Assessment of the effects of menopause on semicircular canal using the video head impulse test.
This cross-sectional study included early menopausal and late menopausal women aged between 40 and 60 years to evaluate the effects of menopause on semicircular canal function. A video head impulse test (vHIT) was performed for all subjects. Vestibulo-ocular reflex (VOR) mean gains of each semicircular canal and gain asymmetry were compared between groups. Of the 87 subjects, 37(42.5%) were reproductive age 28(32.5%) were early menopausal and 22(25.3%) were late menopausal patients. VOR gain of semicircular canals or gain asymmetry values did not differ between groups. In postmenopausal women, presence of vasomotor symptoms was associated with higher gain asymmetry of the left anterior-right posterior (LARP) plane (p = .01), and presence of balance problems was associated with lower right anterior (RA) VOR gain (p = .01). In conclusion semicircular canal function in postmenopausal women was similar to that in women of reproductive age.IMPACT STATEMENTWhat is already known on this subject? During menopause, women face potential risks such as dizziness, balance problems, falls and fractures. Postmenopausal patients were tested with dynamic posturography to measure balance before and after oestrogen treatment, and it was shown that balance problems significantly improved with oestrogen treatment. Healthy vestibular system is one of the components for sustaining normal balance.What do the results of this study add? In postmenopausal women the function of the semicircular canals is normal and the balance deficit in postmenopausal women may not be caused by the vestibular system. In this study changes within normal limits were observed in vestibular system of postmenopausal women.What are the implications of these findings for clinical practice and/or further research? Reported balance deficits might have been due to central origin. Further research to differentiate origin of balance deficits are needed. Specific research on symptomatic postmenopausal patients would reveal more information.


Unsupervised synthesis of realistic coronary artery X-ray angiogram.
Medical image analysis suffers from a sparsity of annotated data necessary in learning-based models. Cardiorespiratory simulators have been developed to counter the lack of data. However, the resulting data often lack realism. Hence, the proposed method aims to synthesize realistic and fully customizable angiograms of coronary arteries for the training of learning-based biomedical tasks, for cardiologists performing interventions, and for cardiologist trainees. 3D models of coronary arteries are generated with a fully customizable realistic cardiorespiratory simulator. The transfer of X-ray angiography style to simulator-generated images is performed using a new vessel-specific adaptation of the CycleGAN model. The CycleGAN model is paired with a vesselness-based loss function that is designed as a vessel-specific structural integrity constraint. Validation is performed both on the style and on the preservation of the shape of the arteries of the images. The results show a PSNR of 14.125, an SSIM of 0.898, and an overlapping of 89.5% using the Dice coefficient. We proposed a novel fluoroscopy-based style transfer method for the enhancement of the realism of simulated coronary artery angiograms. The results show that the proposed model is capable of accurately transferring the style of X-ray angiograms to the simulations while keeping the integrity of the structures of interest (i.e., the topology of the coronary arteries).


Thrombin-induced prostacyclin biosynthesis in human endothelium: role of guanine nucleotide regulatory proteins in stimulus/coupling responses.
The regulation of prostacyclin (PGI2) synthesis by cultured human umbilical vein endothelium (HUVEC) was investigated. HUVEC monolayer generation of PGI2 was monitored by RIA of 6-keto PGF1 alpha and dose-dependent increases observed with human alpha- and gamma-thrombins, histamine, or arachidonate. Alpha thrombin (10 nM) produced levels of 6-keto PGF1 alpha approximating responses with 1 microM gamma-thrombin, 5 microM arachidonate, or 10 microM histamine. Diisopropyl phosphorofluoridate-inactivated alpha-thrombin did not stimulate PGI2 release, demonstrating that catalytic activity was required for thrombin-stimulated PGI2 release. Sodium fluoride (NaF), at concentrations known to activate guanine nucleotide regulatory proteins (G proteins), directly stimulated HUVEC PGI2 synthesis in a dose-dependent and time-dependent manner (20 mM NaF, 4.4 +/- 0.5-fold increase at 10 min, 11.9 +/- 1.5-fold increase at 30 min). Neither alpha-thrombin nor NaF-stimulated PGI2 release was dependent upon the availability of extracellular Ca++). The hypothesis that G proteins are involved in agonist-stimulated PGI2 synthesis was further supported by studies using digitonin-permeabilized HUVEC monolayers challenged with another G protein activator, guanosine 5'-0-3-thiotrisphosphate (GTP gamma S), which effected significant dose-dependent increases in PGI2 synthesis compared with control levels of 6-keto PGF1 alpha. In contrast, the G-protein inhibitor GDP beta S, (guanosine 5'-0-2-thiodiphosphate), attenuated alpha-thrombin-mediated prostaglandin generation. Treatment of HUVEC monolayers with pertussis toxin (1 microgram/ml) did not inhibit the PGI2 synthesis stimulated by either alpha-thrombin, NaF, or histamine but catalyzed the ADP ribosylation of a 40 kDa membrane protein which cross-reacted with antisera against a synthetic peptide corresponding to an amino acid sequence common to the alpha-subunit of other G-proteins. Preincubation of HUVEC microsomal membranes with alpha-thrombin diminished pertussis toxin-catalyzed ADP ribosylation in a time-dependent manner. These data suggest that thrombin stimulation of PGI2 synthesis by HUVEC monolayers requires the catalytically functional enzyme and further suggests that the thrombin-occupied receptor is coupled to phospholipase activities by a pertussis toxin-insensitive guanine nucleotide regulatory protein in human endothelial cell membranes.


Immunoglobulin fragments, F(ab')2, that are cytotoxic to enzyme-treated cells.
Bivalent immunoglobulin fragments of IgG, F(ab')2, prepared from normal murine sera were found to be cytotoxic to neuraminidase-treated cells. The fragments were cytotoxic to both allogenic and syngeneic targets (with respect to the source of the sera), suggesting that the antigen bound by the F(ab')2 is not related to the major histocompatibility locus of mice (H-2).


Variation and Association of Hen Performance and Egg Quality Traits in Individual Early-Laying ISA Brown Hens.
Uniformity in hen and egg traits is an important consideration in commercial layer flocks. There is little information on how individual hen feed consumption and body weight affect egg quality measurements. This study investigated the variation in performance traits of individual hens and associations with egg quality characteristics. Four hundred and fifty-five ISA Brown caged hens in early lay were monitored for 42 days (25 to 30 weeks of age) to collect hen feed consumption and egg production measurements. Forty-four hens from the flock were randomly selected and eggs were collected from the same hen once weekly for albumen, yolk, and shell assessment. The means ± standard deviation of average daily feed intake (ADFI), albumen height, initial body weight (IBW), and final body weight (FBW) were 124 g ± 15, 10.3 mm ± 1.5, 1802 g ± 129, and 2000 g ± 175, respectively. Albumen height was not associated with ADFI (r = 0.18, p = 0.21), IBW (r = -0.04, p = 0.79), or FBW (r = -0.06, p = 0.69). This study showed variation in feed intake, body weight, and albumen quality of individual early-lay hens. Feed intake and body weight did not influence albumen quality.


Mechanisms of the dilator action of cryptotanshinone on rat coronary artery.
In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.


The bear paw: a radiologic sign for congenital ureteropelvic junction obstruction.
This article defines a new radiographic descriptor of high-grade hydronephrosis suggestive of ureteropelvic junction obstruction that is easily recognized by urologists and non-urologists alike. This is useful information for medical personnel participating in the management of children with hydronephrosis.


Managing heart failure care using an internet-based telemedicine system.
Managing patients with heart failure (HF) is labor intensive, and follow-up is often inadequate to detect day-to-day changes that ultimately lead to decompensation. We tested the effect of an Internet-based telemedicine (T) system that provides frequent surveillance and increased communicate between HF patients and their provider on frequency of hospitalization in a cohort of patients with advanced HF. HF patients in NYHA Class II-IV were randomized to usual care (UC, n = 24) or T (T plus UC, n = 24) and followed for 1 year. Office visits, emergency department visits, hospitalizations, telephone calls, and number of Internet communications were measured over the 1-year period. Left ventricular ejection fraction (EF) was assessed by echocardiography in both groups. For T, mean age was 53.2 +/- 2.0 years (72% male, 61% Caucasian, 39% African American). For UC, mean age was 54.1 +/- 2.6 years (76% male, 72% Caucasian, 14% African American, and 14% Hispanic). HF etiologies and EF were similar in both groups. During the 12-month period, UC had 74 total phone calls to the practice, whereas T had 88 telephone calls plus 1887 telemedicine data messages (6.5 messages/patient/month). ER visits were lower in the T group (T 5, UC 12; P < .05). Hospital admissions (T 24, C 40; P = .025) and total hospital days (T 84, UC 226 days; P < .005) were lower in T. Unscheduled clinic visits (T 13, UC 13; P = NS) and scheduled clinic visits (T 78, UC 94; P = NS) were similar in both groups. Frequent monitoring and patient management using a telemedicine system may help to reduce hospitalizations, hospital days, and emergency department visits.


Peirce on the justification of abduction.
What sort of justification can be claimed for abduction? In this paper we reconstruct Peirce's answer to this question. We show that in his early works on the logic of science Peirce provided an abductive justification of abduction, and that in his mature writings the early solution is enriched by a reference to the place abduction has in a typical scientific inquiry. Since abduction is the first stage of inquiry by which a hypothesis is suggested and which then has to be subjected to inductive testing, the fundamental abduction (ur-abduction) that justifies abduction has also to be subjected to a verification by means of a fundamental induction (ur-induction), namely that the abduction that abduction is valid is verified by an appeal to the history of science.


Labeling and functional language in a case of psychological mutism.
Talking was increased in an 11-year-old girl who recently had stopped talking to anyone in any setting, despite the absence of biological factors, mental retardation, and autism. Productive labeling (correctly naming picture cards) and functional language (talking about picture cards in the absence of such pictures) were interspersed with a series of treatment packages (including verbal instructions, imitation, tokens, and praise). Interventions for productive labeling were programmed in a changing-criterion design. Interventions for functional language were programmed in an ABC design. Higher levels of productive labeling and functional language were noted with the introduction of the particular package, in comparison to baseline. The results also showed the generalization of the procedures to the shaping of functional language in the absence of picture cards.


