Viral-induced Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplant.
Hemorrhagic cystitis (HC) is a well-recognized problem that is regularly observed after hematopoietic stem cell transplantation (HSCT). The published data does not report on the potential risk factors for the viral-induced HC that might require prophylactic treatments. We conducted a retrospective analysis of all adult patients who underwent allogeneic HSCT at Jules Bordet Institute between 1992 and 2013. Our institutional protocol consists in monitoring the patient for signs and symptoms of HC on a daily basis during the initial admission for HSCT, then once weekly after discharge until 2 months thereafter. HC was found in 64 patients, of whom 56 (87.5%) had viral-induced HC. The median time between HSCT and HC was 39.5 days (range, 1-2766 days); the median time between detection of a viral infection and HC was 32 days (range, 0-2752 days). In multivariate analysis, HC is correlated to the infection with the BK virus (hazard ratio, 6.0; 95% confidence interval, 5.03-6.90; P = .0001) and the adenovirus (hazard ratio, 4.93; 95% confidence interval, 4.06-5.80; P = .0003). The 5-year overall survival of patients with HC was 36%. The 5-year survival rates were not statistically different between patients with or without HC (25% vs. 39%; P = .20). The presence of the identified risk factors should prompt closer follow-up with screening tests and preventive measures for BK virus and adenovirus infections in patients undergoing HSCT.


Synthetic Attenuation Correction Maps for SPECT Imaging Using Deep Learning: A Study on Myocardial Perfusion Imaging.
(1) Background: The CT-based attenuation correction of SPECT images is essential for obtaining accurate quantitative images in cardiovascular imaging. However, there are still many SPECT cameras without associated CT scanners throughout the world, especially in developing countries. Performing additional CT scans implies troublesome planning logistics and larger radiation doses for patients, making it a suboptimal solution. Deep learning (DL) offers a revolutionary way to generate complementary images for individual patients at a large scale. Hence, we aimed to generate linear attenuation coefficient maps from SPECT emission images reconstructed without attenuation correction using deep learning. (2) Methods: A total of 384 SPECT myocardial perfusion studies that used 99mTc-sestamibi were included. A DL model based on a 2D U-Net architecture was trained using information from 312 patients. The quality of the generated synthetic attenuation correction maps (ACMs) and reconstructed emission values were evaluated using three metrics and compared to standard-of-care data using Bland-Altman plots. Finally, a quantitative evaluation of myocardial uptake was performed, followed by a semi-quantitative evaluation of myocardial perfusion. (3) Results: In a test set of 66 test patients, the ACM quality metrics were MSSIM = 0.97 ± 0.001 and NMAE = 3.08 ± 1.26 (%), and the reconstructed emission quality metrics were MSSIM = 0.99 ± 0.003 and NMAE = 0.23 ± 0.13 (%). The 95% limits of agreement (LoAs) at the voxel level for reconstructed SPECT images were: [-9.04; 9.00]%, and for the segment level, they were [-11; 10]%. The 95% LoAs for the Summed Stress Score values between the images reconstructed were [-2.8, 3.0]. When global perfusion scores were assessed, only 2 out of 66 patients showed changes in perfusion categories. (4) Conclusion: Deep learning can generate accurate attenuation correction maps from non-attenuation-corrected cardiac SPECT images. These high-quality attenuation maps are suitable for attenuation correction in myocardial perfusion SPECT imaging and could obviate the need for additional imaging in standalone SPECT scanners.


Translation and Psychometric Properties of the Copenhagen Burnout Inventory in Iranian Nurses.
Burnout has its focus on exhaustion and it includes persistent response to long-lasting job-related stressful events. It has a special relevance in health care area in which staff is under constant psychological, emotional, and physical stress. The results of several studies on burnout prevalence among Iranian nurses indicate its high incidence. Therefore, more accurate researches are required for better preventive interventions, and to do so, a reliable validated scale is required. One of the suitable and new tools for the measurement of burnout is Copenhagen Burnout Inventory (CBI). This study aimed to translate and investigate psychometric properties of CBI in Iranian nurses. In this methodological study, after the translation process, face and content validities via qualitative and quantitative methods was done. Content validation ratio, scale-level content validated index, item-level content validity index were measured. Then, construct validity was determined through factor analysis. Furthermore, internal consistency reliability and stability were assessed. The questionnaire was sent to 450 nurses who were randomly selected via quota sampling. Face and content validity were acceptable. After translation and cultural adaptation process, exploratory factor analysis suggested a new model based on four factors and fit indices validated this model via confirmatory factor analysis. Internal consistency and stability of CBI were affirmed for each subscale separately. The four-factor Persian version of the CBI proved to enjoy acceptable psychometric properties. It can be applied to evaluate burnout in Iranian nurses or other health care providers.


Process Evaluation of Nutrition Intervention Strategy in a Local Philippine Setting.
Aims: Undernutrition among 0 to 5 years old children remains a public health problem in the Philippines. This process evaluation study documented and examined the implementation of an intervention strategy for young children. Methods: Complementary feeding of 6-month to 2-year-old children was implemented for 120 days by the municipalities of Plaridel and Pulilan in Bulacan, Philippines utilizing local-based food made of rice and mung bean along with nutrition education classes among mothers/caregivers using the developed nutrition modules. A total of 121 mother-/caregiver-child pairs were the program participants of the intervention. Pre-post design were used in the analysis of quantitative data. Qualitative data were encoded verbatim manually using emerging themes. Key informant interviews among community workers and municipal officials and focus group discussions among mothers/caregivers and community workers were conducted to gather the needed data. Results: The municipalities adhered to the program phases of planning, organizing, implementation, monitoring, and evaluation. At end-line, the weight of children participants increased in both municipalities and the mean nutrition knowledge scores of mothers/caregivers increased significantly (P < .05). Conclusions: This process evaluation confirmed that the proposed nutrition intervention strategy for young children can be implemented at the local level. The strong support and active cooperation of the local program implementers and mothers/caregivers and adherence to program requirements were the key factors in the efficient implementation of the intervention. For sustainability, the passing of local ordinance for the adoption of intervention and budget support for implementation of the intervention is recommended.


Challenges and methodology for indexing the computerized patient record.
Patient records contain most crucial documents for managing the treatments and healthcare of patients in the hospital. Retrieving information from these records in an easy, quick and safe way helps care providers to save time and find important facts about their patient's health. This paper presents the scalability issues induced by the indexing and the retrieval of the information contained in the patient records. For this study, EasyIR, an information retrieval tool performing full text queries and retrieving the related documents has been used. An evaluation of the performance reveals that the indexing process suffers from overhead consequence of the particular structure of the patient records. Most IR tools are designed to manage very large numbers of documents in a single index whereas in our hypothesis, one index per record, which usually implies few documents, has been imposed. As the number of modifications and creations of patient records are significant in a day, using a specialized and efficient indexation tool is required.


Relationship among mercury concentration, growth rate, and condition of northern pike: A tautology resolved?
Methylmercury is a bioaccumulative contaminant that biomagnifies in aquatic food webs and adversely affects the health of freshwater fish. Previous studies have documented an inverse relationship between fish condition and concentration of mercury in fish. However, this relationship may be a result of slow-growing fish accumulating large amounts of methylmercury rather than the effects of methylmercury on fish condition and growth. An evaluation was conducted of the relationship among fish condition, growth, and mercury concentration in northern pike Esox lucius from 26 lakes in the western region of the Laurentian Great Lakes (USA-Canada). The relative weight (an index of fish condition) of northern pike was inversely related to mercury concentration in the axial muscle. The concentration of mercury in standard-size northern pike increased with fish age and suggested that fast-growing fish accumulated less mercury than slow-growing fish. However, there was no relationship between the mean relative weight of northern pike in each population and mean age or mercury concentration of standard-size northern pike. These results suggest that the relationship between mercury and fish condition is not because of the effects of mercury on rate of growth, but rather because slow-growing fish bioaccumulate greater concentrations of mercury than fast-growing fish of the same length. Environ Toxicol Chem 2016;35:2910-2915. © 2016 SETAC.


