Determining a role for ventromedial prefrontal cortex in encoding action-based value signals during reward-related decision making.
Considerable evidence has emerged to implicate ventromedial prefrontal cortex in encoding expectations of future reward during value-based decision making. However, the nature of the learned associations upon which such representations depend is much less clear. Here, we aimed to determine whether expected reward representations in this region could be driven by action-outcome associations, rather than being dependent on the associative value assigned to particular discriminative stimuli. Subjects were scanned with functional magnetic resonance imaging while performing 2 variants of a simple reward-related decision task. In one version, subjects made choices between 2 different physical motor responses in the absence of discriminative stimuli, whereas in the other version, subjects chose between 2 different stimuli that were randomly assigned to different responses on a trial-by-trial basis. Using an extension of a reinforcement learning algorithm, we found activity in ventromedial prefrontal cortex tracked expected future reward during the action-based task as well as during the stimulus-based task, indicating that value representations in this region can be driven by action-outcome associations. These findings suggest that ventromedial prefrontal cortex may play a role in encoding the value of chosen actions irrespective of whether those actions denote physical motor responses or more abstract decision options.


Antibiotic Resistance of Campylobacter jejuni and C. coli Isolated from Children with Diarrhea in Thailand and Japan.
A total of 29 Campylobacter jejuni and C. coli strains were isolated from Thai and Japanese children with diarrhea using the Loop-mediated Isothermal Amplification method. The samples were evaluated for mutations in gyrA and 23S rRNA in order to assess resistance against fluoroquinolones and macrolides, respectively. Among the isolated strains, 9 (8 C. jejuni and 1 C. coli) were from Thai children, and the other 20 (C. jejuni) were isolated from Japanese children. High fluoroquinolone resistance rates were observed in Thai (66.7%) and Japanese (90%) children. Macrolide resistance was not observed in Japanese children but was observed at a considerable rate of 12.5% of C. jejuni isolated in the Thai cohort. The results indicate that continuous monitoring of resistance of Campylobacter strains to fluoroquinolones and macrolides is definitely necessary.


Protective effects of Angelica sinensis extract on amyloid beta-peptide-induced neurotoxicity.
The protective effects of alcohol extract from the root of Angelica sinensis (AS) on beta-amyloid peptide (Abeta)-induced toxicity and the mechanism of these effects were investigated. Abeta is a pathological hallmark of Alzheimer's disease; it decreased viability of Neuro 2A cells in a concentration-dependent manner with IC(50) of 14.9 microM. AS extract resulted in dose-dependent anti-Abeta toxicity according to MTT assay. Reactive oxygen species (ROS) analysis revealed a significant production of hydrogen peroxide, decreased glutathione (GSH) levels and increased lipid peroxidation (TBARS value) in the Abeta-treated Neuro 2A cells. The Abeta-treated cells also showed a significant decline in the mitochondrial transmembrane potential (DeltaPsim) and increase in the mitochondrial volume, and portions of the cytoplasm were sequestered by a membrane-bound vacuole. The malfunctions of Neuro 2A cells caused by Abeta were attenuated using AS extract. The AS extract protected cell viability against Abeta-induced oxidative damage (ROS, TBARS, and GSH contents) and rescued the DeltaPsim levels in a dose-dependent manner: the dosages of 25, 50, 100, and 200 microg/ml recovered 77%, 87%, 102%, and 105% of DeltaPsim, respectively. AS extract also recovered the enlarged mitochondria mass with dosages from 25 to 200 microg/ml. The results of this study demonstrated that AS extract possessed the activity to prevent the neurotoxicity induced by Abeta-associated oxidative stress, implying that AS has a potential role in the prevention of Alzheimer's diseases.


The toxicity of Senecio inaequidens DC.
This study was designed to confirm the toxicity of a plant implicated in an outbreak of poisoning of stock in Frankfort, Free State Province, South Africa. Cows died acutely after being introduced into a camp, where an abundant, green shrublet was noted to be heavily grazed. This plant was subsequently identified as Senecio inaequidens DC. (Asteraceae) by the South African National Biodiversity Institute (SANBI). Extraction and chemical analyses for pyrrolizidine alkaloids (PAs) in Senecio inaequidens revealed the presence of 4 different compounds, namely retrorsine and senecionine (known to be hepatotoxic) and 2 unidentified compounds. The average total PA (free base plus N-oxide) concentration in plant parts of S. inaequidens collected at Frankfort during the outbreak was 0.81%, compared with the total alkaloid content in the dried, milled S. inaequidens plant material, collected 7 weeks after the outbreak, of only 0.18%. Male Sprague-Dawley rats (n = 4), aged 8-9 weeks, were dosed per os. Each rat received a different dose of the crude Senecio inaequidens extract, ranging from 0.049 mg/g body weight (b.w.) to 0.25 mg/g b.w. No clinical signs were observed in the rat receiving the lowest dose. Rats receiving higher doses showed depression, an unsteady gait, pilo-erection and jaundice, which was particularly noticeable in the ears. Clinical chemistry evaluation revealed an increase in the activities of ALP (except Rat 4), AST and GGT in all animals. Total serum bilirubin, creatinine and urea concentrations were also elevated. All rats had low serum globulin concentrations with an A/G ratio above 1.2. Post mortem examination of the rats revealed marked hepatic lesions. Histopathologically, these changes were characterised by necrosis (variable in extent) of the centrilobular and midzonal hepatocytes (but sparing the portal hepatocytes), with extensive haemorrhage and congestion. Proliferation of the bile ducts, fibrosis and oedema were also present. Ultrastructural changes in affected rats were characterised by margination of chromatin, the presence of numerous autolysosomes in necrotic hepatocytes, intramitochondrial woolly inclusions and changes in the endoplasmic reticulum. A sheep, also dosed with the crude extract, failed to exhibit clinical signs, clinical chemistry aberrations or macroscopic lesions; however, examination of the liver of this sheep revealed histopathological and ultrastructural changes similar, though milder, to those displayed by the rats. Pyrrolizidine alkaloids were extracted from the liver and kidneys of the rats and the sheep. In the case of the sheep, retrorsine was also detected in the lungs, urine and bile.


Investigation of abundance and determination of dominant species of spider species in Iranian cotton fields.
In the present study, density of abundance of spiders explored and dominant species determined in the cotton major fields i.e., Ardebil, Fars, Golestan and Tehran provinces in 2003-2004. Through regular weekly, specimens collected by shaking bushes and they were carried out for the further study to the Araneae laboratory. A total of 632 specimens were classified in 76 species, 59 genera belonged to 19 families. Twenty seven species and 15 genera of them were new records for spider's fauna of Iran. The collected spiders counted and frequency of each species and dominant species determined. The following species Thanatus formicinus (Clerck), Cheiracanthium pennyi (O.P. Cambridge), Aulonia albimana (Walckenaer), Neoscona adianta (Walckenaer) were dominant species in Tehran, Ardebil, Fars and Golestan cotton fields, respectively.


Alfuzosin (10 mg) does not affect blood pressure in young healthy men.
Alfuzosin 10mg is a uroselective alpha(1)-adrenoceptor antagonist used to treat lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Recent studies have suggested the potential efficacy of alfuzosin in the treatment of distal ureteral stones and prostatitis syndrome, two conditions frequently encountered in young patients. The objective of this study was to evaluate the effect of 10mg alfuzosin on blood pressure (BP) and heart rate (HR) in young healthy volunteers. In a randomized, double-blind, placebo-controlled, crossover study, the effect of alfuzosin 10mg on BP and HR was evaluated in 14 male volunteers (mean age: 28 yr; range: 24-30). BP<135/85 obtained in two separated measurements was a main inclusion criterion. Patients were then randomized to alfuzosin (10mg once a day) or placebo for 1 wk, followed by a washout week, and then crossed over to the other treatment. Patients were instructed to self-measure systolic (SBP) and diastolic (DBP) blood pressure and HR every hour between 8am and 8pm during the first and the last day of each cycle treatment. All 14 enrolled volunteers completed the study. No significant difference in either SBP, DBP, or HR was observed between the placebo and alfuzosin groups at baseline. Alfuzosin did not affect SBP, DBP, or HR. No hypotensive episode (SBP reduction >10%) was recorded during each treatment. This study shows that alfuzosin 10mg is well tolerated by young healthy subjects and may therefore be safely administered to young normotensive patients affected by distal ureteral stones and prostatitis.


Shock Transmission and Fatigue in Human Running.
The goal of this research was to analyze the effects of fatigue on the shock waves generated by foot strike. Twenty-two subjects were instrumented with an externally attached, lightweight accelerometer placed over the tibial tuberosity. The subjects ran on a treadmill for 30 min at a speed near their anaerobic threshold. Fatigue was established when the end-tidal CO2 pressure decreased. The results indicated that approximately half of the subjects reached the fatigue state toward the end of the test. Whenever fatigue occurred, the peak acceleration was found to increase. It was thus concluded that there is a clear association between fatigue and increased heel strike-induced shock waves. These results have a significant implication for the etiology of running injuries, since shock wave attenuation has been previously reported to play an important role in preventing such injuries.


