiopathic thrombocytopenic purpura (ITP). A 78-year-old man developed patches of purpura on his left forearm. His platelet count was 11,000/microl and platelet-associated IgG was elevated. He was diagnosed as having ITP. At the beginning of the following month, he noticed dysesthesia and weakness of his left finger and left lower limb, as well as dysesthesia of his bilateral lower thighs. Neurological examination revealed weakness in the area of the left ulnar nerve and of the left anterior tibial muscle. Dysesthesia presented in the area of the left ulnar nerve and bilateral superficial peroneal nerves. Nerve conduction studies revealed asymmetric axonal sensorimotor neuropathy (mononeuropathy multiplex). A cerebrospinal fluid specimen showed a normal cell count and normal protein level Serum anti-ganglioside antibody was negative. The platelet count gradually increased after the introduction of corticosteroid therapy. His neurological deficits and electrophysiological findings also improved. Immune-mediated neuropathy was suggested as the cause of his mononeuropathy multiplex with ITP.


[The evolution of the quality and price of the pharmaceutical supply financed by the public health system].
To find the evolution of quality and price in the supply of medicines financed over the last 28 years. A descriptive, crossover study of the catalogue of products. Analysis of 11,482 drugs packages financed by the public health system. The intrinsic value of each package, its potential use and its indicator of chronicity were analysed. Me-agains were identified in 3,285 products and me-toos among 879 different active principles. The medicines no longer financed after Act 83/1993 were compared with those still being financed. The supply of medicines financed has tended towards increases in intrinsic value, single-component products and price. Most of the drugs affected by the act are: older, cheaper, poorer quality and with more active principles. 31% of the supply has still not shown any clinical efficacy.


Optogenetic Inhibition of CGRPα Sensory Neurons Reveals Their Distinct Roles in Neuropathic and Incisional Pain.
Cutaneous somatosensory neurons convey innocuous and noxious mechanical, thermal, and chemical stimuli from peripheral tissues to the CNS. Among these are nociceptive neurons that express calcitonin gene-related peptide-α (CGRPα). The role of peripheral CGRPα neurons (CANs) in acute and injury-induced pain has been studied using diphtheria toxin ablation, but their functional roles remain controversial. Because ablation permanently deletes a neuronal population, compensatory changes may ensue that mask the physiological or pathophysiological roles of CANs, particularly for injuries that occur after ablation. Therefore, we sought to define the role of intact CANs in vivo under baseline and injury conditions by using noninvasive transient optogenetic inhibition. We assessed pain behavior longitudinally from acute to chronic time points. We generated adult male and female mice that selectively express the outward rectifying proton pump archaerhodopsin-3 (Arch) in CANs, and inhibited their peripheral cutaneous terminals in models of neuropathic (spared nerve injury) and inflammatory (skin-muscle incision) pain using transdermal light activation of Arch. After nerve injury, brief activation of Arch reversed the chronic mechanical, cold, and heat hypersensitivity, alleviated the spontaneous pain, and reversed the sensitized mechanical currents in primary afferent somata. In contrast, Arch inhibition of CANs did not alter incision-induced hypersensitivity. Instead, incision-induced mechanical and heat hypersensitivity was alleviated by peripheral blockade of CGRPα peptide-receptor signaling. These results reveal that CANs have distinct roles in the time course of pain during neuropathic and incisional injuries and suggest that targeting peripheral CANs or CGRPα peptide-receptor signaling could selectively treat neuropathic or postoperative pain, respectively.SIGNIFICANCE STATEMENT The contribution of sensory afferent CGRPα neurons (CANs) to neuropathic and inflammatory pain is controversial. Here, we left CANs intact during neuropathic and perioperative incision injury by using transient transdermal optogenetic inhibition of CANs. We found that peripheral CANs are required for neuropathic mechanical, cold, and heat hypersensitivity, spontaneous pain, and sensitization of mechanical currents in afferent somata. However, they are dispensable for incisional pain transmission. In contrast, peripheral pharmacological inhibition of CGRPα peptide-receptor signaling alleviated the incisional mechanical and heat hypersensitivity, but had no effect on neuropathic pain. These results show that CANs have distinct roles in neuropathic and incisional pain and suggest that their targeting via novel peripheral treatments may selectively alleviate neuropathic versus incisional pain.


Rural Health Care and an Ethics of Familiarity.
This commentary focuses on the narratives written from a variety of voices describing the unique challenges and rewards faced in rural health care. The authors speak from various areas of the country and from many professions including medicine, nursing, social work, and ethics and reflect the experiences of learners, new graduates, and long-time practitioners. The authors also represent people who were raised in rural environments and those who are from more urban settings. The commentary includes a discussion of some major themes from the rural bioethics literature that are reflected in these very personal narratives. The themes include lack of resources; overlapping relationships; resiliency; the need for partnerships and collaboration; and creativity. The commentary will also explore the dichotomy between learners and experienced practitioners and the possible missing voice of practitioners who could not tolerate the challenges and who left rural practice.


