Knowledge, behavior and precautionary measures related to COVID-19 pandemic among the general public of Punjab province, Pakistan.
The world is facing a formidable challenge to prevent the COVID-19 global outbreak, and health care systems are under pressure globally. The governments alone cannot prevent the spread of this pandemic without creating a sensitive public opinion and cooperation. Therefore, this study analyzed the knowledge, behavior, and precautionary measures taken by the general public to protect themselves from COVID-19 pandemic. For this purpose, snowball sampling technique was used to collect data from 401 respondents through an online survey in the Punjab province of Pakistan. A Multivariate Probit Model was used to determine the factors affecting the choice of precautionary measures to avoid COVID-19 infection. Majority of the respondents (58.1%) belonged to urban areas in this study. The urban respondents had higher knowledge about Coronavirus disease as compared to rural respondents. Similarly, the hygienic behavior of urban respondents was better than rural respondents. But unavailability of hygienic material (mask and hand sanitizer) was the main problem faced by the general public. Public transportation was considered the most risk-prone place to COVID-19 by the respondents. Majority of the respondents perceived medium to highest risk from COVID-19, and it was found one of the most influential factors affecting the adoption of precautionary measures along with knowledge of this pandemic. Government needs to start a comprehensive awareness campaign on social media along with the mainstream media create awareness about the importance of social distancing, washing hands and wearing masks among the general public to enhance knowledge and improve the behavior of the general public about COVID-19.


What was the impact of a participatory research project in Australian Indigenous primary healthcare services? Applying a comprehensive framework for assessing translational health research to Lessons for the Best.
To (1) apply the Framework to Assess the Impact from Translational health research (FAIT) to Lessons from the Best to Better the Rest (LFTB), (2) report on impacts from LFTB and (3) assess the feasibility and outcomes from a retrospective application of FAIT. Three Indigenous primary healthcare (PHC) centres in the Northern Territory, Australia; project coordinating centre distributed between Townsville, Darwin and Cairns and the broader LFTB learning community across Australia. LFTB research team and one representative from each PHC centre. Impact reported as (1) quantitative metrics within domains of benefit using a modified Payback Framework, (2) a cost-consequence analysis given a return on investment was not appropriate and (3) a narrative incorporating qualitative evidence of impact. Data were gathered through in-depth stakeholder interviews and a review of project documentation, outputs and relevant websites. LFTB contributed to knowledge advancement in Indigenous PHC service delivery; enhanced existing capacity of health centre staff, researchers and health service users; enhanced supportive networks for quality improvement; and used a strengths-based approach highly valued by health centres. LFTB also leveraged between $A1.4 and $A1.6 million for the subsequent Leveraging Effective Ambulatory Practice (LEAP) Project to apply LFTB learnings to resource development and creation of a learning community to empower striving PHC centres. Retrospective application of FAIT to LFTB, although not ideal, was feasible. Prospective application would have allowed Indigenous community perspectives to be included. Greater appreciation of the full benefit of LFTB including a measure of return on investment will be possible when LEAP is complete. Future assessments of impact need to account for the limitations of fully capturing impact when intermediate/final impacts have not yet been realised and captured.


Health and treatment priorities of older patients and their general practitioners: a cross-sectional study.
General practitioners (GPs) deal with the multiple health needs of older patients. During patient encounters GPs are often only able to manage a limited number of problems and tend to focus on single diseases resulting in fragmented and overloaded care. A systematic approach that considers multiple health problems simultaneously and sets priorities for treatment is necessary. To disclose patients' and doctors' perspectives on individual health and treatment priorities. Cross-sectional study in which 123 older patients and their 11 GPs evaluated the importance and severity of patients' individual health problems. Patients were systematically enrolled to receive a geriatric assessment. This generated a problem list on the basis of which patients and their GPs independently rated the importance and components of severity (in relation to emotional experience, hindrance in everyday life and prognosis) of each problem. The proportion of important problems and the chance corrected agreement (Cohen's Kappa) of importance between doctors and patients were assessed. Multilevel logistic regression models were used to relate the importance of a problem with its severity components - from the perspective of both the patient and the doctor. Patients and GPs considered about two-thirds of all disclosed health problems important (69% and 64% respectively). However, they perceived different problems as important (Kappa 0.11). Doctors and patients also related different components of severity to the importance of a problem: the strongest predictor of a problem's importance for patients was the emotional experience, whereas for doctors it was an unfavourable prognosis. Patients and doctors have different perspectives on the importance of health problems. Setting priorities for treatment necessitates an open exchange of views on what to treat.


Pancreatic Insufficiency in Cystic Fibrosis: Influence of Inflammatory Response Genes.
Pancreatic insufficiency (PI) in cystic fibrosis (CF) patients is a crucial clinical marker for severity and disease progression. In our study, 125 modifier genes and their SNPs were associated between CF patients with PI or pancreatic sufficiency. We prospectively evaluated 214 CF patients admitted at 1 hospital for a 2-year period. The PI status was associated with clinical variables and SNPs related with inflammatory response considering CFTR mutations. Open Array technique was used to perform the SNPs identification. For PI risk, after correction by multiple test, in CF patients and 2 CFTR mutations class I, II, and/or III, there were 6 SNPs with positive association (P < 0.005). The odds ratio amplitude was 0.087 (95% confidence interval [CI], 0.004-0.544) for rs9870255*CG (CTNNB1 gene) to 11.06 (95% CI, 1.746-252.3) for rs729302*AA (IRF5 gene). For all CF patients at the same time, 9 SNPs showed positive association. The odds ratio amplitude was 0.144 (95% CI, 0.028-0.602) for rs2348071*AA (PSMA3 gene) to 5.809 (95% CI, 1.536-37.54) for rs11702779*AA (RUNX1 gene). In our data, we observed the interaction between CFTR mutations, rs9870255*CTNNB1, rs9378805*IRF4, and rs7664617*KCNIP4 to PI status. Multiple SNPs in inflammatory response genes showed association with PI considering the CFTR mutations screening.


User perspectives on the Swedish Maternal Health Care Register.
Established in 1999, the Swedish Maternal Health Care Register (MHCR) collects data on pregnancy, birth, and the postpartum period for most pregnant women in Sweden. Antenatal care (ANC) midwives manually enter data into the Web-application that is designed for MHCR. The aim of this study was to investigate midwives' experiences, opinions and use of the MHCR. A national, cross-sectional, questionnaire survey, addressing all Swedish midwives working in ANC, was conducted January to March 2012. The questionnaire included demographic data, preformed statements with six response options ranging from zero to five (0 = totally disagree and 5 = totally agree), and opportunities to add information or further clarification in the form of free text comments. Parametric and non-parametric methods and logistic regression analyses were applied, and content analysis was used for free text comments. The estimated response rate was 53.1%. Most participants were positive towards the Web-application and the included variables in the MHCR. Midwives exclusively engaged in patient-related work tasks perceived the register as burdensome (70.3%) and 44.2% questioned the benefit of the register. The corresponding figures for midwives also engaged in administrative supervision were 37.8% and 18.5%, respectively. Direct electronic transfer of data from the medical records to the MHCR was emphasised as significant future improvement. In addition, the midwives suggested that new variables of interest should be included in the MHCR - e.g., infertility, outcomes of previous pregnancy and birth, and complications of the index pregnancy. In general, the MHCR was valued positively, although perceived as burdensome. Direct electronic transfer of data from the medical records to the MHCR is a prioritized issue to facilitate the working situation for midwives. Finally, the data suggest that the MHCR is an underused source for operational planning and quality assessment in local ANC centres.


Complete Reversion of Cardiac Functional Adaptation Induced by Exercise Training.
Long-term exercise training is associated with characteristic cardiac adaptation, termed athlete's heart. Our research group previously characterized in vivo left ventricular (LV) function of exercise-induced cardiac hypertrophy in detail in a rat model; however, the effect of detraining on LV function is still unclear. We aimed at evaluating the reversibility of functional alterations of athlete's heart after detraining. Rats (n = 16) were divided into detrained exercised (DEx) and detrained control (DCo) groups. Trained rats swam 200 min·d for 12 wk, and control rats were taken into water for 5 min·d. After the training period, both groups remained sedentary for 8 wk. We performed echocardiography at weeks 12 and 20 to investigate the development and regression of exercise-induced structural changes. LV pressure-volume analysis was performed to calculate cardiac functional parameters. LV samples were harvested for histological examination. Echocardiography showed robust LV hypertrophy after completing the training protocol (LV mass index = 2.61 ± 0.08 DEx vs 2.04 ± 0.04 g·kg DCo, P < 0.05). This adaptation regressed after detraining (LV mass index = 2.01 ± 0.03 vs 1.97 ± 0.05 g·kg, n.s.), which was confirmed by postmortem measured heart weight and histological morphometry. After the 8-wk-long detraining period, a regression of the previously described exercise-induced cardiac functional alterations was observed (DEx vs DCo): stroke volume (SV; 144.8 ± 9.0 vs 143.9 ± 9.6 μL, P = 0.949), active relaxation (τ = 11.5 ± 0.3 vs 11.3 ± 0.4 ms, P = 0.760), contractility (preload recruitable stroke work = 69.5 ± 2.7 vs 70.9 ± 2.4 mm Hg, P = 0.709), and mechanoenergetic (mechanical efficiency = 68.7 ± 1.2 vs 69.4 ± 1.8, P = 0.742) enhancement reverted completely to control values. Myocardial stiffness remained unchanged; moreover, no fibrosis was observed after the detraining period. Functional consequences of exercise-induced physiological LV hypertrophy completely regressed after 8 wk of deconditioning.