No gene copy number changes in Dupuytren's contracture by array comparative genomic hybridization.
Dupuytren's contracture (DC), a benign disease of unknown origin, is characterized by abnormal fibroblast proliferation and matrix deposition within the palmar and plantar faciae, causing contracture of the digits. Conventional cytogenetic studies of cultured fibroblast cells from DC nodules have revealed nonrecurrent, but usually normal, clonal (mainly +7, +8, and -Y, plus structural changes) and sporadic (nonclonal) numerical/structural rearrangements. No unique cytogenetic features of DC are known so far. We used 44K oligonucleotide-based array comparative genomic hybridization to obtain a wide pattern of chromosomal imbalances in 18 patients with DC. The genome-wide analysis revealed no changes of DNA copy number sequences. Accordingly, gene amplifications or deletions are apparently not involved in the progression of abnormal fibroblast proliferation and matrix deposition that lead to DC.


SARS-CoV-2 Infection in Infants Less than 90 Days Old.
This is a single-center US case series of 18 infants <90 days old who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These infants had a mild febrile illness without significant pulmonary disease. One-half of the infants were hospitalized; 1 had bacterial urinary tract co-infection. Nasopharyngeal viral loads were notably high. Latinx ethnicity was overrepresented.


Rapid and Checkable Electrical Post-Treatment Method for Organic Photovoltaic Devices.
Post-treatment processes improve the performance of organic photovoltaic devices by changing the microscopic morphology and configuration of the vertical phase separation in the active layer. Thermal annealing and solvent vapor (or chemical) treatment processes have been extensively used to improve the performance of bulk-heterojunction (BHJ) organic photovoltaic (OPV) devices. In this work we introduce a new post-treatment process which we apply only electrical voltage to the BHJ-OPV devices. We used the commercially available P3HT [Poly(3-hexylthiophene)] and PC61BM (Phenyl-C61-Butyric acid Methyl ester) photovoltaic materials as donor and acceptor, respectively. We monitored the voltage and current applied to the device to check for when the post-treatment process had been completed. This electrical treatment process is simpler and faster than other post-treatment methods, and the performance of the electrically treated solar cell is comparable to that of a reference (thermally annealed) device. Our results indicate that the proposed treatment process can be used efficiently to fabricate high-performance BHJ-OPV devices.


Classifying migraine subtypes and their characteristics by latent class analysis using data of a nation-wide population-based study.
Migraine neither presents with a definitive single symptom nor has a distinct biomarker; thus, its diagnosis is based on combinations of typical symptoms. We aimed to identify natural subgroups of migraine based on symptoms listed in the diagnostic criteria of the third edition of the International Classification of Headache Disorders. Latent class analysis (LCA) was applied to the data of the Korean Sleep-Headache Study, a nationwide population-based survey. We selected a three-class model based on Akaike and Bayesian information criteria and characterized the three identified classes as "mild and low frequency," "photophobia and phonophobia," and "severe and high frequency." In total, 52.0% (65/125) of the participants were classified as "mild and low frequency," showing the highest frequency of mild headache intensity but the lowest overall headache frequency. Meanwhile, "photophobia and phonophobia" involved 33.6% (42/125) of the participants, who showed the highest frequency of photophobia and phonophobia. Finally, "severe and high frequency" included 14.4% (18/125) of the participants, and they presented the highest frequency of severe headache intensity and highest headache frequency. In conclusion, LCA is useful for analyzing the heterogeneity of migraine symptoms and identifying migraine subtypes. This approach may improve our understanding of the clinical characterization of migraine.


The Intensive Care Unit Liaison Nurse and their value in averting clinical deterioration: A qualitative descriptive study.
Intensive Care Unit Liaison Nurse roles are associated with improved clinical outcomes for patients and financial benefits for healthcare providers. However, there is little academic exploration of the ward nurses' perspectives of the role and whether it can affect ward nurses' confidence in identifying and managing the deteriorating patient. This study addresses this gap by examining both those perspectives. A qualitative descriptive approach was used, utilising semi-structured interviews to garner the perspectives of ward nurses.Interviewswere conducted with ward nurses who had been involved in a MedicalEmergencyTeam/Code Blue call;sought technical or clinical support;or had been at the bedside during a post intensive care unit discharge review. Data were analysed using thematic analysis. A private, not-for-profit, metropolitan acute care hospital. The participants identified four areas that contributed to improved patient care: reduced Medical Emergency Team/Code calls; improved ward based critical care knowledge through education; improved ward nurses' confidence in dealing with the deteriorating patient and provision of technical support. The Intensive Care Unit Liaison Nurse role not only contributes to improved clinical patient outcomes; it also influences confidence levels of the ward nurses in managing deteriorating patients.


A test for the difference between two treatments in a continuous measure of outcome when there are dropouts.
Consider a randomized clinical trial that is designed to compare two treatments in which the treatment continues during the entire period of the study. Some subjects may refuse to complete the protocol and will not return for the final evaluation. Since the reason for dropping out may be related to the subject's self-assessed evaluation of the usefulness of the treatment or to undesirable side effects of the treatment, subjects who drop out cannot be treated as a random sample of those who entered the trial. We consider the situation where the measure of efficacy of the treatment is continuous. Under the assumption that the expected value of the measure for those who drop out is not better (the direction depends on the measure) than that for those who complete the study, we propose an adjustment to the usual test for a difference between treatments that allows for the inclusion of the probable effect of the dropouts; this provides a bound on the test for efficacy of the treatment. First, we estimate a predetermined percentile, such as the median score, of the control, or placebo, group and assign this score to all those who dropped out from both groups and to all subjects in both groups with scores that are worse than the assigned score. A Mann-Whitney statistic is then used to test the equality of the distributions of the two groups. We show by simulation that this modified test is equivalent to a test using the complete data and has greater power than that obtained when including the dropouts by assigning the worst observed score to them. This test will be less sensitive to bias that is induced by exclusion of dropouts from the final evaluation.


Exposure to Violence during Adolescence as a Predictor of Perceived Stress Trajectories in Emerging Adulthood.
Early exposure to violence during adolescence is related to negative psycho-social outcomes later in life. In the present study, we examined the influence of cumulative exposure to violence during adolescence and trajectories of perceived stress in emerging adulthood in a sample of at-risk urban youth (N = 850; 80.1% African American; 50% female). Growth curve modeling indicated an overall decrease in reported stress as individuals aged. Baseline levels of violence exposure (Mage = 14.9) were associated with higher perceived stress levels in emerging adulthood (Mage = 20.1), but also slightly more negative perceived stress slopes from adolescence into emerging adulthood (Mage = 15.9-22.1). Individuals reporting increased violence exposure over time during adolescence also reported higher perceived stress levels in emerging adulthood (Mage = 20.1). Associations held after controlling for demographics and baseline functioning variables. The results suggest that violence exposure may disrupt normative adaptation to daily stressors in emerging adulthood.


IL1β inhibits differentiation of cementoblasts via microRNA-325-3p.
Cementum regeneration is considered the gold standard for the treatment of periodontitis. As one of the most important primary proinflammatory cytokines, interleukin 1β (IL1β) plays an essential role during the early stage of periodontitis and its amounts simultaneously increase dramatically during this stage. Though promising, the differentiation of cementoblasts upon IL1β-induced inflammation of the microenvironment and the relative interaction mechanism are still unknown. Here, we found that IL1β inhibited cementoblast differentiation and microRNA-325-3p (miR-325-3p) was increased during IL1β-stimulated cementoblasts. Bioinformatics analysis and luciferase reporter assay demonstrated miR-325-3p targeted runt-related transcription factor 2 directly. Transfection of miR-325-3p suppressed cementoblast differentiation in vitro and the formation of cementum-like tissues in vivo. The inhibitor of miR-325-3p could mitigate the above effects induced by IL1β. Accordingly, our finding suggests a critical role of miR-325-3p in linking inflammation to impaired cementum regeneration and provides a potential possibility for applying miR-325-3p inhibitors in the treatment of periodontitis-related bone loss.


The Value of Neutrophil to Lymphocyte Ratio in Patients Undergoing Cytoreductive Nephrectomy with Thrombectomy.
The neutrophil-lymphocyte ratio (NLR) is an established signature of inflammation used for evaluating renal cell carcinoma (RCC). To determine the utility of NLR and its relationship with known risk factors associated with poor survival in patients with metastatic RCC and tumor thrombus undergoing cytoreductive nephrectomy (CN). Prognostic variables were reviewed for patients undergoing CN with thrombectomy between 2000 and 2014 from six different institutions. Patients were stratified for NLR >4.0 based on cut point analysis. Kaplan-Meier curves compared overall survival of the total cohort and established risk models (Memorial Sloan Kettering Cancer Center [MSKCC], International Metastatic Renal-Cell Carcinoma Database Consortium [IMDC], and M.D. Anderson Cancer Center [MDACC]) stratified by NLR. Multivariable Cox regression determined predictors of overall survival. Receiver operator characteristic curves tested the predictive accuracy of survival ≥12 mo, and area under the curve (AUC) was compared between models. In total, 332 patients were identified. Patients with NLR ≤4.0 had longer median survival (24.7 vs 15.2 mo, p=0.004). NLR >4.0 distinguished patients with significantly shorter survival for non-poor-risk groups defined by MSKCC, IMDC, and MDACC criteria. Systemic symptoms, low hemoglobin, elevated lactate dehydrogenase, retroperitoneal adenopathy, level IV thrombus, elevated absolute neutrophil count, and NLR >4 were independent predictors of decreased survival (p<0.05). These factors had higher predictive accuracy for survival at 12 mo (AUC=0.755) than MKSCC, IMDC, and MSKCC models. NLR >4.0 independently predicts poor survival and further distinguishes established risk model survival curves. We identified seven preoperative risk factors related to poor survival for patients with metastatic RCC with tumor thrombus undergoing CN. The neutrophil-lymphocyte ratio and six additional preoperative variables can be used to better council patients regarding survival after surgery for metastatic renal cell carcinoma with tumor thrombus.