Opioid peptides: aspects of their origin, release and metabolism.
At the present time there is evidence for two families of related peptides which act as ligands for opiate receptor sites. The endorphin group of peptides are derived from the ACTH/LPH precursor pro-opiocortin. The enkephalins appear to be formed from a separate precursor or precursors that have yet to be fully characterized. There appear to be a number of different types of opiate receptors and this may be related to the multiplicity of peptide ligands that have so far been identified. The enkephalins and related peptides appear to have a much wider distribution than the endorphins but the latter may act as circulating hormones unlike the enkephalins. It is likely that both endorphins and enkephalins are involved in sensory modulation processes and release of these peptides has been demonstrated during brain stimulation for pain relief. The enkephalins are very rapidly inactivated by tissue proteases, the aminopeptidases appear largely responsible for the inactivation of exogenously administered enkephalins but the dipeptidyl carboxypeptidase, termed enkephalinase, may have a special inactivating function at enkephalinergic synapses. Evidence will be presented for the biosynthesis, the release and inactivation of the enkephalins relating to the above points.


Evolved orthogonal ribosome purification for in vitro characterization.
We developed orthogonal ribosome-mRNA pairs in which the orthogonal ribosome (O-ribosome) specifically translates the orthogonal mRNA and the orthogonal mRNA is not a substrate for cellular ribosomes. O-ribosomes have been used to create new cellular circuits to control gene expression in new ways, they have been used to provide new information about the ribosome, and they form a crucial part of foundational technologies for genetic code expansion and encoded and evolvable polymer synthesis in cells. The production of O-ribosomes in the cell makes it challenging to study the properties of O-ribosomes in vitro, because no method exists to purify functional O-ribosomes from cellular ribosomes and other cellular components. Here we present a method for the affinity purification of O-ribosomes, via tagging of the orthogonal 16S ribosomal RNA. We demonstrate that the purified O-ribosomes are pure by primer extension assays, and structurally homogenous by gel electrophoresis and sucrose gradients. We demonstrate the utility of this purification method by providing a preliminary in vitro characterization of Ribo-X, an O-ribosome previously evolved for enhanced unnatural amino acid incorporation in response to amber codons. Our data suggest that the basis of Ribo-X's in vivo activity is a decreased affinity for RF1.


Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype.
The pathologic classification of rhabdomyosarcoma (RMS) into embryonal or alveolar subtype is an important prognostic factor guiding the therapeutic protocol chosen for an individual patient. Unfortunately, this classification is not always straightforward, and the diagnostic criteria are controversial in a subset of cases. Ancillary studies are used to aid in the classification, but their potential use as independent prognostic factors is rarely studied. The aim of this study is to identify immunohistochemical markers of potential prognostic significance in pediatric RMS and to correlate their expression with PAX-3/FKHR and PAX-7/FKHR fusion status. A single tissue microarray containing 71 paraffin-embedded pediatric RMSs was immunostained with antibodies against p53, bcl-2, Ki-67, CD44, myogenin, and MyoD1. The tissue microarray and whole paraffin blocks were studied for PAX-3/FKHR and PAX-7/FKHR gene fusions by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction. Clinical follow-up data were available for each patient. Immunohistochemical staining results and translocation status were correlated with recurrence-free interval (RFI) and overall survival (OS) using the Kaplan-Meier method, the log-rank test, and Cox proportional hazard regression. The minimum clinical follow-up interval was 24 months (median follow-up=57 mo). On univariable analysis, immunohistochemical expression of myogenin, bcl-2, and identification of a gene fusion were associated with decreased 5-year RFI and 10-year OS (myogenin RFI P=0.0028, OS P=0.0021; bcl-2 RFI P=0.037, OS P=0.032; gene fusion RFI P=0.0001, OS P=0.0058). After adjustment for Intergroup Rhabdomyosarcoma Study-TNM stage, tumor site, age, tumor histology, and translocation status by multivariable analysis, only myogenin retained an independent association with RFI (P=0.034) and OS (P=0.0069). In this retrospective analysis, diffuse immunohistochemical reactivity for myogenin in RMS correlates with decreased RFI and OS, independent of histologic subtype, translocation status, tumor site, or stage.


The importance of hyphenated techniques in the discovery of new lead compounds from nature.
Nature represents an extraordinary reservoir of novel molecules and there is currently a resurgence of interest in natural products as a possible source of new lead compounds for introduction into therapeutical screening programmes. To discover new bioactive natural products, the dereplication of crude extracts performed prior to isolation work is of crucial importance for avoiding the tedious isolation of known constituents. In this respect, chemical screening strategies based on hyphenated techniques such as liquid chromatography-ultraviolet photodiode array detection, liquid chromatography-mass spectrometry, liquid chromatography tandom mass spectrometry and liquid chromatography-nuclear magnetic resonance (LC-NMR) are more and more extensively used. In the laboratory of Hostettmann's group, these analytical methods have been fully integrated into the isolation process and are used for the chemical screening of crude plant extracts, in complement with online or at-line bioassays, for rapid localisation and identification of new bioactive compounds. In this paper, possibilities and limitations of hyphenated techniques for de novo online natural product identification are discussed. As LC-NMR is playing a key role in this respect, the main part of the paper is dedicated to this technique. In particular, various ways of integrating NMR in the dereplication process are illustrated and strategies involving either direct or indirect hyphenation are presented.


Ionizing radiation augments glioma tropism of mesenchymal stem cells.
OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment. CONCLUSIONS Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.