Home or Residential Care? The Role of Behavioral and Psychosocial Factors in Determining Discharge Outcomes for Inpatients with Huntington's Disease.
The progressive nature of Huntington's disease (HD) means that families often struggle to cope with increasing care needs of their affected family member. As a result, individuals with HD are likely to be at risk of hospitalization and subsequent early placement into residential care facilities. To explore which factors were associated with early residential care placement in a group of hospitalized patients with HD. A retrospective, systematic medical file audit of a neurological inpatient unit was conducted. Fifty-nine patients with HD were admitted from the community between January 2008 and December 2011; of these, 31 patients were discharged home while 28 patients required discharge to a residential care facility. These two groups were compared on a range of demographic, clinical and psychosocial variables identified as precipitating the hospital admission. Group comparisons were performed using t-tests and chi-square tests with Bonferroni correction for multiple comparisons. A higher proportion of men were placed in residential care than were able to return home (p = 0.045); and the group placed in residential care had longer inpatient hospital stays (p < 0.001). Groups did not differ in age, medications or disease duration. We found that psychosocial difficulties (p < 0.001) and behavioral problems (p = 0.001), but not physical, cognitive, or psychiatric factors, significantly differentiated the groups. Patients with HD discharged to residential care were more likely to have psychosocial and behavioral problems, and lengthy hospital stays. These findings indicate the need for community-based psychosocial and behavior management interventions aimed at preventing residential care admissions for persons with HD.


[Properties of metlegoglobin reductase from lupin root nodules].
The interaction between metlegoglobin reductase from lupin root nodules cytosol and some substrates and inhibitors was studied. The Km values for electron acceptors: dichlorophenol indophenol, potassium ferricyanide, methylene blue and cytochrome c were 5.7 x 10(-5), 2.1 x 10(-5), 1.75 x 10(-4) and 2.5 x 10(-5) M, respectively. The Km value for electron donor NADH was 2.4 x 10(-5) M. Hydroxymercurybenzoate and ethylmaleimide inhibited the metlegoglobin reductase activity; the enzyme activity was also inhibited by NAD. Metlegoglobin reductase was inhibited by quinacrine, which confirmed the flavoproteid nature of the enzyme earlier discovered by the authors. Cytochrome b5 from rabbit liver microsomes can be an electron intermediate during cytochrome c reduction by metlegoglobin reductase. The temperature optimum of metlegoglobin reductase is 40 degrees. The enzyme is comparatively thermostable; and was inactivated by 85% only after 5 min heating at 100 degrees.


The Role of the Paratrigeminal Nucleus in Vagal Afferent Evoked Respiratory Reflexes: A Neuroanatomical and Functional Study in Guinea Pigs.
The respiratory tree receives sensory innervation from the jugular and nodose vagal sensory ganglia. Neurons of these ganglia are derived from embryologically distinct origins and as such demonstrate differing molecular, neurochemical and physiological phenotypes. Furthermore, whereas nodose afferent neurons project to the nucleus of the solitary tract (nTS), recent neuroanatomical studies in rats suggest that jugular neurons have their central terminations in the paratrigeminal nucleus (Pa5). In the present study we confirm that guinea pigs demonstrate a comparable distinction between the brainstem terminations of nodose and jugular ganglia afferents. Thus, microinjection of fluorescently conjugated cholera toxin B (CT-B) neural tracers into the caudal nTS and Pa5 resulted in highly specific retrograde labeling of neurons in the nodose and jugular ganglia, respectively. Whereas, nodose neurons more often expressed 160 KD neurofilament proteins and the alpha3 subunit of Na(+)/K(+) ATPase, significantly more jugular neurons expressed the neuropeptides substance P (SP) and, especially, Calcitonin Gene-Related Peptide (CGRP). Indeed, terminal fibers in the Pa5 compared to the nTS were characterized by their significantly greater expression of CGRP, further supporting the notion that jugular afferents project to trigeminal-related brainstem regions. Electrical stimulation of the guinea pig larynx following selective surgical denervation of the nodose afferent innervation to the larynx (leaving intact the jugular innervation) resulted in stimulus dependent respiratory slowing and eventual apnea. This jugular ganglia neuron mediated response was unaffected by bilateral microinjections of the GABAA agonist muscimol into the nTS, but was abolished by muscimol injected into the Pa5. Taken together these data confirm that jugular and nodose vagal ganglia afferent neurons innervate distinct central circuits and support the notion that multiple peripheral and central pathways mediate sensory responses associated with airway irritations.


Hepatitis C infection of B lymphocytes: more tools to address pending questions.
Hepatitis C virus (HCV) infection spreads primarily via contact with infected blood and can establish a persistent infection in 80% of infected individuals, progressively causing chronic liver disease that can lead to hepatocellular carcinoma or end-stage liver disease requiring a transplant. There is no vaccine, and current treatment with interferon and ribavirin is costly, poorly tolerated and ineffective for a large proportion of patients. Technical limitations have stifled the study of HCV immunology, and hence the correlates of resolution remain elusive. HCV robustly infects hepatocytes in the liver, yet HCV RNA is often found to be associated with peripheral blood lymphocytes and extrahepatic manifestations of the disease include B-cell abnormalities. The few existing characterized viral clones that can replicate in vitro have consistently failed to infect immune cells; however, some groups have detected low levels of replication in peripheral blood cells, hinting that occult forms of infection may be possible. HCV lymphotropism remains a controversial subject that needs to be elucidated in order to identify viral reservoirs that may provide targets for therapeutic intervention. The precise interactions between HCV and immune cells need to be determined to establish if the virus has developed mechanisms to modulate immune responses. In the study by Durand et al., correlations were sought between cell tropism and mutations in the 5 noncoding region of the HCV genome, known as the internal ribosome entry site. Key findings are discussed here, highlighting current experimental challenges that surround the topic of HCV lymphotropism.


MSCs feeder layers induce SMG self-organization and branching morphogenesis.
Dysfunction of salivary glands leads to several oral health problems, including dental caries, mastication and swallowing dysfunctions and multiple oral infections. Conventional treatments for such condition fell short of providing satisfying therapeutic results. Recent advances in organ regeneration therapy which utilize tissue stem cells to fabricate bioengineered 3D organ buds, have introduced a promising therapeutic tool for full functional organ regeneration. However, finding a sustainable and easily accessible cell source for such approaches is still challenging, especially in case of severely atrophied tissues such as irradiated salivary glands. In response to this, we hypothesized that bone marrow derived mesenchymal stem cells (MSCs) could be used as feeder cells to induce salivary epithelial tissues/cells branching. Indeed, in 2D cultures, MSCs supported branching of embryonic submandibular salivary gland (SMG) epithelium. Interestingly, this enhancing effect was dependent on the initial number of MSC feeder cells. In addition, MSCs supported the self-assembly of SMG epithelial progenitor cells into well-patterned and branched 3D salivary organoids. Therefore, these findings propose MSCs as a valuable candidate cell source for induced SMG epithelial branching, which can potentially be applied in future methods for SMG regeneration approaches.


Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis.
In an attempt to isolate disease-associated autoantigens in rheumatoid arthritis (RA), we cloned a new autoantigen named gp130-RAPS, which is a novel soluble form of the IL-6 signal-transducing molecule gp130. gp130-RAPS is a 50-kDa protein translated from alternatively spliced mRNA and has a truncated form of gp130 with a unique sequence, Asn-Ile-Ala-Ser-Phe (NIASF), in its COOH-terminus. We observed serum antibodies to this NIASF sequence frequently in patients with RA, but not in those with other systemic rheumatic diseases or in healthy subjects. In RA, detection of those antibodies was significantly associated with disease activity indices such as serum C-reactive protein (CRP) levels, erythrocyte sedimentation rate, blood platelet counts, and serum IL-6 concentration. In vitro experiments revealed that gp130-RAPS inhibited IL-6 activity, and this inhibition was neutralized by antibodies to the COOH-terminus of gp130-RAPS derived from patients with RA. Thus, autoantibody to gp130-RAPS may play an important role in the progression of RA by promoting IL-6 activity. Inspection of autoantibodies to gp130-RAPS may become a practical clinical test for RA. gp130-RAPS and its autoantibody provide a new clue to the complicated pathogenesis of RA.


Underwater acoustic energy fluctuations during strong internal wave activity using a three-dimensional parabolic equation model.
The three-dimensional Monterey-Miami parabolic equation model is used to simulate a nonlinear internal wave (NIW) crossing the sound field in a shallow water environment. The impetus for this research stems from acoustic measurements taken during the Shallow Water '06 (SW06) field experiment, where a NIW traversed the water column such that soliton wavecrests were nearly parallel to the source-receiver path. Horizontal refraction effects are important in this scenario. A sound speed profile adapted from experimental SW06 data is used to simulate the NIW, assuming variations along the wavecrests (e.g., curvature) are negligible. Broadband and modal energy metrics show acoustic fluctuations due to internal wave activity. Repeated model runs simulate the NIW crossing the parabolic equation (PE) field over space and time. Statistical analysis shows the PE data are best fit by a lognormal distribution but tends to an exponential distribution during certain scenarios. Small angle differences between the acoustic track and the propagating NIW cause substantial differences in energy distribution throughout the PE field. While refraction effects due to the leading edge of the NIW's arrival are important in all cases, the impacts of focusing and defocusing in the perfectly parallel case dominate the field fluctuations. In the non-parallel case, the strong fluctuations introduced by the passage of the NIW are of similar order to the refraction off the leading edge.