New developments in the medical management of overactive bladder.
Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Whilst the majority of women will benefit from initial management with conservative and behavioural intervention a significant number will require medical therapy. Antimuscarinics are currently the most widely prescribed drugs for OAB although very often persistence with medication is limited due to lack of efficacy or intolerable adverse effects. The review, whilst giving a brief overview of OAB syndrome, will focus on new developments in drug therapy for OAB. In addition to evaluating new drugs with different methods of action it will also specifically focus on alternative modalities of treatment and how they may benefit patients with this troublesome and distressing condition.


Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells.
The naturally occurring short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant which is clinically used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-β (TGFβ) pathway. In this study, we evaluate the effects of ALA on thyroid cancer cell proliferation, migration and invasion. We performed in vitro cell proliferation analysis using BCPAP, HTH-83, CAL-62 and FTC-133 cells. ALA suppressed thyroid cancer cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62 and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated β-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFβ production and inhibited induction of p-Smad2 and twist by TGFβ1 or TGFβ2. These findings indicate that ALA reduces cancer cell migration and invasion through suppression of TGFβ production and inhibition of TGFβ signaling pathways in thyroid cancer cells. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for treatment of advanced thyroid cancer, possibly as an adjuvant therapy with other systemic therapeutic agents.


Predictors of caregiver burden in caregivers of older people with physical disabilities in a rural community.
Caring for an aging society is a problem facing many countries including Thailand. This cross-sectional study investigated caregiver burden and related predictive factors among 69 caregivers who had older family members with physical disabilities. Burden Scale, World Health Organization Quality of Life-Bref Thai (QOL), Patient Health Questionnaire-9 (PHQ), Barthel Activity of Daily Living Index (ADL), and Lawton-Brody Instrumental Activities of Daily Living Scale (IADL) assessments were used in addition to demographic data. Thirteen caregivers (18.8%) reported no caregiver burden, 30 (43.5%) reported low-moderate burden, 21 (30.4%) reported moderate-high burden and 5 (7.2%) reported high burden. Using Fisher's Exact Test the factors found to be significantly associated to caregiver burden were: categorical age of the caregiver (p = .000), education level of the caregiver (p = .002), relationship to the care recipient (p = .009), categorical income level of the caregiver (p = .041), QOL of the caregiver (p = .001) and ADL status of the care recipient (p = .003). Forward stepwise linear regression model revealed three factors which were PHQ score (β = .543, p < .000), ADL score (β = -.341, p = .001) and hours of care/week (β = .227, p = .017). Future studies should focus on interventions that impact depression levels, independence with activities of living and hours of care per week.


Signal transduction versus buffering activity in Ca(2+)-binding proteins.
The three-dimensional structure of calbindin D9k in the absence of Ca2+ has been determined using NMR spectroscopy in solution, allowing the first direct analysis of the consequences of Ca2+ binding for a member of the calmodulin superfamily of proteins. The overall response in calbindin D9k is much attenuated relative to the current model for calmodulin and troponin C. These results demonstrate a novel mechanism for modulating the conformational response to Ca(2+)-binding in calmodulin superfamily proteins and provide insights into how their Ca(2+)-binding domains can be fine-tuned to remain essentially intact or respond strongly to ion binding, in relation to their functional requirements.


Assessment of bone-targeting agents use in patients with bone metastasis from breast, lung or prostate cancer using structured and unstructured electronic health records from a regional UK-based hospital.
ObjectiveTo assess use of bone-targeting agents (BTA) in patients with confirmed bone metastases (BM) from breast cancer (BC), non-small cell lung cancer (NSCLC) or prostate cancer (PC). Retrospective cohort study. Regional hospital-based oncology database of approximately 2 million patients in England. Patients aged ≥18 years with a diagnosis of BC, NSCLC or PC as well as BM between 1 January 2007 and 31 December 2018, with follow-up to 30 June 2020 or death; BM diagnosis ascertained from recorded medical codes and unstructured data using natural language processing (NLP). Initiation or non-initiation of BTA following BM diagnosis, time from BM diagnosis to BTA initiation, time from first to last BTA, time from last BTA to death. This study included 559 BC, 894 NSCLC and 1013 PC with BM; median age (Q1-Q3) was 65 (52-76), 69 (62-77) and 75 (62-77) years, respectively. NLP identified BM diagnosis from unstructured data for 92% patients with BC, 92% patients with NSCLC and 95% patients with PC. Among patients with BC, NSCLC and PC with BM, 47%, 87% and 88% did not receive a BTA, and 53%, 13% and 12% received at least one BTA, starting a median 65 (27-167), 60 (28-162) and 610 (295-980) days after BM, respectively. Median (Q1-Q3) duration of BTA treatment was 481 (188-816), 89 (49-195) and 115 (53-193) days for patients with BC, NSCLC and PC. For those with a death record, median time from last BTA to death was 54 (26-109) for BC, 38 (17-98) for NSCLC and 112 (44-218) days for PC. In this study identifying BM diagnosis from both structured and unstructured data, a high proportion of patients did not receive a BTA. Unstructured data provide new insights on the real-world use of BTA.


Radiofrequency capacitive hyperthermia for deep-seated tumors. I. Studies on thermometry.
The thermometry results of radiofrequency (RF) capacitive hyperthermia for 60 deep-seated tumors in 59 patients are reported. Hyperthermia was administered regionally using two RF capacitive heating equipments which the authors have developed in cooperation with Yamamoto Vinyter Company Ltd., (Osaka, Japan). Intratumor temperatures were measured by thermocouples inserted through angiocatheters which were placed 5 cm to 12 cm deep into the tissues. Tumor center temperatures were measured for 307 treatments in all tumors; thermal distributions within tumors and surrounding normal tissues were obtained for 266 treatments of 53 tumors by microthermocouples. Thermometry results obtained were summarized as follows. A maximum tumor center temperature greater than 43 degrees C and 42 degrees C to 43 degrees C was obtained in 23 (38%) and 14 (23%) of the 60 tumors respectively. The time required to reach 43 degrees C in the tumor center was within 20 minutes after the start of hyperthermia in 87% of tumors heated to more than 43 degrees C. Temperature variations within a tumor exceeded 2 degrees C in 81% of tumors heated to more than 43 degrees C. The lowest tumor temperature greater than 42 degrees C was achieved in six of the 53 tumors (11%). Of 42 tumors in which temperatures of the subcutaneous fat, surrounding normal tissues, and the tumor center were compared, 24 (57%) showed the highest temperature in the tumor center and ten (24%) in the subcutaneous fat. When the heating efficacy was assessed in terms of a maximum tumor center, it great deal depended on the treatment site, tumor size, thickness of subcutaneous fat, and tumor type. Tumors in the head and neck, thorax, lower abdomen, and pelvis could be heated better than tumors in the upper abdomen. Greater heating efficacy was shown in patients with large, hypovascular tumors, and with the subcutaneous fat measuring less than 15 mm thick. The predominant limiting factor for power elevation was pain associated with heating. Systemic signs including increases in pulse rate and body temperature were not serious and seldom became limiting factors for power elevation. Our thermometry results indicate that the advantages of deep RF capacitive heating are its applicability to various anatomic sites and negligible systemic effects. The disadvantages are that its primary usefulness is limited to patients with thin subcutaneous fat and with large or hypovascular tumors.


Dissipation of 'dark energy' by cortex in knowledge retrieval.
We have devised a thermodynamic model of cortical neurodynamics expressed at the classical level by neural networks and at the quantum level by dissipative quantum field theory. Our model is based on features in the spatial images of cortical activity newly revealed by high-density electrode arrays. We have incorporated the mechanism and necessity for so-called dark energy in knowledge retrieval. We have extended the model first using the Carnot cycle to define our measures for energy, entropy and temperature, and then using the Rankine cycle to incorporate criticality and phase transitions. We describe the dynamics of two interactive fields of neural activity that express knowledge, one at high and the other at low energy density, and the two operators that create and annihilate the fields. We postulate that the extremely high density of energy sequestered briefly in cortical activity patterns can account for the vividness, richness of associations, and emotional intensity of memories recalled by stimuli.


Prodrug of epigallocatechin-3-gallate alleviates choroidal neovascularization via down-regulating HIF-1α/VEGF/VEGFR2 pathway and M1 type macrophage/microglia polarization.
Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly and is attributed to choroidal neovascularization (CNV), which is a feature of wet AMD. The hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to the pathogenesis of CNV. M1-type macrophages/microglia secrete interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), facilitating the development of CNV. Epigallocatechin-3-gallate (EGCG) is a kind of polyphenol in green tea that exerts anti-inflammatory and antiangiogenic effects. In this study, a prodrug of EGCG (pro-EGCG) alleviated mouse laser-induced CNV leakage and reduced CNV area by down-regulating HIF-1α/VEGF/VEGFR2 pathway; M1-type macrophage/microglia polarization; as well as endothelial cell viability, proliferation, migration and tube formation, indicating a novel potential therapy for AMD.


Volume regulation in human fibroblasts: role of Ca2+ and 5-lipoxygenase products in the activation of the Cl- efflux.
Trypsinized human skin fibroblasts in suspension perform regulatory volume decrease (RVD) after cell swelling in hypotonic medium. During RVD, 36Cl- efflux is dramatically increased and the cell membrane is depolarized, indicating the activation of Cl- channels. This activation of Cl- channels depends on extracellular as well as on intracellular Ca2+. The swelling-induced Cl- efflux and the RVD response are inhibited by the 5-lipoxygenase inhibitor ETH 615-139. Finally, following hypotonic treatment, cellular pH decreases. The pH decrease does not involve the Cl-/HCO3- exchange because it is independent of the external Cl- concentration.


Children's Explanations of Aggressive Incidents at School Within an Attribution Framework.
Previous research suggests children use different types of attribution to explain bullying. The research, however, has not explored links between children's attributions. This study explores the types of, and links between, attributions made by children about bullying situations. Seventeen 9- and 10-year-olds were interviewed at school. Types of attributions and links between attributions were categorised using content analysis. The results suggest that children make a range of linked attributions that can be coded into characterological and behavioural and a new category named 'feelings'. The findings are linked to previous research, and implications for clinical and school interventions are discussed.