Parental Education and Aggressive Behavior in Children: A Moderated-Mediation Model for Inhibitory Control and Gender.
Aggressive behaviors are highly prevalent in children. Given their negative consequences, it is necessary to look for protective factors that prevent or reduce their progress in early development before they become highly unshakable. With a sample of 147 children, the present study aimed to assess the relation between parental education and inhibitory control in the aggressive behavior of children aged from 7 to 10 years. The participants completed a go/no-go task to assess inhibitory control, whilst their parents reported their education level, and their teachers rated the aggressive behavior of the children through the Teacher Rating Scale (TRS) of the Behavior Assessment System for Children 2 (BASC-2). The results showed that both parental education and inhibitory control determined aggressive behavior in children. In addition, inhibitory control partially mediated the associations between parental education and aggressive behavior after accounting for age. However, a moderated mediation model revealed that lower parental education was associated with higher levels of aggressive behavior, which, in girls occurred independently of inhibitory control. In contrast, inhibitory control mediated this relation in boys. These results suggest the importance of parental education and inhibitory control in the aggressive behavior of children, supporting the idea that both constructs are relevant for understanding these conduct problems in schools, particularly in boys. The clinical implications of these findings are discussed, along with possible future lines of investigation.


Motor Transfer and Proactive Interference in Cycling With a Noncircular Chainring.
Athletes must transfer their performance when changing equipment due to innovative developments in sports technology. This kind of transfer has received only moderate attention. The aim of this study was to examine whether a mechanical change in sports equipment disturbs an athlete's performance and affects biomechanical and neurophysiological parameters. Therefore, an experiment was conducted in which 36 participants in three groups pedaled at 70 rounds per minute on a cycling ergometer with a circular and a noncircular (NC) chainring. The dependent variables were the total variability of the cadence, torque effectiveness, and muscle cocontraction (electromyographic cocontraction) of four antagonistic acting muscle pairs. Data were recorded during an acquisition phase, a transfer phase, and a retention phase. The results revealed that practice on a circular chainring induces a positive transfer on the NC chainring for total variability without a proactive interference effect. Torque effectiveness did not change within or between groups during the acquisition, transfer, and retention phases. Torque effectiveness and electromyographic cocontraction were not affected when the chainrings were altered from Day 1 to Day 2. During the retention phase, electromyographic cocontraction was higher when using the NC chainring, but the difference was small in absolute terms. The results regarding transfer and proactive interference seem to be strongly dependent on the movement task and the change in sports equipment. Transfer from the circular to NC chainring indicates refined neuromuscular control and improved movement coordination.


Impacts of Cover Crops and Crop Residues on Phosphorus Losses in Cold Climates: A Review.
The use of cover crops and crop residues is a common strategy to mitigate sediment and nutrient losses from land to water. In cold climates, elevated dissolved P losses can occur associated with freeze-thaw of plant materials. Here, we review the impacts of cover crops and crop residues on dissolved P and total P loss in cold climates across ∼41 studies, exploring linkages between water-extractable P (WEP) in plant materials and P loss in surface runoff and subsurface drainage. Water-extractable P concentrations are influenced by plant type and freezing regimes. For example, WEP was greater in brassica cover crops than in non-brassicas, and increased with repeated freeze-thaw cycles. However, total P losses in surface runoff and subsurface drainage from cropped fields under cold climates were much lower than plant WEP, owing to retention of 45 to >99% of released P by soil. In cold climatic regions, cover crops and crop residues generally prevented soil erosion and loss of particle-bound P during nongrowing seasons in erodible landscapes but tended to elevate dissolved P loss in nonerodible soils. Their impact on total P loss was inconsistent across studies and complicated by soil, climate, and management factors. More research is needed to understand interactions between these factors and plant type that influence P loss, and to improve the assessment of crop contributions to P loss in field settings in cold climates. Further, tradeoffs between P loss and the control of sediment loss and N leaching by plants should be acknowledged.


Evaluating the effectiveness of countywide mask mandates at reducing SARS-CoV-2 infection in the United States.
With the rise of the Delta variant of SARS-CoV-2 and the low vaccination rates in the United States, mitigation strategies to reduce the spread of SARS-CoV-2 are essential for protecting the health of the general public and reducing strain on healthcare facilities. This study compares US counties with and without mask mandates and determines if the mandates are associated with reduced daily COVID-19 infection. US counties have debated whether masks effectively decrease COVID-19 cases, and political pressures have prevented some counties from passing mask mandates. This article investigates the utility of mask mandates in small US counties. This study aims to analyze the effectiveness of mask mandates in small US counties and places where the population density may not be as high as in larger urban counties and to determine the efficacy of countywide mask mandates in reducing daily COVID-19 infection. The counties studied were those with populations between 40,000 and 105,000 in states that did not have statewide mask mandates. A total of 38 counties were utilized in the study, half with and half without mask mandates. Test counties were followed for 30 days after implementing their mask mandate, and daily new SARS-CoV-2 infection was recorded during this timeframe. The counties were in four randomly selected states that did not have statewide mask mandates. The controls utilized were from counties with similar populations to the test counties and were within the same state as the test county. Controls were followed for the same 30 days as their respective test county. Data were analyzed utilizing t-test and difference-in-difference analyses comparing counties with mask mandates and those without. These data showed statistically significant lower averages of SARS-CoV-2 daily infection in counties that passed mask mandates when compared with counties that did not. The difference-in-difference analysis revealed a 16.9% reduction in predicted COVID-19 cases at the end of 30 days. These data support the effectiveness of mask mandates in reducing SARS-CoV-2 infection spread in small US counties where the population density may be less than in urban counties. Small US counties that are considering passing mask mandates for the population can utilize these data to justify their policy considerations.


