Expression of mutant p53 proteins in lung cancer correlates with the class of p53 gene mutation.
We investigated the immunocytochemical staining and immunoblotting characteristics of 33 different p53 mutant proteins identified in lung cancer cell lines (18 small-cell lung cancer and 15 non-small-cell lung cancer) using monoclonal antibodies pAbs 240, 421 and 1801. The p53 mutants studied were representative of those found in lung cancer and included three deletions, four nonsense, seven splicing and 19 missense lesions. Control cell lines included six B-lymphoblastoid cell lines and two lung cancer cell lines without p53 mutations. Immunocytochemistry demonstrated 16 cell lines (48%) with definite overexpression of p53 protein (the high-expresser group of mutants), while in the remainder of cases either no p53 expression or low levels of p53 protein expression were found (the low-expresser group of mutants). The type of p53 mutation correlated with the expresser group. High expressers all had p53 missense mutations in exons 5-8, and immunocytochemistry identified 16/17 (94%) of these mutants. Several classes of p53 mutations occur in the low-expresser groups: deletions, splicing mutants, nonsense mutants and missense mutations outside of exons 5-8 all resulted in very low or undetectable levels of p53 protein. We conclude that there are low- and high-expression groups of p53 mutants in lung cancer and that the detection of protein expression in tumor cells by immunocytochemistry and immunoblotting is dependent upon the type of mutation of the p53 tumor-suppressor gene.


Balancing clinical risk with countertransference management protects Alliance.
The working alliance has been recognized as a predictor of psychotherapy outcome across therapeutic orientations. Despite mixed findings regarding the effect of problem severity on the alliance formation, there is evidence suggesting that therapist factors may interfere in this association. This study examined how clients' baseline clinical features affected the early alliance and the possible role of therapists' countertransference management as a mediator. Thirteen therapeutic dyads were assessed at 2 different time points. Clients' clinical dimensions were assessed prior to the 2nd session, and therapists' countertransference management and clients' ratings of the alliance were measured after the 2nd session. Positive associations were found between clients' subjective wellbeing, social functioning, risk, and global psychological distress and countertransference management dimensions and total score. Empathy-based countertransference management suppressed the negative impact of clinical risk on alliance. Our findings suggest that clinical problems activate countertransference management, which in turn may buffer their negative effect on alliance.


Using Low-Cost Sensors to Assess Fine Particulate Matter Infiltration (PM2.5) during a Wildfire Smoke Episode at a Large Inpatient Healthcare Facility.
Wildfire smoke exposure is associated with a range of acute health outcomes, which can be more severe in individuals with underlying health conditions. Currently, there is limited information on the susceptibility of healthcare facilities to smoke infiltration. As part of a larger study to address this gap, a rehabilitation facility in Vancouver, Canada was outfitted with one outdoor and seven indoor low-cost fine particulate matter (PM2.5) sensors in Air Quality Eggs (EGG) during the summer of 2020. Raw measurements were calibrated using temperature, relative humidity, and dew point derived from the EGG data. The infiltration coefficient was quantified using a distributed lag model. Indoor concentrations during the smoke episode were elevated throughout the building, though non-uniformly. After censoring indoor-only peaks, the average infiltration coefficient (range) during typical days was 0.32 (0.22-0.39), compared with 0.37 (0.31-0.47) during the smoke episode, a 19% increase on average. Indoor PM2.5 concentrations quickly reflected outdoor conditions during and after the smoke episode. It is unclear whether these results will be generalizable to other years due to COVID-related changes to building operations, but some of the safety protocols may offer valuable lessons for future wildfire seasons. For example, points of building entry and exit were reduced from eight to two during the pandemic, which likely helped to protect the building from wildfire smoke infiltration. Overall, these results demonstrate the utility of indoor low-cost sensors in understanding the impacts of extreme smoke events on facilities where highly susceptible individuals are present. Furthermore, they highlight the need to employ interventions that enhance indoor air quality in such facilities during smoke events.


Opioid-Induced Respiratory Depression in Pediatric Palliative Care Patients with Severe Neurological Impairment-A Scoping Literature Review and Case Reports.
Pediatric Palliative Care (PPC) addresses children, adolescents, and young adults with a broad spectrum of underlying diseases. A substantial proportion of these patients have irreversible conditions accompanied by Severe Neurological Impairment (SNI). For the treatment of pain and dyspnea, strong opioids are widely used in PPC. Nonetheless, there is considerable uncertainty regarding the opioid-related side effects in pediatric patients with SNI, particularly concerning Opioid-Induced Respiratory Depression (OIRD). Research on pain and OIRD in pediatric patients with SNI is limited. Using scoping review methodology, we performed a systematic literature search for OIRD in pediatric patients with SNI. Out of n = 521 identified articles, n = 6 studies were included in the review. Most studies examined the effects of short-term intravenous opioid therapy. The incidence of OIRD varied between 0.13% and 4.6%; besides SNI, comorbidities, and polypharmacy were the most relevant risk factors. Additionally, three clinical cases of OIRD in PPC patients receiving oral or transdermal opioids are presented and discussed. The case reports indicate that the risk factors identified in the scoping review also apply to adolescents and young adults with SNI receiving low-dose oral or transdermal opioid therapy. However, the risk of OIRD should never be a barrier to adequate symptom relief. We recommend careful consideration and systematic observation of opioid therapy in this population of patients.


A contrast-enhanced ultrasound study of benign and malignant breast tissue.
To determine the diagnostic value of haemodynamic contrast-enhanced ultrasound assessment in benign and malignant breast tissue, using histological examination as the reference standard. An HDI 5000 Phillips ultrasound scanner with microvascular imaging software and 2.5 ml SonoVue (Bracco spa, Milan) contrast was used to scan 50 consecutive patients (32 malignant and 18 benign, 49 with histologically confirmed breast lesions). Time-intensity curves of the regions of interest (ROI) placed over the lesional and normal breast tissues were acquired using QLAB software. The area under the curve (AUC), time to peak (TTP), in-flow gradient (IFG) and peak enhancement (PE) were determined in a standardised manner for each focal breast lesion and the control/normal breast. IFG and AUC in the periphery, and PE and AUC in the centre of the lesions, differed significantly between malignant and benign tumours. In a logistical regression model, AUC in the periphery and the ratio of PE at the tumour centre to that of normal breast were independently predictive of malignancy (p < 0.001), achieving a diagnostic sensitivity of 97% and a specificity of 80% in the 41 tumours in which central vessels could be distinguished. Haemodynamic contrast-enhanced ultrasound assessment can be used to distinguish between benign and malignant breast lesions.


Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.
The FAS-FASL system plays crucial role in counterattack of cancer cell against immune system. This study examined the effects of FAS (-1377G/A and -670A/G) and FASL (-844T/C and 7896G/C) polymorphisms on breast cancer risk and apoptosis of T lymphocytes. The effect on breast cancer risk was determined by case-control analysis of 840 patients and 840 controls. The effects on T-lymphocyte apoptosis were determined by activation-induced cell death (AICD) of T cells ex vivo and by analyzing apoptotic tumor-infiltrating lymphocytes (TILs) in breast cancer tissue. We found moderately increased risk associated with FAS -1377AG [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.05-1.59] and -1377AA (OR, 1.36; 95% CI, 1.01-1.82) genotypes compared with the -1377GG genotype and decreased risk associated with FASL -844CT (OR, 0.76; 95% CI, 0.62-0.94) and -844TT (OR, 0.66; 95% CI, 0.43-1.00) genotypes compared with the -844CC genotype. T lymphocytes with the FASL -844CC genotype had heightened FASL expression that is associated with increased AICD of the T cells stimulated by MCF-7 cells or phytohemagglutinin compared with the FASL -844TT genotype (10.38 +/- 4.09% and 24.29 +/- 1.50% versus 6.03 +/- 0.41% and 17.96 +/- 3.66%; P < 0.05 and 0.001). Breast cancer patients with the FASL -844CC genotype had higher apoptotic TILs in their cancer tissues than those with the FASL -844TT genotype (33.7 +/- 1.2% versus 19.1 +/- 2.0%; P = 0.007). These findings indicate that functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.


Hysterical seizures: a sequel to incest.
Six cases are described in which hysterical seizures developed after incest and disappeared after psychotherapeutic exploration of the incestuous experience. Patients were adolescents referred for seizures, suicide attempts, sexual problems, and running away. It is suggested that Navajo and Galenic folk beliefs connecting epilepsy with incest may derive from observations of this symptom pattern in incest victims.


The relationship between caregivers' perceptions of end-of-life care in long-term care and a good resident death.
Quality end-of-life (EOL) care is critical for dying residents and their family/friend caregivers. While best practices to support resident comfort at EOL in long-term care (LTC) homes are emerging, research rarely explores if and how the type of care received at EOL may contribute to caregivers' perceptions of a good death. To address this gap, this study explored how care practices at EOL contributed to caregivers' perceptions of a good resident death. This study used a retrospective cross-sectional survey design. Seventy-eight participants whose relative or friend died in one of five LTC homes in Canada completed self-administered questionnaires on their perceptions of EOL care and perceptions of a good resident death. Overall, caregivers reported positive experiences with EOL care and perceived residents to have died a good death. However, communication regarding what to expect in the final days of life and attention to spiritual issues were often missing components of care. Further, when explored alongside direct resident care, family support, and rooming conditions, staff communication was the only aspect of EOL care significantly associated with caregivers' perceptions of a good resident death. The findings of this study suggest that the critical role staff in LTC play in supporting caregivers' perceptions of a good resident death. By keeping caregivers informed about expectations at the very end of life, staff can enhance caregivers' perceptions of a good resident death. Further, by addressing spiritual issues staff may improve caregivers' perceptions that residents were at peace when they died.