Caveats of Using Bacterial Type Three Secretion Assays for Validating Fungal Avirulence Effectors in Wheat.
Functional characterization of effector proteins of fungal obligate biotrophic pathogens, especially confirmation of avirulence (Avr) properties, has been notoriously difficult, due to the experimental intractability of many of these organisms. Previous studies in wheat have shown promising data suggesting the type III secretion system (T3SS) of bacteria may be a suitable surrogate for delivery and detection of Avr properties of fungal effectors. However, these delivery systems were tested in the absence of confirmed Avr effectors. Here, we tested two previously described T3SS-mediated delivery systems for their suitability when delivering two confirmed Avr effectors from two fungal pathogens of wheat, Puccinia graminis f. sp. tritici and Magnaporthe oryzae pathotype tritici. We showed that both effectors (AvrSr50 and AvrRmg8) were unable to elicit a hypersensitive response on wheat seedlings with the corresponding resistance gene when expressed by the Pseudomonas fluorescens "Effector to Host Analyser" (EtHAn) system. Furthermore, we found the utility of Burkholderia glumae for screening Avr phenotypes is severely limited, as the wild-type strain elicits nonhost cell death in multiple wheat accessions. These results provide valuable insight into the suitability of these systems for screening fungal effectors for Avr properties that may help guide further development of surrogate bacterial delivery systems in wheat. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.
Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.


Neonatal lupus erythematosus.
Three infants with neonatal lupus erythematosus (LE) had characteristic sharply marginated erythematous papules and plaques without congenital heart block. Two of the infants were definitely photosensitive, while the third infant's eruption began on a photoexposed area. All three infants and their mothers were positive for Ro Sjögren's syndrome A antigen (SSA) antibody. These three infants have additional evidence supporting the concept that transplacental passage of Ro (SSA) antibody is a serologic marker for neonatal LE.


[The workplace-based learning: a main paradigm of an effective continuing medical education].
On the strength of the literature analysis and the Emilia-Romagna Region experience, we suggest a reflection on the workplace-based learning that goes beyond the analysis of the effectiveness of specific didactic methodologies and aspects related to Continuing Medical Education. Health education and training issue is viewed from a wider perspective, that integrates the three learning dimensions (formal, non formal and informal). In such a perspective the workplace-based learning becomes an essential paradigm to reshape the explicit knowledge conveyed in formal context and to emphasize informal contexts where innovation is generated.


Neutrophil hypersegmentation in children receiving angiotensin converting enzyme inhibitors.
Captopril and enalapril are the most commonly used angiotensin converting enzyme inhibitors in several cardiac diseases in children. On the other hand, the intrinsic renin-angiotensin system in the bone marrow might affect the growth of hematopoietic colonies and cellular production, proliferation and differentiation in physiological and pathological states. Starting with the hypothesis that inhibition of the renin-angiotensin system may have some effects on the hematopoietic system, including morphological changes within the granulocytes, we thus aimed to investigate prospectively whether the use of angiotensin converting enzyme inhibitors has any effect on the morphology, and especially segmentation, of neutrophils in peripheral blood. A total of 40 children with various heart diseases receiving either of two angiotensin converting enzyme inhibitors (captopril or enalapril) aged between 2 to 16 years were enrolled, and 40 healthy age- and sex-matched children were enrolled as controls. Complete blood count, peripheral blood smear, liver and renal function tests, and measurement of serum alkaline phosphatase, ferritin, vitamin B12 and folate levels were performed in all cases. Peripheral blood smears were viewed by two pediatric hematologists in a blinded manner. Neutrophil hypersegmentation was described as presence of five or more neutrophils with five well-separated lobes or at least one neutrophil with six or more lobes among 100 segmented neutrophils. The number of patients with neutrophil hypersegmentation in the study group was significantly higher than in the control group, and the mean lobe count in the study group was significantly higher than in the control group. Neutrophil hypersegmentation, as detected in patients using angiotensin converting enzyme inhibitors in the present study, has not been reported previously. Further studies aiming to explain the pathophysiological mechanism(s) underlying neutrophil hypersegmentation in patients receiving angiotensin converting enzyme inhibitors are needed.


OSMOTIC PROPERTIES OF THE EGG CELLS OF THE OYSTER (OSTREA VIRGINICA).
INVESTIGATIONS OF THE OSMOTIC PROPERTIES OF OYSTER EGGS BY A DIFFRACTION METHOD FOR MEASURING VOLUMES HAVE LED TO THE FOLLOWING CONCLUSIONS: 1. The product of cell volume and osmotic pressure is approximately constant, if allowance is made for osmotically inactive cell contents (law of Boyle-van't Hoff). The space occupied by osmotically inactive averages 44 per cent of cell volume. 2. Volume changes over a wide range of pressures are reversible, indicating that the semipermeability of the cell during such changes remains intact. 3. The kinetics of endosmosis and of exosmosis are described by the equation, See PDF for Equation, where dV is rate of volume change; S, surface area of cell, (P-P(e)), the difference in osmotic pressure between cell interior and medium, and K, the permeability of the cell to water. 4. Permeability to water during endosmosis is 0.6micro(3) of water per minute, per square micron of cell surface, per atmosphere of pressure. The value of permeability for exosmosis is closely the same; in this respect the egg cell of the oyster appears to be a more perfect osmometer than the other marine cells which have been studied. Permeability to water computed by the equation given above is in good agreement with computations by the entirely different method devised by Jacobs. 5. Permeability to diethylene glycol averages 27.2, and to glycerol 20.7. These values express the number of mols x 10(-15) which enter per minute through each square micron of cell surface at a concentration difference of 1 mol per liter and a temperature of 22.5 degrees C. 6. Values for permeability to water and to the solutes tested are considerably higher for the oyster egg than for other forms of marine eggs previously examined. 7. The oyster egg because of its high degree of permeability is a natural osmometer particularly suitable for the study of the less readily penetrating solutes.


Effect of methamphetamine dependence on heart rate variability.
Methamphetamine (METH) is an increasing popular and highly addictive stimulant associated with autonomic nervous system (ANS) dysfunction, cardiovascular pathology and neurotoxicity. Heart rate variability (HRV) has been used to assess autonomic function and predict mortality in cardiac disorders and drug intoxication, but has not been characterized in METH use. We recorded HRV in a sample of currently abstinent individuals with a history of METH dependence compared to age- and gender-matched drug-free comparison subjects. HRV was assessed using time domain, frequency domain, and non-linear entropic analyses in 17 previously METH-dependent and 21 drug-free comparison individuals during a 5 minute rest period. The METH-dependent group demonstrated significant reduction in HRV, reduced parasympathetic activity, and diminished heartbeat complexity relative to comparison participants. More recent METH use was associated with increased sympathetic tone. Chronic METH exposure may be associated with decreased HRV, impaired vagal function, and reduction in heart rate complexity as assessed by multiple methods of analysis. We discuss and review evidence that impaired HRV may be related to the cardiotoxic or neurotoxic effects of prolonged METH use.


Impacts of bunk management on steer performance and ruminal hydrogen sulfide concentrations in steers fed modified distillers grains with solubles.
Two experiments were conducted to evaluate the impacts of bunk management on dry matter intake (DMI), growth performance, carcass characteristic, and hydrogen sulfide (H2S) concentrations in beef steers fed modified distillers grains with solubles (MDGS; DM basis). In Experiment 1, 139 steers (440.4 ± 31.0 kg) were randomly assigned to one of 16 pens with pen randomly assigned to one of two treatments: 1) Control (CON, bunks managed to be devoid of feed prior to feeding), or 2) Over-fed (OVF, bunks managed to have minimum of 2.54 cm of feed remaining each morning) during adaptation. Following adaptation all steers in Experiment 1 were transitioned to CON bunks and followed to finishing. In Experiment 2, 126 steers (445.4 ± 40.63 kg) were randomly assigned to one of 16 pens. Treatments in Experiment 2 were arranged in a 2 × 2 factorial and include the two bunk management strategies utilized in Experiment 1 (OVF or CON) and either 25% MDGS or 50% MDGS (DM basis). Ruminal H2S was measured via rumenocentesis during dietary adaptation. There were no differences (P ≥ 0.13) observed in either experiment for growth performance due to bunk management. In Experiment 1, OVF steers had greater (P = 0.001) DMI during adaptation; however, overall DMI was not different (P = 0.14) between treatments. In Experiment 2, DMI (d 0 to 104) tended to decrease (P = 0.09) with greater MDGS inclusion. Hot carcass weight, ribeye area, marbling score, and quality grade were not affected (P ≥ 0.48) by either bunk management or MDGS inclusion. In Experiment 2, back fat (1.30 vs. 1.17 ± 0.042 cm) and yield grade (3.2 vs. 3.0 ± 0.11) were greater (P = 0.03) for CON steers compared with OVF but were not affected (P = 0.59) by MDGS inclusion. In Experiment 1, H2S tended (P = 0.07) to be greater in steers on OVF compared with CON. In Experiment 2, bunk management strategy did not impact (P = 0.82) H2S concentrations. There was a MDGS inclusion × day interaction for H2S with steers fed 50% MDGS having greater (P < 0.01) H2S concentrations compared with steers fed 25% MDGS on d 28 and 35. Bunk management strategy during adaptation did not impact growth performance but did reduce intake in Experiment 1. Yield grade decreased when OVF bunk management was applied throughout Experiment 2. Response of H2S concentrations in the rumen were variable and likely influenced by inconsistencies in bunk management and resulting DMI during the early portions of the feedlot study.