The use of unipolar intracardiac impedance for discrimination of haemodynamically stable and unstable arrhythmias in man.
To determine the feasibility of discriminating haemodynamically stable from unstable arrhythmias using right ventricular (RV) unipolar intracardiac impedance (Z). A quadrapolar temporary pacing electrode was positioned at the RV apex and unipolar impedance was measured between the tip electrode and a surface patch electrode. Changes in peak-to-peak Z amplitude were measured simultaneously with surface ECG and blood pressure during induced arrhythmias. Haemodynamic instability was defined as a systolic pressure of <90 mmHg. There were 25 episodes of ventricular fibrillation (VF) induced in 15 patients, 18 episodes of ventricular tachycardia in 16 patients, and 33 episodes of supraventricular tachycardia (SVT) in 16 patients. Compared with the baseline rhythm, mean Z amplitude reduced from 51.3+/-7.7 to 11.2+/-7.4 Ohm (P<0.001) during VF, from 52.2+/-6.3 to 21.7+/-10.1 Ohm (P<0.01) during haemodynamically unstable VT, from 55.0+/-6.9 to 39.9+/-11 Ohm (ns) during stable VT, and from 56.4+/-8.4 to 36.9+/-9.3 Ohm during SVT (P<0.001). Right ventricular unipolar impedance is an adequate sensor for determining mechanical ventricular contraction and acts as a surrogate marker for a fall in arterial blood pressure during VF. However, for ventricular and supraventricular tachycardias, variations between patients did not allow adequate discrimination between stable and unstable arrhythmias.


Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases.
Multiple sclerosis is considered a disease of myelin destruction; Parkinson's disease (PD), one of dopaminergic neuron depletion; ALS, a disease of motor neuron death; and Alzheimer's, a disease of plaques and tangles. Although these disorders differ in important ways, they also have common pathogenic features, including inflammation, genetic mutations, inappropriate protein aggregates (e.g., Lewy bodies, amyloid plaques), and biochemical defects leading to apoptosis, such as oxidative stress and mitochondrial dysfunction. In most disorders, it remains uncertain whether inflammation and protein aggregation are neurotoxic or neuroprotective. Elucidating the mechanisms that orchestrate neuronal diseases should facilitate development of neuroprotective and neurorestorative strategies.


Genetic variant in CLPTM1L confers reduced risk of lung cancer: a replication study in Chinese and a meta-analysis.
Rs31489 in the cleft lip and palate transmembrane1-like gene (CLPTM1L) has been identified to be associated with lung cancer through genome-wide association studies (GWAS). However, some recent replication studies yielded inconclusive results. Thus, we undertook this study to investigate the precise effect of rs31489 on lung cancer susceptibility. A hospital-based case-control study in 1,673 Chinese subjects (611 individuals with lung cancer and 1,062 controls) and a meta-analysis among 32,199 subjects (16,364 cases and 15,835 controls) were performed in this study. In our case-control study, rs31489 was inversely associated with lung cancer (AC versus CC: OR=0.68, 95%CI=0.52-0.88; additive model: OR=0.68, 95%CI=0.54-0.85; dominant model: OR=0.65, 95%CI =0.51-0.84). Stratification analysis by smoking status showed a significant association and strong genetic effect in non-smokers but not in smokers. Our meta- analysis further confirmed the association, although with significant heterogeneity contributed by study design and source of controls, as shown by stratified analysis. Sensitive and cumulative analyses both indicated robust stability of our results. In addition, there was no observable publication bias in our meta-analysis. Overall, the findings from our replication study and meta-analysis demonstrated that CLPTM1L gene rs31489 is significantly associated with lung cancer.


Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones.
From the studies described in this review, it is clear that structural information dictates not only the functional properties of exportable proteins, but also their ability to be transported in the intracellular secretory pathway. In ERSDs, the precise nature of the defect determines both the severity of the phenotype and the mode of inheritance. To our knowledge, all genetically inherited ERSDs are attributable to mutations in the coding sequence of exportable proteins; thus far, with the exception of abetalipoproteinemia (see Section IV.D), no mutations in ER chaperones (other than those that scientists have genetically engineered) have been reported as the cause of spontaneous disease. The elevations of ER chaperones in ERSDs may differ between mutations, between tissues, between individual patients, and between different physiological states (i.e., such as before and after hormone replacement therapy) in the same patient. Thus, measurement of ER chaperone levels plays an important diagnostic role, but probably should not be used as the sole basis to classify these illnesses. Moreover, because mutant secretory proteins have been reported to occur in virtually every organ system, ERSDs are more readily classified at the cell biological level, by the responses of the cells that actually synthesize the secretory protein, rather than the hormone deficiency associated with the illness at the end-organ level. With these ideas in mind, we present a schematic view in Fig. 4. According to this schema, all ERSDs begin with ER retention of the affected proteins or their subunits. Mutants may then be divided into two groups: type A, where the biological activity is preserved although the protein is transport-deficient; and type B, where the mutant has no potential for functional activity. Both categories include both recessive and dominant mutations. The primary clinical difference between these two classes is that type A ERSDs may be amenable to therapies designed to down-regulate the quality control of ER export so that potentially functional molecules can escape the ER and reach their intended intracellular destination. In both types of ERSDs, in most cases, the retained mutant protein is efficiently degraded in the ER (subtypes A-I and B-I). In these cases, the predominant, global phenotypes involve the symptoms and signs of hormone deficiency. However, careful biochemical and cell biological studies reveal various abnormalities in glandular function, typically including the elevation of the levels of one or more ER chaperones. As described in Section I.C, such elevations are a consequence of chronic adaptation to the presence of unfolded mutant secretory protein (the synthesis of which is stimulated all the more by endocrine feedback loops). As described in Section III, the elevated chaperones appear to be integrally related to the ER retention as well as perhaps the ERAD process that removes the misfolded proteins. In these cases, the ER compartment may expand, but the secretory cells are likely to survive. In the more unusual subtype II (subtypes B-II and perhaps A-II), the mutant protein exhibits an intrinsic tendency to resist ERAD, creating a potentially dangerous accumulation of indigestible material (Fig. 4). This may be due to the unusual production of novel, protease-resistant protein complexes, or it may be due to the formation of protein assemblies that prevent the reverse translocation of mutant proteins to the cytosol for proteasomal proteolysis. Resistance of untransported mutant protein to ER-associated degradation will predispose to a dominant ERSD (460). In such a case, although the mutant allele could could form oligomeric hybrids with the wild-type allele, complete nonmixing of the normally exported wild-type allele and toxic accumulation of the mutant allele is another distinct scenario that can also produce a dominant mode of inheritance. (ABSTRACT TRUNCATED)


Development and psychometric testing of the Team-Based Learning Student Assessment Instrument.
Team-based learning, an innovative teaching strategy, may be useful in meeting the demands of nursing education. However, educators may be hesitant to adopt this teaching strategy because of the lack of available research. The author discusses a study to determine whether a newly developed instrument, the Team-Based Learning Student Assessment Instrument, accurately measures the 3 subscales of accountability, preference for lecture or team-based learning, and student satisfaction. Results suggest the instrument is valid and reliable and may be a valuable tool in assessing the effectiveness of team-based learning.


[A preliminary fMRI study of moral judgment task in high functioning autistic children].
Autistic patients show social cognitive disorders and hardly recognize their situations. This means it is difficult for them to obey rules or conform to customs. Humans have social intelligence thought to be related to a network connected to amygdala, the orbito-frontal cortex, and the superior temporal gyrus. It has been reported that normal participants judged morality in dilemma sentences through which the medial orbito-frontal cortex and the right lateral prefrontal cortex were activated. However, where autism is concerned, there has been no fMRI study during the moral judgment task. The study herein showed changes of autistic brain areas related to moral judgment. This study included one high-functioning autistic child, one Asperger's syndrome child, and three normal children. Pictures of social situations were painted and the children present were asked to judge whether the contents were moral or immoral. The results of fMRI demonstrated the orbito-frontal cortex was active in normal children but not active in the autistic children with regard to moral judgment. This suggested autistic people have functional disorders in this area. BA11 and BA22 were activated in the control group and these areas are thought to be related to sociality and "theory of mind". Furthermore, BA38 was activated in one control and this area is also related to "theory of mind" and emotions. Moral judgments about personal affairs activate brain areas related to emotions (bilateral medial frontal gyri, bilateral cingulated gyri and bilateral angular gyri) and moral judgments about public affairs activate brain areas related to working memory (left medial frontal gyrus and bilateral temporal cortices). Based on the results above, we think moral judgment is related to "theory of mind" and social cognition, and shares a common sense processing mechanism. Recently Greene et al. reported that the prefrontal cortex was active during moral judgment in an fMRI study of normally developed people. Their result reinforces our results.