ERK1/2 are involved in low potassium-induced apoptotic signaling downstream of ASK1-p38 MAPK pathway in cultured cerebellar granule neurons.
We have recently reported that the ASK1-p38 MAPK pathway has an important role in the low potassium (LK)-induced apoptosis of cultured cerebellar granule neurons. In the present study, we observed that ERK1/2 were significantly activated 6 h after a change of medium from HK (high potassium) to LK. In addition, U0126, a specific inhibitor of MEKs, remarkably prevented the apoptosis of cultured cerebellar granule neurons. Then, we examined the mechanism underlying the activation of ERK1/2 in the LK-induced apoptotic pathway. The addition of SB203580, an inhibitor of p38 MAPK, suppressed the increase in the phosphorylation of ERK1/2 after the change to LK medium. Furthermore, we found that the expression of a constitutively active mutant of ASK1, an upstream kinase of p38 MAPK, enhanced the phosphorylation of ERK1/2. These results suggest that ERK1/2 play a crucial role in LK-induced apoptosis of cultured cerebellar granule neurons and that the LK-stimulated activation of ERK1/2 is regulated by the ASK1-p38 MAPK pathway.


Predicting neo-adjuvant chemotherapy response and progression-free survival of locally advanced breast cancer using textural features of intratumoral heterogeneity on F-18 FDG PET/CT and diffusion-weighted MR imaging.
Predicting response to neo-adjuvant chemotherapy (NAC) and survival in locally advanced breast cancer (LABC) is important. This study investigated the prognostic value of tumor heterogeneity evaluated with textural analysis through F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and diffusion-weighted imaging (DWI). We enrolled 83 patients with LABC who had completed NAC and curative surgery. Tumor texture indices from pretreatment FDG PET and DWI were extracted from histogram analysis and 7 different parent matrices: co-occurrence matrix, the voxel-alignment matrix, neighborhood intensity difference matrix, intensity size-zone matrix (ISZM), normalized gray-level co-occurrence matrix (NGLCM), neighboring gray-level dependence matrix (NGLDM), and texture spectrum matrix. The predictive values of textural features were tested regarding both pathologic NAC response and progression-free survival. Among 83 patients, 46 were pathologic responders, while 37 were nonresponders. The PET texture indices from 7 parent matrices, DWI texture indices from histogram, and 1 parent matrix (NGLCM) showed significant differences according to NAC response. On multivariable analysis, number nonuniformity of PET extracted from the NGLDM was an independent predictor of pathologic response (P = .009). During a median follow-up period of 17.3 months, 14 patients experienced recurrence. High-intensity zone emphasis (HIZE) and high-intensity short-zone emphasis (HISZE) from PET extracted from ISZM were significant textural predictors (P = .011 and P = .033). On Cox regression analysis, only HIZE was a significant predictor of recurrence (P = .027), while HISZE showed borderline significance (P = .107). Tumor texture indices are useful for NAC response prediction in LABC. Moreover, PET texture indices can help to predict disease recurrence.


An Evidence-Based Practice Project to Provide Standardized Education on Skin-to-Skin Contact and Neonatal Hypoglycemia.
To develop and examine the implications of formalized education with staff and familial caregivers on skin-to-skin in relation to neonatal hypoglycemia, including the impact on NICU admission rate, exclusive breastfeeding, and glucose gel administration. Evidence-based practice (EBP) project with a comparison of data pre-/postintervention. Implemented at a large health system in the mid-Atlantic, including four hospitals with postpartum care units. The EBP implementation site had approximately 19,400 births in 2021. Participants included 320 postpartum nurses in addition to the familial neonatal caregivers these nurses provided care for. All team members were provided with online education via the HealthStream learning platform, a microlearning introduction video, weekly huddle messages, and unit-specific champions who shared a champion information sheet that included information such as the hypoglycemia protocol, how to perform safe skin-to-skin care, and how to effectively administer glucose gel. Familial caregiver education included a handout given upon admission with an explanation from the postpartum nurse if the neonate met the criteria for the hospital system's neonatal hypoglycemia protocol. We observed a 4% system-wide increase in exclusive breastfeeding rates, a decrease in NICU admissions by 17.3% at 1-month postimplementation at the smallest hospital site (Hospital A), and a 12.3% reduction in NICU admission rates at the largest hospital site (Hospital B). Two hospitals reported a decrease in the need for glucose gel administration to neonates after the educational intervention. This nurse-led project detailed the process of a system-wide EBP project to implement consistent and standardized education regarding neonatal protocols. Although the benefits of skin-to-skin contact are widely known, this project demonstrated that focused, targeted education on skin-to-skin protocols for neonates at risk for neonatal hypoglycemia may be effective at improving outcomes.


Carbon nanotube-tipped endoscope for in situ intracellular surface-enhanced Raman spectroscopy.
Gold nanoparticle-decorated carbon nanotubes (CNTs) are used to study intracellular environments in situ using surface-enhanced Raman spectroscopy (SERS). CNTs are decorated with gold nanoparticles and assembled onto the tips of pulled glass capillaries to form a SERS-enabled endoscope. The sub-micrometer size and high mechanical strength of the endoscope make it possible to penetrate the cell membrane for intracellular probing and remain positioned inside during lengthy SERS measurements without causing damage to the cell. Using the SERS-enabled endoscope, DNA and other biomolecules are detected in situ within the nucleus of a single human cervical carcinoma cell in a minimally invasive manner. The SERS-enabled endoscopes exhibit high selectivity and sensitivity for detecting trace amounts of analytes (≈1 pM) in biofluid environments, highlighting their capabilities as label-free, biological sensors for real-time in situ cellular diagnostics, biological detection, and pharmaceutical research.


Let loose technique, an option in band migration.
Obesity is nowadays a serious worldwide public health problem. In order to give patients a better quality of live, there are now medical and surgical treatments that may be offered to those patients. Since 2005, the Hospital de Santarém has been doing bariatric surgery. From 77 procedures with laparoscopic adjustable gastric banding, there were three cases of migration. The authors propose a new procedure to deal with migrations, according to a classification for band migration, as an alternative to a removal by laparoscopy or laparotomy. Let loose technique is a procedure that can be used in patients with band migration beyond the angle of Treitz and without other associated complications. It is consist of removing the port under local anaesthesia, leaving the insufflations' tube, hospitalization for monitoring the patient and awaiting for the elimination of the band with faeces. It's less costly and with minimal risks for patient. The first results are satisfactory and encouraging.


A Quantitative and Qualitative Analysis of Electronic Prescribing Incidents Reported by Community Pharmacists.
Electronic prescribing (e-prescribing) technology was introduced as an alternative to handwritten prescriptions allowing health care professionals to send prescriptions directly to pharmacies. While the technology has many advantages, such as improving pharmacy workflow and reducing medication errors, some limitations have been realized. The objective of this study was to examine the frequency, type, and contributing factors of e-prescribing quality-related incidents reported to two national error-reporting databases in the United States. This was a retrospective analysis of voluntarily reports of e-prescribing quality-related incidents. A quantitative and qualitative analysis was conducted of incidents reported between 2011 and 2015 to the Pharmacy Quality Commitment (PQC) and the Pharmacy Provider e-prescribing Experience Reporting Portal (PEER) databases. For the qualitative analysis, events were combined from the PQC and PEER portal and a 10% random sample of events were analyzed. A total of 589 events were reported to the PEER Portal. Of these, problems with patient directions were the most frequent incident type (n = 210) of which 10% (n = 21) reached the patient. Quantity selection (n = 158) and drug selection (n = 96) were the next most frequently reported events, 20% of which reached the patient. The PQC system received 550 reports. The most frequent event type reported to this system was incorrect directions (23.3%, n = 128) followed by incorrect prescriber (17%), incorrect drug (15%), and incorrect strength (12%). The most common theme in the qualitative analysis was a perceived increased likelihood of patient receiving incorrect drug therapy due to e-prescribing. Another theme identified included confusion and frustration of pharmacy personnel as result of e-prescription quality-related events. The use of qualitative and quantitative incident data revealed that patient directions and quantity selection were the most common quality issues with e-prescribing. In turn, this may increase the likelihood of patients receiving incorrect drug therapy.


Diurnal blood pressure loads are associated with lower cognitive performances in controlled-hypertensive elderly individuals.
Hypertension in midlife adults is associated with cognitive decline later in life. In individuals treated for hypertension, blood pressure (BP) loads have been associated with end organ damages. This study examines whether BP load inversely correlates with performance in cognitive tasks in normotensive or controlled hypertensive (CHT) individuals. Participants between 60 and 75 years old were divided into normotensive participants who did not receive antihypertensive treatment (n = 49) and CHT patients (n = 28). They were evaluated for BP using ambulatory blood pressure monitoring and cognitive functions with tests assessing cognitive flexibility, working and episodic memory, and processing speed. Analysis of covariance between normotensive and CHT participants revealed lower cognitive performances on immediate and delayed recall and total number of words of the Rey Auditory Verbal Learning Test (P < 0.001). Spearman's correlations between BP loads and cognitive performances revealed inversed associations between diurnal systolic (SBP) loads and performances on the Trail Making Test Part B (TMTB) (P = 0.009), the TMTB-TMT Part A (P = 0.013), the Switching Cost of the color-word interference test (P = 0.020) and the Digit-Symbol Substitution Score tests (P = 0.018) in CHT. Diurnal diastolic (DBP) loads were inversely correlated to the TMTB (P = 0.014) and TMTB-TMT Part A (P = 0.006). In normotensive subjects, diurnal SBP loads were associated with the delayed recall of the Rey Auditory Verbal Learning Test (P = 0.031) and to the three components of the digit span (P < 0.05). Diurnal BP loads are associated with lower cognitive performances in CHT individuals. These results suggest a lowering of target levels of diurnal BPs and/or its variability.