Chronorisk in cluster headache: A tool for individualised therapy?
The mechanisms behind the severe pain of cluster headache remain enigmatic. A distinguishing feature of the attacks is the striking rhythms with which they occur. We investigated whether statistical modelling can be used to describe 24-hour attack distributions and identify differences between subgroups. Common hours of attacks for 351 cluster headache patients were collected. Probability distributions of attacks throughout the day (chronorisk) was calculated. These 24-hour distributions were analysed with a multimodal Gaussian fit identifying periods of elevated attack risk and a spectral analysis identifying oscillations in risk. The Gaussian model fit for the chronorisk distribution for all patients reporting diurnal rhythmicity (n = 286) had a goodness of fit R2 value of 0.97 and identified three times of increased risk peaking at 21:41, 02:02 and 06:23 hours. In subgroups, three to five modes of increased risk were found and goodness of fit values ranged from 0.85-0.99. Spectral analysis revealed multiple distinct oscillation frequencies in chronorisk in subgroups including a dominant circadian oscillation in episodic patients and an ultradian in chronic. Chronorisk in cluster headache can be characterised as a sum of individual, timed events of increased risk, each having a Gaussian distribution. In episodic cluster headache, attacks follow a circadian rhythmicity whereas, in the chronic variant, ultradian oscillations are dominant reflecting a loss of association with sleep and perhaps explaining observed differences in the effects of specific treatments. The results demonstrate the ability to accurately model chronobiological patterns in a primary headache.


Dysautonomia in the pathogenesis of migraine.
Migraine is a common complex neurological disorder involving multiple brain areas that regulate autonomic, affective, cognitive, and sensory functions. This review explores autonomic nervous system (ANS) dysfunction in migraine headache sufferers. Areas covered: Reference material for this review was obtained through PubMed searches. Migraine attacks can present with up to 4 phases (premonitory, aura, headache, postdrome) each with distinguishable signs and symptoms. Altered ANS tone can be found from the premonitory through the postdrome phases. Features of the migraine attack that are indicative of altered autonomic function, which include nausea, vomiting, diarrhea, polyuria, eyelid edema, conjunctival injection, lacrimation, nasal congestion, and ptosis, are discussed and putative mechanisms explored. In addition, alteration of ANS function by endogenous and exogenous stressors, such as bright lights, hunger, poor sleep quality, menses, and special dietary components is discussed. The influence of currently employed pharmacological treatments on altered autonomic function during the migraine attack is explored. Expert commentary: Migraine-related alterations in ANS function have a complex pattern, but, in general, an imbalance occurs between sympathetic and parasympathetic tone. Through an improved understanding the role of autonomic changes in pathogenesis of migraine, it may be possible to develop even more effective treatments for migraine sufferers.


Reforming the Department of Health's research and development policy: from the devil to the deep blue sea?
Research into health and social services in Britain is largely funded by the Department of Health. Regional NHS research and development has recently been reformed and a new report now proposes replacement of the 13 research units funded by the department with three or four large multidisciplinary centres. Evidence to support such a step is lacking, and many criticisms of the existing units arise from poor departmental planning rather than deficiencies of the units themselves. Large units may make research less responsive to the department's needs, and it is essential that the proposed new structure is thoroughly evaluated before it is introduced.


Uncovering new signaling proteins and potential drug targets through the interactome analysis of Mycobacterium tuberculosis.
Analysis of the pathogen interactome is a powerful approach for dissecting potential signal transduction and virulence pathways. It also offers opportunities for exploring new drug targets. In this study, a protein-protein interaction (PPI) network of Mycobacterium tuberculosis H37Rv was constructed using a homogenous protein mapping method, which has shown molecular chaperones, ribosomal proteins and ABC transporters to be highly interconnected proteins. A further analysis of this network unraveled the function of hypothetical proteins as well as a potential signaling pathway. A hypothetical protein, Rv2752c, which was linked to a metal cation-transporting ATPase, was characterized as a metal-beta-lactamase, through domain analysis in combination with an in vitro activity experiment. A second hypothetical protein, Rv1354c, and an unknown protein kinase, PknK, interacted with a similar group of inner membrane-associated ABC transporters in the PPI network. The interactions of Rv1354 with these proteins were also confirmed by a further bacterial two-hybrid analysis. According to protein domain structures, the unique M. tuberculosis Rv1354c gene was proposed, for the first time, to be responsible for the turnover of cyclic-di-GMP, a second messenger molecule in this bacterium. A further structure-based inhibitors screening for Rv1354c was also performed in silicon. We constructed a comprehensive protein-protein interaction network for M. tuberculosis consisting of 738 proteins and 5639 interaction pairs. Our analysis unraveled the function of hypothetical proteins as well as a potential signaling pathway. The group of ABC transporters, PknK, and Rv1354c were proposed to constitute a potential membrane-associated signaling pathway that cooperatively responds to environmental stresses in M. tuberculosis. The study therefore provides valuable clues in exploring new signaling proteins, virulence pathways, and drug targets.


New biomarkers for acute renal injury.
Incidence of acute kidney injury (AKI) is increasing rapidly to epidemic proportions. Development of AKI, especially in intensive care settings, is associated with increased morbidity, mortality and hospitalization costs. Currently available diagnostic tools are mostly insensitive for early diagnosis, however prompt diagnosis and risk stratification are necessary for guiding therapy and preventing progression of disease. Finding an early, reliable, suitable, easily reproducible, economical and accurate biomarker for AKI is a top research priority. In recent years, many urinary and serum proteins have been investigated as possible early markers of AKI and some of them have shown great promise. This topic reviews some of the emerging biomarkers of AKI.


Reverse Engineering in Orthodontics.
Three-dimensional (3D) imaging has advanced greatly and is used extensively in orthodontics. It is worth outlining and reviewing the developments of reverse engineering (RE) as its applications are growing more widespread and diverse. Data from an existing object are used to create a digital model. A traditional RE process is usually performed in these stages: (1) obtaining data, (2) restructuring the surfaces, and (3) creating a useful model. They are classified as (1) laser projection based and (2) fringe projection based. This digital technology has been used in creating 3D model scanning, 3D digital model superimposition, diagnostic setup, volumetric assessment of tooth wear, soft tissue facial analysis, incorporation of digital model to 3D facial image, lip position and smile reproducibility, analysis of tooth position after orthodontic treatment, and anthropometric measurements. This system has proven itself to have a varied probability of applications and researches in the field of orthodontics. Similar to every single system, even RE has its own benefits and shortcomings. The complexity of the process and high cost are the major disadvantages reported so far. Rapid advancement of this technology possibly will rapidly inverse the negative results that emerged previously. As a future work, innovative use of RE technology is necessary to make this system triumph in the field of orthodontics.


Quantitative analyses of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in fields with different soil types.
Soil type is one of the key factors affecting soil microbial communities. With regard to ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB), however, it has not been determined how soil type affects their community size and soil nitrification activity. Here we quantitatively analyzed the ammonia monooxygenase genes (amoA) of these ammonia oxidizers in fields with three different soil types (Low-humic Andosol [LHA], Gray Lowland Soil [GLS], and Yellow Soil [YS]) under common cropping conditions, and assessed the relationships between soil nitrification activity and the abundance of each amoA. Nitrification activity of LHA was highest, followed by that of GLS and YS; this order was consistent with that for the abundance of AOB amoA. Abundance of AOB amoA showed temporal variation, which was similar to that observed in nitrification activity, and a strong relationship (adjusted R(2)=0.742) was observed between the abundance of AOB amoA and nitrification activity. Abundance of AOA amoA also exhibited a significant relationship (adjusted R(2)=0.228) with nitrification activity, although this relationship was much weaker. Our results indicate that soil type affects the community size of AOA and AOB and the resulting nitrification activity, and that AOB are major contributors to nitrification in soils, while AOA are partially responsible.


An appraisal of the trustworthiness of practice guidelines for depression and anxiety in children and youth.
Little is known about the trustworthiness of clinical practice guidelines (PGs) relevant to child and youth depression or anxiety. To address this gap, we used systematic review methods to identify all available relevant PGs, quality appraise them, and make recommendations regarding which PGs are trustworthy and should be used by clinicians. Prespecified inclusion criteria identified eligible PGs. Two independent trained reviewers applied the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Using three AGREE II domain scores (stakeholder involvement, rigor of development [clinical validity/trustworthiness], and editorial independence), PG quality was designated as (1) minimum (≥50%) and (2) high (≥70%). Of 25 eligible PGs, five met minimum quality criteria (depression, n = 4; anxiety, n = 1); three out of five met high-quality criteria (depression, n = 2; anxiety, n = 1). Among the five minimum quality PGs, developers included government (n = 2), independent expert groups (n = 2), and other (n = 1). No PGs developed by specialty societies achieved minimum or high-quality ratings; eight of 25 PGs were up-to-date. Trustworthy PGs are available to support clinical decisions about depression and anxiety in children and youth, but are few in number. Many existing PGs (up to 80%) may not be clinically valid. Clinicians who implement the high-quality PGs identified here can increase the number of children and youth who receive effective interventions for depression and anxiety, minimize harm, and avoid wasted resources. Clinicians, service planners, youth, and their families should encourage PG developers to increase the pool of high-quality PGs using internationally recognized PG development standards.


Rectal cancer--adequacy of surgical management.
Rectal carcinoma remains a common, lethal form of malignancy. Despite improvement in overall survival due to increased resectability, decreased operative mortality, and possibly earlier detection at a more favorable stage, the cancer-specific survival rate stage for stage following operative treatment is unchanged in recent decades. Overall survival rate should increase further if earlier diagnosis can be made at a time when all lesions are locally confined and resectable for cure and if operative mortality can consistently be kept under 2 percent. The latter will require not only improvement in surgeons' skills to conduct these operations efficiently but also, and perhaps more important, improvement in surgeon's abilities to better select which patients can and should safely undergo a major resection. Improvement in cancer-specific survival rate stage for stage is not likely to result from operative methods but probably depends upon development of effective forms of adjuvant therapy or of totally new forms of therapy designed to supplement or supplant operative intervention. At present, it is discouraging that no such development has occurred, though radiation therapy may prove useful.


Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control.
I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.


Usefulness of soluble interleukin 2 receptor in differentiating tuberculous and carcinomatous pleural effusions.
To evaluate the usefulness of soluble interleukin 2 receptor (sIL-2R) in differentiating tuberculous and carcinomatous pleural effusions. Levels of sIL-2R were measured simultaneously in plasma and pleural fluid in 111 patients with pleural effusions of unknown causes. The causes of pleural effusions were tuberculosis in 42 cases, carcinoma in 41 cases, pneumonia in 18 cases, and heart failure in 10 cases. In all groups of patients, sIL-2R levels were significantly higher in pleural fluid than in plasma. Plasma and effusion levels of sIL-2R were highest in the patients with tuberculosis, followed by those with carcinoma, pneumonia, and heart failure. Levels were significantly higher in the tuberculous group than in the carcinomatous group. To differentiate tuberculous from carcinomatous effusions, the highest plasma and effusion sIL-2R values obtained from the carcinomatous group were chosen as cutoff points (test specificity, 100%). The sensitivities of plasma and effusion sIL-2R levels in differentiating tuberculous and carcinomatous pleural effusions were 50% (21 of 42 samples) and 81% (34 of 42 samples), respectively. Although increased plasma and pleural fluid levels of sIL-2R should not be viewed as a diagnostic test specific for tuberculous pleural effusion, sIL-2R level appears to be clinically useful as a biochemical marker to differentiate tuberculous and carcinomatous pleural effusions.


Serum Potassium Levels and Mortality in Hemodialysis Patients: A Retrospective Cohort Study.
Hyperkalemia is common in patients receiving maintenance hemodialysis. However, few studies have examined the association between serum potassium level and mortality. This study used annual cohorts of hemodialysis patients during 2007-2010. To determine hyperkalemia prevalence, monthly hyperkalemia was defined as serum potassium level ≥5.5 mEq/l; prevalence was calculated as a ratio of hyperkalemia episodes to follow-up time, reported separately by long and short interdialytic interval. To determine the impact of hyperkalemia on mortality, patients in the 2010 cohort were followed from first potassium measurement until death or a censoring event; hyperkalemia was defined, sequentially, by potassium levels 5.5-6.0 mEq/l at 0.1 mEq/l intervals. Time-dependent Cox proportional hazards modeling was used to estimate the association between hyperkalemia and mortality. The 4 annual cohorts ranged from 28,774 to 36,888 patients. Mean age was approximately 63 years, about 56% were men, 51% were white and 44% had end-stage renal disease caused by diabetes. Hyperkalemia prevalence was consistently estimated at 16.3-16.8 events per 100 patient-months. Prevalence on the day after the long interdialytic interval was 2.0-2.4 times as high as on the day after the short interval. Hyperkalemia, when defined as serum potassium ≥5.7 mEq/l, was associated with all-cause mortality (adjusted hazards ratio (AHR) 1.13, 95% CI 1.01-1.28, p = 0.037, vs. <5.7 mEq/l) after adjustment. AHRs increased progressively as the hyperkalemia threshold increased, reaching 1.37 (95% CI 1.16-1.62, p < 0.0001) for ≥6.0 mEq/l. The long interdialytic interval was associated with increased likelihood of hyperkalemia. Hyperkalemia was associated with all-cause mortality beginning at serum potassium ≥5.7 mEq/l; mortality risk estimates increased ordinally through ≥6.0 mEq/l, suggesting a threshold at which serum potassium becomes substantially more dangerous.


Clinicopathological observations in experimental peste des petit ruminants virus and Mannheimia haemolytica A:2 co-infection in goats.
The experiment describes for the first time the clinicopathological features of the co-infection of Peste des petit Ruminants (PPR) virus and Mannheimia haemolytica,in goats. Twenty clinically healthy goats, six months of age were used. 15 goats were infected by intratracheal inoculation of 1ml of pure cultured 106.5 TCID50 PPR virus grown in Baby hamster kidney cell lines, and a week later,1 ml of pure culture (109 CFU) of Mannheimia haemolytica (MH)A2 to study its clinico-pathological features and five goats served as controls. The clinical signs were observed and two goats were euthanized at predetermined intervals for gross examinations, bacteriological, virological and histopathological investigations on tissues collected using standard techniques. The clinical signs were severe and the order of manifestation was anorexia, pyrexia, dyspnea, oculo-nasal discharge, recumbency and death. The lesions observed were severe fibrinous bronchointerstitial pneumonia and pleurisy with thickened alveolar septa, edema and neutrophilic infiltrations of the interstitium with giant cells. There was also marked erosive stomatitis and acute enteritis. The average percentage lung consolidation for the infection was 7.01% and the right lung was more affected (p<0.05) while the overall mortality was 33.3%. MHA:2 and PPR virus were re-isolated from the lungs. The clinicopathological features observed showed that goats were susceptible to co- infection of PPR and Mannheimiosis which was severe and fatal. The data should help veterinarians and other medical experts to recognize cases of bacterial complicated viral infection and be informed of the approach to the treatment of such conditions.


Financial Literacy Among Health Professions Graduate Students.
The impact of student debt management on mental health, career choices, and advanced training in allied health professions is unknown. The purpose of this project was to pilot a survey that identifies students' financial literacy and self-efficacy. A cross-sectional survey containing 43 items related to financial habits, savings knowledge, credit and borrowing strategies, and investment knowledge was administered to assess financial literacy, self-efficacy, and career plans in a group of health professions graduate students. 134 of 268 surveys were completed by a variety of health professions. Financial habits and credit and borrowing categories scored the highest at 50% correct. Students scored the lowest on investment knowledge with an average of 25% correct responses. The overall mean self-efficacy score was 15.5±3.8. Three independent variables had a significant correlation of determination with overall financial literacy, which included marital status, older age, and individuals who identified as white non-Hispanic. Similarly, identification as white non-Hispanic had a significant correlation of determination with financial self-efficacy, but there were no significant differences based on age or marital status. Allied health students demonstrated low financial literacy and self-efficacy. Health care educators should consider delivering educational content to address these deficits.


Readability, Content, and Quality Assessment of Web-Based Patient Education Materials Addressing Neuraxial Labor Analgesia.
Studies in a variety of disciplines have shown that the readability of Web-based patient education materials is above that of the sixth grade reading level recommended by the U.S. Department of Health and Human Services. The aim of this study was to evaluate the readability, content, and quality of English- and Spanish-language patient education materials addressing neuraxial labor analgesia. The websites of 122 U.S. academic medical centers with obstetric anesthesia divisions were searched for English- and Spanish-language patient education materials. Readability of English-language patient education materials was assessed with 3 validated indices: Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook, and Gunning Frequency of Gobbledygook. Readability of Spanish-language patient education materials was assessed using the Spanish Lexile Measure. A 1-sample t test was used to evaluate the mean readability level against the recommended sixth grade reading level. A scoring matrix was developed to evaluate the content of patient education materials. Website quality was assessed using the Patient Education Materials Assessment Tool for Print. We identified 72 English-language and 29 Spanish-language patient education materials. The mean readability levels of all patient education materials were higher than the recommended sixth grade reading level using all indices (Flesch-Kincaid Grade Level: 9.1 ± 1.9, Simple Measure of Gobbledygook: 8.6 ± 1.4, Gunning Frequency of Gobbledygook: 11.8 ± 2.1; P < 0.001 for all). All patient education materials discussed the benefits of neuraxial analgesia. However, only 14% (upper 95% confidence interval: 24%) discussed contraindications to neuraxial anesthesia. Postdural puncture headache and hypotension were the most commonly addressed complications (92%). All other complications were addressed by less than half of patient education materials. Patient Education Materials Assessment Tool for Print scores were consistent with poor website understandability (median score, 64%; interquartile range, 64-73). The mean readability of Web-based patient education materials addressing neuraxial labor analgesia was above the recommended sixth grade reading level. Although most patient education materials explained the benefits of neuraxial analgesia, possible contraindications and complications were not consistently presented. The content, readability, and quality of patient education materials are poor and should be improved to help patients make more informed decisions about analgesic options during labor and delivery.


Cytodiagnosis of unusual metastases in parotid gland.
Documentation of metastatic lesions in the parotid gland diagnosed by fine-needle aspiration cytology (FNAC) is limited in the cytopathology literature. The metastases within the parotid masquerades clinically as primary neoplasm of parotid. The authors of present case report intent to highlight the importance of FNAC in the diagnosis of metastases in parotid. These diagnoses enable the search for the locations of unknown primaries. The nodules within the parotid masquerading as primary neoplasm have undergone FNAC in five cases. The cytomorphological interpretation of the smears was performed. The diagnosis on cytology was compared with subsequent histological evaluation of the suggested primary neoplasm. FNAC in the five cases revealed the following cytodiagnosis: metastases of ductal carcinoma (2), melanoma (1), deposits of small cell carcinoma (1) and metastases of clear cell renal cell carcinoma (RCC) (1). There was complete concordance when these cytodiagnoses were compared with histological evaluation from the suggested sites of primaries as well-differentiated ductal carcinoma of the breast (2), melanoma of the scalp (1), small cell carcinoma of the lung (1) and clear cell RCC of the kidney (1). The metastases within the parotid can masquerade as primary neoplasm. The cytomorphological patterns and features of metastases are similar to that of their primary neoplasm. Therefore, FNAC over the nodules within the parotid unsuspected for metastases provides valuable information to search for primary neoplasm.