Trends in treated ventricular fibrillation in out-of-hospital cardiac arrest: ischemic compared to non-ischemic heart disease.
The incidence of ventricular fibrillation (VF) out-of-hospital cardiac arrest (OHCA) treated by first responders has declined over the past decade. Since VF OHCA occurs primarily in the setting of severe coronary artery disease, primary and secondary prevention strategies may in part account for the decline. However, such strategies may not have a similar impact on non-ischemic arrest. All Rochester Minnesota residents who presented with a VF OHCA from 1991 to 2004, treated by emergency medical services (EMS), were included in the study. Incidence rates were calculated based on the population for Rochester during the time period. Changes over time were tested using Poisson regression models. The significance of the trends was estimated according to the Mantel-Haenszel test for association, and two-tailed p-values reported. The overall incidence of EMS-treated VF OHCA in Rochester during the study period was 10.6 per 100,000 (95% CI 9.1-11.8). The incidence decreased significantly (p<0.001) over the study period [1991-1994: 18.2/100,000 (95% CI 13.4-21.9); 1995-1999: 11.8/100,000 (95% CI 10.4-17.9); 2000-2004: 8.7/100,000 (95% CI 6.0-13.0)]. The incidence of VF OHCA with ischemic heart disease also declined [1991-1994: 13.4/100,000 (95% CI 8.9-16.9); 1995-1999: 11.1/100,000 (95% CI 8.2-15.9); 2000-2004: 5.5/100,000 (95% CI 3.8-8.2), p<0.001]. In contrast, the incidence VF OHCA with non-ischemic heart disease increased [1991-1994: 2.1/100,000 (95% CI 1.13-3.1); 1995-1999: 2.3/100,000 (95% CI 1.9-3.7); 2000-2004: 2.9/100,000 (95% CI 2.0-3.4), p<0.001]. The incidence of VF OHCA is declining. The decline is attributable to the reduction of VF cardiac arrest with ischemic heart disease; suggesting an impact of treatment strategies targeted at coronary artery disease. The relative increasing incidence of non-ischemic VF OHCA suggests that more efforts are required to minimize mortality in this cohort population.


Painful thyroiditis in postpartum period.
Destructive thyroiditis commonly occurs during the postpartum period, with a prevalence rate of 5% to 16%, and is mainly due to postpartum autoimmune thyroiditis (PPT) and, very rarely, to subacute thyroiditis. The thyroiditis is similar to Hashimoto's thyroiditis and is generally painless in nature, although cases with painful thyroiditis have been described. We report a case of painful destructive thyroiditis occurring during the postpartum period, which was clinically and biochemically indistinguishable from the variant of painful PPT or subacute thyroiditis. Fine needle aspiration cytology showed multi-nucleated giant cells diagnostic of subacute thyroiditis.


Survey of curriculum and instruction: continuing education courses in pain control.
Pain and anxiety control is taught at the continuing education level in a large number of diverse courses. This paper reports the results of a survey of those courses held in 1976. The majority of courses centered on the use of inhalation or intravenous sedation. Relatively few courses were offered on the other aspects of pain and anxiety control. Very little attempt is being made at formally evaluating the competence of participants in these courses. Few courses appear to adequately cover the prevention and management of complications. Suggestions for changes in the teaching of pain and anxiety control at the continuing education level are made based on these findings.Pain and anxiety control encompasses the application of various physical, chemical and psychological modalities in the prevention and treatment of peri-operative patient apprehension and pain. Patient apprehension about dental procedures is felt to influence the seeking of remedial and preventive dental care by a significant portion of the population. Efforts to improve the training of dentists in pain and anxiety control modalities have included several workshops sponsored by the American Dental Society of Anesthesia, the formulation of guidelines for courses at the predoctoral, postdoctoral and continuing education levels, and the establishment of postdoctoral pain control training programs at several dental schools.Recent graduates have been trained in pain control in predoctoral programs which vary widely in content and length. A large number of practitioners seek training in pain control through continuing education courses offered by dental schools, hospitals and a variety of other institutions. This paper reports the results of a survey of these courses and suggests several recommendations based on the findings.


WHO Grade 2 Neuroendocrine Tumor in a 15-Year-Old Male: A Case Report and Literature Review.
Neuroendocrine tumors, distinguished from adenocarcinomas by their neuroendocrine differentiation, are the most common pediatric epithelial malignancy that most often occurs in the appendix. In 2010, the WHO classified neuroendocrine neoplasms into three grades based on morphology, mitotic count, and Ki67 proliferation index. A 15-year-old male with a history of anemia and failure to thrive was diagnosed with a well-differentiated neuroendocrine tumor in the jejunum that invaded into the subserosal soft tissue and metastasized to four lymph nodes. Pediatric neuroendocrine tumors frequently arise within hereditary tumor syndromes with pancreatic neuroendocrine tumors being the most common. Several studies also indicate an elevated risk of small intestinal neuroendocrine tumors in which children born to a parent with a history of neuroendocrine tumors in the small intestine have a significant increased risk of developing one.


In pursuit of nanocarbons.
With the advent of the Krätschmer-Huffman historical breakthrough on the macroscopic synthesis of C(60) in the late summer of 1990, I decided to stop all my research so far in the area of spectroscopy of gas-phase molecular microclusters. Since then, my odyssey in and quest for the so-called nanocarbons started. Thanks to the brand-new and enchanting world of fullerenes, metallofullerenes, carbon nanotubes and nano-peapods, I have been able to entertain (and still am entertaining!) "the pleasure of finding things out", as Richard Feynman once put it in an interview by a BBC television program in 1981. I believe that as long as one has big dreams and lays the groundwork for the dreams, one will achieve them. My quest for nanocarbons is still on its way.


Cognitive-behavioural therapy-based intervention to reduce fear of falling in older people: therapy development and randomised controlled trial - the Strategies for Increasing Independence, Confidence and Energy (STRIDE) study.
Falls cause fear, anxiety and loss of confidence, resulting in activity avoidance, social isolation and increasing frailty. The umbrella term for these problems is 'fear of falling', seen in up to 85% of older adults who fall. Evidence of effectiveness of physical and psychological interventions is limited, with no previous studies examining the role of an individually delivered cognitive-behavioural therapy (CBT) approach. Primary objective To develop and then determine the effectiveness of a new CBT intervention (CBTi) delivered by health-care assistants (HCAs) plus usual care compared with usual care alone in reducing fear of falling. Secondary objectives To measure the impact of the intervention on falls, injuries, functional abilities, anxiety/depression, quality of life, social participation and loneliness; investigate the acceptability of the intervention for patients, family members and professionals and factors that promote or inhibit its implementation; and measure the costs and benefits of the intervention. Phase I CBTi development. Phase II Parallel-group patient randomised controlled trial (RCT) of the new CBTi plus usual care compared with usual care alone. Multidisciplinary falls services. Consecutive community-dwelling older adults, both sexes, aged ≥ 60 years, with excessive or undue fear of falling per Falls Efficacy Scale-International (FES-I) score of > 23. Phase I Development of the CBTi. The CBTi was developed following patient interviews and taught to HCAs to maximise the potential for uptake and generalisability to a UK NHS setting. Phase II RCT. The CBTi was delivered by HCAs weekly for 8 weeks, with a 6-month booster session plus usual care. These were assessed at baseline, 8 weeks, 6 months and 12 months. Primary outcome measure Fear of falling measured by change in FES-I scores at 12 months. Secondary outcome measures These comprised falls, injuries, anxiety/depression [Hospital Anxiety and Depression Scale (HADS)], quality of life, social participation, loneliness and measures of physical function. There were process and health-economic evaluations alongside the trial. Four hundred and fifteen patients were recruited, with 210 patients randomised to CBTi group and 205 to the control group. There were significant reductions in mean FES-I [-4.02; 95% confidence interval (CI) -5.95 to -2.1], single-item numerical fear of falling scale (-1.42; 95% CI -1.87 to 1.07) and HADS (-1; 95% CI -1.6 to -0.3) scores at 12 months in the CBTi group compared with the usual care group. There were no differences in the other secondary outcome measures. Most patients found the CBTi acceptable. Factors affecting the delivery of the CBTi as part of routine practice were identified. There was no evidence that the intervention was cost-effective. Our new CBTi delivered by HCAs significantly improved fear of falling and depression scores in older adults who were attending falls services. There was no impact on other measures. Further work should focus on a joint CBTi and physical training approach to fear of falling, more rational targeting of CBTi, the possibility of mixed group and individual CBTi, and the cost-effectiveness of provision of CBTi by non-specialists. Current Controlled Trials ISRCTN78396615. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 56. See the NIHR Journals Library website for further project information.