Angiotensin II and the maintenance of GFR and renal blood flow during renal artery narrowing.
The time course of the renal blood flow and GFR responses to narrowing of the renal artery in conscious dogs is reviewed. The initial response to this threat to renal perfusion is renal vasodilatation, but within minutes a secondary vasoconstriction mediated by angiotensin II begins to develop. Angiotensin II-mediated contraction of mesangial cells is also demonstrable, but this does not apparently reduce the filtration surface area of the glomerular capillaries. The intrarenal effects of angiotensin II restore GFR back to normal within one to two weeks, by which time circulating plasma angiotensin II levels are no longer elevated. In contrast to its effects on GFR, angiotensin II has minimal effects on renal blood flow after stenosis. This may be because, (i) blood flow is mainly determined by the hydraulic resistance of the stenosis; (ii) renal vasoconstriction has relatively little effect on flow due to the particular hemodynamic properties of the stenoses, and (iii) a major site of action of angiotensin II may be within the glomerulus. Thus angiotensin II has a homeostatic role in the maintenance of GFR during renal artery narrowing and one component of this role may involve mesangial contraction.


[Local senile ocular amyloidosis in the pathogenesis of open-angle glaucoma and pseudo-exfoliative syndrome].
A total of 173 biopsy samples of the iris and drainage apparatus obtained at anti-glaucoma operations from 115 patients, aged 32 to 90, with primary open-angle glaucoma and pseudoexfoliative syndrome of different severity degrees were morphologically examined. Similar anatomofunction embryological peculiarities of the eye and brain create prerequisites for the development, in the eye, of processes analogical to Alzheimer's disease. Amyloid angiopathy of the iris is a key element of ischemia, which triggers the mechanisms of apoptosis and lipid peroxidation in the pigment epithelium membranes; this process is accompanied by an intensified synthesis and conformation of fibrous structures of tauprotein and beta-amyloid. Defradation of melanin and proteoglycans leads to the formation of neurotoxic metabolites. The above processes result in suppressing the protective antioxidant reactions as well as in blocking, by fibrous structures, the cellular cytoplasm and extracellular matrix.


Differential response of nonadapted ammonia-oxidising archaea and bacteria to drying-rewetting stress.
Climate change is expected to increase the frequency of severe drought events followed by heavy rainfall, which will influence growth and activity of soil microorganisms, through osmotic stress and changes in nutrient concentration. There is evidence of rapid recovery of processes and adaptation of communities in soils regularly experiencing drying/rewetting and lower resistance and resilience in nonadapted soils. A microcosm-based study of ammonia-oxidising archaea (AOA) and bacteria (AOB), employing a grassland soil that rarely experiences drought, was used to test this hypothesis and also whether AOB were more resistant and resilient, through greater tolerance of high ammonia concentrations produced during drought and rewetting. Treated soils were dried, incubated for 3 weeks, rewetted, incubated for a further 3 weeks and compared to untreated soils, maintained at a constant moisture content. Nitrate accumulation and AOA and AOB abundance (abundance of respective amoA genes) and community composition (DGGE analysis of AOA amoA and AOB 16S rRNA genes) were poorly adapted to drying-rewetting. AOA abundance and community composition were less resistant than AOB during drought and less resilient after rewetting, at times when ammonium concentration was higher. Data provide evidence for poor adaptation of microbial communities and processes to drying-rewetting in soils with no history of drought and indicate niche differentiation of AOA and AOB associated with high ammonia concentration.


Risk factors for readmission following ileal pouch-Anal anastomosis: an American College of Surgeons National Surgical Quality Improvement Program analysis.
The purpose of this study was to identify preventable reasons for readmission and to delineate risk factors for readmission in the perioperative period for patients with chronic ulcerative colitis undergoing ileal pouch-anal anastomosis (IPAA). Patients with a diagnosis of chronic ulcerative colitis undergoing either total proctocolectomy with IPAA or proctectomy with IPAA were identified in the American College of Surgeons National Surgical Quality Improvement Program database from 2012-2015. Unplanned 30-d readmissions were reviewed and categorized by reason for readmission. The unplanned readmission rate within 30 d was calculated by the person-days method. Multivariable Cox proportional hazard regression models determined independent risk factors for overall 30-d unplanned readmissions and readmissions sorted by primary readmission diagnosis. Three thousand four hundred one patients had an IPAA performed during the study period. The overall unplanned readmission rate was 32.9% per 30 person-days. Leading diagnoses for unplanned readmission included infectious complications, dehydration, and venous thromboembolism (VTE). Multivariable analysis found Hispanic white and black/African American race/ethnicity (both versus non-Hispanic white) to be independently associated with unplanned 30-d readmission. Obesity, operative time 330+ min (versus <189 min), and Hispanic white race/ethnicity (versus non-Hispanic white) were associated with readmission for infectious complications. Age 57+ y (versus age 18-32 y) and hypertension requiring medication were associated with readmission for dehydration. Total proctocolectomy with IPAA (versus proctectomy with IPAA) was associated with readmission for VTE. One-third of patients undergoing IPAA experience an unplanned 30-d readmission. Infectious complications and dehydration account for most of the unplanned readmissions. Outpatient pathways to prevent dehydration and the use of extended VTE prophylaxis after two-stage IPAA may help reduce the rates of readmission following IPAA.


Repetitive mammalian dwarfing during ancient greenhouse warming events.
Abrupt perturbations of the global carbon cycle during the early Eocene are associated with rapid global warming events, which are analogous in many ways to present greenhouse warming. Mammal dwarfing has been observed, along with other changes in community structure, during the largest of these ancient global warming events, known as the Paleocene-Eocene Thermal Maximum [PETM; ~56 million years ago (Ma)]. We show that mammalian dwarfing accompanied the subsequent, smaller-magnitude warming event known as Eocene Thermal Maximum 2 [ETM2 (~53 Ma)]. Statistically significant decrease in body size during ETM2 is observed in two of four taxonomic groups analyzed in this study and is most clearly observed in early equids (horses). During ETM2, the best-sampled lineage of equids decreased in size by ~14%, as opposed to ~30% during the PETM. Thus, dwarfing appears to be a common evolutionary response of some mammals during past global warming events, and the extent of dwarfing seems related to the magnitude of the event.


Key lifestyles and interim health outcomes for effective interventions in general populations: A network analysis of a large international observational study.
The interconnected nature of lifestyles and interim health outcomes implies the presence of the central lifestyle, central interim health outcome and bridge lifestyle, which are yet to be determined. Modifying these factors holds immense potential for substantial positive changes across all aspects of health and lifestyles. We aimed to identify these factors from a pool of 18 lifestyle factors and 13 interim health outcomes while investigating potential gender and occupation differences. An international cross-sectional study was conducted in 30 countries across six World Health Organization regions from July 2020 to August 2021, with 16 512 adults self-reporting changes in 18 lifestyle factors and 13 interim health outcomes since the pandemic. Three networks were computed and tested. The central variables decided by the expected influence centrality were consumption of fruits and vegetables (centrality = 0.98) jointly with less sugary drinks (centrality = 0.93) in the lifestyles network; and quality of life (centrality = 1.00) co-dominant (centrality = 1.00) with less emotional distress in the interim health outcomes network. The overall amount of exercise had the highest bridge expected influence centrality in the bridge network (centrality = 0.51). No significant differences were found in the network global strength or the centrality of the aforementioned key variables within each network between males and females or health workers and non-health workers (all P-values >0.05 after Holm-Bonferroni correction). Consumption of fruits and vegetables, sugary drinks, quality of life, emotional distress, and the overall amount of exercise are key intervention components for improving overall lifestyle, overall health and overall health via lifestyle in the general population, respectively. Although modifications are needed for all aspects of lifestyle and interim health outcomes, a larger allocation of resources and more intensive interventions were recommended for these key variables to produce the most cost-effective improvements in lifestyles and health, regardless of gender or occupation.


Label-free analysis of physiological hyaluronan size distribution with a solid-state nanopore sensor.
Hyaluronan (or hyaluronic acid, HA) is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication. Both the abundance and size distribution of HA in biological fluids are recognized as robust indicators of various pathologies and disease progressions. However, such analyses remain challenging because conventional methods are not sufficiently sensitive, have limited dynamic range, and/or are only semi-quantitative. Here we demonstrate label-free detection and molecular weight discrimination of HA with a solid-state nanopore sensor. We first employ synthetic HA polymers to validate the measurement approach and then use the platform to determine the size distribution of as little as 10 ng of HA extracted directly from synovial fluid in an equine model of osteoarthritis. Our results establish a quantitative method for assessment of a significant molecular biomarker that bridges a gap in the current state of the art.


Autologous point-of-care cellular therapies variably induce equine mesenchymal stem cell migration, proliferation and cytokine expression.
Autologous cellular therapy products including adipose-derived stromal vascular fraction (SVF), bone marrow mononuclear cells (BMMNs), cord blood mononuclear cells (CBMNs) and platelet rich plasma are options for treatment of acute orthopaedic lesions while mesenchymal stem cells (MSCs) are culture expanded. These products may contribute to healing by secreting matrix proteins or growth factors, but they may also act on endogenous MSCs to facilitate healing. To determine the effects of cell therapy products on MSCs function in vitro. The hypothesis was that cell therapy products promote MSCs functions including proliferation, migration and mediator release. Fat, bone marrow (BM), cord blood and platelets were obtained from 6 Quarter Horses. The BM-MSCs and their autologous cell therapy products were co-incubated in transwells. Mesenchymal stem cells proliferation, migration, gene expression and cytokine concentrations were determined. All cell therapy products increased MSCs proliferation, but SVF induced significantly more proliferation than any other product. Also SVF elicited more MSCs chemotaxis and, along with BMMNs, significantly more MSCs chemoinvasion. Cord blood mononuclear cells stimulated MSCs to produce high concentrations of interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), and prostaglandin E(2) (PGE(2)). Stromal vascular fraction and platelet lysate did not stimulate MSCs but SVF and platelet lysate themselves contained high concentrations of PGE(2) and IL-6 (SVF) and TGF-β1 (platelet lysate). Autologous cell products variably stimulate MSCs functions with 2 primary patterns apparent. Products either contained preformed mediators that may have intrinsic healing function, or products stimulated MSCs to secrete mediators. The specific clinical indications for these products may differ to include administration as a sole treatment modality prior to MSCs injection for intrinsic cell and cytokine activity (i.e. SVF) or administration concurrently with MSCs to activate MSCs for treatment of chronic lesions (i.e. CBMNs).