A genome-guided analysis of energy conservation in the thermophilic, cytochrome-free acetogenic bacterium Thermoanaerobacter kivui.
Acetogenic bacteria are able to use CO2 as terminal electron acceptor of an anaerobic respiration, thereby producing acetate with electrons coming from H2. Due to this feature, acetogens came into focus as platforms to produce biocommodities from waste gases such as H2+CO2 and/or CO. A prerequisite for metabolic engineering is a detailed understanding of the mechanisms of ATP synthesis and electron-transfer reactions to ensure redox homeostasis. Acetogenesis involves the reduction of CO2 to acetate via soluble enzymes and is coupled to energy conservation by a chemiosmotic mechanism. The membrane-bound module, acting as an ion pump, was of special interest for decades and recently, an Rnf complex was shown to couple electron flow from reduced ferredoxin to NAD+ with the export of Na+ in Acetobacterium woodii. However, not all acetogens have rnf genes in their genome. In order to gain further insights into energy conservation of non-Rnf-containing, thermophilic acetogens, we sequenced the genome of Thermoanaerobacter kivui. The genome of Thermoanaerobacter kivui comprises 2.9 Mbp with a G+C content of 35% and 2,378 protein encoding orfs. Neither autotrophic growth nor acetate formation from H2+CO2 was dependent on Na+ and acetate formation was inhibited by a protonophore, indicating that H+ is used as coupling ion for primary bioenergetics. This is consistent with the finding that the c subunit of the F1FO ATP synthase does not have the conserved Na+ binding motif. A search for potential H+-translocating, membrane-bound protein complexes revealed genes potentially encoding two different proton-reducing, energy-conserving hydrogenases (Ech). The thermophilic acetogen T. kivui does not use Na+ but H+ for chemiosmotic ATP synthesis. It does not contain cytochromes and the electrochemical proton gradient is most likely established by an energy-conserving hydrogenase (Ech). Its thermophilic nature and the efficient conversion of H2+CO2 make T. kivui an interesting acetogen to be used for the production of biocommodities in industrial micobiology. Furthermore, our experimental data as well as the increasing number of sequenced genomes of acetogenic bacteria supported the new classification of acetogens into two groups: Rnf- and Ech-containing acetogens.


Rehabilitation in spinal cord disorders. 3. Comprehensive management of spinal cord injury.
This self-directed learning module highlights advances in the management of the person with a spinal cord deficit. Traumatic spinal cord injury is being used as the model, but the principles apply to all patients with spinal cord deficits. This article is part of the chapter on rehabilitation of spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. Specifically, this section contains information regarding prehospital care, acute assessment and management, primary rehabilitation by systems, sexuality and psychosocial issues, management of pain and spasticity, functional goals, the role of functional electrical stimulation, and long-term follow-up.


Contaminant accumulation and biomarker responses in caged fish exposed to effluents from anthropogenic sources in the Karnaphuly River, Bangladesh.
The possible ecotoxicological effects of a paper and pulp mill effluent were investigated by measuring selected contaminants and biomarkers in caged Nile tilapia (Oreochromis niloticus) and sharptooth catfish (Clarias gariepinus) from the Karnaphuly River, Bangladesh. Fish were caged for 28 d at two upstream reference sites (2 and 4 km) and four downstream sites (3, 5, 8, and 12 km) from the effluent outlets. Organochlorine contaminants and bile biomarkers were bioaccumulated to higher levels at downstream polluted sites than at the reference sites, including hexachlorobenzene (HCB), hexachlorocyclohexane (HCH), polychlorinated biphenyls (PCBs) in liver, and chlorophenolic compounds like 2,4-dichlorophenol and 2,4,6-trichlorophenol in bile. Levels of glucose, protein, and aspartate aminotransferase were analyzed in plasma, whereas cytochrome P4501A (CYP1A) levels were determined in S-12 supernatants of liver. The results, including CYP1A induction and bile biomarkers, clearly indicated that, in addition to the paper and pulp mill effluents, the downstream sites appear to receive other inputs of contaminants. This field assessment in a Bangladeshi river demonstrates biomarker measurements in caged fish as a promising approach for evaluating accumulation and effects of industrial effluents in fish of developing countries.


FLAN: a web server for influenza virus genome annotation.
FLAN (short for FLu ANnotation), the NCBI web server for genome annotation of influenza virus (http://www.ncbi.nlm.nih.gov/genomes/FLU/Database/annotation.cgi) is a tool for user-provided influenza A virus or influenza B virus sequences. It can validate and predict protein sequences encoded by an input flu sequence. The input sequence is BLASTed against a database containing influenza sequences to determine the virus type (A or B), segment (1 through 8) and subtype for the hemagglutinin and neuraminidase segments of influenza A virus. For each segment/subtype of the viruses, a set of sample protein sequences is maintained. The input sequence is then aligned against the corresponding protein set with a 'Protein to nucleotide alignment tool' (ProSplign). The translated product from the best alignment to the sample protein sequence is used as the predicted protein encoded by the input sequence. The output can be a feature table that can be used for sequence submission to GenBank (by Sequin or tbl2asn), a GenBank flat file, or the predicted protein sequences in FASTA format. A message showing the length of the input sequence, the predicted virus type, segment and subtype for the hemagglutinin and neuraminidase segments of Influenza A virus will also be displayed.


Outcome of cardiac sarcoidosis after radiofrequency ablation and placement of AICD- A propensity matched analysis.
Cardiac Sarcoidosis (CS) can lead to life-threatening ventricular dysrhythmias and sudden death. Immunosuppressive medications, radiofrequency ablation (RFA), and implantable cardioverter defibrillators (ICD) have been utilized to manage ventricular dysrhythmias but their benefits remain poorly defined. The aim of this study is to assess the durability of RFA in CS population and to determine outcome predictors after RFA. We compared the CS patients who had RFA±ICD against those with only ICD placement and contemporaneous patients with arrhythmogenic right ventricular dysplasia (ARVD) who had RFA. We analyzed time to a composite first event of appropriate ICD therapy, subsequent RFA, cardiac transplantation or death. We also evaluated variables predicting recurrence of ventricular dysrhythmias, including LVEF, cardiac involvement on PET scan, percent of ventricular ectopic beats, number of inducible VT foci and success of the RFA procedure. We used propensity matching and multivariable regression to adjust for baseline differences between the groups to identify outcome predictors. Thirty ablations for VT were performed in 20 CS patients (13 had concomitant ICD placement); 12 ablations were done in eight ARVD patients and 33 CS patients with only ICD placements were included in this cohort. The median follow-up period was 48 (9-173) months. Fourteen (70%) patients reached composite end points after RFA compared to 13 (63%) following ICD placement and five (87%) in the ARVD cohort. There was a significant time difference to reach composite end points (p=0.02) in favor of ICD only cohort. The median number of ICD therapies were higher in the CS-RFA group (p=0.01). The requirement for ICD therapy increased over time following RFA, especially after 12 months. Variables predicting earlier time-to-event were EF <40% (OR=13.2) and unsuccessful RFA procedure (OR=7.9). The presence of more than one inducible VT morphology was associated with higher likelihood of unsuccessful RFA (p=0.03). RFA can be an effective modality for the short-term treatment of ventricular dysrhythmias in cardiac sarcoidosis; however, after more than 12 months, the number of appropriate therapies escalates. Accordingly, ICD placement is recommended for all patients who undergo RFA for VT associated with CS, whether it is successful or not. Low LVEF and unsuccessful ablation were strong predictors of future events.


Horner's syndrome: an electron microscopic study of a human iris.
Electron microscopy was performed on the irides of a man with a history of a long standing Horner's syndrome which resulted in iris heterochromia. Comparison of his normal brown iris with the depigmented blue iris showed depletion of anterior border cells and absence of sympathetic nerve fibres. Stromal melanocyte numbers were also diminished but melanosome numbers within the residual cells were not significantly different. Postnatal maintenance of stromal and anterior border zone pigmentation, derived from the neural crest, would appear to be dependent on an intact sympathetic nerve supply in contrast to the iris pigment epithelium which remains normally unaffected in Horner's syndrome.


Asian primate species richness correlates with rainfall.
Previous studies of meta-analyses found significantly positive correlations between primate species richness and rainfall for Africa, Madagascar and the Neotropics, with the exception of Asia, leaving the open question whether that anomaly is the result of sampling bias, biogeography, or some other factor. This study re-examines the question using modelled data, with primate species richness data from the Southeast Asian Mammals Databank and rainfall data from the Climatic Research Unit. Data processing with Geographical Information Systems resulted in 390 sample points. Reduced major axis and ordinary least squares regressions were employed to examine the relationship for six regions, including the whole study area of Southeast Asia, and the subareas of Huxley West, Huxley East, Mainland Southeast Asia, Borneo, and Sumatra. The results showed a significant positive relationship between primate species richness and mean annual rainfall for Southeast Asia (r = 0.26, P<0.001). Comparing the results for the large islands and Mainland Southeast Asia showed that Sumatra had the highest correlation (r = 0.58; P<0.05). After controlling for the major biogeographic effect associated with Huxley's Line, our results showed that primate species richness is positively associated with mean annual rainfall in Southeast Asia. Our findings contrast to prior studies of meta-analyses that showed no relationship between rainfall and primate species richness in Asia, and thereby bring Asia into agreement with results showing significant positive correlations between rainfall and primate species richness everywhere else in the world. The inference is that previous anomalous results for Asia were result of sampling bias in the meta-analysis.


Application of Machine Learning Classification to Improve the Performance of Vancomycin Therapeutic Drug Monitoring.
Bayesian therapeutic drug monitoring (TDM) software uses a reported pharmacokinetic (PK) model as prior information. Since its estimation is based on the Bayesian method, the estimation performance of TDM software can be improved using a PK model with characteristics similar to those of a patient. Therefore, we aimed to develop a classifier using machine learning (ML) to select a more suitable vancomycin PK model for TDM in a patient. In our study, nine vancomycin PK studies were selected, and a classifier was created to choose suitable models among them for patients. The classifier was trained using 900,000 virtual patients, and its performance was evaluated using 9000 and 4000 virtual patients for internal and external validation, respectively. The accuracy of the classifier ranged from 20.8% to 71.6% in the simulation scenarios. TDM using the ML classifier showed stable results compared with that using single models without the ML classifier. Based on these results, we have discussed further development of TDM using ML. In conclusion, we developed and evaluated a new method for selecting a PK model for TDM using ML. With more information, such as on additional PK model reporting and ML model improvement, this method can be further enhanced.