[Glutamine as a key ingredient in protein metabolism].
Glutamine has a number of unique properties which suggest that this amino acid plays an important role in health and disease. Glutamine is considered a conditionally essential amino acid, because during periods of severe metabolic stress the body's requirements of glutamine may exceed the individual's ability to produce sufficient amounts of the amino acid. Studies with glutamine-enriched nutrition show beneficial effects on nitrogen balance, muscle protein metabolism, gastrointestinal mucosa, and immune status. In certain patient categories addition of glutamine reduces the number of infectious complications, improves long-term survival, and shortens hospital stay, e.g. bone marrow transplantation patients, neonates with severely subnormal weight, patients with multiple organ failure, multi-trauma patients. More studies are needed to document the dose-response and to identify the patients that are likely to benefit from glutamine supplementation.


Low hepatitis C virus reinfection rate despite ongoing risk following universal access to direct-acting antiviral therapy among people living with HIV.
To evaluate changes in injecting and sexual risk behaviours, and hepatitis C virus (HCV) reinfection incidence among people with HIV/HCV coinfection following unrestricted access to direct-acting antiviral therapy in Australia. Prospective observational cohort study (2014-2018). Among people enrolled in the Control and Elimination of HCV from HIV-infected individuals within Australia study, changes in injecting and sexual behaviour were evaluated, including injecting drug use (IDU) in the last 6 months and last month, frequency of IDU and equipment sharing, condom-less anal intercourse with casual male partner(s), and group sex. HCV reinfection incidence was evaluated with follow-up through May 2018. Overall, 272 HIV/HCV antibody-positive participants [median age; 50 years, 96% male, 83% identified as gay and bisexual men (GBM)] had behavioural data at enrolment and follow-up (median 2.91 years) available for analysis. The proportion reporting IDU in the last 6 months remained stable from enrolment (35%) to follow-up (39%). Among GBM, the proportion reporting condom-less anal intercourse with casual partner(s) at enrolment (48%) and follow-up (46%) was also similar. Reinfection was detected in five individuals (all GBM) during total follow-up of 474 person-years for an overall incidence of 1.05 per 100 person-years (95% confidence interval, 0.44-2.53). No change was observed in levels of injecting or sexual risk behaviour for HCV infection following unrestricted access to direct-acting antiviral therapy in an Australian HIV/HCV cohort. Incidence of HCV reinfection was low potentially reflecting high levels of treatment coverage within this population. Continued screening and rapid retreatment of reinfection will be required to maintain progress towards elimination.


Comparison between cystourethrography and sonourethrography in preoperative diagnostic management of patients with anterior urethral strictures.
To evaluate the urethral lesions and the degree of spongiofibrosis using cystourethrography (CUG) and sonourethrography (SUG) in order to propose the best imaging method for further surgical treatment. The study involved 66 patients with anterior urethral strictures with indication for urethroplasty. Results of CUG and SUG were compared with each other and data from surgical protocol. Totally 72 strictures were detected; 47 in the bulbar part of urethra and 25 in the penile urethra. The mean length of the stenosis was 16.43 mm for CUG and 27.41 mm for SUG and 31.05 mm during surgery. The correlation levels between imaging techniques and intraoperative measurements were 0.55 (p<0.001) for CUG and 0.73 (p<0.001) for SUG. After dividing the strictures according to their location, better correlation for stenoses was obtained in penile urethra: 0.66 (p<0.001) for CUG and 0.86 (p<0.001) for SUG. SUG seems to be a simple and fast examination to evaluate urethral strictures. It is more accurate in comparison to CUG and gives a possibility to assess the spongiofibrosis. This information suggests that SUG can be a good complement to CUG in diagnosis of anterior urethtral strictures.


The Maghreb - one more important biodiversity hot spot for tiger beetle fauna (Coleoptera, Carabidae, Cicindelinae) in the Mediterranean region.
The tiger beetle fauna of the Maghreb region is one of the richest in the Palaearctic, including 22 species and 5 subspecies and 19% of all Palaearctic species of Cicindelinae. Assembled to their chorotypes, the Maghreb tiger beetles fall into eight different groups that include Maghreb endemics (26% of fauna), Mediterranean (7%), West Mediterranean (40%), North African (4%), Mediterranean-Westturanian (4%), West Palaearctic (4%), Afrotropico-Indo-Mediterranean (4%), and Saharian (11%) species. The Mediterranean Sclerophyl and Atlas Steppe are the Maghreb biogeographical provinces with the highest species richness, while the Sahara Desert has the lowest Cicindelinae diversity. Twenty-five cicindelid species and subspecies (93% of Maghreb fauna) are restricted to only one or two habitat types in lowland areas. Only Calomeralittoralislittoralis and Lophyraflexuosaflexuosa are recognized as eurytopic species and occur in three types of habitat. The highest tiger beetle diversity characterizes salt marshes and river banks (in both cases 11 species and subspecies or 41% of Maghreb fauna). Approximately 85% of all Maghreb tiger beetle species and subspecies are found in habitats potentially endangered by human activity.