The size and conformation of Artemia (brine-shrimp) ribosomal RNA free in solution.
The RNA was isolated from the large ribosomal subunits of the brine shrimp Artemia, and its conformation free in solution was studied by determining its sedimentation and diffusion coefficients. A comparison was made of the hydrodynamic radius of the ribosomal subunit and its isolated RNA in various buffers. The conformation of the rRNA free in solution is more extended than when it is incorporated in the ribosome. This is not only the case when the rRNA solution lacks bivalent and polyvalent cations, but even in the presence of Mg2+ and spermidine, which cause a tightening of RNA. Thus the ribosomal proteins should induce a further tightening of the rRNA during the assembly of the ribosome. In the discussion, the reported data on Escherichia coli rRNA species are presented in such a way that large discrepancies between various studied are revealed, and that they can be compared with the data reported here on the larger rRNA of an eukaryote.


[Surgical treatment of intra-articular calcaneal fractures].
PURPOSE OF THE STUDY The calcaneus is one of the most complex bones in the human body. If fractured, restoration of its anatomy is demanding and displaced fractures may have permanent consequences affecting both daily living and work activities of the patient. In this prospective study, the authors present the results of surgical treatment of 48 dislocated intra-articular fractures of the heel bone. MATERIAL In the period from September 2006 to September 2009, 48 dislocated intra-articular fractures in 41 patients were surgically treated at the Department of Trauma Surgery in Bratislava-Kramare. Seven (17 %) patients, six men and one woman, had bilateral calcaneal fractures. In the group of 41 patients, 32 (78 %) were men and nine (22 %) were women. The average age of the group was 41 years (range, 16 - 64 years). METHODS Based on computed tomography scans, the fractures (n=48) were classified according to the Sanders system into Sanders II to IV subgroups. This included 26 Sanders II fractures (54 %), 15 Sanders III fractures (31 %) and seven Sanders IV fractures (15 %). Minimally invasive reduction and osteosynthesis (MIOS) was used to treat 16 Sanders II fractures (33.33 %) and two Sanders IV fractures (4.16 %). Open reduction and internal fixation (ORIF) was employed in 10 Sanders II fractures (20.83 %), all 15 Sanders III fractures (31 %) and one Sanders IV fracture (2.08 %). Four comminuted fractures (8.33 %) classified as Sanders IV fractures were stabilised with an external fixator. The surgical technique was selected in accordance with the bone morphology, soft tissue condition and patient's overall state. RESULTS The patients were followed up for 6 to 36 months and clinical assessment was based on the Creighton Nebraska Health Foundation scoring system (C-N score) and the AOFAS Ankle-Hindfoot Scale (A-H score). The functional outcomes were excellent in 25 fractures (52 %), good in nine (18.75 %), less satisfactory in eight (16.6 %) and poor in six fractures (12.5 %). Complications of wound healing were recorded in three fractures (6.25 %) treated by ORIF, and only involved superficial marginal wound necrosis. There was no deep wound infection. Algodystrophic syndrome developed in two cases (4.16 %). X-ray measurements were used to assess the final Böhler's angle, whose value after treatment ranged from 8° to 38°, with an average of 27°. DISCUSSION At present the selection of an operative technique is being discussed. The advocates of MIOS emphasise a lower com- plication rate associated with wound healing and the possibility of using this technique when the treated tissues are in a critical condition. The advantage of ORIF lies in exact open reduction and stable osteosynthesis. CONCLUSIONS The method of percutaneous reduction and osteosynthesis is the optimal treatment for Sanders II dislocated fractures. Severely dislocated fractures (Sanders II and III) require open reduction and plate osteosynthesis. Comminuted fractures should be treated first by external fixation and by arthrodesis at the second stage if problems arise.


Separate attentional resources for vision and audition.
Current models of attention, typically claim that vision and audition are limited by a common attentional resource which means that visual performance should be adversely affected by a concurrent auditory task and vice versa. Here, we test this implication by measuring auditory (pitch) and visual (contrast) thresholds in conjunction with cross-modal secondary tasks and find that no such interference occurs. Visual contrast discrimination thresholds were unaffected by a concurrent chord or pitch discrimination, and pitch-discrimination thresholds were virtually unaffected by a concurrent visual search or contrast discrimination task. However, if the dual tasks were presented within the same modality, thresholds were raised by a factor of between two (for visual discrimination) and four (for auditory discrimination). These results suggest that at least for low-level tasks such as discriminations of pitch and contrast, each sensory modality is under separate attentional control, rather than being limited by a supramodal attentional resource. This has implications for current theories of attention as well as for the use of multi-sensory media for efficient informational transmission.


Clinical features, treatment patterns and short-term outcomes of children with inflammatory bowel disease evaluated in rheumatology clinic.
This study evaluated the clinical features, treatment patterns, and short-term outcomes of children with inflammatory bowel disease (IBD)-associated musculoskeletal manifestations. This was a retrospective cohort study of children with IBD evaluated for joint complaints in a paediatric rheumatology clinic from 2015 to 2020. The index visit was the date of initial rheumatology evaluation. Clinical features were evaluated using standard descriptive statistics. Differences in outcomes over time were compared using rank-sum tests. Univariate logistic regression was used to test associations between clinical features and persistent arthritis or enthesitis. Seventy-five patients met inclusion criteria. 61% had active arthritis or enthesitis at initial evaluation, 1/3 of whom were not yet diagnosed with IBD. Of those with known IBD, over half with joint complaints had arthritis or enthesitis. Active joint disease was common even among patients already receiving tumour necrosis factor (TNF) inhibitors or other immunomodulatory medications for IBD and despite inactive gastrointestinal disease. Treatment escalation was often needed to control articular disease, which included changes in immunomodulatory therapy and NSAIDs. Treatment outcomes for arthritis were good and significant improvements in functional mobility were observed (p<0.01), while enthesitis often persisted at follow-up (11/28, 39%). Moreover, a significant proportion of patients with pain at the index visit reported persistent pain at follow-up (29/44, 65%). This study provides several findings relevant to the multidisciplinary care of children with IBD, including high rates of active arthritis and enthesitis despite ongoing use of immunomodulatory medications for the management of IBD, responses to treatment, and pain management.


[Treatment of renal colic with intravenous ketoprofen].
In view of the part played by renal prostaglandins in the mechanisms responsible for pain in renal colic, it was worth trying to find out whether nonsteroidal anti-inflammatory agents, which inhibit prostaglandin synthesis, have an analgesic effect of their own. In a double-blind trial the effects of ketoprofen 100 mg administered intravenously alone or associated with noramidopyrine were investigated in 62 patients divided at random into two equal groups. A rapid analgesic effect was observed with no significant difference between the groups. No severe side-effects were recorded. The double-blind method made it possible to confirm that ketoprofen administered alone relieved pain in 97% of the patients (with complete sedation in 45%) and acted within 5 minutes. Owing to their effectiveness and safety nonsteroidal anti-inflammatory drugs (especially ketoprofen) may be proposed as an alternative to conventional treatments of renal colic. But because of their activity they should not be prescribed until a firm diagnosis has been made. The cause of the colic should also be rapidly determined in order to treat it as well as the pain it produces.


Unique metabolism of a novel antiviral L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil: a substrate for both thymidine kinase and deoxycytidine kinase.
2'-Fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) is the first L-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other L-nucleoside analogs examined. L-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. L-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of L-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of L-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.


Simultaneous blocking of the pan-RAF and S100B pathways as a synergistic therapeutic strategy against malignant melanoma.
Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five-year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF-selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan-RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan-RAF and S100B pathways.