Development of a clinical prediction score for detection of suspected cases of equine grass sickness (dysautonomia) in France.
Equine grass sickness (EGS) (equine dysautonomia) is a neurodegenerative condition of grazing equines. Pre-mortem diagnosis of EGS is a challenge for practitioners as definitive diagnosis requires ileal/myenteric lymph node biopsies. This study aimed to develop a clinical score that could be used by practitioners to improve the detection of acute or subacute EGS cases in the field. Suspected EGS cases were declared by veterinary practitioners. A case was classified as confirmed positive if ileal or rectal biopsy samples showed neuronal degeneration typical of EGS. A semi-quantitative scoring system, including epidemiological and clinical data, was created to attempt to classify suspected EGS horses into confirmed positive or negative cases. Each variable was weighted based on a boosted regression trees model, while taking into account its clinical relevance. Twenty-eight EGS cases were confirmed by biopsy during the entire study period. The best cut-off value for the score to have a high sensitivity while maximizing specificity was 8, with a sensitivity of 100% and a specificity of 53%. In our dataset, 77% of animals would be correctly classified with this cut-off value of 8. Highest sensitivity was chosen in order to detect the highest number of potential cases. Our score represents an inexpensive and useful tool to aid in the identification of suspected EGS cases in the field and selection for further diagnostics procedures to confirm or rule out the disease. Application of the score to larger populations of animals would be required to further adapt and refine the score.


Diagnosis of peripheral occlusive disease: comparison of clinical evaluation and noninvasive laboratory.
One hundred and two patients with peripheral vascular disease were evaluated by the attending surgeon, residents and students, and the vascular laboratory prior to arteriography to test their ability to make a correct anatomic diagnosis. The attending surgeons made a correct anatomic diagnosis in 98 patients and were at least partially correct in the other four. Surgical housestaff and students were 62% totally correct, 35% partially correct, and 3% totally wrong. The vascular laboratory results were almost identical with the attending surgeon, but two patients could not be evaluated because of calcified arteries. The operation that was eventually performed was suggested initially by the laboratory and the attending surgeon in 98% of the patients.


Characterization of smooth and rough morphotypes of Peptostreptococcus micros.
Isolation of the smooth (Sm) morphotype of Peptostreptococcus micros, a suspected oral pathogen, is sometimes accompanied by isolation of a rough (Rg) morphotype of P. micros. The Rg type readily changes to a Sm-like variant (RgSm) in broth culture. Sm and Rg isolates and RgSm variants were compared to determine whether these three types are the result of phase variation. The RgSm variants resembled the Sm morphotype in colony morphology; furthermore, the Sm type and the RgSm type did not have the fibrillar surface structures characteristic of the Rg type, and the Sm and RgSm types were more hydrophobic than the Rg type. However, when we compared the sodium dodecyl sulfate-polyacrylamide gel electrophoresis patterns of whole-cell proteins, serotyping data, pyrolysis mass spectrometry data, 16S ribosomal DNA sequences, and hemolytic activities, the RgSm variants and the Rg isolates were very similar and were clearly distinct from the Sm isolates. These results suggest that the Rg and RgSm types form a cluster distinct from the Sm type and thus provide evidence that P. micros can be differentiated into two groups, one consisting of the Sm type and the other consisting of the Rg and RgSm types.


An evaluation of renal tubular DNA laddering in response to oxygen deprivation and oxidant injury.
It has recently been suggested that endonuclease activation and/or apoptosis, possibly triggered by oxidant stress, are important pathogenetic mechanisms in oxygen deprivation/reoxygenation-induced proximal tubular cell death. To explore this possibility, DNA "laddering," a characteristic feature of these processes, was sought in: (1) postischemic rat kidneys (25- or 40-min arterial clamping; 0, 1, 4, 8, 24, and 48 h and 6 days reflow); (2) posthypoxic isolate rat proximal tubular segments and (3) cultured human kidney proximal tubular cells (HK-2) subjected either to energy depletion plus Ca2+ overload (antimycin A plus 2-deoxyglucose plus Ca2+ ionophore A23187), or to H2O2-induced cell death. DNA was subsequently extracted, electrophoresed through agarose gels, and visualized with ethidium bromide or Southern blotting. To maximize ladder detection, DNA samples were also end-labeled with 32P dideoxyadenosine triphosphate with terminal deoxynucleotidyl transferase (tdt), followed by electrophoresis. None of the postischemic DNA samples demonstrated any laddering by either ethidium bromide staining or Southern analysis (apoptotic lymphocyte DNA was a positive control). However, trace laddering was apparent by the tat technique, commencing at 1 h of reflow, peaking at 24 h, and resolving slowly thereafter. This finding correlated with the morphologic expression of tubular necrosis, not apoptosis. Hypoxia/reoxygenation caused proximal tubular segment death (44 to 64%), and HK-2 cells were slowly killed by both the H2O2 and the energy depletion/Ca(2+)-loading protocols. However, neither protocol induced ethidium bromide- or tdt-detectable DNA laddering. It was concluded that: (1) minimal DNA laddering develops postischemia, and this change is reliably detected only by the tdt method; (2) it correlates with the morphologic expression of tubular necrosis, not apoptosis; and (3) in vitro oxidative- and energy depletion-mediated proximal tubular cell death can be dissociated from DNA ladder formation.


Multinuclear cytotoxic metallodrugs: physicochemical characterization and biological properties of novel heteronuclear gold-titanium complexes.
An unprecedented series of titanocene-gold bi- and trimetallic complexes of the general formula [[(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)](m)AuCl(x)](q+) (n = 0, 2, or 4; m = 1, x = 1, q = 0 or m = 2, x = 0, q = 1) have been prepared and characterized spectroscopically. The luminescence spectroscopy and photophysics of one of the compounds, [[(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)PPh(2))TiCl(2)](2)Au]PF(6), have been investigated in 2MeTHF solution and in the solid state at 77 and 298 K. Evidence for interfragment interactions based on the comparison of electronic band positions and emission lifetimes, namely, triplet energy transfer (ET) from the Au- to the Ti-containing chromophores, is provided. The cytotoxicity of the complexes was evaluated on A2780 ovarian cancer cells and on their cisplatin-resistant cell line A2780cisR; the compounds showed activity in the low micromolar range that was markedly more active than the corresponding titanocene-phosphine precursors [(η(5)-C(5)H(5))(η(5)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)], cisplatin, and, for some of them, the gold analogue [(PPh(3))AuCl]. In an attempt to draw preliminary structure-activity relationships, cell uptake measurements and interaction studies with plasmid DNA and the model protein ubiquitin (Ub) have been undertaken on some of the compounds.


Imparting chemical specificity to nanometer-spaced electrodes.
In this paper we are demonstrating an electrochemically driven self-assembling approach to achieve the space-resolved chemical functionalization of nanoelectrodes. After forming a self-assembled monolayer of electroactive quinones on a pair of nano-spaced (<100 nm) electrodes, we enabled the binding of ssDNA exclusively on a single nanoelectrode by controlling the oxidation state at each modified electrode. This procedure attained the chemical differentiation of otherwise identical nanoelectrodes as the immobilized ssDNA retained its hybridization ability. Furthermore, we established that Kelvin probe force microscopy is a suitable space-resolved analytical technique for detecting this chemical functionalization at the nanoscale. The reported approach, enabling the space-selective patterning of (bio)molecules on nanoelectrode surfaces, can find application in complex nanosensor structure and molecular electronics implementations.


Where Do Agricultural Producers Get Safety and Health Information?
There is little empirical guidance regarding communication sources and channels used and trusted by agricultural producers. The goal of this study was to characterize frequency of use and levels of trust in agricultural safety and health information sources and channels accessed by agricultural producers. A sample of 195 agricultural producers was surveyed at county fairs in Iowa. Information was collected about the frequency of use and level of trust in 14 information sources and channels. Associations between age, gender, and education level and use and trust of each information source or channel were estimated using logistic regression. The sample consisted of 72% men with a mean age of 50.1 (SD = 15.6) years. Newspaper and magazine articles were the most commonly used agricultural safety and health information source or channel; 77% (n = 140) of respondents reporting using them at least monthly. Among those reporting monthly or more frequent use, 75% reported trusting mostly or completely, compared with 58% using and 49% trusting the Internet. High levels of use and trust of newspaper and magazine articles did not vary significantly by age, gender, or education level. Age in the highest tertile (57-83 years) was marginally associated with lower odds of using, as well as using and trusting, all the information sources and channels studied except for medical clinics (use only: odds ratio [OR], 3.51, 95% confidence interval [CI], 0.79-15.64; use and trust: OR, 5.90, 95% CI, 0.91-38.42). These findings suggest that traditional media may be more effective than digital media for delivering agricultural safety and health information to agricultural producers. Medical clinics may be an untapped venue for communicating with older agricultural producers.


In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus.
Ad[I/PPT-E1A] is an oncolytic adenovirus that specifically kills prostate cells via restricted replication by a prostate-specific regulatory element. Off-target replication of oncolytic adenoviruses would have serious clinical consequences. As a proposed ex vivo test, we describe the assessment of the specificity of Ad[I/PPT-E1A] viral cytotoxicity and replication in human nonprostate primary cells. Four primary nonprostate cell types were selected to mimic the effects of potential in vivo exposure to Ad[I/PPT-E1A] virus: bronchial epithelial cells, urothelial cells, vascular endothelial cells, and hepatocytes. Primary cells were analyzed for Ad[I/PPT-E1A] viral cytotoxicity in MTS assays, and viral replication was determined by hexon titer immunostaining assays to quantify viral hexon protein. The results revealed that at an extreme multiplicity of infection of 500, unlikely to be achieved in vivo, Ad[I/PPT-E1A] virus showed no significant cytotoxic effects in the nonprostate primary cell types apart from the hepatocytes. Transmission electron microscopy studies revealed high levels of Ad[I/PPT-E1A] sequestered in the cytoplasm of these cells. Adenoviral green fluorescent protein reporter studies showed no evidence for nuclear localization, suggesting that the cytotoxic effects of Ad[I/PPT-E1A] in human primary hepatocytes are related to viral sequestration. Also, hepatocytes had increased amounts of coxsackie adenovirus receptor surface protein. Active viral replication was only observed in the permissive primary prostate cells and LNCaP prostate cell line, and was not evident in any of the other nonprostate cells types tested, confirming the specificity of Ad[I/PPT-E1A]. Thus, using a relevant panel of primary human cells provides a convenient and alternative preclinical assay for examining the specificity of conditionally replicating oncolytic adenoviruses in vivo.