Closed bipolar electrochemistry in a four-electrode configuration.
Closed bipolar electrochemistry in a 4-electrode configuration is a highly versatile, but under-utilized, technique with major potential to emerge as a powerful methodology impacting areas as diverse as spectro-electroanalysis, energy storage, electrocatalysis and electrodeposition. In this perspective, we provide the thermodynamic framework for understanding all such future applications of closed bipolar electrochemistry in a 4-electrode configuration. We distinguish the differences between open and closed bipolar electrochemical cells. In particular, the use of the 4-electrode configuration in both open and closed bipolar electrochemical cells with immiscible aqueous-organic solutions is outlined. A comprehensive overview of the influence of external bias on the thermodynamics underpinning electron transfer from an organic redox couple to an aqueous redox couple, or vice versa, by electrons flowing along a conducting bipolar electrode serving as an electronic bridge is provided. Fermi level equilibration between redox species at opposite poles of a bipolar electrode under external bias is discussed. The concept of the Line of Zero Overpotential (LZO) on the bipolar electrode at steady-state conditions under an external bias is introduced. The influence of a series of experimental variables (redox potential of each redox couple, rate constant of electron transfer at each pole, an excess bulk concentration of one redox couple over the other, and areas of the poles of the bipolar electrode in contact with each electrolyte solution) on the final position of the LZO on the bipolar electrode is highlighted. A cyclic voltammogram obtained using a closed bipolar electrochemical cell in a 4-electrode configuration with immiscible aqueous-organic electrolyte solutions is explained using the thermodynamic theory detailed throughout the perspective. The theory presented herein is equally applicable to a closed bipolar electrochemical cell in a 4-electrode configuration with aqueous electrolyte solutions, each containing redox active species, in both compartments connected by a bipolar electrode.


Lymphatic and Mixed Malformations.
Lymphatic and mixed malformations are rare and variable in presentation. They arise due to errors in vascular and lymphatic formation during early embryonic development. This leads to persistent infiltration of lymph fluid into soft tissues and causes a locally invasive mass with pathologic sequelae. Departing from historically descriptive terminology, such as "cystic hygroma," lymphatic malformations are now categorized as macrocystic, microcystic, or mixed lesions, based on size. Advances in imaging modalities, such as ultrasonography and magnetic resonance imaging, have made accurate characterization of these lesions possible and ultimately allow for early diagnosis and implementation of appropriate treatment based on the morphology of the lymphatic malformation. Management of lymphatic malformations can be quite challenging, and a multidisciplinary approach is most effective for optimum aesthetic and functional outcomes. New discoveries in the molecular biology of lymphatic malformations have provided treatment targets and established a role for pharmacotherapy. Sclerotherapy, laser, and radiofrequency ablation have all proven to be effective as minimally invasive treatment options for lymphatic malformations. Surgical intervention has a role in the treatment of focal lesions recalcitrant to these less invasive techniques. Operative planning is dictated by clinical goals, size, anatomic location, characteristics, and extent of infiltration.


Excessive expression of acetylcholinesterase impairs glutamatergic synaptogenesis in hippocampal neurons.
Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated protein-protein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic beta-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of beta-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions.


The tract terminations in the temporal lobe: Their location and associated functions.
Temporal lobe networks are associated with multiple cognitive domains. Despite an upsurge of interest in connectional neuroanatomy, the terminations of the main fibre tracts in the human brain are yet to be mapped. This information is essential given that neurological, neuroanatomical and computational accounts expect neural functions to be strongly shaped by the pattern of white-matter connections. This paper uses a probabilistic tractography approach to identify the main cortical areas that contribute to the major temporal lobe tracts. In order to associate the tract terminations to known functional domains of the temporal lobe, eight automated meta-analyses were performed using the Neurosynth database. Overlaps between the functional regions highlighted by the meta-analyses and the termination maps were identified in order to investigate the functional importance of the tracts of the temporal lobe. The termination maps are made available in the Supplementary Materials of this article for use by researchers in the field.


Regulation of PTH receptor-adenylate cyclase system of canine kidney: influence of Mn2+ on effects of Ca2+, PTH, and GTP.
Metal ions play important roles in the regulation of the activation of adenylate cyclase. Previous studies have suggested that an important site of action of metal ions is at or closely related to the nucleotide regulatory protein. The present studies examine the nature of the regulation of enzyme activity by divalent cations and the influence of Mn2+ on hormone binding and stimulation of adenylate cyclase. Studies were performed in canine renal cortical membranes. Substitution of Mg2+ by Mn2+ was associated with a progressive decline in the ability of GTP or PTH to stimulate adenylate cyclase activity. Mn2+ did not alter specific binding of an iodinated PTH analogue. However, in spite of the loss of guanine nucleotide stimulation of enzyme activity, the effects of guanine nucleotide on PTH binding were not altered in the presence of Mn2+. Substitution of Mg2+ by Mn2+ abolished the inhibitory effect of Ca2+ on basal adenylate cyclase activity. Similarly, the effects of GTP or PTH to enhance the inhibitory effects of Ca2+ on enzyme activity were abolished in the presence of Mn2+. Since Mg2+ and Ca2+ compete for a common allosteric site and Mn2+ abolished the effects of these cations, it would appear that Mn2+ also competes for the binding site of Mg2+ and Ca2+. The present studies demonstrating that Mn2+ does not affect hormone binding or the actions of guanine nucleotides on hormone binding yet totally eliminates the effect of GTP on enzyme activity indicate that the effect of Mn2+ occurs at the level of the interactions of the nucleotide regulatory component with the catalytic unit. In addition, these data suggest that there are two functionally distinct sites of guanine nucleotides with different ionic requirements.


Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis.
Complete pathologic response (CPR) after neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer seems associated with improved survival compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single-institution design. A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR and NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Study end points included rates of CPR, local recurrence (LR), distant recurrence (DR), 5-year overall survival (OS), and disease-free survival (DFS). Twelve studies (1,913 patients) with rectal cancer treated with CMT were included. CPR was observed in 300 patients (15.6%). CPR and NPR patient groups were similar with respect to age, sex, tumor size, distance of tumor from the anus, and stage of disease before treatment. Median follow-up ranged from 23 to 46 months. CPR patients had lower rates of LR [0.7% vs. 2.6%; odds ratio (OR) 0.45, 95% confidence interval (CI) 0.22-0.90, P = 0.03], DR (5.3% vs. 24.1%; OR 0.15, 95% CI 0.07-0.31, P = 0.0001), and simultaneous LR + DR (0.7% vs. 4.8%; OR 0.32, 95% CI 0.13-0.79, P = 0.01). OS was 92.9% for CPR versus 73.4% for NPR (OR 3.6, 95% CI 1.84-7.22, P = 0.002), and DFS was 86.9% versus 63.9% (OR 3.53, 95% CI 1.62-7.72, P = 0.002). CPR after CMT for rectal cancer is associated with improved local and distal control as well as better OS and DFS.


[Perinatal anatomopathological diagnosis].
The authors propose a synthetic scheme of perinatal anatomo-pathological diagnosis which, on the one hand, contains conventional concepts of wide interpretation of basic disease in mono-, bi- and multicausal genesis of the disease and death and, on the other hand, the order of placing clinical data about mother's diseases, complications of pregnancy and delivery, information about external causes of the child's (fetus's) death and placenta pathology. Nosological characteristics of "Single states arising in perinatal period" (class XVI, POO-P96 rubrics) are presented and 10 principles of their uniform explanation in documentation of perinatal anatomo-pathological diagnosis are formulated.


Injuries of the adolescent girl athlete: a review of imaging findings.
With the rising participation of girls in sports at both the recreational and elite levels, there has also been increased awareness of injuries common in this athlete population. Anatomic differences between boys and girls cause girl athletes to be predisposed to certain injuries. Certain behavioral patterns, such as eating disorders, also cause problems specific to girl athletes that may result in injury. Imaging plays a large role in diagnosis and ongoing management, but there has been only scant literature dedicated to the specific topic of imaging in girl athletes. The purpose of this article is to review the imaging findings and recommendations for injuries and other conditions affecting the adolescent girl athlete. This article first provides an overview of the key anatomic differences between boys and girls, including both static and dynamic factors, as well as non-anatomic differences, such as hormonal factors, and discusses how these differences contribute to the injury patterns that are seen more typically in girls. The article then reviews the imaging findings in injuries that are commonly seen in girl athletes. There is also a discussion of the "female athlete triad," which consists of osteoporosis, disordered eating, and amenorrhea, and the role of imaging in this condition.