Characterization of Burkholderia pseudomallei and Burkholderia pseudomallei-like strains.
Previous reports in the literature suggest that Burkholderia pseudomallei strains can be differentiated on the basis of animal virulence. Twenty environmentally and clinically derived isolates of Burkholderia pseudomallei were examined for the production of exoenzymes, morphological and biochemical phenotypes and virulence for Syrian golden hamsters. The partial sequence of the 16S ribosomal RNA [rRNA] genes from a number of these strains was also determined. Based upon these observations, it is suggested that highly virulent Burkholderia pseudomallei strains are true Burkholderia pseudomallei strains. The DNA sequences of the 16S rRNA genes of the true Burkholderia pseudomallei strains were identical to the published sequences for Burkholderia pseudomallei while differences were revealed between the published sequences and those of the lowly virulent strains. Thus, these latter strains have been designated as Burkholderia pseudomallei-like organisms since they demonstrate significant differences in exoenzyme production, hamster virulence and 16S rRNA gene sequences.


Electrical Control of Lifetime-Limited Quantum Emitters Using 2D Materials.
Solid-state quantum emitters are a mainstay of quantum nanophotonics as integrated single-photon sources (SPS) and optical nanoprobes. Integrating such emitters with active nanophotonic elements is desirable in order to attain efficient control of their optical properties, but it typically degrades the photostability of the emitter itself. Here, we demonstrate a tunable hybrid device that integrates state of the art lifetime-limited single emitters (line width ∼40 MHz) and 2D materials at subwavelength separation without degradation of the emission properties. Our device's nanoscale dimensions enable ultrabroadband tuning (tuning range >400 GHz) and fast modulation (frequency ∼100 MHz) of the emission energy, which renders it an integrated, ultracompact tunable SPS. Conversely, this offers a novel approach to optical sensing of 2D material properties using a single emitter as a nanoprobe.


Hemodynamic effect of carotid endarterectomy.
Cerebral blood flow was measured by the intravenous xenon-133 technique at rest and during cerebral vasodilation with acetazolamide in 32 patients before and after uncomplicated carotid endarterectomy. The results were compared with the internal carotid artery perfusion pressure measured during surgery. A significant improvement in side-to-side cerebral blood flow asymmetry occurred in 6 patients studied at baseline and in 11 patients during provoked cerebral vasodilation. These patients all belonged to a group of 14 patients who, in addition to a severe stenosis of the internal carotid artery, presented a reduction in cerebral perfusion pressure of at least 20%. No improvements occurred in 18 patients with no or only minor reduction in perfusion pressure, irrespective of the degree of stenosis. These findings indicate an improved perfusion reserve following carotid endarterectomy in most patients with marked reduction in perfusion pressure, whereas only some of these patients will experience an improvement in baseline cerebral blood flow.


Acquired coronary angiogenesis after myocardial infarction.
Acquired coronary artery microvascular fistulas have been reported in only a few patients after myocardial infarction. We describe 1 patient in whom serial coronary angiography demonstrated the development of coronary angiogenesis at the site of an old myocardial infarction. The area of neovascularity was associated with a large apical left ventricular thrombus. This finding suggests that growth-promoting mitogens are present in myocardium and thrombus and that angiogenesis occurs in some patients following myocardial infarction.


Comparisons of Activity Budgets, Interactions, and Social Structures in Captive and Wild Chimpanzees (Pan troglodytes).
Chimpanzees in zoos with sufficient and appropriate environmental enrichment devices are expected to exhibit behaviors, interactions, and societies similar to those in the wild. In this study, we compared the activity budgets of each observed behavior, characteristics of social grooming, and social networks of captive chimpanzees at Tama Zoological Park (Tama) with those of wild chimpanzees at Mahale Mountains National Park, Tanzania (Mahale), and tested our predictions. We surveyed 16 chimpanzees in both Tama and Mahale and recorded the behaviors and individuals in proximity of each focal individual and social grooming the focal individuals participated in. The proportion of time spent collecting foraging was significantly lower in Tama than in Mahale. Additionally, the percentage of mutual grooming was much higher in Tama than in Mahale. All focal individuals in Mahale performed mutual grooming interactions, including grooming handclasp (GHC) but this was not observed in Tama. The result of a high rate of mutual grooming in chimpanzees in Tama without GHC and the finding that individuals forming the core of their social network are sex independent suggest that chimpanzees placed in an appropriate environmental enrichment have idiosyncratic grooming or social features, even in captivity.


Adult motor patterns produced by moth pupae during development.
Muscle potentials were recorded extracellularly from developing pupae and adults of the saturniid moths Antheraea polyphemus and A. pernyi and the sphingid moth Manduca sexta. During the week prior to the terminal ecdysis, developing moths still enclosed within the pupal cuticle produced motor patterns similar to those recorded from adults during flight and shivering. The pupal patterns had a longer cycle time and were more variable than the adult motor patterns. Characteristic inter-family differences in adult motor patterns were apparent in pupal motor patterns. Development of motor patterns was followed over several days by observing individuals with chronically implanted leads. Early in the pupal period potentials were small and infrequent. The amount of activity gradually increased and became more patterned. As development proceeded adult patterns were produced for increasing lengths of time, although the patterns changed quickly and spontaneously. Restricting the wing movements of A. polyphemus adults increased the cycle time, increased the number of spikes per burst in muscles opposing the restraint, and did not alter the interspike interval within a burst. The flight patterns produced by pharate moths, in which the wings are also immobile, also have a longer cycle time than that of adult flight, but the number of spikes per burst the same and the interspike interval is longer than in adult flight. These observations suggest that the differences between pupal and adult patterns are not necessarily due to the confinement of the wings by the pupal cuticle.


[Perioperative Infusion Therapy in Children].
The composition and type of intravenous fluids during paediatric anaesthesia have been subjects of debates for decades. Errors in perioperative infusion therapy in children may lead to serious complications and a negative outcome. Therefore, in this review historical and recent developments and recommendations for perioperative fluid management in children are presented, based on physiology and focused on safety and efficacy. Recent studies showed that optimized preoperative fasting times and liberal clear fluid intake until 1 h improve patient comfort and metabolic and haemodynamic condition after induction of anaesthesia. Physiologically composed balanced isotonic electrolyte solutions are safer than hypotonic electrolyte solutions or saline 0.9% to protect young children against the risks of hyponatraemia and hyperchloremic acidosis. For intraoperative maintenance infusion, addition of 1 - 2% glucose is sufficient to avoid hypoglycaemia, lipolysis or hyperglycaemia. Modified fluid gelatine or hydroxyethyl starch in balanced electrolyte solution can safely be used to quickly normalize blood volume in case of perioperative circulatory instability and blood loss. In conclusion, physiologically composed infusion solutions are beneficial for maintaining homeostasis, shifting the status more towards the normal range in children with pre-existing imbalances and have a wide safety margin in case of accidental hyperinfusion.


Low-Level Laser Therapy to the Bone Marrow Reduces Scarring and Improves Heart Function Post-Acute Myocardial Infarction in the Pig.
Cell therapy for myocardial repair is one of the most intensely investigated strategies for treating acute myocardial infarction (MI). The aim of the present study was to determine whether low-level laser therapy (LLLT) application to stem cells in the bone marrow (BM) could affect the infarcted porcine heart and reduce scarring following MI. MI was induced in farm pigs by percutaneous balloon inflation in the left coronary artery for 90 min. Laser was applied to the tibia and iliac bones 30 min, and 2 and 7 days post-induction of MI. Pigs were euthanized 90 days post-MI. The extent of scarring was analyzed by histology and MRI, and heart function was analyzed by echocardiography. The number of c-kit+ cells (stem cells) in the circulating blood of the laser-treated (LT) pigs was 2.62- and 2.4-fold higher than in the non-laser-treated (NLT) pigs 24 and 48 h post-MI, respectively. The infarct size [% of scar tissue out of the left ventricle (LV) volume as measured from histology] in the LT pigs was 3.2 ± 0.82%, significantly lower, 68% (p < 0.05), than that (16.6 ± 3.7%) in the NLT pigs. The mean density of small blood vessels in the infarcted area was significantly higher [6.5-fold (p < 0.025)], in the LT pigs than in the NLT ones. Echocardiography (ECHO) analysis for heart function revealed the left ventricular ejection fraction in the LT pigs to be significantly higher than in the NLT ones. LLLT application to BM in the porcine model for MI caused a significant reduction in scarring, enhanced angiogenesis and functional improvement both in the acute and long term phase post-MI.