Risk Factors for Post-Thrombotic Syndrome in Patients With a First Proximal Deep Venous Thrombosis Treated With Direct Oral Anticoagulants.
The incidence of post-thrombotic syndrome (PTS) in patients with deep vein thrombosis (DVT) treated with direct oral anticoagulants (DOACs) remains a matter of debate. Hence, our endeavor to investigate a large cohort of patients with a first episode of proximal DVT treated with DOACs to ascertain the incidence and predisposing risk factors for PTS. All consecutive patients referred to the Thrombotic and Haemorrhagic Diseases Unit of Padova University Hospital (Italy) between January 2014 and January 2018 for a first episode of proximal DVT were considered for enrollment. Participants received DOACs for a minimum period of 3 months. PTS was assessed using the Villalta score up to 36 months after DVT diagnosis. Among 769 enrolled patients (M/F 353/416, age range 26-87 years), 152 (19.8%) developed PTS and 30 (3.9%) developed severe PTS. The adjusted hazard ratio was significant for obesity (1.64, 95% CI 1.28-2.39) and DVT site (femoral and/or iliac veins vs popliteal vein) (1.23, 95% CI 1.15-3.00). The incidence of PTS is not negligible in patients with proximal DVT despite the use of DOACs. We identified obesity and iliofemoral DVT as possible risk factors for PTS. Larger prospective studies are needed to confirm our findings and optimize therapeutic strategies.


Simulation of a localized surface-plasmon-resonance-based fiber optic temperature sensor.
A fiber optic temperature sensor based on localized surface plasmon resonance of spherical gold nanoparticles embedded in a dielectric layer around the unclad core of a small portion of the fiber has been analyzed. Simulations have been carried out for a number of dielectric materials that show considerable changes in their refractive indices due to a change in the temperature in addition to having refractive indices higher than that of the fiber core. The analysis is based on the spectral interrogation method. The surface plasmons in metal nanoparticles have been excited by the light refracted through the core and the dielectric interface. The sensitivity of the sensor has been determined for each dielectric material used, and it is found to be the maximum for CdGeP(2) as a sensing medium. The temperature sensing range of the present sensor is also wide because the melting points of the metal and the fiber core, as well as the sensing medium, are large. The proposed fiber optic temperature sensor is compact, light weight, and highly sensitive with a wide temperature sensing range.


Motor reserve and novel area recruitment: amplitude and spatial characteristics of compensation in Parkinson's disease.
Motor symptoms of Parkinson's disease (PD) do not appear until the majority of dopaminergic cells in the substantia nigra pars compacta are lost, suggesting significant redundancy or compensation in the motor systems affected by PD. Using functional magnetic resonance imaging, we examined whether compensation in PD is manifested by changes in amplitude and/or spatial extent of activity within normal networks (active motor reserve) and/or newly recruited regions [novel area recruitment (NAR)]. Ten PD subjects off and on medication and 10 age-matched controls performed a visually guided sinusoidal force task at 0.25, 0.5 and 0.75 Hz. Regression was used to determine the combination of regions where activation amplitude scaled linearly with movement speed in controls. We then determined the activation of PD subjects in this network, as well as the corresponding PD network. To measure the spatial variance of activation, we used an invariant spatial feature approach. Control subjects monotonically increased activity within striato-thalamo-cortical and cerebello-thalamo-cortical regions with increasing movement speed. In PD subjects, the activity of this network at low speeds was similar to that in controls at higher speeds. Additionally, PD subjects off medication demonstrated NARs of the bilateral cerebellum and primary motor cortex, which were incompletely normalized by levodopa. Our results suggest that PD subjects tap into motor reserve, increase the spatial extent of activation and demonstrate NAR to maintain near-normal motor output.


Strategic human resource management practitioners' emotional intelligence and affective organizational commitment in higher education institutions in Georgia during post-COVID-19.
The COVID-19 pandemic has significantly affected the global workforce, presenting unprecedented challenges to managers and practitioners of strategic human resource management. Pandemic-influenced changes in the employment relationship highlighting the need for adaptation in order to facilitate a return to pre-pandemic conditions. Crises such as this can have a detrimental effect on employees' psychological contract, which in turn can hinder the organization's ability to thrive in the post-COVID-19 era and impede the development of high commitment levels in the aftermath of the crisis. Emotional intelligence plays an increasingly vital role in effectively navigating the crisis and providing support to employees, while also facilitating the reconstruction of the psychological contract. Therefore, this study aims to explain the role of emotional intelligence of strategic human resource management practitioners on affective organizational commitment and the possible mediating effect of the psychological contract in that relationship. A quantitative study took place in February 2023 among 286 HR directors, HR managers, and HR officers in higher education institutions in Georgia. Partial Least Squares for Structural Equation Modelling was applied for data analysis. The results revealed that the emotional intelligence of strategic human resource management practitioners has a positive impact on the psychological contract and the affective organizational commitment. This study supports the idea that emotional intelligence can transform strategic human resource management practitioners into individuals who engage in people-orientated activities. These activities aim to effectively acquire, utilize, and retain employees within an organization. The study also suggests that emotional intelligence can provide solutions to maintain high employee commitment during times of crisis and in the aftermath of unprecedented situations.


Successful transplantation of kidneys from deceased donors with acute renal failure: Three-year results.
Kidneys from deceased donors with acute renal failure (ARF) are generally not accepted for transplantation because of the expected poor outcome. This prospective study examined the utilization of kidneys from donors with ARF for transplantation and the outcomes. Fifty-five kidneys from donors with ARF were transplanted. The outcome was compared with concurrent and matched 55 recipients of standard criteria donor (SCD) kidneys and 55 expanded criteria donor (ECD) kidneys. ARF kidneys were accepted from donors aged <50 years, a negative history for kidney disease, and a negative pretransplant biopsy for chronic structural changes. The immunosuppression was similar in all three groups. The outcome measurements included three-year patient and graft survival, biopsy-proven acute rejection (BPAR), subclinical acute rejection (SCAR), and chronic allograft nephropathy (CAN), serum creatinine, and creatinine clearance. Three-year patient and graft survival was 90% and 90% in ARF group, 100% and 89% in SCD group and 83% and 66% in ECD group. BPAR and SCAR were comparable in the groups but CAN was significantly higher in ECD group. Mean serum creatinine levels were 1.9+/-1.1, 1.9+/-0.9, and 2.2+/-1.3 mg/dl and mean creatinine clearances were 66+/-15, 68+/-14, and 58+/-10 mls/minute in ARF, SCD, and ECD groups, respectively (SCD and ARF vs. ECD P = 0.04). Transplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expand the donor pool to overcome the current acute shortage of kidneys.


3D phase unwrapping using global expected phase as a reference: application to MRI global shimming.
MRI phase data often suffers from phase wrapping (i.e., phase may be discontinuous by 2π jumps). Numerous MRI phase unwrapping strategies were developed in the past using a criterion based on phase information of local or neighboring voxels. In this study, an alternative and novel three dimensional phase unwrapping strategy is introduced. This method considers the global character of the phase distribution and utilizes continuous trigonometric functions to construct an expected phase map as an unwrapping reference, which is then used to guide the phase correction of every individual voxel. The original phase is estimated by analyzing the derivative of the wrapped phase image. Simulations of various phase wrapped situations were performed and this new method was also used for an in vivo application (i.e., MRI automatic global shimming). Both simulated and experimental results demonstrate that our proposed method is more reliable and robust than traditional algorithms at obtaining correct phase maps, especially in regions of low-signal and air cavities, such as the abdomen and pelvis.


Microfibrillar elements in the synovial joint: presence of type VI collagen and fibrillin-containing microfibrils.
The aims were to isolate and positively identify the microfibrillar elements which have been observed in the synovial lining. In addition, synovial fluid was examined for these elements to improve the understanding of the role of these structures in health and disease. Bacterial collagenase digestion of bovine synovial linings and human and bovine synovial fluids was used to release intact, non-denatured microfibrillar elements. The microfibrils were isolated by Sepharose CL-2B chromatography and viewed by rotary shadowing. They were characterised by immunogold labelling with specific antibodies. Intact type VI collagen microfibrils and fibrillin-containing microfibrils were isolated and positively identified in the synovial lining from bovine ankle joints by immunogold labelling. Type VI collagen microfibrils were also present in the synovial fluid. The role of the microfibrillar elements in vivo is not fully understood, but their distribution in the synovial lining suggests they have an important role in the mechanical and physical properties of this tissue. The presence of type VI collagen microfibrils in synovial fluid poses the intriguing possibility that it may represent a product of microfibril turnover and a potential early marker for rheumatoid arthritis. Alternatively, type VI collagen may be specifically secreted into the synovial fluid to interact with hyaluronan and form part of the structure of synovial fluid.