A gene for resistance to a necrosis-inducing isolate of Pyrenophora tritici-repentis located on 5BL of Triticum aestivum cv. Chinese Spring.
Several sources of high-level resistance to tan spot caused by Pyrenophora tritici-repentis have been identified in hexaploid wheat (Triticum aestivum L.). This study was conducted to determine the number and chromosome location of a gene(s) in the cultivar Chinese Spring (CS) that confers resistance to a tan necrosis inducing isolate (nec+chl−) of P. tritici-repentis, 86-124, and insensitivity to Ptr necrosis toxin. Reciprocal crosses were made between CS (resistant-insensitive) and 'Kenya Farmer' (KF) (susceptible-sensitive). Analysis of the CS/KF F1and F2 populations and F2-derived F3 families identified a single nuclear recessive gene governing resistance to isolate 86-124 and Ptr necrosis toxin. Evaluation of the CS(KF) substitution series, F2 monosomic analysis, and screening of a series of 19 CS compensating nullitetrasomic and two ditelosomic lines (2AS and 5BL) indicated that the resistance gene was located on chromosome arm 5BL. No linkage exists between Lr18 and the tan necrosis resistance gene on chromosome arm 5BL. It is proposed that the gene for resistance to the tan necrosis inducing isolate 86-124 (nec+chl−) of P. tritici-repentis and Ptr necrosis toxin be named tsn1. Key words : wheat, Triticum aestivum L., tan spot resistance, Pyrenophora tritici-repentis (Died.) Drechs., chromosome location, Ptr necrosis toxin.


The barriers in protein folding.
Elimination of an interaction which forms in denatured cytochrome c enables the majority of the molecules to fold to the native state on a 15 ms time scale, without populating observable intermediates. These results are contrary to the current view that particular steps in protein folding, including the supposedly rate-limiting molten globule to native transition, are intrinsically slow. Instead it appears that intermediates characterized so far may be kinetically trapped by barriers that are optional rather than integral to the folding process. Major barriers may result from misorganization of the chain in the initial condensation step.


The horse as a model of naturally occurring osteoarthritis.
Osteoarthritis (OA) is an important cause of pain, disability and economic loss in humans, and is similarly important in the horse. Recent knowledge on post-traumatic OA has suggested opportunities for early intervention, but it is difficult to identify the appropriate time of these interventions. The horse provides two useful mechanisms to answer these questions: 1) extensive experience with clinical OA in horses; and 2) use of a consistently predictable model of OA that can help study early pathobiological events, define targets for therapeutic intervention and then test these putative therapies. This paper summarises the syndromes of clinical OA in horses including pathogenesis, diagnosis and treatment, and details controlled studies of various treatment options using an equine model of clinical OA.


Variation of finger forces in maximal isometric grasp tests on a range of cylinder diameters.
An investigation of maximal isometric cylindrical grasping actions of the hand is reported. A dynamometer is described which allows simultaneous measurement of both the normal forces and the tangential shear forces imposed by each of the three phalangeal segments of a finger during a test. Seventeen subjects were tested, grasping cylinders 31-116 mm in diameter. Normal grasp forces decreased significantly as cylinder size increased, while with large diameters, shear forces moved the skin towards the finger tip. In all cases the distal segments of the fingers imposed forces significantly larger than those of the middle and proximal segments. The mean contributions of fingers from index to little were: 30, 30, 22 and 18%, proportions that did not vary significantly for the range of grasp diameters. Forces acting during grasping activities are reported in greater detail, for a wider range of hand gripping postures, than previously available. These data are useful in the design of hand operated controls or in the prediction of tendon and joint forces in vivo for the design of implants.


Complement system dysregulation in patients affected by Idiopathic Generalized Epilepsy and the effect of antiepileptic treatment.
Complement system dysregulation has been hypothesized as a possible pathogenetic factor triggering epileptogenesis in both animal models and human studies. The aim of the present study is to evaluate the complement system in adult patients affected by idiopathic generalized epilepsy (IGE), either untreated or treated by antiepileptic drugs (AEDs). Thirty-seven IGE patients were compared to a population of 20 matched healthy controls. IGE patients underwent neurological investigation, epilepsy diary, 24-h EEG recording, and blood sample for the assessment of the complement factors C3 and C4, fibrinogen, and C-reactive protein (CRP) serum levels. We excluded patients with clinical and subclinical seizures in the 24h before obtaining the blood sample. We observed decreased C3 and C4 serum levels in IGE patients with respect to controls (p<0.05), and in untreated compared to treated IGE patients (p<0.05). We found significant correlations in the IGE group linking C3 to C4 (R=0.34), CRP (R=0.49), and fibrinogen serum levels (R=0.61). This study proved a significant alteration of the complement system in IGE patients not related to ictal conditions. The hyperactivation of the complement cascade was more significant in untreated than in treated IGE patients. Hence, this study documented the complement factors dysregulation in patients affected by IGE. However, the impact of complement system alteration in the epileptogenetic process needs to be clarified.


Far lateral approach without occipital condylar resection for intradural ventral/ventrolateral foramen magnum tumors and aneurysms of V4 segment of vertebral artery: Review of surgical results.
Controversies exist regarding the need and extent of condylar resection for safe surgical management of intradural ventral/ventrolateral foramen magnum (VFM) tumors and aneurysms of V4 segment of vertebral artery (VA) by far lateral approach. This retrospective study was conducted to evaluate the results of basic far lateral approach(retrocondylar approach) without upfront occipital condylar resection. Twenty one patients underwent surgery via far lateral approach for intradural VFM tumors and aneurysms of V4 segment of VA at Sri Sathya Sai Institute of Higher Medical Sciences during 9 years(2008-2016) study period. Eight patients had VA aneurysms and 13 patients had intradural VFM tumors. After basic far lateral approach(retrocondylar approach), dura was opened and checked if the exposure was adequate for safe surgery. Retrocondylar approach provided adequate exposure for all these lesions and resection of occipital condyle/jugular tubercle was not required in any of these cases. Skeletonization or transposition of VA was not done in any of these cases. Gross total resection of the tumor could be done in 9 patients(9/13-69.2 %) and near total excision (>95 %) in 4 patients (4/13-30.8 %). Seven of the 8 VA aneurysms were successfully clipped. Outcome at a final follow up of 3 months or more was good(mRS<2) in 19 patients(19/21-90.5 %) and poor in 2 patients. Complications included lower cranial nerve deficits [transient-2/21(9.5 %), persisting-2/21(9.5 %)], motor deficits(2/21-9.5%), seventh nerve paresis(1/21-4.8%), sixth nerve paresis(2/21-9.5%) and pseudomeningocele(1/21-4.8%). Basic far lateral (retrocondylar) approach provides excellent exposure for majority of VFM tumors and aneurysms of V4 segment of VA. Condylar resection(transcondylar approach), drilling of jugular tubercle (transtubercular approach), skeletonization/transposition of VA might not be required for safe surgical management of majority of these lesions.


Pertechnetate SPECT-CT in corrosive gastric injury.
We report a 24-year-old woman with corrosive poisoning who was subjected to pertechnetate scintigraphy to evaluate gastric injury. Fusion imaging (SPECT-CT) provided valuable information regarding viability of gastric mucosa, and it helped guide appropriate management.


The expression of β3-adrenoceptor and muscarinic type 3 receptor immuno-reactivity in the major pelvic ganglion of the rat.
Bladder afferent outflow, linked to sensation, plays a critical role in bladder pathology: abnormal outflow results in altered sensation, leading to increased voiding frequency, urge and often incontinence. β3-adrenoceptor agonists have been suggested to be beneficial in treating these symptoms. However, the absence of a significant sympathetic innervation of the detrusor and only a modest relaxation of bladder muscle by β3 agonists has questioned the therapeutic site of action of β3 agonists in the bladder. The present study was done to explore the possibility that β3-adrenoceptors might be located in the pelvic plexus. Using the rat, where the pelvic plexus is located primarily within a single ganglion, the major pelvic ganglion (MPG), immuno-histochemical approaches were used to identify structures expressing β3-adrenoceptor immuno-reactivity (β3AR-IR). The only structures found to express β3AR-IR were small-diameter tyrosine hydroxylase and vesicular mono-amine transporter immuno-reactive (TH-IR and vmat-IR) neurones. These neurones, found in clusters or singly on the periphery of the ganglion, or dispersed in smaller clumps throughout the MPG, are similar to the small intensely fluorescent (SIF) cells described previously. Not all small cells expressed β3AR-IR. A population of the small cells were also immuno-reactive to the type 3 muscarinic receptor (M3R-IR) and the P2X3 purinergic receptor (P2X3-IR). Clumps of small cells were associated with calcitonin gene-related peptide immuno-reactive (CGRP-IR) nerve fibres (putative sensory fibres) and a small number were contacted by putative cholinergic nerves expressing immuno-reactivity to vesicular acetylcholine transporter (vacht-IR). These observations are consistent with the idea that small cells are interneurons and one of the components making up complex neural circuits within the MPG. The precise physiological role of these neural elements in the MPG is unknown. However, as one therapeutic action of β3-adrenoceptor agonists is to modulate sensation, it is possible that these neural circuits may be involved in the regulation of afferent outflow and sensation.


Peritonitis from injury of an aberrant subvesical bile duct during laparoscopic cholecystectomy: A rare case report.
Aberrant subvesical bile ducts are rare anatomical structures. Damage to these ducts leads to bile leakage and can result in life-threatening complications. Surgeons should be cautious that such a structure may be present, and surgery should be performed with the correct surgical field to prevent damage to these structures.