Prevalence of incomplete ossification of the humeral condyle and other abnormalities of the elbow in English Springer Spaniels.
To determine the prevalence of incomplete ossification of the humeral condyle (IOHC) and other osseous abnormalities of the elbow in English Springer Spaniels with no history of lameness. Prospective observational study of English Springer Spaniels with no recent history of lameness. Computed tomography scans of both elbows were obtained from dogs older than six months of age which were anaesthetized or sedated for reasons unrelated to this study. Computed tomography scans were reviewed for the presence of IOHC and other abnormalities of the elbow. Radioulnar incongruity (RUI) measurements from normal elbows were compared to elbows with IOHC and elbows with medial coronoid process (MCP) abnormalities. Computed tomography scans from 50 dogs (100 elbows) were reviewed. The prevalence of IOHC was 14% (8 elbows in 7 dogs). All condylar fissures were incomplete with a mean length of 2.6 mm. Fifty percent of the dogs (44% of elbows) had abnormalities of the medial coronoid process and 60% of the elbows had periarticular osteophytes. Group RUI meansurements for IOHC and MCP were not significantly different from normal elbows. Small IOHC fissures, periarticular osteophytes and MCP abnormalities may be identified in English Springer Spaniels without forelimb lameness. Abnormalities of the MCP are more common than IOHC.


Improving the identification rate of endogenous peptides using electron transfer dissociation and collision-induced dissociation.
Tandem mass spectrometry (MS/MS) combined with bioinformatics tools have enabled fast and systematic protein identification based on peptide-to-spectrum matches. However, it remains challenging to obtain accurate identification of endogenous peptides, such as neuropeptides, peptide hormones, peptide pheromones, venom peptides, and antimicrobial peptides. Since these peptides are processed at sites that are difficult to predict reliably, the search of their MS/MS spectra in sequence databases needs to be done without any protease setting. In addition, many endogenous peptides carry various post-translational modifications, making it essential to take these into account in the database search. These characteristics of endogenous peptides result in a huge search space, frequently leading to poor confidence of the peptide characterizations in peptidomics studies. We have developed a new MS/MS spectrum search tool for highly accurate and confident identification of endogenous peptides by combining two different fragmentation methods. Our approach takes advantage of the combination of two independent fragmentation methods (collision-induced dissociation and electron transfer dissociation). Their peptide spectral matching is carried out separately in both methods, and the final score is built as a combination of the two separate scores. We demonstrate that this approach is very effective in discriminating correct peptide identifications from false hits. We applied this approach to a spectral data set of neuropeptides extracted from mouse pituitary tumor cells. Compared to conventional MS-based identification, i.e., using a single fragmentation method, our approach significantly increased the peptide identification rate. It proved also highly effective for scanning spectra against a very large search space, enabling more accurate genome-wide searches and searches including multiple potential post-translational modifications.


Hypertensive Stimuli Indirectly Stimulate Lymphangiogenesis through Immune Cell Secreted Factors.
(1) Background: Renal immune cells and lymphatic vessel (LV) density have been reported previously to be increased in multiple mouse models of hypertension (HTN). However, whether interstitial levels of HTN stimuli such as angiotensin II, salt, or asymmetric dimethylarginine have a direct or indirect effect on lymphangiogenesis is unknown. We hypothesized that these 3 HTN stimuli directly increase lymphatic endothelial cell (LEC) proliferation, LEC 3-D matrix invasion and vessel formation, and sprouting of mouse mesometrial LVs. (2) Methods: Human LECs (hLECs) and mouse LECs (mLECs) were treated with HTN stimuli while explanted mouse mesometrial LVs were treated with either the same HTN stimuli or with HTN stimuli-conditioned media. Conditioned media was prepared by treating murine splenocytes with HTN stimuli. (3) Results: HTN stimuli had no direct effect on hLEC or mLEC proliferation. Treatment of hLECs with HTN stimuli increased the number of lumen-forming structures and invasion distance (both p < 0.05) in the 3-D matrix but decreased the average lumen diameter and the number of cells per invading structure (both p < 0.05). Conditioned media from HTN-stimuli-treated splenocytes significantly attenuated the decrease in sprout number (aside from salt) and sprout length of mouse mesometrial LVs that is found in the HTN stimuli alone. (4) Conclusions: These data indicate that HTN stimuli indirectly prevent a decrease in lymphangiogenesis through secreted factors from HTN-stimuli-treated immune cells.


Prevalence of traumatic myiasis in Hungary: a questionnaire survey of veterinarians.
Veterinarians in Hungary were asked to complete a questionnaire on traumatic myiasis; of the 664 veterinarians contacted, 247 replied (37.2 per cent) and of these 209 (84.6 per cent) reported myiasis to be a problem among the livestock they treated. Infestation levels of > 10 per cent of animals were reported in sheep, cattle and horses. The myiasis season lasted from March to November with most cases reported in July and August. Significantly more respondents reported that fly larvae were present deep in wounds rather than superficially, consistent with infestations due to the obligate parasite Wohlfahrtia magnifica (Diptera: Sarcophagidae). Frequent inspections and the treatment of infested animals were reported by 64.1 per cent of respondents as contributing to the economic impact of traumatic myiasis, and approximately half of the respondents (51.4 per cent) reported that inspections and treatments were carried out at least weekly during the summer. The most common form of treatment was the manual removal of larvae followed by topical application of insecticides, particularly organophosphates. More than half of the respondents (56.6 per cent) reported that there had been no change in the importance of myiasis over the last five to 10 years, but of those who reported a change, more reported an increase (28.3 per cent) than a decrease (15.2 per cent).


National Trends in Acellular Dermal Matrix Utilization in Immediate Breast Reconstruction.
Implant-based reconstruction is the most common method of immediate breast reconstruction in the United States, with acellular dermal matrices (ADMs) playing a significant role in implant support and coverage. This study evaluated recent national trends in ADM use in immediate breast reconstruction and assessed patient characteristics and 30-day complication rates. The authors queried the American College of Surgeons National Surgical Quality Improvement Program database for all patients undergoing immediate breast reconstruction from 2015 to 2020. Primary outcomes were major surgical and medical complications, as well as ADM use per year. Subset analysis was performed to compare patients undergoing immediate breast reconstruction with ADM in 2015 versus 2020. In 39,800 immediate breast reconstructions, ADMs were used in 55.5% of cases ( n = 22,087). ADM usage increased annually from 2015 through 2020. Direct-to-implant reconstruction was significantly associated with ADM use ( P < 0.001). Compared with the no-ADM cohort, there was a significantly increased rate of return to the operating room for any reason ( P < 0.001). When comparing the 2015 and 2020 ADM cohorts, the 2020 ADM cohort had a significantly higher rate of superficial infections. Obesity, smoking history, and insulin-dependent diabetes were independent risk factors for superficial wounds in patients receiving ADM. ADM use in immediate breast reconstruction increased significantly from 2015 to 2020, likely reflecting national trends in increasing direct-to-implant and prepectoral breast reconstruction. Obesity, smoking history, and insulin-dependent diabetes were independent risk factors for superficial wound infections in the ADM cohort. Patients with ADM had a slight increased incidence of return to the operating room. Risk, II.


Nuclear factor one X regulates the development of multiple cellular populations in the postnatal cerebellum.
Development of the cerebellum involves the coordinated proliferation, differentiation, maturation, and integration of cells from multiple neuronal and glial lineages. In rodent models, much of this occurs in the early postnatal period. However, our understanding of the molecular mechanisms that regulate this phase of cerebellar development remains incomplete. Here, we address the role of the transcription factor nuclear factor one X (NFIX), in postnatal development of the cerebellum. NFIX is expressed by progenitor cells within the external granular layer and by cerebellar granule neurons within the internal granule layer. Using NFIX⁻/⁻ mice, we demonstrate that the development of cerebellar granule neurons and Purkinje cells within the postnatal cerebellum is delayed in the absence of this transcription factor. Furthermore, the differentiation of mature glia within the cerebellum, such as Bergmann glia, is also significantly delayed in the absence of NFIX. Collectively, the expression pattern of NFIX, coupled with the delays in the differentiation of multiple cell populations of the developing cerebellum in NFIX⁻/⁻ mice, suggest a central role for NFIX in the regulation of cerebellar development, highlighting the importance of this gene for the maturation of this key structure.


Maternal nutrient restriction affects properties of skeletal muscle in offspring.
Maternal nutrient restriction (NR) affects fetal development with long-term consequences on postnatal health of offspring, including predisposition to obesity and diabetes. Most studies have been conducted in fetuses in late gestation, and little information is available on the persistent impact of NR from early to mid-gestation on properties of offspring skeletal muscle, which was the aim of this study. Pregnant ewes were subjected to 50% NR from day 28-78 of gestation and allowed to deliver. The longissimus dorsi muscle was sampled from 8-month-old offspring. Maternal NR during early to mid-gestation decreased the number of myofibres in the offspring and increased the ratio of myosin IIb to other isoforms by 17.6 +/- 4.9% (P < 0.05) compared with offspring of ad libitum fed ewes. Activity of carnitine palmitoyltransferase-1, a key enzyme controlling fatty acid oxidation, was reduced by 24.7 +/- 4.5% (P < 0.05) in skeletal muscle of offspring of NR ewes and would contribute to increased fat accumulation observed in offspring of NR ewes. Intramuscular triglyceride content (IMTG) was increased in skeletal muscle of NR lambs, a finding which may be linked to predisposition to diabetes in offspring of NR mothers, since enhanced IMTG predisposes to insulin resistance in skeletal muscle. Proteomic analysis by two-dimensional gel electrophoresis demonstrated downregulation of several catabolic enzymes in 8-month-old offspring of NR ewes. These data demonstrate that the early to mid-gestation period is important for skeletal muscle development. Impaired muscle development during this stage of gestation affects the number and composition of fibres in offspring which may lead to long-term physiological consequences, including predisposition to obesity and diabetes.