The Idea and Application of Tuina in the Prevention and Treatment of COVID-19.
While traditional Chinese medicine has displayed a positive and effective role in saving lives of COVID-19 patients, Tuina, which is an important component in Chinese medicine, has also shown its merits in enhancing the immune function and relieving symptoms in COVID-19 patients. This article elaborates the long history of Tuina in treating and preventing epidemic diseases and its effect in improving the immune function. It also introduces some special Tuina methods, for instance, sputum drainage by the back-patting method to enable the discharge of sputum; slant-scrubbing method applied on the hypochondriac regions to bring the effect of soothing the liver to regulate qi, which may also relieve anxiety of patients with COVID-19; and spine-pinching method to enhance human resistance to diseases, which is more suitable for the elderly and for children with mild or common types of COVID-19 and can also be used for health care and disease prevention among the general population. Tuina methods for children using the common children's specific Tuina points and manipulations to improve children's body constitution are also mentioned in the article. Self-acupoint Tuina for health care, including acupoints for prevention purposes, acupoints for early clinical stage (mild stage) and recovery stage, as well as acupoints for children health care and specific operations, is also illustrated in the article. Moreover, basic exercises for health care, such as eight-section brocade, Shaolin internal exercises, six-character formula, and change of tendons, are also presented. In the final analysis, this article is aimed at some ideas and feasible applications of Tuina therapy in the prevention and treatment of COVID-19, in the hope to provide some worthy experience and introduce methods in preventing and fighting against COVID-19 to people all over the world.


Vitamin B12 in neurology and ageing; clinical and genetic aspects.
The classic neurological and psychiatric features associated with vitamin B12 deficiency have been well described and are the subject of many excellent review articles. The advent of sensitive diagnostic tests, including homocysteine and methylmalonic acid assays, has revealed a surprisingly high prevalence of a more subtle 'subclinical' form of B12 deficiency, particularly within the elderly. This is often associated with cognitive impairment and dementia, including Alzheimer's disease. Metabolic evidence of B12 deficiency is also reported in association with other neurodegenerative disorders including vascular dementia, Parkinson's disease and multiple sclerosis. These conditions are all associated with chronic neuro-inflammation and oxidative stress. It is possible that these clinical associations reflect compromised vitamin B12 metabolism due to such stress. Physicians are also increasingly aware of considerable inter-individual variation in the clinical response to B12 replacement therapy. Further research is needed to determine to what extent this is attributable to genetic determinants of vitamin B12 absorption, distribution and cellular uptake.


Phenotype-environment correlations in a putative whitefish adaptive radiation.
1. The adaptive radiation of fishes into benthic (littoral) and pelagic (lentic) morphs in post-glacial lakes has become an important model system for speciation. Although these systems are well studied, there is little evidence of the existence of morphs that have diverged to utilize resources in the remaining principal lake habitat, the profundal zone. 2. Here, we tested phenotype-environment correlations of three whitefish (Coregonus lavaretus) morphs that have radiated into littoral, pelagic and profundal niches in northern Scandinavian lakes. We hypothesized that morphs in such trimorphic systems would have a morphology adapted to one of the principal lake habitats (littoral, pelagic or profundal niches). Most whitefish populations in the study area are formed by a single (monomorphic) whitefish morph, and we further hypothesized that these populations should display intermediate morphotypes and niche utilization. We used a combination of traditional (stomach content, habitat use, gill raker counts) and more recently developed (stable isotopes, geometric morphometrics) techniques to evaluate phenotype-environment correlations in two lakes with trimorphic and two lakes with monomorphic whitefish. 3. Distinct phenotype-environment correlations were evident for each principal niche in whitefish morphs inhabiting trimorphic lakes. Monomorphic whitefish exploited multiple habitats, had intermediate morphology, displayed increased variance in gillraker-counts, and relied significantly on zooplankton, most likely due to relaxed resource competition. 4. We suggest that the ecological processes acting in the trimorphic lakes are similar to each other, and are driving the adaptive evolution of whitefish morphs, possibly leading to the formation of new species.


Secretions from the ventral eversible gland of Spodoptera exigua caterpillars activate defense-related genes and induce emission of volatile organic compounds in tomato, Solanum lycopersicum.
Plant induced defense against herbivory are generally associated with metabolic costs that result in the allocation of photosynthates from growth and reproduction to the synthesis of defense compounds. Therefore, it is essential that plants are capable of sensing and differentiating mechanical injury from herbivore injury. Studies have shown that oral secretions (OS) from caterpillars contain elicitors of induced plant responses. However, studies that shows whether these elicitors originated from salivary glands or from other organs associated with feeding, such as the ventral eversible gland (VEG) are limited. Here, we tested the hypothesis that the secretions from the VEG gland of Spodoptera exigua caterpillars contain elicitors that induce plant defenses by regulating the expression of genes involved in the biosynthesis of volatile organic compounds (VOCs) and other defense-related genes. To test this hypothesis, we quantified and compared the activity of defense-related enzymes, transcript levels of defense-related genes and VOC emission in tomato plants damaged by S. exigua caterpillars with the VEG intact (VEGI) versus plants damaged by caterpillars with the VEG ablated (VEGA). The quantified defense-related enzymes (i.e. peroxidase, polyphenol oxidase, and lipoxigenase) were expressed in significantly higher amounts in plants damaged by VEGI caterpillars than in plants damaged by VEGA caterpillars. Similarly, the genes that encode for the key enzymes involved in the biosynthesis of jasmonic acid and terpene synthase genes that regulate production of terpene VOCs, were up-regulated in plants damaged by VEGI caterpillars. Moreover, the OS of VEGA caterpillars were less active in inducing the expression of defense genes in tomato plants. Increased emissions of VOCs were detected in the headspace of plants damaged by VEGI caterpillars compared to plants damaged by VEGA caterpillars. These results suggest that the VEG of S. exigua caterpillars contains elicitors of late plant defense signaling in tomato which trigger defense-related enzymatic activity, regulate expression of defense-related genes, and induce emission of plant VOCs. These signaling cascades may have important ramifications for plant-insect and tritrophic interactions.


A cognitive evaluation of four online search engines for answering definitional questions posed by physicians.
The Internet is having a profound impact on physicians' medical decision making. One recent survey of 277 physicians showed that 72% of physicians regularly used the Internet to research medical information and 51% admitted that information from web sites influenced their clinical decisions. This paper describes the first cognitive evaluation of four state-of-the-art Internet search engines: Google (i.e., Google and Scholar.Google), MedQA, Onelook, and PubMed for answering definitional questions (i.e., questions with the format of "What is X?") posed by physicians. Onelook is a portal for online definitions, and MedQA is a question answering system that automatically generates short texts to answer specific biomedical questions. Our evaluation criteria include quality of answer, ease of use, time spent, and number of actions taken. Our results show that MedQA outperforms Onelook and PubMed in most of the criteria, and that MedQA surpasses Google in time spent and number of actions, two important efficiency criteria. Our results show that Google is the best system for quality of answer and ease of use. We conclude that Google is an effective search engine for medical definitions, and that MedQA exceeds the other search engines in that it provides users direct answers to their questions; while the users of the other search engines have to visit several sites before finding all of the pertinent information.


Development of an ex vivo xenogeneic bone environment producing human platelet-like cells.
The efficiency of in vitro platelet production is considerably low compared with physiological activity due to the lack of pivotal factors that are essential in vivo. We developed an ex vivo platelet production system, introducing human megakaryocytes into an isolated porcine thighbone and culturing in closed circuit. The efficiency of the ex vivo platelet production system was compared to those in vivo and in vitro. CD61+ platelet-like cells were counted by immunostaining and flow cytometry. Results showed that 4.41 ± 0.27 × 103 CD61+ platelet-like cells were produced by 1 × 103 megakaryocytes in the ex vivo system, while 3.80 ± 0.87 × 103 and 0.12 ± 0.02 × 103 were produced in the in vivo and in vitro systems, respectively. Notably, ex vivo and in vitro production systems generated cells that responded well to thrombin stimulation and expressed functional molecules, such as CD62P. Overall, our ex vivo production system was comparable to in vivo production system and produced platelet-like cells that were functionally superior to those produced in vitro. In future, the present ex vivo production system implementing xenogeneic bone marrow would offer a promising alternative for industrial-scale production of platelet-like cells.


A time-comparison circuit in the electric fish midbrain. II. Functional morphology.
The weakly electric fish Eigenmannia is able to detect temporal disparities as small as 400 nsec between two signals from different parts of the body surface (Carr et al., 1986). The elements of this time-comparison circuit have been identified by EM reconstruction of its component cells. Information about the timing of the zero-crossing of signals on each area of the body surface is coded in phase-coder receptors, a subset of tuberous electroreceptors. Electroreceptors on the body surface are innervated by primary afferents with their central termination on the spherical cells of the medullary electrosensory lateral line lobe. These cells project to lamina VI of the midbrain torus, a structure similar to the inferior colliculus. Afferents entering lamina VI form a very restricted terminal arbor in which they synapse on the three cell types of this lamina. Each afferent makes gap-junction synapses on one or two giant cell somata and morphologically mixed synapses on the distal dendrites of two types of small cell. The afferent terminals thus encode the timing of the electric signal on a local patch of the body surface, forming a somatotopic map of the body surface in lamina VI. The giant cells are adendritic and their axonal arbor is such as to distribute timing information originating from one part of the body surface throughout lamina VI, so that each region of lamina VI receives information about the timing of zero-crossings from the entire body surface from giant cells, as well as information from a local portion of the body surface from the afferent terminals. The giant cells terminate exclusively on the cell bodies of the small cells of lamina VI, shown to be sensitive to small temporal disparities by Heiligenberg and Rose (1985). Thus, each small cell receives a single synapse on its soma from a giant cell that conveys phase-coding information from some portion of the body surface and receives local phase-coding input onto its dendrites from spherical cell afferents. The sensitivity of the small cells to temporal disparities appears to be conferred by their segregation of inputs from two different parts of the body surface onto dendrites and soma, respectively. We propose that the dendritic input acts as a delay line, and the small cell fires maximally when the inputs from the dendrites and the giant cell input onto the soma coincide.