Preventing intrahepatic infection after ablation of liver tumours in biliary-enteric anastomosis patients.
To assess the value of bowel preparation plus targeted antibiotics for preventing intrahepatic infections after MWA of liver tumours in BEA patients. This retrospective study included 21 patients (divided into two groups) with a history of BEA undergoing ultrasound-guided MWA of liver tumours from November 2008 to June 2014. Group A (n = 10) received single-antibiotic therapy (cefazedone 2 g bid 4, amoxicillin and flucloxacillin sodium 2 g bid 3, levofloxacin 0.5 g qd 3) after ablation, and group B (n = 11) received bowel preparation before ablation plus combined antibiotic therapy (imipenem and cilastatin sodium 1 g 1/12 h, linezolid 0.6 g 1/12 h). Patients were followed for 3 months. Incidences of fever, bacteraemia, and intrahepatic infections were compared, including the duration of fever and length of hospital stay. Following ablation, in group A, 90% of the patients (9/10) had fever, 60% (6/10) had bacteraemia, 60% (6/10) had liver abscess, and 10% (1/10) had biliary tract infection. In group B, no cases of bacteraemia or intrahepatic infection were reported, and the incidences of fever, bacteraemia, and liver abscess were substantially lower than group A (p = 0.002, 0.004, 0.004). Duration of fever and length of hospital stay were markedly shorter than group A (p = 0.002 0.003). Bowel preparation plus targeted antibiotic therapy can significantly reduce the incidences of fever, bacteraemia, and intrahepatic infections in BEA patients undergoing MWA of liver tumours. These preliminary results need to be further validated in randomised trials.


Molecularly imprinted polypyrrole-based synthetic receptor for direct detection of bovine leukemia virus glycoproteins.
Preparation and basic characterization of polypyrrole-based molecularly imprinted polymer (MIP) for label-free detection of bovine leukemia virus (BLV) glycoprotein gp51 (gp51) is firstly described. Polypyrrole (Ppy) was selected as a matrix for preparation of MIP. Polypyrrole doped by gp51 (gp51/Ppy) was prepared by electrochemical deposition of this polymer on the surface of platinum-black electrode. Then, molecules of gp51 were removed from polymeric backbone and molecularly imprinted polypyrrole (mPpy) was ready for recognition of gp51 in the aqueous solution. Pulsed amperometric detection (PAD) was applied for label-free detection of gp51 in the samples. Anti-gp51 antibodies and secondary antibodies labeled with horseradish peroxidase (HRP) were involved as markers for the control of mPpy preparation procedures. Control experiments were also simultaneously performed by spectrophotometrical detection of HRP activity. Application of anti-gp51 and HRP labelled secondary antibodies confirmed that generation of analytical signal was based on redoping of mPpy by gp51. During our experiments, only few mPpy redoping/dedoping cycles were effective, but generally this method seems to be very effective for the future development of mPpy-based MIPs. Preparation, electrochemical investigation and control procedures are described in the current paper.


Clinicopathological correlation of oral candidiasis - Our experience in a tertiary centre over two decades.
Oral candidiasis is one of the most common fungal infections that has been widely reported around the world. In Malaysia, the available studies for this infection are scarce. This is a 20-year retrospective study aimed to investigate the prevalence, demographic characteristics, clinical presentations, and the association of oral candidiasis with clinical parameters in oral candidiasis cases reported in the Faculty of Dentistry, Universiti Malaya from 1999 until 2019. A total of 12,964 histopathological records from the Oral Pathology Diagnostic and Research Laboratory (OPDRL) between 1999 to 2019 were retrieved. Oral candidiasis cases were selected according to the inclusion and exclusion criteria. Information of interest was obtained and analysed. From the total records retrieved, 378 oral candidiasis cases were recorded and 82.8% were diagnosed from smear test. This study showed that oral candidiasis was predominantly reported in female (64.2%) and Indian population (64.2%). The peak incidence was in the sixth decades of life (27.0%). The most commonly affected site was tongue and coated tongue was the most common clinical presentation. More than 50% of the cases had comorbidity and 10.6% were associated with dentures. Ethnicity and site of occurrence were significantly associated (p<0.05) with oral candidiasis. This is the first large-scale study of oral candidiasis cases in Malaysia. The findings of this study are useful for clinical assessment of patients suspected of oral candidiasis.


Shenmai Injection Improves Energy Metabolism in Patients With Heart Failure: A Randomized Controlled Trial.
In recent years, the application of Shenmai (SM) injection, a traditional Chinese medicine (TCM), to treat heart failure (HF) has been gradually accepted in China. However, whether SM improves energy metabolism in patients with HF has not been determined due to the lack of high-quality studies. We aimed to investigate the influence of SM on energy metabolism in patients with HF. This single-blind, controlled study randomly assigned 120 eligible patients equally into three groups receiving SM, trimetazidine (TMZ), or control in addition to standard medical treatment for HF for 7 days. The primary endpoints were changes in free fatty acids (FFAs), glucose, lactic acid (LA), pyroracemic acid (pyruvate, PA) and branched chain amino acids (BCAAs) in serum. The secondary outcomes included the New York Heart Association (NYHA) functional classification, TCM syndrome score (TCM-s), left ventricular injection fraction (LVEF), left ventricular internal diastolic diameter (LVIDd), left ventricular internal dimension systole (LVIDs), and B-type natriuretic peptide (BNP). After treatment for 1 week, the NYHA functional classification, TCM-s, and BNP level gradually decreased in the patients in all three groups, but these metrics were significantly increased in the patients in the SM group compared with those in the patients in the TMZ and control groups (P < 0.05). Moreover, energy metabolism was improved in the NYHA III-IV patients in the SM group compared with those in the patients in the TMZ and control groups as evidenced by changes in the serum levels of FFA, LA, PA, and BCAA. Integrative treatment with SM in addition to standard medical treatment for HF was associated with improved cardiac function compared to standard medical treatment alone. The benefit of SM in HF may be related to an improvement in energy metabolism, which seems to be more remarkable than that following treatment with TMZ.


Laryngeal involvement in mitochondrial myopathy.
A patient with a slowly progressive mitochondrial myopathy is presented. Mitochondrial myopathies are a diverse group of disorders both clinically and at the cellular level. In common with other neuromuscular disorders, bulbar symptoms may occur. However, though pharyngeal symptoms have been documented in all forms of the disorder, no previous account has described problems at the laryngeal level. We discuss the clinical findings and comment on the therapeutic options.


Effect of Degradation in Small Intestinal Fluids on Mechanical Properties of Polycaprolactone and Poly-l-lactide-co-caprolactone.
Polycaprolactone and poly-l-lactide-co-caprolactone are promising degradable biomaterials for many medical applications. Their mechanical properties, especially a low elastic modulus, make them particularly interesting for implantable devices and scaffolds that target soft tissues like the small intestine. However, the specific environment and mechanical loading in the intestinal lumen pose harsh boundary conditions on the design of these devices, and little is known about the degradation of those mechanical properties in small intestinal fluids. Here, we perform tensile tests on injection molded samples of both polymers during in vitro degradation of up to 70 days in human intestinal fluids. We report on yield stress, Young's modulus, elongation at break and viscoelastic parameters describing both materials at regular time steps during the degradation. These characteristics are bench-marked against degradation studies of the same materials in other media. As a result, we offer time dependent mechanical properties that can be readily used for the development of medical devices that operate in the small intestine.