The effectiveness of a community playground intervention.
This study assessed whether an upgrade of playgrounds in a community was associated with changes in the physical activity of local children. The study used a natural experiment design with a local authority project to upgrade two community playgrounds as the intervention and a matched control community. Children's physical activity was measured by an Actigraph GT1M accelerometer worn for 8 days, enabling up to 6 days of data to be analyzed. A self-administered parent/guardian questionnaire was used to collect additional data, including perceptions of the neighborhood, school-travel modes, days involved in extracurricular activities, ethnicity, caregiver age, caregiver sex, household vehicle access, and household income. At baseline, 184 children (5-10 years old) participated. Of these, 156 completed the 1-year follow-up assessment (20% lost to follow-up). There was statistically significant evidence that change in mean total daily physical activity was associated with on an interaction between participant's body mass index (BMI) z-score and her or his community of residence (p = 0.006), with the intervention being associated with higher levels of activity for children with lower BMIs but lower levels for children with higher BMIs. Physical activity is not the only focus of local authority playground provision as playgrounds also have benefits for social development and fundamental movement skills. However, making sure that physical activity is always included in the design rationale and that playgrounds are designed to encourage and sustain physical activity could be a useful population health intervention. The effects of such interventions on different subgroups are of importance, especially if the effects differ over levels of BMI.


Commentary on Adrenal wash-out CT: moderate diagnostic value in distinguishing benign from malignant masses.
The increasing use of cross-sectional imaging, mainly CT, results in an accelerating number of incidental findings, for instance of adrenal tumours. Although most 'adrenal incidentalomas' are benign, it is important to identify the malignant and the hormone producing (functional) tumours. For a small fraction of adrenal incidentalomas, the diagnosis is apparent on imaging, but the large majority requires radiological characterisation. To this end, a previous joint European Society of Endocrinology and European Network for the Study of Adrenal Tumours publication in this jounal, recommends CT measurements of the native (non-contrast) tumour attenuation ≤10 Hounsfield units, consistent with a lipid-rich benign adrenocortical adenoma, and imaging at least 6 months apart, on which unchanged tumour size implies a benign tumour. Because of weak evidence, calculation of CT contrast medium washout was not recommended as a means for tumour characterisation, but this technique has nevertheless still been applied in several countries. The recent article by Schloetelburg et al. in this journal is important because, in the largest study to date, the authors confirm that calculation of CT contrast medium washout with established thresholds is insufficient to reliably characterise adrenal tumours. Their results are therefore expected to impact the management of these patients.


Discrepancies in survival after conversion to open in minimally invasive pancreatoduodenectomy.
The extent by which conversion to open (CTO) during minimally invasive procedures for pancreatic cancer impact survival outcomes is not fully understood. The 2010-2017 National Cancer Database identified 12,424 non-metastatic patients who underwent pancreatoduodenectomy for ductal adenocarcinoma. Patients were stratified into three cohorts: open (OPD), completed MIPD (cMIPD), and CTO. Subgroups were dichotomized by hospital MIPD volume. Across the study period, 80.6% of patients underwent OPD, 19.4% MIPD, and 24% were CTO. Median overall survival was worse after CTO (21.8 months) than for OPD (23.6 months) or cMIPD (25.2 months) (p < 0.001). Although this effect persisted for <10 MIPD/year, CTO did comparably to OPD at hospitals performing ≥10MIPD/year (CTO = 26.8 months, OPD = 27.9 months; p = 0.128). Ninety-day mortality after CTO was worse at ≤ 10 MIPD/year hospitals (9.3% vs. 2.6%). Short and long-term survival is impacted by CTO after MIPD, especially at lower surgical volumes, stressing careful adoption while ascending the learning curve.


Bladder entrance of microplastic likely induces toxic effects in carnivorous macrophyte Utricularia aurea Lour.
The global distribution of microplastic (particle size < 5 mm) is of growing concern, especially in aquatic environments where it may cause adverse effects on resident organisms. To date, however, few studies have focused on the impacts of microplastic on aquatic plants. Here, we conducted a microcosm study to investigate the toxic effects of microplastic on the carnivorous aquatic macrophyte Utricularia aurea Lour. Based on microscopic images and Raman spectrum analysis, we found that most polyvinyl chloride (PVC) particles were smaller than the valve of U. aurea bladders, thus allowing entrance into the plant, but this was not so for polyethylene (PE) particles. Furthermore, PVC (50 mg L-1) had significantly negative effects on growth and physiological parameters such as macrophyte length, chlorophyll content, and fluorescence, whereas, at the same concentration, PE had no such effects. Further analysis revealed that after bladder removal, the macrophytes did not respond to PVC particle toxicity. Thus, intake of microplastics (i.e., PVC) through bladders is likely responsible for inducing toxic effects to the growth and physiological parameters of U. aurea.


Identification and characterization of Pestalotiopsis-like fungi related to grapevine diseases in China.
Pestalotiopsis-like fungi are an important plant pathogenic genus causing postharvest fruit rot and trunk diseases in grapevine in many countries. Pestalotiopsis-like fungi diseases were studied in vineyards in nine provinces across China. Multi-gene (ITS, β-tubulin and tef1) analysis coupled with morphology showed that a Neopestalotiopsis sp. and Pestalotiopsis trachicarpicola are associated in causing grapevine fruit rot and trunk diseases in China. Pestalotiopsis trachicarpicola is reported as the causative agent of grapevine diseases in the world for the first time. Neopestalotiopsis sp. caused significantly longer lesions than the other taxon present. This study represents the first attempt to identify and characterize the Pestalotiopsis-like fungi causing grapevine diseases in China using both morphological and molecular approaches.


Role of neuropeptide receptor systems in vanilloid VR1 receptor-mediated gastric acid secretion in rat brain.
Previously, we reported that the injection of capsaicin into the lateral cerebroventricle (i.c.v.) stimulated gastric acid secretion via vanilloid VR1 receptors and the vagal cholinergic pathways in anesthetized rats. In the present study, we investigated the involvement of receptor systems for neurokinin A, calcitonin gene-related peptide (CGRP) and glutamate in the vanilloid VR1 receptor-mediated response. The i.c.v. injection of neurokinin A (30 nmol) stimulated gastric acid secretion in the presence of cis-2-(diphenylmethyl)-N-[(2-iodophenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine oxalate (L-703606, a tachykinin NK1 receptor antagonist, 30 nmol) and the effect was inhibited by cyclo[Gln-Trp-Phe-Gly-Leu-Met] (L-659877, a tachykinin NK2 receptor antagonist, 30 nmol); the values were 145.9 +/- 32.3 and 21.1 +/- 16.6 microEq HCl per 120 min, respectively. The value in the control group was 14.3 +/- 3.8 microEq HCl. The tachykinin NK2 receptor-mediated secretion was inhibited by i.c.v. injections of antagonists of the CGRP1 receptor (human CGRP fragment 8-37, 15 nmol) and non-N-methyl-D-aspartate (non-NMDA)-type glutamate receptor (6-cyano-7-nitroquinoxaline-2,3-dione, 10.9 nmol); the values were 30.8+/-29.8 and 5.7+/-16.9 microEq HCl, respectively. Gastric acid secretion induced by the i.c.v. injection of 30 nmol capsaicin (178.4 +/- 34.0 microEq HCl) was inhibited by antagonists of tachykinin NK2 (23.7 +/- 6.2) and CGRP1 (21.2 +/- 8.5), but not tachykinin NK1 (181.4 +/- 37.0), receptors. The gastric acid secretion induced by capsaicin was decreased by the i.c.v. pre-injection of low doses of neurokinin A or CGRP, which alone had no effect on the secretion. These findings suggest the involvement of tachykinin NK2, CGRP and non-NMDA receptor systems in the vanilloid VR1 receptor-mediated regulation of gastric acid secretion in the rat brain regions close to the lateral cerebroventricle.


Metabolic correlates of behavioral and affective disturbances in frontal lobe pathologies.
Although previous studies have shown that the human frontal cortex is involved in the experience of emotions as well as in social behavior, data regarding the exact anatomical substrates of behavioral and affective deficits in frontal lobe pathologies are still scarce. The aim of this study was to investigate the metabolic correlates of these deficits in a group of non-selected consecutive patients with frontal lobe lesions. Clinicometabolic correlations between several emotional and social parameters and metabolic patterns in the frontal cortex and amygdala were investigated in 32 patients with frontal lobe pathologies. The behavioral disturbances were evaluated using the Lhermitte's informant questionnaire. Regional cerebral glucose metabolism was measured with [(18)F] fluorodeoxyglucose and high-resolution positron emission tomography. Statistical analysis was performed using both single variable correlation and multiple regression analyses. Both single variable and multivariate analyses demonstrate that decreased regional glucose metabolism in the right medial area 10 was associated with apathy. There were also significant negative relationships between metabolism in the right orbitofrontal cortex and stereotypy and indifference to rules. Impulsiveness, personality disturbances and loss of emotional control were associated with decreased metabolism in the left amygdala. In terms of clinicometabolic correlations, the present data support the implication of different functional anatomic systems in frontal lobe-related behavioral and affective disturbances. In particular, they imply that the classically described symptoms of impaired behavioral control may be related to right orbitofrontal cortex hypometabolism whereas impaired regulation of emotions may result from a functional damage of the left amygdala.


A method of mass cultivation of Toxoplasma gondii in cell culture.
Large quantities of Toxoplasma gondii were cultivated in human larynx carcinoma cells (H.Ep 2, heteroploid). Virulent Toxoplasma gondii, strain RH, which were obtained from the peritoneal exsudate of mice 2 days after infection served as inoculum. As culture medium for the cells and for growth medium, Minimum Essential Medium (MEM) supplemented by 5% foetal calf serum and 200,000 IE/1 Penicillin plus 20 mg/1 Sulmycin was used. 2--3 days after inoculation, 150--200 times the amount of the inoculated Toxoplasmas could be harvested in one or several harvests.