Cerebral atrophy in infants with protein energy malnutrition.
Central nervous system manifestations are common in infants suffering from protein energy malnutrition. Computed tomography was used to search for pathology in the brain that might explain these symptoms. Subjects were 40 infants with protein malnutrition. All had mental symptoms. The bifrontal index was taken as the best parameter for measuring central atrophy, and the width of the sylvian fissure was used as the parameter for cortical atrophy. Ventricular dilatation and widened sylvian fissure of various degrees were found in every patient. The severity of atrophy correlated with the duration of the illness.


Multiple elements required for translation of plastid atpB mRNA lacking the Shine-Dalgarno sequence.
The mechanism of translational initiation differs between prokaryotes and eukaryotes. Prokaryotic mRNAs generally contain within their 5'-untranslated region (5'-UTR) a Shine-Dalgarno (SD) sequence that serves as a ribosome-binding site. Chloroplasts possess prokaryotic-like translation machinery, and many chloroplast mRNAs have an SD-like sequence, but its position is variable. Tobacco chloroplast atpB mRNAs contain no SD-like sequence and are U-rich in the 5'-UTR (-20 to -1 with respect to the start codon). In vitro translation assays with mutated mRNAs revealed that an unstructured sequence encompassing the start codon, the AUG codon and its context are required for translation. UV crosslinking experiments showed that a 50 kDa protein (p50) binds to the 5'-UTR. Insertion of an additional initiation region (SD-sequence and AUG) in the 5'-UTR, but not downstream, arrested translation from the authentic site; however, no inhibition was observed by inserting only an AUG triplet. We hypothesize for translational initiation of the atpB mRNA that the ribosome enters an upstream region, slides to the start codon and forms an initiation complex with p50 and other components.


First Clinical Experience Using Stereotactic Breast Biopsy Guided by 99mTc-Sestamibi.
The purpose of this study is to evaluate a new device using molecular breast imaging (MBI) for 99mTc-sestamibi-guided stereotactic lesion localization as a complementary biopsy tool. From December 2012 to May 2016, a total of 38 consecutive women (mean age, 59 years; range, 41-77 years) underwent 99mTc-sestamibi-guided biopsy using a new MBI-based device and were retrospectively reviewed. The biopsy modality used five steps: stereotactic localization of the 99mTc-sestamibi-avid lesion, calculation of coordinates of the lesion location using dedicated software, placement of the needle, verification of the correct needle position, and tissue sampling with a vacuum-assisted device followed by placement of a radiologic marker at the biopsy site and ex vivo measurement of the biopsy specimens. The procedure was technically successful in all 38 lesions. In all cases, biopsy samples were radioactive and adequate for histopathologic analysis. Nineteen lesions (50%) were found to be malignant, and the remaining lesions were found to be benign. The mean procedure time was 71 minutes (range, 44-112 minutes). The radiologic marker was successfully deployed in 37 lesions (97%). Two hematomas and three vasovagal reactions were observed. Technetium-99m sestamibi-guided biopsy performed using a dedicated MBI-based device is technically feasible and represents a valuable complementary biopsy tool in breast lesion diagnosis.


Choroidal laser Doppler flowmeter with enhanced sensitivity based on a scattering plate.
A portable choroidal laser Doppler flowmeter (LDF) with enhanced sensitivity based on a scattering plate is developed. The portable LDF is weighted 2 kg operated at center wavelength of 780 nm, leading to a better penetration into the eye fundus in contrast to the previous LDF operated at center wavelength of 670 nm. Enhancement of number of detected photons that undergo Doppler scattering and improved measured speed of choroidal blood flow are achieved with the use of a scattering plate positioned in front of the eye. The mechanism of detection and sensitivity enhancement is theoretically analyzed. Evaluation of system performance is done by in vivo measurements on ten volunteers. The results demonstrate that an increased percentage of backscattering light at high Doppler shift frequency is collected due to utilization of the scattering plate. However, this kind of light detection influences spatial resolution of the system and decreases the total signal measured. The proposed method for detection and sensitivity enhancement might be useful in a case where the perception of very slight alternation of blood flow is pursued and the spatial resolution is not as critical as that in a choroidal vascular bed.


Raman spectroscopy based on a single-crystal sapphire fiber.
We demonstrate the advantages of using a single-crystal sapphire fiber to perform Raman spectroscopy over using a standard glass fiber. The narrow Raman peaks and the low background signal of a single-crystal sapphire fiber allow for the detection of weaker Raman signals or Raman signals much closer to the incident laser wavelength than with a standard glass fiber, which has a strong broadband Raman spectrum of its own. The Raman spectra of calcite, single-walled carbon nanotubes, and aqueous sodium carbonate solution were collected using a 50 cm long, 200 μm diameter sapphire fiber, and then they were compared with the results using a 50 cm long, 100 μm diameter glass fiber. The Raman spectrum of each tested material becomes indistinguishable due to the background Raman signal of the glass fiber but can easily be seen using the sapphire fiber, which has only a few narrow Raman peaks of its own.


Pulling cylindrical particles using a soft-nonparaxial tractor beam.
In order to pull objects towards the light source a single tractor beam inevitably needs to be strongly nonparaxial. This stringent requirement makes such a tractor beam somewhat hypothetical. Here we reveal that the cylindrical shape of dielectric particles can effectively mitigate the nonparaxiality requirements, reducing the incidence angle of the partial plane waves of the light beam down to 45° and even to 30° for respectively dipole and dipole-quadrupole objects. The optical pulling force attributed to the interaction of magnetic dipole and magnetic quadrupole moments of dielectric cylinders occurs due to the TE rather than TM polarization. Therefore, the polarization state of the incident beam can be utilized as an external control for switching between the pushing and pulling forces. The results have application values towards optical micromanipulation, transportation and sorting of targeted particles.


Marital adjustment and depressive symptoms among Chinese perinatal women: a prospective, longitudinal cross-lagged study.
The objective was to assess the prevalence of perinatal depressive symptoms and determine the trajectories of marital adjustment and depressive symptoms and their reciprocal relationships among Chinese perinatal women. This was a prospective, longitudinal cross-lagged study. The study was conducted at the outpatient department of the largest women's and children's hospital in China, which is located in Chengdu, Sichuan Province. Four hundred and sixty-three mothers were conveniently sampled. The Dyadic Adjustment Scale and the Chinese version of the Edinburgh Postnatal Depression Scale were used to evaluate marital adjustment and depressive symptoms, respectively, at three time points: the first trimester of pregnancy (T1), the third trimester of pregnancy (T2) and 6 weeks after childbirth (T3). Descriptive statistics were used to assess the prevalence of perinatal depressive symptoms, and repeated-measures analysis of variance (ANOVA) was used to determine the trajectories of marital adjustment and depressive symptoms among the participants. A cross-lagged model was used to explore the reciprocal relationship between marital adjustment and depressive symptoms. The prevalence of perinatal depressive symptoms among our participants ranged from 21.2% to 24.0%. Repeated-measures ANOVA showed that during the perinatal period there was a significant tendency towards worse marital adjustment (F=33.031, p=0.000) and a slight but not significant reduction in depressive symptoms (F=1.883, p=0.153) among the participants. The cross-lagged model showed that maternal marital adjustment at T1 significantly and negatively predicted depressive symptoms at T2 (β=-0.165, p<0.001), and that depressive symptoms at T2 significantly and negatively predicted marital adjustment at T3 (β=-0.135, p<0.001). However, the predictive effects of depressive symptoms at T1 on marital adjustment at T2 and that of marital adjustment at T2 on depressive symptoms at T3 were not significant. The prevalence of perinatal depressive symptoms ranged from 21.2% to 24.0% among the participants. During the perinatal period, the marital adjustment of women tended to be worse; however, there was no significant change in depressive symptoms. This study showed that better marital adjustment at T1 was a protective factor against maternal depressive symptoms at T2, and a higher level of depressive symptoms at T2 was a risk factor for worse marital adjustment at T3.


Haemostatic derangement in advanced peripheral occlusive arterial disease.
Dysbalance of the coagulation and fibrinolysis system was suspected to be a further risk factor for the progression of peripheral occlusive arterial disease (POAD). Reports on disturbed platelet function in advanced disease, however, were contradictory. Therefore, we studied haemostasis parameters and platelet function in symptomatic patients with peripheral arterial disease. 60 peripheral arterial disease patients hospitalised for invasive diagnostic procedures were included into this comparative study. Patients were clinically stratified according to the criteria for chronic limb ischemia (grade I: n=36; grade II: n=11; grade III: n=13). Plasma fibrinogen, antithrombin III, von Willebrand factor, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) prothrombin time, and activated partial thromboplastin time were determined using standard methods. We measured flow cytometrically, the platelet activation marker P-selectin on nonstimulated, ADP- and TRAP-6-stimulated platelets. Angiographic data were assessed using the Bollinger score. Plasma levels of the procoagulant proteins fibrinogen (grade I: 3.7/grade II: 3.9/grade m: 4.0 g/l) and vWF (158/156/178%) increased and of antithrombin III (109/103/102%) and the PAI-1/tPA ratio (5.2/5.0/4.1) decreased with progressive disease. Highest platelet activation levels were observed in the CLI grade II subgroup. A significant correlation of disease severity was seen with the ankle-brachial pressure index (p=0.006; r=0.39) and with the Bollinger score (p=0.002; r=-0.41). Progressive peripheral obstructive arterial disease was associated with platelet hyper-reactivity, haemostatic dysbalance of pro- and anticoagulant proteins, and a counterregulatory increase of fibrinolytic activity. Therapeutic concepts should include these pathogenetic mechanisms.