Membrane dynamics and cell polarity: the role of sphingolipids.
In recent years, glycosphingolipids (GSLs) have attracted widespread attention due to the appreciation that this class of lipids has a major impact on biological life. Inhibition of the synthesis of glucosylceramide, which serves as a precursor for the generation of complex glycosphinglipids, is embryonic lethal. GSLs play a major role in growth and development. Metabolites of sphingolipids, such as ceramide, sphinganine, and sphingosine, may function as second messengers or regulators of signal transduction that affect events ranging from apoptosis to the (co)regulation of the cell cycle. In addition, GSLs can provide a molecular platform for clustering of signal transducers. The ability of sphingolipids, with or without cholesterol, to form microdomains or rafts is critical in sorting and membrane transport that underlies the biogenesis of polarized membrane domains. Here, a brief summary is presented of some recent developments in this field, with a particular emphasis on raft assembly and membrane transport in the establishment of membrane polarity.


Correlation of COX-2 and MMP-13 expressions with gastric cancer and their effects on prognosis.
To study the expressions of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-13 (MMP-13) genes in gastric cancer, and to investigate the correlation between them and gastric cancer and their effects on prognosis. 80 cases of tumor tissues and 40 cases of normal tumor-adjacent tissues were collected from patients with gastric cancer admitted to the Surgical Department of our hospital. The mRNA expression levels of COX-2 and MMP-13 in tumor tissues and normal tumor-adjacent tissues were detected via real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR). The expressions of COX-2 and MMP-13 in gastric cancer tissues and normal tumor-adjacent tissues were detected via immunohistochemical method. The clinical data of patients were recorded and the correlation between the COX-2 and MMP-13 expressions and the pathological parameters and prognosis of patients with gastric cancer were analyzed. RT-PCR results showed that the mRNA expressions of COX-2 and MMP-13 in gastric cancer tissues were significantly higher than those in normal tumor-adjacent tissues. Immunohistochemical results showed that the positive expression rates of COX-2 and MMP-13 in gastric cancer tissues were 76.25% (60/80) and 71.25% (57/80), respectively and the high expression was related to the invasion, metastasis and tumor stage. The 5-year overall survival of patients was 16.6% (13/80). Single-factor survival analysis showed that both COX-2 and MMP-13 were factors influencing the overall survival of patients with gastric cancer (p<0.01). The high expressions of COX-2 and MMP-13 are closely related to the pathological parameters of patients with gastric cancer, especially the invasion, metastasis and tumor stage. COX-2 and MMP-13 can be used as reference indexes to guide the treatment of gastric cancer and predict the disease prognosis.


Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults.
Understanding the predictive utility of previously derived polygenic risk scores (PRSs) for long-term risk of coronary heart disease (CHD) and its additive value beyond traditional risk factors can inform prevention strategies. Data from adults 20 to 59 years of age who were free of CHD from the FOS (Framingham Offspring Study) and the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Because the PRS was derived from samples of predominantly European ancestry, individuals who self-reported White race were included. The sample was stratified by age and cohort: young (FOS, 20-39 years [median, 30 years] of age), early midlife (FOS, 40-59 years [median, 43] years of age), and late midlife (ARIC, 45-59 years [median, 52 years] of age). Two previously derived and validated prediction tools were applied: (1) a 30-year traditional risk factor score and (2) a genome-wide PRS comprising >6 million genetic variants. Hazard ratios for the association between each risk estimate and incident CHD were calculated. Predicted and observed rates of CHD were compared to assess discrimination for each model individually and together with the optimism-corrected C index (95% CI). Among 9757 participants, both the traditional risk factor score (hazard ratio per 1 SD, 2.60 [95% CI, 2.08-3.27], 2.09 [95% CI, 1.83-2.40], and 2.11 [95% CI, 1.96-2.28]) and the PRS (hazard ratio, 1.98 [95% CI, 1.70-2.30], 1.64 [95% CI, 1.47-1.84], and 1.22 [95% CI, 1.15-1.30]) were significantly associated with incident CHD in young, early midlife, and late midlife, respectively. Discrimination was similar or better for the traditional risk factor score (C index, 0.74 [95% CI, 0.70-0.78], 0.70 [95% CI, 0.67-0.72], and 0.72 [95% CI, 0.70-0.73]) compared with an age- and sex-adjusted PRS (0.73 [95% CI, 0.69-0.78], 0.66 [95% CI, 0.62-0.69], and 0.66 [95% CI, 0.64-0.67]) in young, early-midlife, and late-midlife participants, respectively. The ΔC index when PRS was added to the traditional risk factor score was 0.03 (95% CI, 0.001-0.05), 0.02 (95% CI, -0.002 to 0.037), and 0.002 (95% CI, -0.002 to 0.006) in young, early-midlife, and late-midlife participants, respectively. Despite a statistically significant association between PRS and 30-year risk of CHD, the C statistic improved only marginally with the addition of PRS to the traditional risk factor model among young adults and did not improve among midlife adults. PRS, an immutable factor that cannot be directly intervened on, has minimal clinical utility for long-term CHD prediction when added to a traditional risk factor model.


In situ localization of the major capsid protein during lytic infection by herpes simplex virus.
The intracellular localization of the major capsid protein (ICP5) of herpes simplex virus was studied during virogenesis. Except for a brief period at the onset of synthesis, this protein was found almost exclusively inside the nucleus. Its localization was not at random since 80% was tightly bound to the nuclear matrix as early as 4 h after infection. Discrete modifications of the fluorescence pattern occurred in an orderly fashion during the progression of the infection. Immunoelectron microscopic studies using Protein A-gold labelling demonstrated that this protein is synthesized on cytoskeleton-bound polyribosomes and accumulates in the central part of the nucleus where formation of viral capsids occurs; no gold particles were found in association with the peripheral chromatin or with the nucleolus.


NTera2: a model system to study dopaminergic differentiation of human embryonic stem cells.
NTera2, a human embryonal carcinoma (EC) stem cell line, shares many characteristics with human embryonic stem cells (hESCs). To determine whether NTera2 can serve as a useful surrogate for hESCs, we compared global gene expression between undifferentiated NTera2, multiple undifferentiated hESC cell lines, and their differentiated derivatives, and we showed that NTera2 cells share multiple markers with hESCs. Similar to hESCs, NTera2 cells differentiated into TH-positive cells that express dopaminergic markers including AADC, DAT, Nurr1, TrkB, TrkC, and GFRA1 when co-cultured with PA6 cells. Flow cytometry analysis showed that tyrosine hydroxylase (TH) and neural cell adhesion molecule (NCAM) expression increased, whereas SSEA4 expression decreased as cells differentiated. Medium conditioned by PA6 cells stimulated differentiation of NTera2 cells to generate TH-positive cells that expressed dopaminergic markers. Flow cytometry selected polysialylated (PSA-NCAM) cells responded to medium conditioned by PA6 cells by differentiating into TH-positive cells and expressed dopaminergic markers. Sorted cells differentiated for 4 weeks in PA6 cell conditioned media included functional neurons that responded to neurotransmitters and exhibited electronic excitability. Therefore, NTera2 cell dopaminergic neuronal differentiation and PSA-NCAM enrichment provides a useful system for the future study of hESCs.


Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence.
Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type-specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types. A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time. For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%). HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA-negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.


Content and composition of hopanoids in Zymomonas mobilis under various growth conditions.
By using a new method for quantification of the different hopanoid derivatives, a total hopanoid content of about 30 mg/g (dry cell weight) was observed in Zymomonas mobilis. This value is the highest reported for bacteria so far. The major hopanoids in Z. mobilis were the ether and glycosidic derivatives of tetrahydroxy-bacteriohopane, constituting about 41 and 49% of the total hopanoids. Tetrahydroxybacteriohopane itself, diplopterol, and hopene made up about 6, 3, and 1%, respectively. Only minor changes in hopanoid composition were observed with changes in growth conditions. Earlier reports on a correlation between hopanoid content and ethanol concentration in the medium could not be confirmed. Over a wide range of ethanol concentrations (5 to 60 g/liter), growth rates (0.08 to 0.25 h-1), and temperatures (25 to 37 degrees C), the molar ratio of hopanoids to phospholipids in the cells amounted to about 0.7. Only at growth rates of greater than 0.30 h-1 did the molar ratio increase to about 1.


Potential approaches to the treatment of Ewing's sarcoma.
Ewing's sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low. Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients. Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES.