Out-of-Frame Mutations in ACTN2 Last Exon Cause a Dominant Distal Myopathy With Facial Weakness.
To clinically, genetically, and histopathologically characterize patients presenting with an unusual combination of distal myopathy and facial weakness, without involvement of upper limb or shoulder girdle muscles. Two families with a novel form of actininopathy were identified. Patients had been followed up over 10 years. Their molecular genetic diagnosis was not clear after extensive investigations, including analysis of candidate genes and FSHD1-related D4Z4 repeats. Patients shared a similar clinical phenotype and a common pattern of muscle involvement. They presented with a very slowly progressive myopathy involving anterior lower leg and facial muscles. Muscle MRI finding showed complete fat replacement of anterolateral compartment muscles of the lower legs with variable involvement of soleus and gastrocnemius but sparing thigh muscles. Muscle biopsy showed internalized nuclei, myofibrillar disorganization, and rimmed vacuoles. High-throughput sequencing identified in each proband a heterozygous single nucleotide deletion (c.2558del and c.2567del) in the last exon of the ACTN2 gene. The deletions are predicted to lead to a novel but unstructured slightly extended C-terminal amino acid sequence. Our findings indicate an unusual form of actininopathy with specific molecular and clinical features. Actininopathy should be considered in the differential diagnosis of distal myopathy combined with facial weakness.


Audiologic Natural History of Small Volume Cochleovestibular Schwannomas in Neurofibromatosis Type 2.
To characterize the audiometric natural progression in patient-ears with small volume (<1,000 mm), treatment-naïve cochleovestibular schwannomas (CVSs) in Neurofibromatosis Type 2 (NF2). Prospective, longitudinal cohort study. Quaternary medical research institute. One hundred eleven ears in 71 NF2 patients with small, treatment-naïve CVSs observed from July 2006 to July 2016. Serial audiometric testing, including pure tone audiometry, speech audiometry, and magnetic resonance imaging (MRI). Four-frequency pure tone average (4f-PTA) of 0.5, 1, 2, and 4 kHz and word recognition score (WRS) were recorded. Their changes were compared with MRI changes in CVS volume over time. Times to significant hearing loss (10 dB loss in 4f-PTA) and WRS based on 95% critical difference were measured. Linear regression analysis showed a significant correlation with baseline hearing level (4f-PTA) and internal auditory canal (IAC) tumor volume to annual hearing decrease rate (AHDR) (p = 0.003, p = 0.0004). Hearing level at baseline and tumor volume correlate with AHDR while tumor volume growth rate does not. Two-way analysis of variance found significant differences in AHDR, risk of significant hearing loss, and risk of critical difference in WRS based on baseline hearing level (abnormal or normal) and IAC tumor volume (greater or less than 200 mm). Subjects with normal baseline hearing and small IAC tumor component had a low AHDR and low risk of significant hearing loss and may warrant conservative management while the presence of baseline hearing loss and large IAC volume resulted in higher ADHR and greater risk for further hearing loss and may benefit from early treatment interventions.


Physiological Demands of Exergames in Older Adults-A Systematic Literature Review.
New approaches are needed to address low physical activity levels among older adults and to promote daily physical activity tailored to their interests and abilities. This study aimed to review the current literature analyzing the physiological demands of exergames in older adults. A systematic database search was conducted in October 2020 and March 2022. A total of 3,540 studies were screened, and 16 were incorporated into the data analysis. The studies included 527 participants, 61% female, with a mean age of 72.3 ± 4.7 years. Analyzed physiological parameters included mean heart rate, rate of perceived exertion, and metabolic equivalents or oxygen uptake. Exergames are capable of offering light- to moderate-intensity activity for older adults (mean heart rate: 108 ± 9.1 bpm; mean rate of perceived exertion: 11.5 ± 1.8; metabolic equivalents: 2.7 ± 0.7). Although implications are positive, high diversity was found in the study design according to intervention duration and assessment of physiological parameters.


Fourier-transform infrared study on effects of ageing, oestrogen level and altered dietary loading on rat mandibular condylar cartilage.
Mandibular condylar cartilage (MCC) of the rat was examined with the Fourier-transform infrared (FITR) spectroscopic imaging to study the effects of ageing, oestrogen level and altered dietary loading on the structure of MCC. The Sprague-Dawley rats (n = 96) aged 5 and 14 months were divided into 12 subgroups according to age, oestrogen status (ovariectomized [OVX], non-ovariectomized [non-OVX)]) and diet (hard, normal, soft). Specimens of the MCC were examined with FTIR spectroscopic imaging to quantify the distribution of collagens and proteoglycans. MCC was divided sagittally into three segments: anterior, most superior and posterior. From each segment, the collagen and proteoglycan contents at different depths of cartilage were statistically compared between the groups using an N-way analysis of variance (ANOVA). The amount of collagen content was significantly associated with old age in the deep layer of the anterior segment and in the middle layer of the posterior segment of MCC. In the deep layer of the most superior segment, the collagen content also increased with ageing. The amount of proteoglycan content increased significantly when dietary loading increased, and the oestrogen level decreased in the deep layer of the most superior segment of MCC. Ageing, oestrogen level and altered dietary loading have a significant effect on the location and content of collagens and proteoglycans of rat MCC. Ageing significantly increased the amount of collagen content in the superior and posterior segments, being highest in the older soft-diet rats. Decreased oestrogen levels and increased dietary loading increased the amount of proteoglycan content.


Genotypes of the betaENaC gene have little influence on blood pressure level in the Japanese population.
The gene for the beta-subunit of the epithelial sodium channel (betaENaC) is one of the most prominent candidate genes being analyzed for an association with human essential hypertension. It is known that a deletion or alteration of PY motif in exon 12 of betaENaC is responsible for Liddle's syndrome. Although the localization of genetic polymorphisms of betaENaC is unique to each population, intensive analysis of individuals of white and African ancestry has demonstrated that genetic variants are localized in exons 8 and 12, with two frequent polymorphisms, G442V in exon 8 and T594M in exon 12. These two mutations are both found in individuals of African ancestry, and might be associated with elevated blood pressure (BP). Previously, we have screened the last two-thirds of exon 12 in the Japanese population, and demonstrated the absence of the T594M mutation and the presence of a novel P592S mutation. In the present study, we further examined the rest of exon 12 and exon 8 in a general population from Ohasama, Japan (the Ohasama Study), using single-strand conformational polymorphism (SSCP) analysis. We screened 803 subjects randomly selected from the representative participants, who measured their home and casual BP. The PCR products presenting a shift in SSCP gels, as well as controls, were directly sequenced by autoanalyzer to identify the mutation. A novel gel shift was noted in exon 12 (n = 8) and sequencing identified a polymorphism at codon Ser 520, leading to no change in amino acid sequence (G77576C TCG-->TCC). In exon 8, all three SSCP variants were heterogynous for V434M (GTG-->ATG), which is coincident with a rare polymorphism in whites. The G442V mutation, however, was absent from the Japanese population. A novel mutation of exon 12 was not associated with a significant difference in clinical features. These results indicate that Japanese people possess three polymorphisms in exon 12, all of which are unique, and one in exon 8. These genetic variants of betaENaC may not influence the BP level of Japanese people.


HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization.
The Tax protein of human T cell leukemia virus type-1 (HTLV-I) transcriptionally activates the HTLV-I promoter. This activation requires binding sites for activating transcription factor (ATF) proteins, a family of cellular proteins that contain basic region-leucine zipper (bZIP) DNA binding domains. Data are presented showing that Tax increases the in vitro DNA binding activity of multiple ATF proteins. Tax also stimulated DNA binding by other bZIP proteins, but did not affect DNA binding proteins that lack a bZIP domain. The increase in DNA binding occurred because Tax promotes dimerization of the bZIP domain in the absence of DNA, and the elevated concentration of the bZIP homodimer then facilitates the DNA binding reaction. These results help explain how Tax activates viral transcription and transforms cells.


The International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) External Cause-of-injury Framework for Categorizing Mechanism and Intent of Injury.
Background-External cause-of-injury frameworks, or matrices, based on the International Classification of Diseases (ICD) provide standardized categories for reporting injuries by mechanism and intent of injury. In 2014, the National Center for Health Statistics (NCHS) and the National Center for Injury Prevention and Control (NCIPC) published a proposed external cause-of-injury matrix for use with data coded using the ICD, 10th Revision, Clinical Modification (ICD-10-CM). At the time the proposed matrix was developed, ICD-10-CM coded data were not available to evaluate the performance of the proposed matrix. When data became available, NCHS and NCIPC collaborated with the Council of State and Territorial Epidemiologists and state and local health departments to evaluate the proposed matrix to identify any changes needed before finalization. This report describes the results of that evaluation. Methods-With guidance from NCHS and NCIPC, state and local injury epidemiologists from five jurisdictions analyzed their hospital discharge and emergency department administrative claims data. The epidemiologists applied the ICD-9-CM matrix to ICD-9-CM coded data and the 2014 proposed ICD-10-CM matrix to ICD-10-CM coded data for similar time periods (e.g., January through December). The numbers for each mechanism and intent category in each of the two matrices were calculated and compared, and major differences were explored. Results-Based on the findings, several adjustments were made to the original placement of codes in the 2014 proposed ICD-10-CM external cause-of-injury matrix. These changes involved codes related to Drowning/submersion, Firearm, Motor vehicle-Traffic, Overexertion, and Unspecified mechanisms. In addition, new external cause codes not available at the time the 2014 proposed matrix was developed were added to create the 2019 final matrix. Conclusions-The 2019 final ICD-10-CM external cause-of-injury matrix provides standard categories for reporting injuries by mechanism and intent of injury. Use of this tool promotes consistency for comparisons across populations and over time.