Solid anaerobic digestion batch of bio-waste as pre-treatment for improving amendment quality: The effect of inoculum recirculation.
The effect of solid anaerobic digestion batch (SADB) on bio-waste performed with and without inoculum on the quality of the final amendment was investigated by means of determining the content of organic carbon, humic and fulvic acids and the degree of humification. Two different processes were compared: composting and SADB with post-composting. Six parallel tests were performed. In three of these tests the SADB was inoculated mixing the bio-waste with the digestate from the previous run in a 1:1 ratio by weight. The amendment obtained by the SADB with post-composting treatment, in which the SADB was not inoculated, had an organic carbon content ranging from 15.5% TS to 30.3% TS resulting from 1% up to 14% higher than that of the corresponding composting processes. Similar results were achieved for the degree of humification. On the other hand SADB in which the inoculum was used generated about 300NL/kgVS of biogas instead of about 267NL/kgVS for non-inoculated runs.


Severe meningo-radiculo-neuritis associated with ipilimumab.
Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) to promote antitumoural immunity. In phase III trials, ipilimumab was shown to be the first agent to improve survival in advanced melanoma patients, regardless of previous treatment. We report a case of severe neurologic disease after ipilimumab treatment. Neurologic symptoms including facial diplegia, tetraplegia, areflexia progressed with time a few days after the fourth monthly ipilimumab infusion. Analysis of the cerebro-spinal fluid showed elevated proteinorachy and lymphocytic meningitis. Despite high doses of steroids and symptomatic treatment, the symptoms worsened. Veinoglobulins were then infused and the patient began to improve and recovered almost normal activity two years later. The adverse event profile associated with ipilimumab was primarily immune-related. This is the first case in which such a severe event has been reported.


Changes in the cytoplasmic distribution of microtubule-associated protein 2 during the differentiation of cultured cerebellar granule cells.
The distribution of microtubule-associated protein 2 in cultured cerebellar granule cell neurons was followed by immunohistochemical staining with specific antibodies. During differentiation in vitro, the neurites of these cells pass through a series of developmental stages. At first the emergent processes contain only trace levels of microtubule-associated protein 2 which is most concentrated in and near the cell body. When the neurites are between two and five cell diameters long they exhibit both microtubule-associated protein 2 and tubulin, apparently evenly distributed, throughout their length. Subsequently microtubule-associated protein 2 is limited to an initial, usually varicose portion of the neurite whereas its long distal extension contains abundant tubulin but is apparently devoid of microtubule-associated protein 2. Thus microtubule-associated protein 2 and tubulin are not necessarily co-distributed with a single neuronal process. In both morphological appearance and in the different distributions of microtubule-associated protein 2 and tubulin they contain, these processes show a mixture of axonal and dendritic properties. Since these same cells do not develop their characteristic dendritic arborizations, our results suggest that when removed from the developing brain, cerebellar granule neurons achieve part but not all of their normal morphological and cytoskeletal differentiation.


Lack of effect of central nervous system-active doses of nabilone on capsaicin-induced pain and hyperalgesia.
The aim of the present study was to investigate the effects of nabilone on capsaicin-induced pain and hyperalgesia, as well as on biomarkers of cannabinoid central nervous system (CNS) effects. A randomized, double-blind, placebo-controlled, crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone (1, 2 or 3 mg). Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale (0-100 mm). Capsaicin cream was applied to the calf to induce hyperalgesia. Primary hyperalgesia was assessed by measuring heat pain thresholds, whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful. Pain and hyperalgesia were measured at baseline and 2-3.5 h after dosing. The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling 'stimulated', 'anxious', 'sedated' and 'down'. Plasma samples for pharmacokinetic analysis were obtained up to 24 h after drug administration. Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia, whereas dose-dependent CNS effects were observed from 1.5 to 6 h after dosing, being maximal at 4-6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1-2 h after dosing. Adverse events (AE) were common on nabilone treatment. Four subjects withdrew due to pronounced CNS AE (anxiety, agitation, altered perception, impaired consciousness). Although nabilone had marked CNS effects, no analgesic or antihyperalgesic effects were observed.


Morphological differentiation of embryonic rat sympathetic neurons in tissue culture. II. Serum promotes dendritic growth.
In the preceding paper, we reported that embryonic rat sympathetic neurons formed axons, but not dendrites, when they were maintained in the absence of serum and nonneuronal cells. To assess the effects of serum-derived factors on cellular morphology, cultures were initially maintained in serum-free medium while nonneuronal cells were eliminated. Subsequently some cultures were chronically exposed either to fetal calf serum (10%) or to a high-molecular-weight ammonium sulfate fraction of serum (P40 material, 500 micrograms/ml). Phase-contrast microscopy revealed that serum and P40 material did not alter neuronal survival, but did cause flattening of the somata and fasciculation of processes. When neurons exposed to serum or P40 material were injected with Lucifer Yellow, it was found that the majority (greater than or equal to 90%) had local, tapered processes that could be identified as dendrites by light microscopic criteria. These local processes also exhibited other dendritic characteristics in that (1) they reacted with monoclonal antibodies to nonphosphorylated forms of the M and H neurofilament subunits and to microtubule-associated protein 2; and (2) they had substantial amounts of RNA as determined by [3H]uridine autoradiography. Quantitative measurements of the effects of serum and P40 material on dendritic morphology revealed that (1) an 8-day exposure caused most neurons (greater than 80%) to form dendrites; (2) neurons typically had more than one dendrite (mean of 4.1 +/- 0.2 dendrites/cell after a 28-day exposure); and (3) the dendrites were relatively short with the maximum extent of the dendritic arbor being 110 +/- 13 micron after 4 weeks. Serum and P40 material did not routinely cause the formation of supernumerary axons, did not alter radial axonal outgrowth from ganglion explants, and did not significantly increase [3H]leucine incorporation. Thus, serum contains a factor (or factors) which selectively stimulates the extension of dendrites, but not axons. If such a factor were operative in situ, it could play an important role in determining the morphology of sympathetic neurons. In examining the mechanism of serum-induced dendritic growth, we found that even high concentrations (5 micrograms/ml) of nerve growth factor failed to promote dendritic growth in the absence of serum; thus, nerve growth factor by itself is not a sufficient condition for the extension of dendrites.(ABSTRACT TRUNCATED AT 400 WORDS)


Use of a polymer-bound flavin derivative for the rapid regeneration of NAD(P)+ from NAD(P)H in dehydrogenase systems.
An aldehyde derivative of riboflavin was covalently attached by reductive alkylation to soluble polycationic supports. The flavopolymers so obtained were stable under operational conditions. The catalytic efficiency towards oxidation of NADH by these flavopolymers was demonstrated, and the kinetic parameters (Km and kcat) revealed an overall catalytic efficiency (kcat/Km) 185-fold greater compared to riboflavin. Various factors affecting the chemical regeneration of NAD+ from NADH such as pH, ionic strength, nature of the buffer etc. were studied. The most interesting result was the highly favourable influence of borate ions which increased the reaction rate by a factor 2-4 compared to the other buffers. The flavopolymers are very effective for in situ recycling of NAD(P)+. With up to 300-fold NADH----NAD+ conversions for the system using yeast alcohol dehydrogenase and up to 1500-fold NADPH----NADP+ regenerations for the system using glucose-6-phosphate dehydrogenase. These flavopolymers are superior to previous chemical recycling systems.


Postoperative administration of donor B cells induces rat kidney allograft acceptance: lack of association with Th2 cytokine expression in long-term accepted grafts.
Although donor leukocytes are only thought to prolong survival when administered before transplantation, recent evidence shows that they are effective at transplantation. This study aims to identify the leukocyte subset that is most active in prolonging kidney allograft survival and examine the cytokine expression in long-term acceptance. PVG rat kidneys were transplanted to completely MHC class I and class II-mismatched DA recipients. Donor B cells or T cells, purified by negative selection, were injected i.v. at the time of transplantation. Expression of interleukin (IL)-2, IL-4, IL-10, interferon (IFN)-gamma, and transforming growth factor-beta mRNA was measured by quantitative real-time polymerase chain reaction (PCR). Immunohistochemical analysis and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL) staining was used to identify infiltrating cells and apoptotic cells, respectively, in sections of kidney allografts. Median kidney graft survival time (MST) of B cell-treated animals (n=5) was >300 days, compared with 7 days in untreated animals (n=7) (P=0.003), whereas animals treated with the same number of T cells (n=6) had a MST of 17 days (P=0.1 vs. untreated, P=0.03 vs. B cell-treated). Examination of the long-term (>300 days) accepted grafts from B cell-treated recipients showed little evidence of kidney damage but a moderate perivascular infiltrate consisting of T and B cells. This infiltrate seemed to be quiescent because there was no detectable expression of IL-2 receptors or of apoptotic cells. It produced little or no cytokine mRNA, because expression in the long-term accepted grafts was similar to levels in normal kidneys or syngeneic transplants. There was a marked increase of cytokine mRNA early after transplantation in both leukocyte-treated and untreated grafts, with more rapid appearance of IFN-gamma and IL-10 in leukocyte-treated grafts. Donor B cells efficiently induce long-term acceptance of transplanted kidneys in a fully MHC-mismatched rat model when administered at transplantation, by a mechanism that seems to be independent of Th2 cytokine expression within the long-term accepted graft.


Unequal allocation of overt and covert attention in Multiple Object Tracking.
In many real-life contexts, where objects are moving around, we are often required to allocate our attention unequally between targets or regions of different importance. However, typical multiple object tracking (MOT) tasks, primarily investigate equal attention allocation as the likelihood of each target being probed is the same. In two experiments, we investigated whether participants can allocate attention unequally across regions of the visual field, using a MOT task where two regions were probed with either a high and low or with equal priority. Experiment 1 showed that for high-priority regions, accuracy (for direction of heading judgments) improved, and participants had more frequent and longer fixations in that region compared with a low-priority region. Experiment 2 showed that eye movements were functional in that they slightly improved accuracy when participants could freely move their eyes compared with when they had to centrally fixate. Replicating Experiment 1, we found better tracking performance for high compared with low-priority regions, in both the free and fixed viewing conditions, but the benefit was greater for the free viewing condition. Although unequal attention allocation is possible without eye movements, eye movements seem to improve tracking ability, presumably by allowing participants to fixate more in the high-priority region and get a better, foveal view of the objects. These findings can help us better understand how observers in real-life settings (e.g., CCTV monitoring, driving) can use their limited attentional capacity to allocate their attention unequally in a demand-based manner across different tracking regions.


Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomised controlled trials.
Disease-free survival (DFS) is increasingly being used as surrogate end-point for overall survival (OS) in cancer trials. So far, there has been no validation of the surrogacy of DFS for OS for neoadjuvant treatment of gastroesophageal adenocarcinoma. The study uses individual patient data (IPD) from eight randomised controlled trials (RCTs) (n = 1126 patients) comparing neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. Correlation between OS time and DFS time was calculated to evaluate individual-level surrogacy. For each trial, survival curves using the Kaplan-Meier method were plotted and hazard ratios (HRs) on the treatment effects were calculated for OS and DFS separately. Those HRs were pooled in a random-effects meta-analysis. Observed HRs were compared with predicted HRs for OS using results from an error-in-variables linear regression model accounting for the uncertainty about the estimated effect. The strength of the association was quantified by the coefficient of determination to assess trial-level surrogacy. The surrogate threshold effect was calculated to determine the minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS. A strong correlation between OS time and DFS time was observed, indicating a high individual-level surrogacy. For all RCTs, estimated HRs for OS and DFS were highly similar. In the meta-analysis, the overall HR for OS was virtually identical to that for DFS. The estimated coefficient of determination r2 for the association between HRs for OS and DFS was 0.912 (95% confidence interval: 0.75-1.0), indicating a very good fit of the regression model and thus a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect based on the regression analysis was 0.79. Based on strong correlations between DFS and OS, as well as a strong correlation of the treatment effects of the two end-points in the error-in-variable regression, DFS seems an appropriate surrogate marker for OS in randomised trials of neoadjuvant chemotherapy or chemoradiotherapy for gastroesophageal adenocarcinoma.


Outcomes in endocrine cancer surgery are affected by racial, economic, and healthcare system demographics.
Surgeon experience has been recognized in several clinical fields as a significant element of superior management outcomes. In this study, we seek to assess the association between surgeon volume and patients' community health status with the outcomes of thyroid and parathyroid surgery indicated for primary malignancies. A cross-sectional study utilizing the State Inpatient Databases, 2010-2011, for Florida, New York, and Washington was merged with the County Health Rankings database. International Classification of Diseases, Ninth Revision codes were used to identify adult (≥18 years) patients who underwent thyroidectomy or parathyroidectomy indicated for primary malignancies. A total of 6,347 records were included. Compared to high-volume surgeons, patients treated by low-volume surgeons were more likely to develop postoperative complications in the 1-month period after the operation (odds ratio: 4.34, 95% confidence interval: 3.31-5.70, P < .001). Furthermore, both low- and intermediate-volume surgeons were associated with a longer hospital stay (>2 days) and a higher risk of admission to the intensive care unit (P < .01 each). Cost of health services was significantly in the highest quartile (>$10,254.66) for patients treated by low-volume surgeons (P < .001). Patients who lived in communities of poor health measures had a higher risk of postoperative complications (16.3% vs. 11.8%, P = .030) independent of the clinical presentation and management type. Patients living in high health-risk communities and those of black and Hispanic backgrounds were more likely to be treated by low-volume surgeons (P < .001 each). The surgeon's volume and the patient's living conditions are crucial and independent factors in multiple aspects of endocrine cancer management. 4 Laryngoscope, 126:775-781, 2016.


Investigation of STW 5 (Iberogast®) preventive effects in experimental sepsis.
STW 5 (Iberogast(®)) is a well known herbal combination drug containing glycosides and flavonoids for which multiple pharmacological properties have been shown. In this study, attempts were made to assess whether STW 5, an aqueous ethanol solution, has a preventive effect against liver and lung pathological damage in rats after experimental induction of sepsis [cecal ligation and puncture (CLP)]. Experimental sepsis was induced in rats using CLP operation. The rats (n = 36) were divided into six groups (six/group): Sham-operated (SOP); CLP; CLP + STW 5 (2.5, 5 and 10 mg/kg) and CLP + indomethacin. The drugs were injected intraperitoneally immediately after sepsis induction. It was found that induction of sepsis 24 h after CLP was associated with significant liver and lung damage, also remaining after STW 5 administration. It appears that STW 5, which has a pronounced efficacy in functional gastro-intestinal diseases, has no effect on septic liver and lung damage in the CLP rat model.


Pediatric contact allergens in the neonatal intensive care unit.
The degree of neonatal exposure to potentially sensitizing agents on neonatal intensive care units (NICUs) and the process by which personal care products are selected for use in the NICU are poorly documented. We evaluated personal care products used in three NICUs for potentially sensitizing agents. We interviewed NICU staff to analyze how products are selected and approved for use. Twenty-four personal care products were evaluated. 75% contained one or more potential contact allergen, with fragrances being most common. Staff preference, brand loyalty, cost, and small product size were often considered when approving NICU products. The prevalence of potentially sensitizing agents in the products indicates a need for improvement in the evaluation and acquisition process of over-the-counter products used for neonatal skin care. The involvement of dermatology in this process may be beneficial.


Pityriasis versicolor--epidemiological and therapeutical study.
Seventy-six patients with extensive pityriasis versicolor were divided into 3 groups and treated orally with ketoconazole, 200 mg daily, for 10, 20 or 30 days respectively. 50 patients out of this number completed the study. After 6 months, 46 patients were checked up. Eight of them developed relapses effectively treated with ketoconazole for another 15 days. Six out of these 8 patients belonged to the first group using ketoconazole for 20 days only. On the basis of this observation, we do not consider a 10 days' treatment to be sufficient and recommend that the patient should be treated for at least 20 days. As a preventive measure we recommend a daily bath with salicylic acid and sulphur soap. The frequency of the infection was higher in males (71.4%) than in females (28.6%). The youngest of the male patients was 4 months of age and the oldest 70 years. The youngest female was 4 months old and the oldest 50 years. Pityriasis versicolor was found to be predominant in the age group of 21--30 years. The sites most commonly involved were back, chest and the upper extremities.


Conditional survival for non-metastatic muscle-invasive adenocarcinoma of the urinary bladder after radical cystectomy.
To test the effect of conditional survival on 36-months' cancer-specific mortality (CSM)-free survival in non-metastatic muscle-invasive adenocarcinoma of the bladder (ACB). Within the Surveillance, Epidemiology, and End Results database (2000-2018), ACB patients treated with radical cystectomy (RC) were identified. Multivariable competing risks regression (CRR) analyses assessed the independent predictor status of organ-confined (OC, T2N0M0) vs non-organ-confined stage (NOC, T3-4N0M0 or TanyN1-3M0) on CSM. Conditional 36-months' CSM-free survival estimates were computed based on event-free intervals of 12, 24, 36, 48 and 60 months after RC, according to stage. Of 475 ACB patients, 132 (28%) harbored OC vs 343 (72%) harbored NOC stage. In multivariable CRR models, NOC vs OC stage independently predicted lower CSM (hazard ratio 3.55; 95% CI 2.66, 5.83; p < 0.001). Conversely, neither chemotherapy nor radiotherapy were independently associated with CSM. In OC stage, 36-months' CSM-free survival rate was 84% at baseline. Provided event-free intervals of 12, 24, 36, 48 and 60 months, conditional 36-months' CSM-free survival estimates were 84, 87, 87, 89 and 89%. In NOC stage, 36-months' CSM-free survival rate was 47% at baseline. Provided event-free intervals of 12, 24, 36, 48 and 60 months, conditional 36-months' CSM-free survival estimates were 51, 62, 69, 78 and 85%. Conditional survival estimates provide better insight into survival of patients with longer event-free follow-up. In consequence, conditional survival estimates might be highly valuable for individual patient counselling.


Efficient segmentation using domain adaptation for MRI-guided and CBCT-guided online adaptive radiotherapy.
Delineation of regions of interest (ROIs) is important for adaptive radiotherapy (ART) but it is also time consuming and labor intensive. This study aims to develop efficient segmentation methods for magnetic resonance imaging-guided ART (MRIgART) and cone-beam computed tomography-guided ART (CBCTgART). MRIgART and CBCTgART studies enrolled 242 prostate cancer patients and 530 nasopharyngeal carcinoma patients, respectively. A public dataset of CBCT from 35 pancreatic cancer patients was adopted to test the framework. We designed two domain adaption methods to learn and adapt the features from planning computed tomography (pCT) to MRI or CBCT modalities. The pCT was transformed to synthetic MRI (sMRI) for MRIgART, while CBCT was transformed to synthetic CT (sCT) for CBCTgART. Generalized segmentation models were trained with large popular data in which the inputs were sMRI for MRIgART and pCT for CBCTgART. Finally, the personalized models for each patient were established by fine-tuning the generalized model with the contours on pCT of that patient. The proposed method was compared with deformable image registration (DIR), a regular deep learning (DL) model trained on the same modality (DL-regular), and a generalized model in our framework (DL-generalized). The proposed method achieved better or comparable performance. For MRIgART of the prostate cancer patients, the mean dice similarity coefficient (DSC) of four ROIs was 87.2%, 83.75%, 85.36%, and 92.20% for the DIR, DL-regular, DL-generalized, and proposed method, respectively. For CBCTgART of the nasopharyngeal carcinoma patients, the mean DSC of two target volumes were 90.81% and 91.18%, 75.17% and 58.30%, for the DIR, DL-regular, DL-generalized, and the proposed method, respectively. For CBCTgART of the pancreatic cancer patients, the mean DSC of two ROIs were 61.94% and 61.44%, 63.94% and 81.56%, for the DIR, DL-regular, DL-generalized, and the proposed method, respectively. The proposed method utilizing personalized modeling improved the segmentation accuracy of ART.