Effect of watching a movie on family members' anxiety level during their relatives' surgery.
Surgery is a stressful condition for both patient and family members. This anxiety may interfere with the adequate family functioning and in providing positive support for the patient. Thus, specialized assessment and interventions to reduce anxiety level of family members are essential. The aim of this study was to assess the effect of watching movie on anxiety level of family members during their relatives' surgery. This was a before-after trial study conducted in Alzahra Medical Center, Isfahan, Iran. Between February 2010 and November 2010, 164 eligible family members in the surgical waiting room who met the inclusion criteria entered in the study. Before and after watching movie, the anxiety level was evaluated using the State-Trait Anxiety Inventory (STAI). Chi-squares, ANOVA and paired-t test were used for analysis using the Statistical Package for Social Sciences (SPSS, Version 14) for Microsoft Windows. The study population were 164 people, of whom 87 (53%) were female and 77 (47%) were male. The mean age of participants was 36.6 (SD: 8.4) years ranging from 18 to 67 years. After watching movie, the mean STAI score reached from 46.06 (SD: 9.26) to 39.15 (SD: 11.81) and this difference was statistically significant (p = 0.003). The results of this study indicated that watching movie could reduce family members' anxiety during surgery. The findings suggested that movie might be a simple and cost-effective tool to help family members to manage anxiety during surgery of their relatives.


Exploring the effects of eugenol, menthol, and lidocaine as anesthetics on zebrafish glucose homeostasis.
Zebrafish (Danio rerio) are widely employed as an experimental model in various scientific fields. The investigation of glucose metabolism dysfunctions has gained recent significant prominence. Considering that certain anesthetics may impact glycemic levels, it is imperative to carefully select an anesthetic that does not induce such side effects, thereby mitigating potential adverse influences on research outcomes. In this sense, this study aimed to evaluate potential glucose alterations and induction and recovery times resulting from the use of eugenol, menthol and lidocaine as anesthetics in zebrafish. A total of 150 adult male and female zebrafish were divided into ten groups, comprising a control group euthanized by rapid chilling, and three groups anesthetized with low (40 mg/L eugenol, 60 mg/L menthol, 100 mg/L lidocaine), intermediate (60 mg/L eugenol, 90 mg/L menthol, 225 mg/L lidocaine), and high (80 mg/L eugenol, 120 mg/L menthol, 350 mg/L lidocaine) anesthetic concentrations. Glucose levels and induction and recovery times were assessed. The findings reveal that eugenol and menthol did not cause glucose level alterations at any of the investigated concentrations, while lidocaine caused a non-concentration-dependent hyperglycemia. Eugenol and menthol also exhibited similar recovery times at different concentrations, while lidocaine recovery times were concentration-dependent. This study, therefore, concludes that eugenol and menthol are safe and satisfactory anesthetics for use in zebrafish research involving glucose analyses, while lidocaine use can cause biases due to altered glucose levels and safety concerns. Researchers should, therefore, carefully consider anesthetic selection to ensure reliable results in zebrafish assessments.


The effect of breastfeeding and its duration on acute otitis media in children in Brno, Czech Republic.
We designed this study to assess the effect of breastfeeding and its duration on acute otitis media (AOM) in children of our geographical region. Our main aim was to determine the period of breastfeeding, necessary to achieve optimal preventive results against AOM. The children that, according to the questionnaire, had suffered AOM infections in the past were used as the study group with the rest of the children used as control. The duration of breastfeeding was divided into months and the odds ratios for the occurrence of AOM were calculated for the children breastfed for more than or equal to a certain period, compared to the children breastfed for less than that period. This was repeated for each month separately and the results plotted on a graph of the confidence interval (CI) for the odds ratio values, against months of breastfeeding. The results of our study show that breastfeeding for a period of up to 11 months can play a significant preventive role against AOM (odds ratio and lower 90% CI > 1). Breastfeeding for longer periods of time is also beneficial, with breastfeeding up to 18 months being associated with some preventive effect against the disease (odds ratio > 1), but the reduction in the incidence of AOM is not statistically significant after the 11th month. Furthermore, there are marked differences in the importance of breastfeeding during the first 11 months, with a vital protective effect during the first 4 months of life which, however, drops by the 5th month and then rises again from the beginning of the 6th to the end of the 8th month. The protective effect then drops once more, although it remains positive and statistically significant until the 11th month of life and positive, but not statistically significant, until the 18th. Our study has revealed that for an optimal preventive effect to be achieved, the child should be breastfed for at least the first 11 months of its life. Continuing after this for up to the 18th month shows some preventive effect, which however is not statistically significant. Our results support the hypothesis that the importance of breastfeeding varies with the development of the child, its changing environment and to the new immunological challenges this brings.


Outlier analyses to test for local adaptation to breeding grounds in a migratory arctic seabird.
Investigating the extent (or the existence) of local adaptation is crucial to understanding how populations adapt. When experiments or fitness measurements are difficult or impossible to perform in natural populations, genomic techniques allow us to investigate local adaptation through the comparison of allele frequencies and outlier loci along environmental clines. The thick-billed murre (Uria lomvia) is a highly philopatric colonial arctic seabird that occupies a significant environmental gradient, shows marked phenotypic differences among colonies, and has large effective population sizes. To test whether thick-billed murres from five colonies along the eastern Canadian Arctic coast show genomic signatures of local adaptation to their breeding grounds, we analyzed geographic variation in genome-wide markers mapped to a newly assembled thick-billed murre reference genome. We used outlier analyses to detect loci putatively under selection, and clustering analyses to investigate patterns of differentiation based on 2220 genomewide single nucleotide polymorphisms (SNPs) and 137 outlier SNPs. We found no evidence of population structure among colonies using all loci but found population structure based on outliers only, where birds from the two northernmost colonies (Minarets and Prince Leopold) grouped with birds from the southernmost colony (Gannet), and birds from Coats and Akpatok were distinct from all other colonies. Although results from our analyses did not support local adaptation along the latitudinal cline of breeding colonies, outlier loci grouped birds from different colonies according to their non-breeding distributions, suggesting that outliers may be informative about adaptation and/or demographic connectivity associated with their migration patterns or nonbreeding grounds.