Radioimmunoassay for central nervous system myelin-specific proteolipid protein.
A double-antibody radioimmunoassay (RIA) has been developed with antisera to purified rat brain myelin proteolipid protein (PLP). The addition of Triton X-100 allowed antibody-antigen interaction and immune precipitation in the presence of sodium dodecyl sulfate (SDS). The RIA will accurately measure 8-80 ng of PLP in buffer or human serum. The RIA is highly specific for myelin PLP and does not cross-react with material in tissues (heart, kidney, muscle, testicle, and intestine) other than the central nervous system. The antibodies to rat myelin PLP cross-react with PLP from bovine brain homogenate or myelin. Myelin PLP was found to account for 55 and 52% of total myelin protein from bovine and rat brain, respectively. Furthermore, there is a higher concentration of PLP in white than in gray matter corresponding to the degree of myelination. Unlike myelin basic protein, myelin PLP was undetectable in both bovine and rat peripheral nervous system.


Polycystic kidney disease: prospective analysis of nonazotemic patients and family members.
To develop a profile of nonazotemic polycystic kidney disease as it occurs in families, we identified and studied 164 persons with autosomal-dominant polycystic kidney disease, 81 persons suspected of having the disease, and 250 family members without the disease. Because symptoms were absent in 32% of patients with the disease but present in 30% of persons without the disease, symptoms are not reliable in screening for the disease. Hypertension and palpable kidneys and liver were significantly commoner in patients with the disease, but systolic murmur unrelated to hypertension (10.5%) and peripheral edema (9.3%) also were common. Normal laboratory values do not exclude the diagnosis of polycystic kidney disease. Ultrasonography appears to be more sensitive than excretory urography in detecting the disease and also can detect hepatic cysts. Berry aneurysms can occur and are an important cause of mortality and morbidity. The relation of renal cysts to signs, symptoms and renal function is discussed.


[Experience in application of modified ballistic cardiography in assessment of contractile myocardial function in patients with coronary atherosclerosis].
Complex examination of myocardial contractility (MC) including modified (vertical) ballistocardiography (MBCG) covered 109 patients with coronary atherosclerosis. The MBCG registers early MC defects typical for patients with coronary atherosclerosis, ischemic heart disease. It is highly sensitive. Algorithms for diagnosis of the above defects have been developed. MBCG can be widely used in practical cardiology as a highly informative method for MC evaluation.


Variations in the anatomy of the third common digital nerve and landmarks to avoid injury to the third common digital nerve with carpal tunnel release.
The third common digital nerve (TCDN) has been described as the most commonly injured digital nerve during carpal tunnel release (CTR). Anatomic variations of the origin and course of the TCDN from the median nerve may place this structure at risk. Anatomic landmarks may be useful to predict the location of the TCDN to minimize the risk for injury to this structure during CTR. Twenty cadaveric hands were used to determine the origin and course of the TCDN. The origin of the TCDN from the median nerve was identified in relation to the transverse carpal ligament (TCL), cardinal line, and superficial palmar arch. The course of the TCDN was inspected in relation to the scaphoid tubercle and ring finger. Three specific anatomic variations for the origin of the TCDN were identified: type 1 originating proximal to the distal edge of the TCL (3 of 20 patients), type 2 originating distal to the TCL but proximal to the superficial palmar arch (14 of 20 patients), and type 3 originating distal to the TCL and at or distal to the superficial palmar arch (3 of 20 patients). The origin of the TCDN was measured as an average of 5.0 +/- 1.2 mm distal to the cardinal line. The TCDN coursed along an oblique vector from the scaphoid tubercle to the midpoint of the palmar digital crease of the ring finger for type 2 or type 3 variations. Near the cardinal line, the oblique course of the TCDN traverses the vector of the longitudinal incision used for CTR. The TCDN is one of the most frequently damaged neurological structures during CTR. Iatrogenic injury to this structure can be disabling and even devastating to patients. A detailed knowledge of the carpal tunnel and its underlying structures can prevent inadvertent injury to the TCDN. Anatomic landmarks to predict the origin and the course of the TCDN allow the surgeon to preoperatively predict the possible locations and paths of this important structure. This information can prove to be useful in avoiding injury to the TCDN by clinicians performing CTR in their practice, whether via the open or via endoscopic technique.


The motional Stark effect diagnostic on NSTX.
This work describes the implementation and recent results from the motional Stark effect (MSE) collisionally induced fluorescence diagnostic on NSTX. Due to the low magnetic field on NSTX the MSE diagnostic requires a new approach for the viewing optics and spectral filter. This has been accomplished with a novel optical design that reduces the geometric Doppler broadening, and a high throughput, high resolution spectral filter to optimize signal-to-noise ratio. With these improvements the polarization fraction is approximately 30%-40% and, combined with the large throughput, a time resolution of approximately 5 ms. The MSE diagnostic presently has 16 sight lines operating, providing measurements of the magnetic field line pitch from the plasma center to near the outboard edge of the plasma.


Clinical trials involving carbon-ion radiation therapy and the path forward.
To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.


Perceptual influence of elementary three-dimensional geometry: (2) fundamental object parts.
Objects usually consist of parts and the question arises whether there are perceptual features which allow breaking down an object into its fundamental parts without any additional (e.g., functional) information. As in the first paper of this sequence, we focus on the division of our world along convex to concave surface transitions. Here we are using machine vision to produce convex segments from 3D-scenes. We assume that a fundamental part is one, which we can easily name while at the same time there is no natural subdivision possible into smaller parts. Hence in this experiment we presented the computer vision generated segments to our participants and asked whether they can identify and name them. Additionally we control against segmentation reliability and we find a clear trend that reliable convex segments have a high degree of name-ability. In addition, we observed that using other image-segmentation methods will not yield nameable entities. This indicates that convex-concave surface transition may indeed form the basis for dividing objects into meaningful entities. It appears that other or further subdivisions do not carry such a strong semantical link to our everyday language as there are no names for them.


Transcriptional Profiling of the Chicken Tracheal Response to Virulent Mycoplasma gallisepticum Strain Rlow.
Mycoplasma gallisepticum, the primary etiologic agent of chronic respiratory disease (CRD) in poultry, leads to prolonged recruitment and activation of inflammatory cells in the respiratory mucosa. This is consistent with the current model of immune dysregulation that ostensibly allows the organism to evade clearance mechanisms and establish chronic infection. To date, studies using quantitative reverse transcription-PCR (qRT-PCR) and microarrays have shown a significant transient upregulation of cytokines and chemokines from tracheal epithelial cells (TECs) in vitro and tracheal tissue ex vivo in response to virulent strain Rlow that contributes to the infiltration of inflammatory cells into the tracheal mucosa. To expand upon these experiments, RNA was isolated from tracheas of 20 chickens infected with M. gallisepticum Rlow and 20 mock-infected animals at days 1, 3, 5, and 7 postinoculation, and samples were analyzed for differential gene expression using Illumina RNA sequencing. A rapid host response was observed 24 h postinfection, with over 2,500 significantly differentially expressed genes on day 3, the peak of infection. Many of these genes have immune-related functions involved in signaling pathways, including Toll-like receptor (TLR), mitogen-activated protein kinase, Jak-STAT, and the nucleotide oligomerization domain-like receptor pathways. Of interest was the increased expression of numerous cell surface receptors, including TLR4 and TLR15, which may contribute to the production of cytokines. Metabolic pathways were also activated on days 1 and 3 postinfection, ostensibly due to epithelial cell distress that occurs upon infection. Early perturbations in tissue-wide gene expression, as observed here, may underpin a profound immune dysregulation, setting the stage for disease manifestations characteristic of M. gallisepticum infection.