Impairing the amphetamine conditioning in rats through the inhibition of hippocampal calcium/calmodulin-dependent protein kinase II activity.
Amphetamine is an addictive drug, possessing reinforcing properties that are believed to be associated with an environmental cue, which resembles a behavioral learning process. This study investigates the role of calcium/calmodulin-dependent protein kinase II (CaM-kinase II) in the acquisition of the amphetamine-produced conditioned place preference (CPP). In Experiment I, rats were trained in an amphetamine-produced (2 mg/kg, i.p.) CPP task. The amphetamine-saline pairing rats spent significantly more time in the box that was associated with the amphetamine injection. Moreover, these rats' hippocampal CaM-kinase II showed significantly higher Ca(2+)-independent activity than that of the controls. In experiment II, the rats received an intra-hippocampal or intra-accumbens injection of specific CaM-kinase II inhibitor (KN-93) or a controlled agent (KN-92) before training in the amphetamine-produced CPP task. The rats receiving the preconditioning intra-hippocampal KN-93 injection showed no amphetamine-produced CPP effect. These results, taken together, indicate that the biological basis of amphetamine-produced place preference behavior might be regulated by the hippocampal CaM-kinase II activity.


Impact of an electronic medical record on diabetes quality of care.
This study was designed to evaluate the impact of electronic medical record (EMR) implementation on quality of diabetes care. We conducted a 5-year longitudinal study of 122 adults with diabetes mellitus at an intervention (EMR) clinic and a comparison (non-EMR) clinic. Clinics had similarly trained primary care physicians, similar patient populations, and used a common diabetes care guideline that emphasized the importance of glucose control. The EMR provided basic decision support, including prompts and reminders for diabetes care. Preintervention and postintervention frequency of testing for glycated hemoglobin (HbA1c) and low-density lipoprotein (LDL) levels were compared with and without adjustment for patient age, sex, comorbidity, and baseline HbA1c level. Frequency of HbA1c tests increased at the EMR clinic compared with the frequency at the non-EMR clinic (P < .001). HbA1c levels improved in both clinics (P < .05) with no significant differences between clinics 2 years (P = .10) or 4 years (P = .27) after EMR implementation. Similar results were observed for LDL levels. In this controlled study, EMR use led to an increased number of HbA1c and LDL tests but not to better metabolic control. If EMRs are to fulfill their promise as care improvement tools, improved implementation strategies and more sophisticated clinical decision support may be needed.


Days alive and out of hospital after surgical treatment of epithelial ovarian cancer: A Danish nationwide cohort study.
Days alive and out of hospital (DAOH) is a validated outcome measure in perioperative trials integrating information on primary hospitalization, readmissions, and mortality. It is negatively associated with advanced age. However, DAOH has not been described for surgical treatment of epithelial ovarian cancer (EOC), primarily diagnosed in older patients. We conducted a Danish nationwide cohort study including patients undergoing debulking surgery for EOC from 2013 to 2018. DAOH was explored for 30 (DAOH30), 90 (DAOH90), and 180 (DAOH180) postoperative days in younger (<70 years) and older (≥70 years) patients with advanced-stage disease stratified by surgical modality (primary (PDS) or interval debulking surgery (IDS)). We examined the associations between patient- and surgical outcomes and low or high DAOH30. Overall, 1168 patients had stage IIIC-IV disease and underwent debulking surgery. DAOH30 was 22 days [interquartile range (IQR): 18, 25] and 23 days [IQR: 18, 25] for younger and older patients treated with PDS, respectively. For IDS, DAOH30 was 25 days [IQR: 22, 26] for younger and 25 days[IQR: 21, 26] for older patients. We found no significant differences between age cohorts regarding DAOH30, DAOH90, and DAOH180. Low DAOH30 was associated with poor performance status, PDS, extensive surgery, and long duration of surgery in adjusted analysis. DAOH did not differ significantly between age cohorts. Surgical rather than patient-related factors were associated with low DAOH30. Our results likely reflect a high selection of fit older patients for surgery, reducing the patient-related differences between younger and older patients receiving surgical treatment.


Tryptophan as a link between psychopathology and somatic states.
Several somatic illnesses are associated with psychiatric comorbidity. Evidence is provided that availability of the essential amino acid tryptophan, which is the precursor of serotonin, may cause this phenomenon. We performed a database search to find relevant articles published between 1966 and 2002. For our search strategy, we combined several diseases from the categories hormonal, gastrointestinal, and inflammatory with the search terms "tryptophan" and "serotonin." The catabolism of tryptophan is stimulated under the influence of stress, hormones and inflammation by the induction of the enzymes tryptophan pyrrolase (in the liver) and IDO (ubiquitous). Because of the reduction in blood levels of tryptophan under these circumstances the formation of cerebral serotonin is decreased. It is argued that the coupling of peripheral tryptophan levels and cerebral serotonin levels has physiological significance. The clinical implications and therapeutic consequences of changes in tryptophan and consequently serotonin metabolism are discussed.


Use of Tapered Balloons to Recanalize Occluded Below-the-Knee Arteries in Diabetic Patients with Critical Limb Ischemia.
The aim of this study was to evaluate the outcome of tapered balloon use in recanalization of long occlusions of below-the-knee (BTK) arteries in diabetic patients with critical limb ischemia (CLI). Forty-nine occluded BTK arteries in 35 diabetic patients with CLI were revascularized in our Diabetic Foot Center between January and September 2014 using tapered balloons. Twelve-month outcomes were evaluated in terms of healing of the lesions, survival, limb salvage, primary patency, primary assisted patency, and secondary patency. The patients were predominantly male (27/35, 77.1%) with a mean age of 70.9 years (±10.3 standard deviation [SD]). During the follow-up (mean duration 12.4 months ± 4 SD), healing of the lesions was obtained in 27 of the 35 cases (77.1%). Estimated 12-month survival and limb salvage were 85.7% and 91.1%, respectively. Estimated 12-month primary patency, primary assisted patency, and secondary patency were 78.3%, 79%, and 88.9%, respectively. Univariate analysis demonstrated that the presence of chronic renal failure affected survival (P = 0.005), and assignment to Rutherford class 6 affected limb salvage (P = 0.005), primary patency (P < 0.001), and primary assisted patency (P < 0.001). Furthermore, the presence of coronary artery disease affected primary patency (P = 0.001) and primary assisted patency (P = 0.05). Tapered balloons are a safe and effective means to recanalize long occlusions of BTK arteries in diabetic patients with CLI. Outcomes are poorer in patients with major tissue loss and with a history of coronary artery disease. Further experience with larger groups is needed to validate these outcomes.


Efficacy of auditory-verbal therapy in children with hearing impairment: A systematic review from 1993 to 2015.
Auditory verbal therapy (AVT) is one of the primary treatment approaches for developing spoken language in children with hearing impairment (HI), but its outcomes have not been thoroughly investigated. The current study aimed to systematically review past studies investigating AVT outcomes in children with HI. A systematic search was conducted in six databases. Fourteen articles that met the final inclusion criteria were grouped under three categories based on the outcome measures: receptive and expressive language development, auditory/speech perception and mainstreaming. Articles under "receptive and expressive language development" category indicated AVT can even help children with HI beyond three years of age to develop age appropriate language skills and catch up with their hearing peers. Articles under "auditory /speech perception" category suggested that children receiving AVT can learn to recognize words accurately even in the presence of background noise. Articles grouped under "mainstreaming" category indicated that children receiving AVT can be successfully mainstreamed. Although studies suggest that AVT can have a positive impact on developing speech and language skills in children with HI, it is difficult to generalize these findings due to limited evidence. Future studies should utilize well-controlled group designs to minimize the role of external variables as well as strengthen the evidence-base for AVT.


Identification of lipophilic components in Citri Reticulatae Pericarpium cultivars by supercritical CO2 fluid extraction with ultra-high-performance liquid chromatography-Q Exactive Orbitrap tandem mass spectrometry.
To systematically identify the lipophilic constituents of Citri Reticulatae Pericarpium from different cultivars, supercritical CO2 fluid extraction and ultra-high-performance liquid chromatography-Q Exactive Orbitrap tandem mass spectrometry were integrated for the component analysis of 18 batches of Citri Reticulatae Pericarpium from 12 cultivars for the first time. A total of 57 components from the supercritical CO2 fluid extracts were demonstrably or tentatively identified by the obtained parent peaks, fragment peaks, and retention times. In total, two flavonoids, six organic acids, nine coumarins, three aldehydes, seven esters, three terpenes, one limonoid, and five other compounds were detected for the first time; notably, coumarin components have not yet been reported in Citri Reticulatae Pericarpium. Furthermore, the extract constituents differed between cultivars. In particular, organic acids were more abundant in Citrus reticulata "Chachi" than in other cultivars, and pterostilbene was exclusively found in Citrus reticulata "Yichangju". The results showed that a greater variety of compounds in Citri Reticulatae Pericarpium could be extracted by supercritical CO2 fluid extraction and detected by ultra-high-performance liquid chromatography-Q Exactive Orbitrap tandem mass spectrometry. This study provides a more scientific basis for further analysis of the pharmacological activity and quality of Citri Reticulatae Pericarpium components from different cultivars.


Artificial neural networks in prediction of bone density among post-menopausal women.
Artificial neural networks (ANN) are promising tools in learning complex interplay of factors on a particular outcome. We performed this study to compare the predictive power of ANN and conventional methods in prediction of bone mineral density (BMD) in Iranian post-menopausal women. A database of 10 input variables from 2158 participants was randomly divided into training (1400), validation (150) and test (608) groups. Multivariate linear regression and ANN models were developed and validated on the training, and validation sets and outcomes (femoral neck and lumbar T-scores) were predicted and compared on the test group using different numbers of input variables. Results were evaluated by comparing the mean square of differences between predicted and reference values (non-central chi-square test) and by measuring area under the receiver operating characteristic curve (AUROC) around cut-off value of -2.5 for T-scores. For models with less than 3 input variables in femoral neck and 4 variables in spinal column, performance of regression and ANN models was almost the same. As more variables imported into models, ANN outperformed linear regression models. AUROC varied in 2 to 10 variable models as follows: for ANN in spine, from 0.709 to 0.774; linear models in spine, from 0.709 to 0.744; ANN in femoral neck, from 0.801 to 0.867; linear models in femoral neck, from 0.799 to 0.834. The ANN model performed better than five established patient selection tools in the test group. Superior performance of neural networks than linear models demonstrate their advantage especially in mass screening applications, when even a slight enhancement in performance results in significant decrease in number of misclassifications.