Endoscopes used in positive and critically ill patients are SARS-CoV-2 negative at virological assessment.
The risk of SARS-CoV-2 transmission in endoscopy is not only between patients and endoscopy staff but is also through inadequately reprocessed endoscopes. There are no studies that could confirm the efficacy of current ways of endoscope reprocessing on the elimination of SARS-CoV-2. The aim of this pilot study was to evaluate the efficacy of high disinfection of endoscopes with peracetic acid on eliminating SARS-CoV-2, but surprisingly we found that the virus cannot be detected on any part of endoscopes used in critically ill patients due to SARS-CoV-2 and this was the same for all types of endoscopies and procedures. If confirmed in larger studies, these findings will probably open a new scenario in the overall understanding of the real impact of the virus.


Evaluation of the efficacy of six nutritional screening tools to predict malnutrition in the elderly.
Malnutrition in the elderly is a multifactorial problem, more prevalent in hospitals and care homes. The absence of a gold standard in evaluating nutritional risk led us to evaluate the efficacy of six nutritional screening tools used in the elderly. Two hundred forty eight elderly patients (129 men, 119 female women, aged 75.2 ± 8.5 years) were examined. Nutritional screening was performed on admission using the following tools: Nutritional Risk Index (NRI), Geriatric Nutritional Risk Index (GNRI), Subjective Global Assessment (SGA), Mini Nutritional Assessment - Screening Form (MNA-SF), Malnutrition Universal Screening Tool (MUST) and Nutritional Risk Screening 2002 (NRS 2002). A combined index for malnutrition was also calculated. Nutritional risk and/or malnutrition varied greatly, ranging from 47.2 to 97.6%, depending on the nutritional screening tool used. MUST was the most valid screening tool (validity coefficient = 0.766, CI 95%: 0.690-0.841), while SGA was in better agreement with the combined index (κ = 0.707, p = 0.000). NRS 2002 although was the highest in sensitivity (99.4%), it was the lowest in specificity (6.1%) and positive predictive value (68.2%). MUST seem to be the most valid in the evaluation of the risk for malnutrition in the elderly upon admission to the hospital. NRS 2002 was found to overestimate nutritional risk in the elderly.


Temperature-responsive genetic loci in the plant pathogen Pseudomonas syringae pv. glycinea.
Plant-pathogenic bacteria may sense variations in environmental factors, such as temperature, to adapt to plant-associated habitats during pathogenesis or epiphytic growth. The bacterial blight pathogen of soybean, Pseudomonas syringae pv. glycinea PG4180, preferentially produces the phytotoxin coronatine at 18 degrees C and infects the host plant under conditions of low temperature and high humidity. A miniTn5-based promoterless glucuronidase (uidA) reporter gene was used to identify genetic loci of PG4180 preferentially expressed at 18 or 28 degrees C. Out of 7500 transposon mutants, 61 showed thermoregulated uidA expression as determined by a three-step screening procedure. Two-thirds of these mutants showed an increased reporter gene expression at 18 degrees C whilst the remainder exhibited higher uidA expression at 28 degrees C. MiniTn5-uidA insertion loci from these mutants were subcloned and their nucleotide sequences were determined. Several of the mutants induced at 18 degrees C contained the miniTn5-uidA insertion within the 32.8 kb coronatine biosynthetic gene cluster. Among the other mutants with increased uidA expression at 18 degrees C, insertions were found in genes encoding formaldehyde dehydrogenase, short-chain dehydrogenase and mannuronan C-5-epimerase, in a plasmid-borne replication protein, and in the hrpT locus, involved in pathogenicity of P. syringae. Among the mutants induced at 28 degrees C, insertions disrupted loci with similarities to a repressor of conjugal plasmid transfer, UV resistance determinants, an isoflavanoid-degrading enzyme, a HU-like DNA-binding protein, two additional regulatory proteins, a homologue of bacterial adhesins, transport proteins, LPS synthesis enzymes and two proteases. Genetic loci from 13 mutants did not show significant similarities to any database entries. Results of plant inoculations showed that three of the mutants tested were inhibited in symptom development and in planta multiplication rates. Temperature-shift experiments suggested that all of the identified loci showed a rather slow induction of expression upon change of temperature.


Managing cognitive impairment in the elderly: conceptual, intervention and methodological issues.
With the aging of society, the incidence of dementia in the elderly is also increasing, and thus results in increased numbers of individuals with cognitive impairment. Nurses and other researchers have investigated issues concerning the management of cognitive impairment. This article highlights conceptual, intervention and methodological issues associated with this phenomenon. Cognitive change is a multivariate construct that includes alterations in a variety of information processing mechanisms such as problem solving ability, memory, perception, attention and learning, and judgement. Although there is a large body of research, conceptual, intervention and methodological issues remain. Much of the clinical research on cognitive impairment is atheoretical, with this issue only recently being addressed. While many clinical interventions have been proposed, few have been adequately tested. There are also various methodological concerns, such as small sample sizes and limited statistical power; study design issues (experimental vs. non-experimental), and internal and external validity problems. Clearly, additional research designed to intervene with these difficult behaviors is needed. A variety of psychosocial, environmental and physical parameters must be considered in the nursing care of persons with cognitive impairment. Special attention has been given to interventions associated with disruptive behaviors. Interventions are complex and knowledge must be integrated from both the biomedical and behavioral sciences in order to deal effectively with the numerous problems that can arise over a long and changing clinical course. Some researchers and clinicians have suggested that a new culture regarding dementia care is needed, one that focuses on changing attitudes and beliefs about persons with dementia and one that changes how organizations deliver that care. This review identifies key conceptual, intervention and methodological issues and recommends how these issues might be addressed in the future.