Usefulness of ultrastructure studies for the estimation of the postmortem interval. A systematic review.
Establishing the postmortem interval (PMI) is vital in legal medicine as it allows to retrospectively estimate the hour of death, which is essential for the police as a starting point for their inquiries (especially in violent deaths). Ultrastructure studies aimed specifically to detect autolytic changes are scarcely identified in the scientific literature. Moreover, they are performed in a variety of conditions (different temperatures, species, in vitro ÷ in situ, and so on), making the results difficult to interpret for legal medicine purposes. The main aim of this review is to determine the potential usefulness of ultrastructure studies for the estimation of the postmortem interval and to provide a summary of relevant scientific literature in the area, which might be useful as a starting point for more specific and detailed studies in the field. We performed a search on the ISI Thomson Web of Knowledge database using a series of predefined keywords; the articles fulfilling the inclusion criteria were systematically analyzed to identify ultrastructure changes associated with autolysis. Our investigation revealed 20 relevant articles, which detailed ultrastructure changes in the brain, heart, liver, pancreas, kidney, bone, sweat glands, thyroid, skeletal muscle, cartilage and sweat glands. For each organ, we arranged systematically postmortem ultrastructure changes that were described by various authors. Ultrastructure changes appear early and may be useful in determining the time since death in the early postmortem interval. However, most studies published in this area followed methodologies that could not allow a proper reproducibility in forensic circumstances. Therefore, before using ultrastructure for estimating the PMI in practical environments, further studies are needed. They should be performed ideally on human samples, obtained at regular intervals after death, at variable, decreasing temperatures.


Systematic identification of phosphorylation-mediated protein interaction switches.
Proteomics techniques can identify thousands of phosphorylation sites in a single experiment, the majority of which are new and lack precise information about function or molecular mechanism. Here we present a fast method to predict potential phosphorylation switches by mapping phosphorylation sites to protein-protein interactions of known structure and analysing the properties of the protein interface. We predict 1024 sites that could potentially enable or disable particular interactions. We tested a selection of these switches and showed that phosphomimetic mutations indeed affect interactions. We estimate that there are likely thousands of phosphorylation mediated switches yet to be uncovered, even among existing phosphorylation datasets. The results suggest that phosphorylation sites on globular, as distinct from disordered, parts of the proteome frequently function as switches, which might be one of the ancient roles for kinase phosphorylation.


Some medical aspects of North Sea oil industry.
Most illness and injury cases seen in the Sick Bays of North Sea Oil Installations are similar to those in industry generally. Some are due to the sea depth and the hostile environment. The course of treatment may be affected by the isolated situation. The basic plan to meet a disaster situation may in the event be unworkable because of installation air traffic disturbance. Transportation of casualties to pre-arranged destinations may be affected by weather or the availability of suitable helicopters or ships. Practice to meet different medical contingencies is essential. For efficient rescue there must be a reliable, uninterrupted communication system between installation and base.


[Spontaneous pneumothorax--a study of medical records. High age is the most significant risk factor of prolonged length of stay].
In this retrospective study 53 consecutive in-hospital patients with spontaneous pneumothorax were studied. The most common initial treatments were tube drainage (n = 38) and needle drainage (n = 8). The median length of stay at hospital was 6 days, with increasing age as the strongest predictor. About one third of the patients had some sort of complication, but these were in general not so serious. During the follow up period (6-44 months) we found that 21% of the patients needed a second hospitalisation because of pneumothorax. Women had an increased risk for recurrence. Our results indicate that needle drainage, in selected situations, is a valuable alternative to tube drainage, with a shorter length of stay and less complications.


Establishing value in managed care: cost-effectiveness or budgetary impact?
In the managed care setting, pharmacy benefit managers face considerable challenges when making decisions regarding drug coverage. Although scientifically valid data may be available from randomized, double-blind, placebo-controlled trials, this type of information does not shed light on potential differences between medications in the same class. Furthermore, properly designed, comparative trials are rarely conducted. Randomized naturalistic or pragmatic pharmacoeconomic studies can provide valuable information but are likewise infrequently performed. Economic modeling is an alternative but is not widely accepted because of the potential for bias. Retrospective analyses of information from patient surveys or existing databases are emerging as more popular methods of supporting informed formulary decisions. In the absence of a large-scale, prospective, naturalistic, pharmacoeconomic study, an alternative indication of product superiority can be derived from a continuum of different types of studies (from basic science to clinical trials to retrospective pharmacoeconomic analysis) conducted in a variety of patient care settings. The consistency with which a product demonstrates superiority across all types of studies is critical and is a crucial determinant of whether a health care provider would be likely to use the information for the purpose of decision making.


Decreased Axon Flare Reaction to Electrical Stimulation in Patients With Chronic Demyelinating Inflammatory Polyneuropathy.
In chronic inflammatory demyelinating polyradiculopathy (CIDP), the impairment of unmyelinated nerve fibers appears unexpected. The measurement of the electrically induced axon flare reflex is a clinical test to assess the peripheral C-nociceptor function. In this study, we compared the flare area in patients suffering from CIDP with healthy subjects. We examined 18 patients fulfilling the criteria for CIDP (11 men, mean age 51.8 years, SD 15.1) and 18 age-matched adult healthy volunteers (control group) (11 men, mean age 51.9 years, SD 15.8). The flare responses were elicited by transcutaneous electrical stimulation and recorded by laser Doppler imaging. There was a significant reduction of electrically induced maximum flare area in the foot dorsum of patients with CIDP (t-value 2.08, P = 0.04) which proved to be length-dependent measured by a numerical index comparing the results with the forearm and thigh. The repeatedmeasures ANOVA revealed statistically significant smaller flare areas in all body regions for the CIDP group (P < 0.001). The axon flare reaction to electrical stimulation was decreased in patients with chronic demyelinating inflammatory polyneuropathy. The evaluation of the axon flare response can be proposed as a noninvasive objective functional test to detect an impaired C-fiber function in CIDP patients with the advantages of simplicity of the procedure, time economy, and objectivity.


Acute severe diarrhoea and hyponatremia after zoledronic acid infusion: an acute phase reaction.
Zoledronic acid (ZA), an intravenous aminobisphosphonate, is prescribed widely for postmenopausal osteoporosis. It is a relatively safe drug but may cause adverse effects including acute phase reaction. Oral non-aminobisphosphonates are known to cause diarrhoea that is usually mild and self-limited. Intravenous amino-bisphosphonates are not known to cause diarrhoea. We describe a case of acute watery diarrhoea complicated by severe hyponatremia and hypotension following ZA infusion. The patient needed intensive care for four days. To the best of our knowledge, this type of acute diarrhoea complicated by severe hyponatremia, following ZA infusion, is not reported so far. Strong temporal relation with ZA administration makes it the most likely cause. Furthermore, all laboratory and imaging parameters indicate that the secretory diarrhoea may be a component of acute phase reaction. According to World Health Organization (WHO) causality scale, ZA was a probable cause of acute watery diarrhoea in our patient. Clinicians should be aware that ZA administration can cause acute watery diarrhoea and may lead to severe hypotension and hyponatremia.


Management of acute 'pink pulseless' hand in pediatric supracondylar fractures of the humerus.
The management of a persistent pink pulseless hand after a satisfactory closed reduction in a pediatric supracondylar fracture of the humerus is controversial. Several recent publications have recommended vascular exploration in contrast to a more conservative approach accepted traditionally. We report the results of seven patients with a mean follow-up of 36.6 months with a persistent pulseless, but well-perfused hand postreduction. All patients were managed conservatively without vascular exploration. A palpable return of the radial pulse was seen in six patients at 3 weeks and at 6 weeks follow-up in the other patient with no long-term dysfunction. We believe that the management of a persistent pink pulseless hand remains a 'watchful expectancy'. Surgical exploration should be recommended only if there is either severe pain in the forearm persisting for more than 12 h after the injury or if there are signs of a deteriorating neurological function.


[Two cases of tuberculous pericarditis--diagnostic difficulties].
Some difficulties etiological diagnosis were presented in an example of two clinical cases. In the first patient with exudative pericarditis tuberculosis was determined in histopathological examination of lymph node (caseous necrosis). After antituberculotic treatment the majority of clinical symptoms was disappeared. In the second patient with chronic constrictive pericarditis the tuberculous etiology was accepted according to highly positive tuberculin reaction and signs of pericardial calcification. Patient was qualified to pericardiectomy.


Practical review of pharmacology concepts.
Pharmacology concepts are used routinely in nursing practice. These concepts may be as simple as drug names and side effects, or as complex as pharmacokinetics or pharmacodynamics. All play major roles in drug efficacy and safety. A practical review of pharmacology, including pharmacokinetic and pharmacodynamic concepts, will be presented.