URF13, a ligand-gated, pore-forming receptor for T-toxin in the inner membrane of cms-T mitochondria.
URF13 is the product of a mitochondrial-encoded gene (T-urf13) found only in maize plants containing the Texas male-sterile cytoplasm (cms-T), and it is thought to be responsible for both cytoplasmic male sterility and the susceptibility of cms-T maize to the fungal pathogens Bipolaris maydis race T and Phyllosticata maydis. Mitochondria isolated from cms-T maize are uniquely sensitive to pathotoxins (T-toxin) produced by these fungi and to methomyl (a commercial insecticide). URF13 acts as a receptor that specifically binds T-toxin to produce hydrophilic pores in the inner mitochondrial membrane. When expressed in Escherichia coli cells, URF13 also forms hydrophilic pores in the plasma membrane if exposed to T-toxin or methomyl. Topological studies established that URF13 contains three membrane-spanning alpha-helices, two of which are amphipathic and can contribute to pore formation. Chemical cross-linking of URF13 was used to demonstrate the existence of URF13 oligomers in cms-T mitochondria and E. coli cells. The ability of the carboxylate-specific reagent, N,N'-dicyclohexycarbodiimide, to cross-link URF13 was used in conjunction with site-directed mutagenesis to establish that the URF13 tetramer has a central core consisting of a four-alpha-helical bundle which undergoes a conformational change after interaction with T-toxin or methomyl. Overall, the experimental evidence indicates that URF13 functions as a ligand-gated, pore-forming T-toxin receptor in cms-T mitochondria.


Primer: Demystifying risk--understanding and communicating medical risks.
Assessments of risk are a critical part of the practice of evidence-based medicine. Comprehension of various risk measures, such as absolute risk, relative risk, attributable risk, odds ratio, and hazard ratio, is essential to understand the medical literature, and to communicate health risks effectively. Complex risk measures, including number needed to treat and survival estimates that are adjusted for competing risks, are often misunderstood. Communication of these concepts to patients can be a challenge. The patient's perception of risk stems not only from the way risks are stated, but also from family history, personal experiences, cultural norms, and beliefs. A multifaceted approach to risk communication that uses both qualitative and quantitative assessments of risk, and addresses the timing and permanence of risks, is necessary to ensure the patient understands the potential risks. Successful communication involves interaction with the patient to understand the patient's perspective and to aid in personalized decision-making. In the face of uncertainty, making a provisional decision with a plan to review it later can be a good strategy. Verifying the patient's comprehension can help ensure that the decisions reached are informed and acceptable.


Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy.
Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.


Effects of micro-bubble aeration on the pollutant removal and energy-efficient process in a floc-granule sludge coexistence system.
To investigate energy-saving approaches in wastewater treatment plants and decrease aeration energy consumption, this study successfully established a floc-granule coexistence system in a sequencing batch airlift reactor (SBAR) employing micro-bubble aeration. The analysis focused on granule formation and pollutant removal under various aeration intensities, and compared its performance with a traditional floc-based coarse-bubble aeration system. The results showed that granulation efficiency was positively associated with aeration intensity, which enhanced the secretion of extracellular polymeric substances (EPSs) and facilitated granule formation. The SBAR with the micro-aeration intensity of 30 mL·min-1 showed the best granulation performance (granulation efficiency 52.6%). In contrast to the floc-based system, the floc-granule coexistence system showed better treatment performance, and the best removal efficiencies of NH4+-N, TN, and TP were 100.0, 77.0, and 89.5%, respectively. The floc-granule coexistence system also enriched higher abundance of nutrients removal microbial species, such as Nitrosomonas (0.05-0.14%), Nitrospira (0.14-2.32%), Azoarcus (2.95-12.17%), Thauera (0.43-1.95%), and Paracoccus (0.76-2.89%). The energy-saving potential was evaluated, which indicated it is feasible for the micro-aeration floc-granule coexistence system to decrease the aeration consumption by 14.4% as well as improve the effluent.


Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment.
In vitro and animal studies indicate that a moderate temperature of 41 degrees C maintained for approximately 1 h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41 degrees C is a more feasible goal than the goal of >42 degrees C needed for sequential treatment. Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7 Gy). Hyperthermia was delivered with 915 MHz microwave or 1-3.5 MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 x 3.6 x 1.7 cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 x 6.1 x 2.9 cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30 Gy. Radiation dose per fraction was 4 Gy with hyperthermia and 2 Gy or 4 Gy (depending on protocol) on non-hyperthermia days. Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41 degrees C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42 degrees C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41 degrees C which exceeded 60 min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51%) and 7/41 (17%) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21%) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80 Gy and complete response to treatment. Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.


Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures.
Networks of GABAergic interneurons are of utmost importance in generating and promoting synchronous activity and are involved in producing coherent oscillations. These neurons are characterized by their fast-spiking rate and by the expression of the Ca(2+)-binding protein parvalbumin (PV). Alteration of their inhibitory activity has been proposed as a major mechanism leading to epileptic seizures and thus the role of PV in maintaining the stability of neuronal networks was assessed in knockout (PV-/-) mice. Pentylenetetrazole induced generalized tonic-clonic seizures in all genotypes, but the severity of seizures was significantly greater in PV-/- than in PV+/+ animals. Extracellular single-unit activity recorded from over 1000 neurons in vivo in the temporal cortex revealed an increase of units firing regularly and a decrease of cells firing in bursts. In the hippocampus, PV deficiency facilitated the GABA(A)ergic current reversal induced by high-frequency stimulation, a mechanism implied in the generation of epileptic activity. We postulate that PV plays a key role in the regulation of local inhibitory effects exerted by GABAergic interneurons on pyramidal neurons. Through an increase in inhibition, the absence of PV facilitates synchronous activity in the cortex and facilitates hypersynchrony through the depolarizing action of GABA in the hippocampus.


Noise-aided computation within a synthetic gene network through morphable and robust logic gates.
An important goal for synthetic biology is to build robust and tunable genetic regulatory networks that are capable of performing assigned operations, usually in the presence of noise. In this work, a synthetic gene network derived from the bacteriophage λ underpins a reconfigurable logic gate wherein we exploit noise and nonlinearity through the application of the logical stochastic resonance paradigm. This biological logic gate can emulate or "morph" the AND and OR operations through varying internal system parameters in a noisy background. Such genetic circuits can afford intriguing possibilities in the realization of engineered genetic networks in which the actual function of the gate can be changed after the network has been built, via an external control parameter. In this article, the full system characterization is reported, with the logic gate performance studied in the presence of external and internal noise. The robustness of the gate, to noise, is studied and illustrated through numerical simulations.


Ingestion of Lactobacillus rhamnosus modulates chronic stress-induced feather pecking in chickens.
Feather pecking (FP) is a stress-induced neuropsychological disorder of birds. Intestinal dysbiosis and inflammation are common traits of these disorders. FP is, therefore, proposed to be a behavioral consequence of dysregulated communication between the gut and the brain. Probiotic bacteria are known to favorably modulate the gut microbiome and hence the neurochemical and immune components of the gut-brain axis. Consequently, probiotic supplementation represents a promising new therapeutic to mitigate widespread FP in domestic chickens. We monitored FP, gut microbiota composition, immune markers, and amino acids related to the production of neurochemicals in chickens supplemented with Lactobacillus rhamnosus or a placebo. Data demonstrate that, when stressed, the incidence of FP increased significantly; however, L. rhamnosus prevented this increase. L. rhamnosus supplementation showed a strong immunological effect by increasing the regulatory T cell population of the spleen and the cecal tonsils, in addition to limiting cecal microbiota dysbiosis. Despite minimal changes in aromatic amino acid levels, data suggest that catecholaminergic circuits may be an interesting target for further studies. Overall, our findings provide the first data supporting the use of a single-strain probiotic to reduce stress-induced FP in chickens and promise to improve domestic birds' welfare.


Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.


Large-scale genomic survey and characterization of mcr genes carried by foodborne Cronobacter isolates.
Cronobacter is an emerging foodborne opportunistic pathogen, which can cause neonatal meningitis, bacteremia, and NEC by contaminating food. However, the entire picture of foodborne Cronobacter carriage of the mcr genes is not known. Here, we investigated the mcr genes of Cronobacter isolates by whole-genome sequencing and found 133 previously undescribed Cronobacter isolates carrying mcr genes. Further genomic analysis revealed that these mcr genes mainly belonged to the mcr-9 and mcr-10. Genomic analysis of the flanking structures of mcr genes revealed that two core flanking structures were prevalent in foodborne Cronobacter isolates, and the flanking structure carrying IS1R was found for the first time in this study.


[Goblet-cell carcinoid tumor of the appendix (invasive mucinous adenoma)].
Goblet-cell carcinoid of the vermiform process is a well-differentiated epithelial tumor consisting predominantly of mucus-forming cells among which endocrine and Paneth's cells are found not infrequently. Despite the invasive nature of the tumor growth, the prognosis of the disease is most frequently favourable, although not as much as in carcinoid of the vermiform process. Considering the cell composition and the level of the tumor tissue differentiation, the so-called goblet-cell carcinoid should be regarded as a peculiar invasive mucous adenoma but not as a variety of carcinoid (apudoma).