Compositional and toxicological analysis of a GM potato line with reduced α-solanine content--a 90-day feeding study in the Syrian Golden hamster.
Steroidal glycoalkaloids (GAs) are toxins, produced by plants of the Solanaceae family. The potato plant (Solanum tuberosum L.) and its tubers predominantly contain the two GAs α-chaconine and α-solanine. These compounds are believed to act in synergy, and the degree of toxicity may therefore depend on their ratio in the potato. To determine the influence of α-solanine: α-chaconine ratio in potatoes on toxicity, a GM potato line (SGT 9-2) with reduced α-solanine content, and the parental control line (Desirée wild-type) having a traditional α-solanine: α-chaconine ratio were (1) studied for compositional similarity by analysing for a range of potato constituents, and (2) used in a 90-day feeding trial with the Syrian Golden hamster to study differential toxicity. The animal feeding study used diets with up to 60% freeze-dried potato powder from either line. Whilst data indicated some compositional differences between the GM line and its wildtype control these did not raise concerns related to nutritional value or safety. Results of the feeding trials showed a low number of significant differences between potato lines with different α-solanine: α-chaconine ratio but none were considered to raise safety concerns with regard to human (or animal) consumption.


Markers of bile duct tumors.
Biliary tract carcinomas are relatively rare, representing less than 1% of cancers. However, their incidence has increased in Japan and in industrialized countries like the USA. Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease; therapeutic treatment options are often limited and of minimal utility. Recent studies have shown the importance of serum and molecular markers in the diagnosis and follow up of biliary tract tumors. This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors. Some considerable tumor markers are cancer antigen 125, carbohydrate antigen 19-9, carcinoembryonic antigen, chromogranin A, mucin 1, mucin 5, alpha-fetoprotein, claudins and cytokeratins.


Nitric oxide production is increased during murine vaccinia virus infection, but may not be essential for virus clearance.
Recent reports have highlighted a potential antiviral activity for nitric oxide (NO). The purpose of this study was to investigate the production of NO in mice during vaccinia virus (VV) or herpes simplex virus type 1 infection, and to assess the role of NO in clearance of VV. Reactive nitrogen intermediates (RNI; NO and its stable oxidation products, nitrite and nitrate) were significantly elevated in the plasma of mice infected with these viruses. Furthermore, spleen cells from virus-infected mice produced elevated RNI levels following stimulation in vitro with LPS. NO production during VV infection was critically dependent on the cytokines tumor necrosis factor and interferon-gamma, and on the presence of both CD4+ and CD8+ T lymphocytes. Treatment of VV-infected mice with the nitric oxide synthase inhibitor N(G)-methyl-L-arginine did not alter the course of infection, suggesting that NO may not be essential for the clearance of this virus.


Neuroanatomical Framework of the Metabolic Control of Reproduction.
A minimum amount of energy is required for basic physiological processes, such as protein biosynthesis, thermoregulation, locomotion, cardiovascular function, and digestion. However, for reproductive function and survival of the species, extra energy stores are necessary. Production of sex hormones and gametes, pubertal development, pregnancy, lactation, and parental care all require energy reserves. Thus the physiological systems that control energy homeostasis and reproductive function coevolved in mammals to support both individual health and species subsistence. In this review, we aim to gather scientific knowledge produced by laboratories around the world on the role of the brain in integrating metabolism and reproduction. We describe essential neuronal networks, highlighting key nodes and potential downstream targets. Novel animal models and genetic tools have produced substantial advances, but critical gaps remain. In times of soaring worldwide obesity and metabolic dysfunction, understanding the mechanisms by which metabolic stress alters reproductive physiology has become crucial for human health.


Clinical effectiveness and cost-effectiveness of monitoring blood pressure of hypertensive employees at work.
In this randomized controlled trial, the value of using occupational health nurses (OHNs) to monitor the care of hypertensive employees at work was compared with regular care (RC) delivered in the community. One year after entry, the blood pressure level, medication history, compliance with treatment, and cost of hypertensive care of the participants were determined by independent evaluators. The reduction in diastolic blood pressure (DBP), the measure of effectiveness, was 10.5 +/- 1.1 mm Hg (mean +/- SEM) in the OHN group and 7.7 +/- 1.1 mm Hg in the RC group, and the proportion under good blood pressure control was 41.8% and 31.0% respectively. These between-group differences were not statistically significant. Although the employees in the OHN group were more medicated and had a lower treatment dropout rate, neither difference was statistically significant. In addition, the proportion of employees who were compliant with prescribed medication was virtually identical in both groups. The cost of the care received by employees in the OHN group of $ 404.14 for the year was substantially higher than that of $ 250.15 in the RC group with the difference principally related to the cost of visiting the OHNs and a significant difference in drug cost (p less than 0.006). The incremental cost-effectiveness (C/E) ratio of $ 53.67 per mm Hg DBP reduction per year for onsite blood pressure monitoring was higher than the base C/E ratio of $ 32.65 per mm Hg for regular care. Our findings indicate that monitoring the blood pressure of hypertensive employees at work is neither clinically effective nor cost-effective.(ABSTRACT TRUNCATED AT 250 WORDS)