Phenotypic alterations and IL-1beta production in CD34(+) progenitor- and monocyte-derived dendritic cells after exposure to allergens: a comparative analysis.
Dendritic cells (DC) have been shown to capture and process antigens and play an initiating role in contact sensitization. Cells with dendritic morphology can be generated in vitro either from CD34(+) cord blood cells or from CD14(+) peripheral monocytes. The aim of this study was to determine the state of maturation/activation of both populations after exposure to several concentrations of four well-established model allergens (nickel sulfate, eugenol, alpha-hexylcinnamaldehyde and 2,4,6-trinitrobenzene sulfonic acid) or the irritant sodium dodecyl sulfate. We analyzed the surface expression of CD86, CD83 and HLA-DR and the production of IL-1beta. DC from the two sources were generated separately in two laboratories, but challenged using identical test protocols. Using both DC populations it was possible to detect the allergens under investigation, though minor differences regarding effective concentrations were noted. The non-responsiveness of CD34-DC to CIN was probably due to non-optimal concentrations. Ni(2+), known as a moderate allergen in vivo, showed the most prominent effect in both cell systems. CD86 expression was the most reliable phenotypic marker for the in vitro identification of allergens. Due to substantial individual variations it was difficult to draw any definite conclusions as to the relevance of IL-1beta production as an activation endpoint. We conclude that both test systems are able to respond to allergens, but CD34-DC must be exposed to higher concentrations to demonstrate significant phenotypic changes. On the other hand, Mo-DC from only some of the donors reacted to allergens, in contrast to CD34-DC, which responded to allergens irrespective of the donor, thus necessitating the use of Mo-DC cultures from several blood donors.


Padanamides A and B, highly modified linear tetrapeptides produced in culture by a Streptomyces sp. isolated from a marine sediment.
Two highly modified linear tetrapeptides, padanamides A (1) and B (2), are produced by laboratory cultures of a Streptomyces sp. obtained from a marine sediment. Padanamide B is cytotoxic to Jurkat cells, and a chemical genomics analysis using Saccharomyces cerevisiae deletion mutants suggested that padanamide A inhibits cysteine and methionine biosynthesis or that these amino acids are involved in the yeast's response to the peptide.


Metabolic reprogramming: an innate cellular defence mechanism against intracellular bacteria?
The limited metabolic resources of a cell represent an intriguing 'conflict of interest' during host-pathogen interactions, as the battle for nutrients might determine the outcome of an infection. To adapt their metabolic needs, innate immune cells such as monocytes, macrophages or dendritic cells reprogram their metabolism upon activation by microbial compounds. In turn, infection by intracellular bacteria provokes metabolic alterations of the host cell that benefit the pathogen. Here, we discuss the state-of-the-art knowledge on metabolic reprogramming of host cells upon activation or infection with intracellular bacteria. The study of the host-driven and pathogen-driven metabolic alterations that seem to co-exist during infection is an emerging field that will define the metabolic pathways that might be targeted to combat infection.


Acute norovirus-induced agranulocytosis in a pediatric kidney transplant recipient.
Norovirus (NoV) infection is usually limited to the gastrointestinal (GI) tract. However, in immunocompromised patients, this infection might lead to severe life-threatening complications. We herein describe a pediatric kidney transplant patient who presented with an acute NoV infection complicated by febrile agranulocytosis that resolved with improvement of her GI illness. This unusual presentation has not been described before, to our knowledge. The aim of this article is to highlight the sometimes dramatic clinical presentation of NoV infection in immunosuppressed patients, and the importance of including this infection in the differential diagnosis of neutropenia in that specific population.


Giovanni Maria Lancisi: De bovilla peste and stamping out.
Giovanni Maria Lancisi (1654-1720) was a physician, archiater of the pope, well-known as an anatomist and epidemiologist, who made an important contribution to veterinary medicine of when rinderpest (cattle plague) affected Europe in the XVIIIth century. His times, his life and career and his main contributions to medicine are described. the main features of the great epidemic of rinderpest which started in 1711 are presented. His book De bovilla peste, published in 1715, illustrates the characteristics of cattle plague and, above all, the control measures is discussed. Of the control measures, the most relevant were the introduction of stamping out, with special instructions for the killing and burial of affected animals, the prohibition of animal movements, the adoption of special hygienic and political measures. The relationships between cattle plague and poverty and famine are described, together with the actions taken to deal with them. Lancisi points out the relationship between politics and history on the one hand and cattle plague on the other. He may be considered the modern co-inventor (along with Bates) of stamping out.


Dental health literacy and California's clarion call.
Demographic changes in California require a multicultural paradigm shift in oral health care. The shift encompasses attention to health literacy in all forms of communication: signage, oral and written communication, consent forms, postop instructions, and patient education materials. California dentists may find it necessary to adapt their practices to reflect community demographics and health literacy needs. This article provides a toolbox of recommendations to address these needs.


Cytokeratin expression in subungual squamous cell carcinoma.
Cytokeratin expression in subungual squamous cell carcinoma was investigated in order to evaluate the origin and state of differentiation of the tumour. The tumour nests contained cytokeratin 14, 16 and 17, which were also expressed in the nail bed. Therefore, cytokeratin expression in subungual squamous cell carcinoma may reflect its indolent clinical prognosis.


[Abdominal pregnancy: description of a case observed in Madagascar].
We report a case of primary abdominal pregnancy observed at the maternity clinic in Befelatanana, Madagascar. A 36-year-old woman, gravida 2, para 2, with no medical history presented at 40 weeks and 2 days of amenorrhea for sudden disappearance of fetal movements. Prenatal visits had been performed on an irregular basis by a private-practice midwife. Fetal death was confirmed by ultrasonographic examination and subsequent plain abdominal radiographic imaging suggested abdominal pregnancy. Laparotomy confirmed diagnosis of primitive abdominal pregnancy. Postoperative recovery was uneventful. Based on this rare case, the literature is reviewed and the importance of clinical follow-up and ultrasonography in detection and management is stressed.


The Neuroimmune Interplay in Joint Pain: The Role of Macrophages.
Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.


[Local treatment of purulent-necrotic complications of diabetic foot syndrome].
Diabetic foot syndrome is the most frequent and severe complication of diabetes. At present, problem has not been fully resolved, which may lead to the development of more effective ways of correction of purulent complications. The study investigates the efficacy of Hydrogel bandage (Miramistin) combined with physiotherapeutic methods in the treatment of purulent-necrotic lesions of foot. Eighty-three patients with purulent-necrotic lesions of foot were treated at the Clinic of Surgical Diseases №1. The proposed method of treatment demonstrated a greater efficacy than currently available treatments: better cleaning of wounds, reduction of the severity of intoxication and pain, decrease of the duration of inpatient treatment from 28-30 days to 18-19. Hydrogel bandage (Miramistin) is the most efficient drug in prevention and treatment of purulent and infectious complications.


Brain amino acid reductions in one family with chromosome 6p-linked dominantly inherited olivopontocerebellar atrophy.
We measured the levels of aspartate, glutamate, gamma-aminobutyric acid (GABA), and other amino acids in autopsied brain of 6 patients from one family (Pedigree S) with dominantly inherited olivopontocerebellar atrophy. A previous demonstration of reduced aspartate concentration in plasma of affected members of this family suggested the possibility of a generalized disorder of amino acid metabolism affecting the brain. As compared with the control levels, mean levels of aspartate and glutamate were markedly reduced by about 70 and 40%, respectively, in the degenerated cerebellar cortex from the patients. Since the cerebellar aspartate reduction likely exceeds the amount that could be explained by neuronal loss, other factors such as abnormal aspartate metabolism, neurotransmitter turnover, or both are probably involved. Mean aspartate, glutamate, and GABA levels were also reduced by about 10 to 30% in most of the 16 examined extracerebellar brain areas in which no or, at most, mild neuronal cell loss was observed by semiquantitative estimation. Concentrations of taurine, glutamine, and omicron-phosphoethanolamine were normal in all brain areas examined. Our biochemical data provide support to the presence of a generalized, but quantitatively mild, disturbance in amino acid metabolism in patients with olivopontocerebellar atrophy from Pedigree S. The regionally widespread amino acid reductions in the brain, of as yet unknown pathophysiological significance, could be due to a failure of one or more enzymes involved in aspartate and glutamate metabolism.