Protective Role of Curcumin and Flunixin Against Acetic Acid-Induced Inflammatory Bowel Disease via Modulating Inflammatory Mediators and Cytokine Profile in Rats.
Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present study is to evaluate the effect of flunixin and curcumin in experimentally induced ulcerative colitis in rats. Animals were randomly divided into four groups, each consisting of 12 animals: normal control group, acetic acid group, curcumin-treated group, and flunixin-treated group. Induction of colitis by intracolonic administration of 4% acetic acid produced severe macroscopic inflammation in the colon, 14 days after acetic acid administration as assessed by the colonic damage score. Microscopically, colonic tissues showed ulceration, edema, and inflammatory cells infiltration. Biochemical studies revealed increased serum levels of lactate dehydrogenase (LDH), colonic alkaline phosphatase (ALP), and myeloperoxidase (MPO). Oxidative stress was indicated by elevated lipid peroxide formation and depleted reduced glutathione concentrations in colonic tissues. After induction of colitis, treatment with curcumin (50 mg/kg daily, p.o.) and flunixin (2.5 mg/kg daily, s.c.) decreased serum LDH, ALP, interleukin (IL)-1β, and tumor necrosis factor-α levels, as well as colonic MPO and lipid peroxide levels, whereas increased colonic prostaglandin E2 and IL-10 concentrations were observed. Moreover, effective doses of curcumin and flunixin were effective in restoring the histopathological changes induced by acetic acid administration. The findings of the present study provide evidence that flunixin may be beneficial in patients with inflammatory bowel disease.


[Increased specificity of immunoenzyme analysis for diagnosing meningococcal infection].
The ELISA test system for the detection of polysaccharide antigens of meningococci, groups A and C, on the basis of the neutralization of specific antibodies has been developed. The specificity of this reaction is determined by the chemically pure preparations of group A and C meningococcal polysaccharides. The sensitivity of this test system based on the neutralization of antibodies is not inferior to that of ELISA with the use of double antiserum.


Stimulated vasopressin synthesis by a fetal hypothalamic factor.
The hypothalamo-neurohypophyseal complex (HNC) of the fetal guinea pig shows a dramatic increase in its content of vasopressin and neurophysin between the 40th and 55th days of gestation. The values for radioimmunoassayable hormone and binding protein are at day 40, 2 milliunits and less than 0.1 microgram; and at day 55, about 100 milliunits and 10 micrograms, respectively. Isotope incorporation experiments with organ cultures of the fetal HNC taken prior to the 35th day of gestation added additional confirmation of the inability of the hypothalamic neurosecretory cells to synthesize vasopressin or neurophysin at this time. However, by the 45th day, similar organ cultures show a vigorous incorporation of labeled amino acids into both hormone and binding protein. Furthermore, the HNC of the 45-day-old fetus apparently contains a factor that stimulates specifically the biosynthesis of vasopressin and neurophysin in HNC cultures from the adult guinea pig. This factor is not detectable in either cortex or liver of the 45-day-old fetus or in the fetal HNC taken prior to or after the period of exponential rise (40th to 55th days) of hormone and binding protein.


A repetitive probe for FISH analysis of bovine interphase nuclei.
The purpose of this study was to generate repetitive DNA sequence probes for the analysis of interphase nuclei by fluorescent in situ hybridisation (FISH). Such probes are useful for the diagnosis of chromosomal abnormalities in bovine preimplanted embryos. Of the seven probes (E1A, E4A, Ba, H1A, W18, W22, W5) that were generated and partially sequenced, five corresponded to previously described Bos taurus repetitive DNA (E1A, E4A, Ba, W18, W5), one probe (W22) shared no homology with other DNA sequences and one (H1A) displayed a significant homology with Rattus norvegicus mRNA for secretin receptor transmembrane domain 3. Fluorescent in situ hybridisation was performed on metaphase bovine fibroblast cells and showed that five of the seven probes hybridised most centromeres (E1A, E4A, Ba, W18, W22), one labelled the arms of all chromosomes (W5) and the H1A probe was specific to three chromosomes (ch14, ch20, and ch25). Moreover, FISH with H1A resulted in interpretable signals on interphase nuclei in 88% of the cases, while the other probes yielded only dispersed overlapping signals.


Characteristics of an explosive blast-induced brain injury in an experimental model.
Mild traumatic brain injury resulting from exposure to an explosive blast is associated with significant neurobehavioral outcomes in soldiers. Little is known about the neuropathologic consequences of such an insult to the human brain. This study is an attempt to understand the effects of an explosive blast in a large animal gyrencephalic brain blast injury model. Anesthetized Yorkshire swine were exposed to measured explosive blast levels in 3 operationally relevant scenarios: simulated free field (blast tube), high-mobility multipurpose wheeled vehicle surrogate, and building (4-walled structure). Histologic changes in exposed animals up to 2 weeks after blast were compared to a group of naive and sham controls. The overall pathologic changes in all 3 blast scenarios were limited, with very little neuronal injury, fiber tract demyelination, or intracranial hemorrhage observed. However, there were 2 distinct neuropathologic changes observed: increased astrocyte activation and proliferation and periventricular axonal injury detected with β-amyloid precursor protein immunohistochemistry. We postulate that the increased astrogliosis observed may have a longer-term potential for the exacerbation of brain injury and that the pattern of periventricular axonal injury may be related to a potential for cognitive and mood disorders.


In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines.
Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models. HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model. Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response. Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.


Axonal localisation of the CAM-like tyrosine phosphatase CRYP alpha: a signalling molecule of embryonic growth cones.
Migrating embryonic growth cones require multiple, membrane-associated signalling molecules to monitor and respond to guidance cues. Here we present the first evidence that vertebrate cell adhesion molecule-like protein tyrosine phosphatases are likely to be components of this signalling system. CRYP alpha, the gene for an avian cell adhesion molecule-like phosphatase, is strongly expressed in the embryonic nervous system. In this study we have immunolocalised the protein in the early chick embryo and demonstrated its predominant localisation in axons of the central and peripheral nervous systems. This location suggests that the major, early role of the enzyme is in axonal development. In a study of sensory neurites in culture, we furthermore show that this phosphatase localises in migrating growth cones, within both the lamellipodia and filopodia. The dependence of growth cone migration on both cell adhesion and signalling through phosphotyrosine turnover, places the cell adhesion molecule-like CRYP alpha phosphatase in a position to be a regulator of these processes.


Pediatric training and practice of Canadian chiropractic and naturopathic doctors: a 2004-2014 comparative study.
To assess chiropractic (DC) and naturopathic doctors' (ND) knowledge, attitudes, and behaviour with respect to the pediatric patients in their practice. Cross-sectional surveys were developed in collaboration with DC and ND educators. Surveys were sent to randomly selected DCs and NDs in Ontario, Canada in 2004, and a national online survey was conducted in 2014. Data were analyzed using descriptive statistics, t-tests, non-parametric tests, and linear regression. Response rates for DCs were n = 172 (34%) in 2004, n = 553 (15.5%) in 2014, and for NDs, n = 171 (36%) in 2004, n = 162 (7%) in 2014. In 2014, 366 (78.4%) of DCs and 83 (61%) of NDs saw one or more pediatric patients per week. Pediatric training was rated as inadequate by most respondents in both 2004 and 2014, with most respondents (n = 643, 89.9%) seeking post-graduate training by 2014. Respondents' comfort in treating children and youth is based on experience and post-graduate training. Both DCs and NDs that see children and youth in their practices address a broad array of pediatric health concerns, from well child care and preventative health, to mild and serious illness. Although the response rate in 2014 is low, the concerns identified a decade earlier remain. The majority of responding DCs and NDs see infants, children, and youth for a variety of health conditions and issues, but self-assess their undergraduate pediatric training as inadequate. We encourage augmented pediatric educational content be included as core curriculum for DCs and NDs and suggest collaboration with institutions/organizations with expertise in pediatric education to facilitate curriculum development, especially in areas that affect patient safety.


[The characteristics of antioxidant action in the heart of old rats under stress].
The studies have demonstrated that the inhibitory effect of urea, peroxidase, catalase, its combination with superoxide dismutase on HADPH-dependent lipid peroxidation in the old rat heart is higher than that in young animals. Exposure of young rats to stress is followed by enhanced antioxidative effects of all the parameters under study. This effect is not found in the old animals exposed to stress.


Recent advances in the understanding of retinoblastoma.
Two distinct disease entities are recognisable in retinoblastoma. In the commonest form of the condition a solitary tumour involves only one eye and may be of relatively late onset. Less frequently, multiple tumours are encountered and may involve both eyes. Onset tends to be early and this form of the disease is transmitted in an autosomal dominant fashion. Although in the genetically determined form of retinoblastoma all retinal cells contain abnormal genetic material, only a very few undergo neoplastic change. Individually, the resultant tumours are indistinguishable in terms of clinical appearance and response to treatment from those of non-genetic retinoblastoma. The intriguing similarities of the different forms of the tumour may be explained by a new hypothesis which suggests that retinoblastoma may result from the loss of a pair of suppressor genes. When present, this pair of genes may also have a suppressor effect for other types of tumour. Loss of this suppression for tumours other than retinoblastoma may explain why survivors of genetic disease are highly susceptible to second, non-ocular neoplasms. If the gene can be identified using DNA probes, antenatal diagnosis of those who inherit the retinoblastoma gene may be possible in certain families.


Topochemical Engineering of Cellulose-Carboxymethyl Cellulose Beads: A Low-Field NMR Relaxometry Study.
The demand for more ecological, highly engineered hydrogel beads is driven by a multitude of applications such as enzyme immobilization, tissue engineering and superabsorbent materials. Despite great interest in hydrogel fabrication and utilization, the interaction of hydrogels with water is not fully understood. In this work, NMR relaxometry experiments were performed to study bead-water interactions, by probing the changes in bead morphology and surface energy resulting from the incorporation of carboxymethyl cellulose (CMC) into a cellulose matrix. The results show that CMC improves the swelling capacity of the beads, from 1.99 to 17.49, for pure cellulose beads and beads prepared with 30% CMC, respectively. Changes in water mobility and interaction energy were evaluated by NMR relaxometry. Our findings indicate a 2-fold effect arising from the CMC incorporation: bead/water interactions were enhanced by the addition of CMC, with minor additions having a greater effect on the surface energy parameter. At the same time, bead swelling was recorded, leading to a reduction in surface-bound water, enhancing water mobility inside the hydrogels. These findings suggest that topochemical engineering by adjusting the carboxymethyl cellulose content allows the tuning of water mobility and porosity in hybrid beads and potentially opens up new areas of application for this biomaterial.