The Modified Pancreatitis Activity Scoring System Shows Distinct Trajectories in Acute Pancreatitis: An International Study.
The aims of this study were to: (1) assess the performance of the Pancreatitis Activity Scoring System (PASS) in a large intercontinental cohort of patients with acute pancreatitis (AP); and (2) investigate whether a modified PASS (mPASS) yields a similar predictive accuracy and produces distinct early trajectories between severity subgroups. Data was prospectively collected through the Acute Pancreatitis Patient Registry to Examine Novel Therapies In Clinical Experience (APPRENTICE) consortium (2015-2018) involving 22 centers from 4 continents. AP severity was categorized per the revised Atlanta classification. PASS trajectories were compared between the three severity groups using the generalized estimating equations model. Four mPASS models were generated by modifying the morphine equivalent dose (MED), and their trajectories were compared. A total of 1393 subjects were enrolled (median age, 49 years; 51% males). The study cohort included 950 mild (68.2%), 315 (22.6%) moderately severe, and 128 (9.2%) severe AP. Mild cases had the lowest PASS at each study time point (all P < .001). A subset of patients with outlier admission PASS values was identified. In the outlier group, 70% of the PASS variation was attributed to the MED, and 66% of these patients were from the United States centers. Among the 4 modified models, the mPASS-1 (excluding MED from PASS) demonstrated high performance in predicting severe AP with an area under the receiver operating characteristic curve of 0.88 (vs area under the receiver operating characteristic of 0.83 in conventional PASS) and produced distinct trajectories with distinct slopes between severity subgroups (all P < .001). We propose a modified model by removing the MED component, which is easier to calculate, predicts accurately severe AP, and maintains significantly distinct early trajectories.


The challenges of early discharge. Common newborn problems in the first few weeks of life.
In a thorough discussion of a published series on early discharge, Britton, Britton and Beebe note that methodological limitations, study design problems and heterogeneity sorely limit the conclusions that may be drawn from published studies about early discharge. These authors found that the 1980 recommendations of the AAP about early discharge are still appropriate. They recommend individualizing the discharge decision based on mother-infant health, as well as on psychosocial and socioeconomic factors. These authors apparently seek to temper the headlong rush to early discharge with an awareness of the wider societal context within which childbirth must be understood. Although the literature paints a positive picture of early home discharge, existing research still lacks the statistical power and scientific evidence to support this practice. There are many positive reasons for the early discharge of a mother-infant dyad, but they may have nothing to do with monetary savings. As with many things we do in our clinical practice, there is much room for the input of nurse practitioners, not only in providing care, but also in the shaping of health care policy.


[Hydroxypropylmethyl-containing eyedrops in the treatment of sicca syndrome].
The author reports on 16 patients (9 with keratoconjunctivitis sicca, 7 with Sjögren's syndrome) treated with Isopto-Naturale eye drops for 10 months. Reduction of photophobia, burning, dryness and foreign-body sensation were achieved by local administration of the drug 2 to 5 times a day. The lesions in the corneal epithelium also improved significantly during the treatment period. Thus, Isopto-Naturale eye drops have proved to be more effective than 1% methylcellulose or 1.4% PVA artificial tear eye drops in the treatment of dry-eye syndrome.


Physiologic mechanism and preoperative prediction of new-onset dysphagia after laparoscopic Nissen fundoplication.
The aim of this study was to determine whether preoperative physiologic factors can account for and be used to predict the development of postoperative dysphagia after laparoscopic Nissen fundoplication. One hundred sixty-three patients with gastroesophageal reflux disease underwent laparoscopic Nissen fundoplication with a median follow-up of 14 months (range 6 to 81 months). Preoperative dysphagia was present in 37% (60 of 163) and was relieved in all but five patients (92%). Female sex (P = 0.01) and the presence of a stricture (P = 0.02) were the only preoperative variables associated with the presence of preoperative dysphagia. Eight percent (8 of 103) of patients without preoperative dysphagia developed new-onset dysphagia, and of these 63% (5 of 8) had a normal lower esophageal sphincter (LES) (pressure >6 mm Hg; length >2 cm; abdominal length >1 cm). New-onset dysphagia was significantly more common in patients with a normal LES (22% [5 of 23] vs. 4% [3 of 80], P = 001). Patients with a normal LES had almost a sixfold increase in the risk of developing dysphagia as those with an abnormal LES (relative risk = 5.8). Only a preoperative normal LES (P = 0.02) or mean LES pressures (P = 0.04) were positively associated with the development of postoperative dysphagia. The severity of this dysphagia also showed a strong positive trend of increasing with mean preoperative LES pressures (P = 0.07). Finally, preoperative LES pressure significantly correlated with postoperative LES pressure (r = 0.48, P = 0.01) and with mean residual LES (nadir) pressure (r = 0.33, P = 0.05) offering insight into the mechanism of this dysphagia. In conclusion, preoperative LES parameters play a role in the development of dysphagia after laparoscopic Nissen fundoplication. Patients with a normal LES or high mean LES pressures are at increased risk for developing this complication and should be informed of this before laparoscopic Nissen fundoplication.