Transplantable delivery systems for in situ controlled release of bisphosphonate in orthopedic therapy.
Bisphosphonates (BPs), structurally similar to pyrophosphates and functionally superior in restraining osteoclast-induced bone resorption, have been widely used as clinical drugs in the treatment of osteoporosis, bone voids and associated inflammation. However, owing to their high aqueous solubility and the consequently high rate of loss during oral administration, the loading and targeting of BPs pose major challenges in practice. Alternative delivery routes such as nasal, subcutaneous/intramuscular injection have contributed little to improving the bioavailiability and efficacy of BPs. To improve and optimize the delivery efficiency and efficacy of BPs, numerous strategies have been developed and adopted. Studies on controlled release of BPs provide important information on the fabrication of BP delivery systems for in situ treatment. As BPs play an important therapeutic role in osteoporosis and similar diseases, it has become essential and vital to survey various reported fabrication methodologies of these systems and the consequential orthopedic treatments so as to keep abreast with advances in their clinical use. Transplantable delivery systems for controlled release of BP are reviewed from literature published since 2000. The fabrication pathways and the release of BPs from various material systems are discussed in case studies. Recent progress in CaP models based on the strong and specific chelation between BPs and calcium phosphate crystals is highlighted. This review offers an outline of the advances in BP controlled release and delivery systems for orthopedic therapy. Understanding the cutting-edge BP controlled release and delivery systems for in situ treatment is key to the successful design of a more promising and perfect delivery system for orthopedic therapy. Moreover, developing such delivery systems incorporating the numerous advantages of BPs and controlled release environment requires substantially more flexible models to control better the fate of BP drugs.


Case-control matching-guided exposure-efficacy relationship for avelumab in patients with urothelial carcinoma.
Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case-control matching to account for this bias and better understand the E-R relationship for avelumab in urothelial carcinoma, a PD-L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN-100 was utilized which is a phase III study of avelumab in first-line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best-supportive care leading to approval in the United States, Europe, and other countries. A post hoc case-control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.


Modification of nociception in a model of localized inflammatory pain by long-term administration of naloxone.
Inoculation of the right hind paw with Mycobacterium butyricum led to an inflammation reflected in a reduction in the threshold to respond to noxious pressure. Chronic perfusion of naloxone at a 'high' dose of 3.0 mg/kg/hr blocked the antinociceptive action of the mu-agonist, morphine, and the kappa-agonist, U69 593. In contrast, a 'low' dose of 0.16 mg/kg/hr antagonized the action only of morphine. Two days postimplantation, the hyperalgesia to pressure was potentiated in rats receiving the high, but not the low dose of naloxone. At 6 days, this difference was no longer seen. At 7 days, pumps were removed; one day later, in rats which had been receiving the high, (but not low) dose of naloxone, thresholds on the inflamed paw no longer differed from those on the uninflamed paw. This may reflect supersensitivity to an endogenous opioid. The data suggest that kappa-receptors may contribute to control of nociception in inflammatory pain. However, this role does not appear to be essential.


Perceptual learning of motion leads to faster flicker perception.
Critical flicker fusion thresholds (CFFT) describe when quick amplitude modulations of a light source become undetectable as the frequency of the modulation increases. The threshold at which CFF occurs has been shown to remain constant under repeated testing. Additionally, CFF thresholds are correlated with various measures of intelligence, and have been regarded by clinicians as a general measure of cortical processing capacity. For these reasons, CFF is used as a cognitive indicator in drug studies, as a measure of fatigue, and has been suggested as a diagnostic measure for various brain diseases. Here we report that CFFT increases dramatically in subjects who are trained with a motion-direction learning procedure. Control tasks demonstrate that CFFT changes are tightly coupled with improvements in discriminating the direction of motion stimuli, and are likely related to plasticity in low-level visual areas that are specialized to process motion signals. This plasticity is long-lasting and is retained for at least one year after training. Combined, these results show that CFFT relates to a specialized sensory process and bring into question that CFFT is a measure of high-level, or general, processes.


A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1.
An observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype-genotype correlations. Ten FSHD1 probands carrying 4-9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels. The maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats. This family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling.


Life-long optimization of the symbolic model of indoor environments for a mobile robot.
The use of a symbolic model of the spatial environment becomes crucial for a mobile robot that is intended to operate optimally and intelligently in indoor scenarios. Constructing such a model involves important problems that are not solved completely at present. One is called anchoring, which implies to maintain a correct dynamic correspondence between the real world and the symbols in the model. The other problem is adaptation: among the numerous possible models that could be constructed for representing a given environment, optimization involves the selection of one that improves as much as possible the operations of the robot. To cope with both problems, in this paper, we propose a framework that allows an indoor mobile robot to learn automatically a symbolic model of its environment and to optimize it over time with respect to changes in both the environment and the robot operational needs through an evolutionary algorithm. For coping efficiently with the large amounts of information that the real world provides, we use abstraction, which also helps in improving task planning. Our experiments demonstrate that the proposed framework is suitable for providing an indoor mobile robot with a good symbolic model and adaptation capabilities.


The interactions of dietary tomato powder and soy germ on prostate carcinogenesis in the TRAMP model.
The interactions between bioactive-rich food components within a complex human diet for the inhibition of prostate carcinogenesis are largely unknown and difficult to quantify in humans. Tomato and soy products have each shown anti-prostate cancer (PCa) activity in laboratory studies. The objective of this study was to determine the efficacy of dietary tomato and soy germ, alone and in combination, for the inhibition of PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. At 4 weeks of age, male C57BL/6 × FVB TRAMP mice (n = 119) were randomized to consume: AIN-93G control, 10% whole tomato powder (TP), 2% soy germ powder (SG), or 10% tomato powder with 2% soy germ powder (TP+SG) for 14 weeks. One hundred percent of mice fed the control diet had PCa, whereas PCa incidence was significantly lower in mice consuming TP (61%, P < 0.001), SG (66%, P < 0.001), and TP+SG (45%, P < 0.001). Although the protection offered by the combination of TP and SG was not synergistic, it was the most effective intervention. TP, SG, and TP+SG increased apoptotic index (AI) and modestly reduced the proliferative index (PI) in the prostate epithelium of TRAMP mice exhibiting primarily prostatic intraepithelial neoplasia. The dramatic reduction in the PI/AI ratio by the dietary interventions suggests that the control mice experience a stronger stimulus for malignant progression in the prostate microenvironment. Maximally effective and safe strategies for PCa prevention may result from optimizing combinations of nutrients and bioactives through an orchestration of dietary patterns.


Late anastomotic ulceration after ileocolic resection in childhood [corrected].
Anastomotic ulcers are a rare late complication of ileocolic resection in children. The authors describe the cases of two patients who presented 10 and 8 years, respectively, after ileocolic resection. Both had suffered from iron-deficiency anemia caused by an anastomotic ulcer. In one patient the anemia improved after resection of the ulcer; in the second patient cholestyramine and a lactose-free diet resolved the problems of anemia and diarrhea. Anastomotic ulceration should be suspected in any child who has undergone an ileocolic anastomosis and subsequently presents with persistent iron-deficiency anemia and occult blood in the stool.


A striving towards 'normality': illness-related beliefs among individuals living with a psychotic disorder.
Beliefs related to illness constrain or facilitate health and wellbeing, and are of importance in how people understand and manage their illness. The aim of this study was to identify illness beliefs among individuals living with illness from a psychotic disorder. Data collected through two qualitative interview studies was secondary analysed by means of a method for directed content analysis. Beliefs of being different and odd, and of what constitutes 'normality', are prominent and constrain, in several respects, wellbeing among the individuals with psychotic illness. Beliefs about possible wellbeing are preferably related to existential, human desires of caretaking and responsibility for self and others. An awareness among mental healthcare staff that one does not hold the unequivocal truth about what is normal and healthy, is of importance. They need to ask questions about illness beliefs and not ignore or judge the answers received, but instead discuss them. Relationship-centred care, where a mutual dialogue occurs between the individual, the family and mental healthcare staff, is highlighted.


Infection in hip arthroplasty after previous injection of steroid.
Immunosuppression following intra-articular injections of steroid into the hip may interfere with asepsis in a subsequent total hip arthroplasty (THA). We have undertaken a retrospective, matched, cohort study of infective complications after THA, in 40 patients who had received such an injection and 40 who had not. In the injection group there were five revisions, four of which were for deep infection. There were none in the matched group. The overall rate of revision in our database of 979 primary THAs was 1.02%. Six additional patients who had received injections underwent investigation for infection because of persistent problems in the hip as compared with one in the control group.


A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.
MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer. Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity.


Admission Leukocyte Count is Associated with Late Cardiogenic Shock Development and All-Cause 30-Day Mortality in Patients with St-Elevation Myocardial Infarction.
Thirty-day mortality in ST-elevation myocardial infarction (STEMI) patients is primarily driven by cardiogenic shock (CS). High neutrophil counts and high neutrophil/lymphocyte ratios (NLR) have previously been associated with mortality in STEMI patients; however, there is only sparse knowledge regarding their association with CS. We sought to assess the associations between neutrophil count and NLR with the development of CS as well as 30-day mortality in STEMI patients. Patients admitted with STEMI at two tertiary Heart Centres throughout 1 year were included in the study and stratified into quartiles according to the level of leukocyte count upon admission. The primary endpoint was development of CS both before (early CS) and after leaving the catheterization laboratory (late CS). The secondary endpoint was all-cause 30-day mortality. A total of 1,892 STEMI patients were included, whereof 194 (10%) developed CS while 122 (6.4%) died within 30 days. Patients in the highest quartile of neutrophils (OR: 2.54; 95% CI: 1.40-4.60; P = 0.002) and NLR (OR: 3.64; 95% CI: 2.02-6.54; P<0.0001) were at increased risk of developing late CS compared with patients in the lower quartiles, whereas there was no risk difference across quartiles regarding development of early CS. Both biomarkers correlated strongly to an increased 30-day mortality (plogrank<0.0001) and, moreover, a high level of neutrophils was independently associated with 30-day mortality (HR: 1.95; 95% CI: 1.25-3.03; P = 0.003). High levels of neutrophils and a high NLR upon admission for STEMI were independently associated with an increased risk of developing late CS and, additionally, both biomarkers showed association to 30-day mortality.


Crustacean cardioactive peptide-immunoreactive neurons in the ventral nervous system of crayfish.
Crustacean cardioactive peptide-immunoreactive neurons have been mapped in whole-mount preparations and sections of the ventral nervous system of the crayfish Astacus astacus and Orconectes limosus. Based on their morphology, projection patterns, and staining characteristics, two types of contralaterally projecting neurons are individually identifiable. In both species, these neurons occur in all neuromers as apparent serial homologs. In adult specimens, one type of cell has a small, densely stained dorsal lateral perikaryon, and a descending axon, and appears to be an interneuron. Each neuromer contains a single pair of these cells. Only in maxillary ganglia, these cells may have an additional ascending projection. The other type, a neurosecretory cell, has a larger, weakly stained perikaryon and a projection to the segmental third root of the next anterior neuromer. All neuromers contain a single pair of these neurons adjacent to the interneurons except for the abdominal neuromers, which contain two pairs of the neurosecretory cells. Central arborizations and varicose processes toward the surface of the third roots and within the perineural sheath of the ventral nerve cord arise from these neurons. Electron microscopy of granule-containing terminals substantiated that these newly discovered extensive neurohemal areas are release sites for the peptide. In young immature specimens, the perikarya of both neuron types do not differ in size. Additional weakly stained small perikarya occur in all neuromers of Astacus astacus. These two types of crayfish neurons and other comparable aminergic and peptidergic neurons of crayfish and lobster are differentially distributed in the ventral cord. Furthermore, comparison of similar neuron types in crab, locust, meal worm, and moth species indicates intra- and interphyletic structural homologies.


β-Nitro derivatives of iron corrolates.
Two different methods for the regioselective nitration of different meso-triarylcorroles leading to the corresponding β-substituted nitrocorrole iron complexes have been developed. A two-step procedure affords three Fe(III) nitrosyl products-the unsubstituted corrole, the 3-nitrocorrole, and the 3,17-dinitrocorrole. In contrast, a one-pot synthetic approach drives the reaction almost exclusively to formation of the iron nitrosyl 3,17-dinitrocorrole. Electron-releasing substituents on the meso-aryl groups of the triarylcorroles induce higher yields and longer reaction times than what is observed for the synthesis of similar triarylcorroles with electron-withdrawing functionalities, and these results can be confidently attributed to the facile formation and stabilization of an intermediate iron corrole π-cation radical. Electron-withdrawing substituents on the meso-aryl groups of triarylcorrole also seem to labilize the axial nitrosyl group which, in the case of the pentafluorophenylcorrole derivative, results in the direct formation of a disubstituted iron μ-oxo dimer complex. The influence of meso-aryl substituents on the progress and products of the nitration reaction was investigated. In addition, to elucidate the most important factors which influence the redox reactivity of these different iron nitrosyl complexes, selected compounds were examined by cyclic voltammetry and thin-layer UV-visible or FTIR spectroelectrochemistry in CH(2)Cl(2).


Administration of AVP to the area postrema alters response of NTS neurons to afferent inputs.
This study was designed to determine if arginine vasopressin (AVP) facilitates the response of nucleus of the solitary tract (NTS) neurons to baroreceptor input. In anesthetized sinoaortic-denervated vagotomized rabbits, AVP was intravenously infused (15 microg x kg(-1) x min(-1), 1 min) or microinjected into the area postrema (AP; 1 ng/nl, 10 nl). Extracellular recordings of evoked NTS neuronal responses to electrical stimulation of the aortic depressor nerve (ADN) or vagus nerve (1 Hz, 2-20 V, 0.05-0.6 ms) were evaluated before and after AVP administration. In neurons receiving input from the ADN (n = 19), 58% of them increased their responses after AVP (40.3 +/- 5.0 to 71.5 +/- 4,8%, P < 0.001). Similarly, in neurons activated by vagal stimulation (n = 22), 55% of them were facilitated during AVP administration (59.7 +/- 12.8 to 90.8 +/- 10.7%, P < 0.01). This action of AVP was independent of the mode of AVP administration, since either microinjection or venous infusion was effective in augmenting responses of NTS neurons to aortic/vagal stimulation. In an additional 37 spontaneous NTS neurons, AVP showed no effect on the mean baseline firing rate (8.9 +/- 1.3 vs. 9.6 +/- 1.3 spikes/s, P > 0.05), but increased neuronal activity in 54% of neurons (6.9 +/- 1.3 vs. 13.1 +/- 1.7 spikes/s, P < 0.01). In two rabbits pretreated with vasopressin antagonist (15 microg/kg iv), AVP failed to produce facilitatory effects (n = 8). The results of this study provide evidence in support of the hypothesis that circulating peptides modulate the arterial baroreflex via activation of neurons in the AP.


Preclinical therapy of disseminated HER-2⁺ ovarian and breast carcinomas with a HER-2-retargeted oncolytic herpesvirus.
Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2⁻/⁻;Il2rg⁻/⁻ mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity.


Development of an electronic medical record-based child physical abuse alert system.
Physical abuse is a leading cause of pediatric morbidity and mortality. Physicians do not consistently screen for abuse, even in high-risk situations. Alerts in the electronic medical record may help improve screening rates, resulting in early identification and improved outcomes. Triggers to identify children < 2 years old at risk for physical abuse were coded into the electronic medical record at a freestanding pediatric hospital with a level 1 trauma center. The system was run in "silent mode"; physicians were unaware of the system, but study personnel received data on children who triggered the alert system. Sensitivity, specificity, and negative and positive predictive values of the child abuse alert system for identifying physical abuse were calculated. Thirty age-specific triggers were embedded into the electronic medical record. From October 21, 2014, through April 6, 2015, the system was in silent mode. All 226 children who triggered the alert system were considered subjects. Mean (SD) age was 9.1 (6.5) months. All triggers were activated at least once. Sensitivity was 96.8% (95% CI, 92.4-100.0%), specificity was 98.5% (95% CI, 98.3.5-98.7), and positive and negative predictive values were 26.5% (95% CI, 21.2-32.8%) and 99.9% (95% CI, 99.9-100.0%), respectively, for identifying children < 2 years old with possible, probable, or definite physical abuse. Triggers embedded into the electronic medical record can identify young children with who need to be evaluated for physical abuse with high sensitivity and specificity.


Sulforaphane and bladder cancer: a potential novel antitumor compound.
Bladder cancer (BC) is a common form of urinary tract tumor, and its incidence is increasing annually. Unfortunately, an increasing number of newly diagnosed BC patients are found to have advanced or metastatic BC. Although current treatment options for BC are diverse and standardized, it is still challenging to achieve ideal curative results. However, Sulforaphane, an isothiocyanate present in cruciferous plants, has emerged as a promising anticancer agent that has shown significant efficacy against various cancers, including bladder cancer. Recent studies have demonstrated that Sulforaphane not only induces apoptosis and cell cycle arrest in BC cells, but also inhibits the growth, invasion, and metastasis of BC cells. Additionally, it can inhibit BC gluconeogenesis and demonstrate definite effects when combined with chemotherapeutic drugs/carcinogens. Sulforaphane has also been found to exert anticancer activity and inhibit bladder cancer stem cells by mediating multiple pathways in BC, including phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), zonula occludens-1 (ZO-1)/beta-catenin (β-Catenin), miR-124/cytokines interleukin-6 receptor (IL-6R)/transcription 3 (STAT3). This article provides a comprehensive review of the current evidence and molecular mechanisms of Sulforaphane against BC. Furthermore, we explore the effects of Sulforaphane on potential risk factors for BC, such as bladder outlet obstruction, and investigate the possible targets of Sulforaphane against BC using network pharmacological analysis. This review is expected to provide a new theoretical basis for future research and the development of new drugs to treat BC.