Pathophysiology and Individualized Management of Vasovagal Syncope and Postural Tachycardia Syndrome in Children and Adolescents: An Update.
Vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) are the main forms of orthostatic intolerance in pediatrics and both are underlying causes of neurally-mediated syncope. In recent years, increasing attention has been paid to the management of VVS and POTS in children and adolescents. A number of potential mechanisms are involved in their pathophysiology, but the leading cause of symptoms varies among patients. A few studies thus have focused on the individualized treatment of VVS or POTS based on selected hemodynamic parameters or biomarkers that can predict the therapeutic effect of certain therapies and improve their effectiveness. This review summarizes the latest developments in individualized treatment of VVS and POTS in children and indicates directions for further research in this field.


Chronic fatigue syndrome: implications for women and their health care providers during the childbearing years.
Chronic fatigue syndrome is a complex debilitating medical disorder that affects approximately 4 million persons in the United States, predominantly women. There has been little scientific exploration about the experience of pregnancy, childbirth, and the postpartum period for women with this disorder. A review of the literature and current research findings addressing the epidemiology, diagnosis, symptoms, and treatment of chronic fatigue syndrome are presented, as well as the currently available data regarding the experience of women with chronic fatigue syndrome anticipating or experiencing pregnancy and the postpartum period. Expert opinion is presented along with current evidence to provide guidelines for the care of women with chronic fatigue syndrome during pregnancy, labor and birth, lactation, and the postpartum period.


Synergistic effects of butyrate on platelet responses to arachidonate, A23187, PGE1, and forskolin.
With eukaryotic cells, butyrate is known to induce a series of morphological and biochemical changes that mimic cellular differentiation. With platelets, we have found that butyrate (10 mmol/L) caused an approximately threefold increase in sensitivity to calcium ionophore A23187 and arachidonate. Maximum aggregation was observed at agonist concentrations of 3 mumol/L and 170 mumol/L, respectively, as compared with required concentrations of 10 mumol/L and 400 mumol/L in the absence of butyrate. Similar effects were seen with isobutyric acid, and about one-half the effect was shown with valerate and caproate, but lower homologues showed no synergistic effect. No ultrastructural changes were observed in platelets incubated with butyrate, and the aggregation effects were reversible and returned to normal on removal of butyrate. Membrane fluidity was unchanged by butyrate as measured by changes in the fluorescence depolarization of diphenylhexatriene. Butyrate caused a 60% to 70% increase in the uptake of 3H-arachidonate. Butyrate also potentiated the inhibition of platelet function by prostaglandin E1 and forskolin and uptake of 3H-forskolin was increased approximately 20%. In contrast, platelet response to other agonists (ADP, epinephrine, collagen, thrombin, and platelet-activating factor) was essentially unaffected by butyrate. These results suggest that butyrate may increase the uptake of certain hydophobic agonists and antagonists by platelets. Similar mechanisms for uptake of endogenous effectors may explain the response of eukaryotic cells to butyrate in culture.


Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor.
The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ-CD8 interactions require CD8-MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck.


Post-thymic T-cell development in the rat.
The presence or absence of CD4, CD8, Thy-1, RT6 and CD45RC revealed a number of T-cell subpopulations in the rat. Vascular thymus transplantation was used in RT7 congenics to establish the lineage relationship between these subpopulations by following phenotypic changes after thymus emigration. We found that recent thymic emigrants exhibit the Thy-1+/RT6-/CD45RC- phenotype and express either CD4 or CD8. Within 11 days after emigration, these cells differentiated into Thy-1-/RT6+/CD45RC+ cells. From 33 to 76 days following transplantation, a proportion of the latter lost RT6 and/or CD45RC expression, suggesting further differentiation. The pathway of 'mature' T-cell differentiation could be reconstructed from these data and analysis of the differences between T-cell subsets in thymectomized and normal control rats. End-stages of post-thymic T-cell differentiation in the rat were most likely to be Thy-1-/RT6+/CD45RC- and Thy-1-/RT6-/CD45RC+ T cells.


Body composition, protein and energy efficiencies, and requirements for growth of F1 Boer × Saanen goat kids.
We conducted a study in which body composition, energy and protein requirements, and efficiency of MP and ME were determined in F1 Boer × Saanen goat kids of 5 to 25 kg BW by using the comparative slaughter technique. Two experiments were performed: Exp. 1 estimated the maintenance requirements of kids from 15 to 25 kg BW, and Exp. 2 estimated the gain requirements of kids from 5 to 25 kg BW. In Exp. 1, 28 intact male F1 Boer × Saanen goat kids were utilized, with 7 kids slaughtered (BW of 15.0 ± 0.35 kg) at the onset for estimation of initial body composition and the remaining 21 kids assigned to a randomized block design. Within each block, kids were subjected to 3 levels of feed intake treatments (ad libitum [100%] or restricted to 70% or 40% ad libitum). All kids in each block were slaughtered when the animals fed ad libitum reached 25 kg BW. The NE, ME for maintenance, and partial efficiency of use of ME for NE were 321.6 kJ/kg BW, 525.9 kJ/kg BW, and 0.61, respectively. The net protein and MP for maintenance were 2.43 g/kg of BW and 4.41 g/kg of BW, respectively; thus, the estimated partial efficiency of MP for maintenance was 0.55. In Exp. 2, 32 intact male F1 Boer × Saanen goat kids were distributed in a completely randomized design and slaughtered at 5.6 ± 0.85 kg BW ( = 6), 10.0 ± 0.35 kg BW ( = 6), 15.3 ± 0.52 kg BW ( = 7), 20.4 ± 0.66 kg BW ( = 6), and 25 ± 0.46 kg BW ( = 7). Body composition was then fitted to allometric equations. Body fat composition increased from 37 to 114 g/kg empty BW (EBW; < 0.001), and body protein composition decreased by 10% (from 203.2 to 180.6 g/kg EBW; < 0.001) when kids grew from 5 to 25 kg BW. The NE increased by approximately 60% (from 7.2 to 11.5 MJ/kg of empty BW gain [EWG]; < 0.001), and the net protein for gain decreased by 10% (from 186 to 166 g/kg of EWG; < 0.001). The partial efficiency of the utilization of ME to NE for growth was 0.32 ( < 0.0001), and the partial efficiencies of the utilization of ME for the synthesis of protein and fat were 0.19 and 0.59 ( < 0.011), respectively. These results demonstrate that the protein and energy maintenance requirements in young crossbred goat kids are greater than values reported previously in feeding system studies. In addition, their requirements for gain depend on body composition and are driven by efficiencies of deposition.


Femtosecond supercontinuum generation in water in the vicinity of absorption bands.
We show that it is possible to overcome the perceived limitations caused by absorption bands in water so as to generate supercontinuum (SC) spectra in the anomalous dispersion regime that extend well beyond 2000 nm wavelength. By choosing a pump wavelength within a few hundred nanometers above the zero-dispersion wavelength of 1048 nm, initial spectral broadening extends into the normal dispersion regime and, in turn, the SC process in the visible strongly benefits from phase-matching and matching group velocities between dispersive radiation and light in the anomalous dispersion regime. Some of the SC spectra are shown to encompass two and a half octaves.


Acyclovir-induced colitis.
Three patients developed acute colitis, either de novo, or as an exacerbation of pre-existing colitis, following the use of oral acyclovir, prescribed for Herpes zoster or Herpes simplex infection. Rechallenge with oral acyclovir was performed in one patient, and resulted in a recurrence of colitic symptoms. It is speculated that acyclovir can have a direct irritant effect on large bowel mucosa.


Time-resolved immunofluorometric assay of human prostate-specific antigen.
Assay of human serum prostate-specific antigen (PSA) is gaining importance in diagnosis and follow-up of prostatic cancer. In this time-resolved immunofluorometric assay of PSA, strip-wells were coated with a polyclonal antibody against PSA. To prepare the label, a monoclonal antibody displaying high affinity towards PSA was purified and derivatized with diethylenetriaminepentaacetic acid. With use of this derivative, seven to eight Eu atoms could be combined with one antibody molecule with no decrease in immunoreactivity. The minimum detectable concentration of PSA was 0.12 microgram/L. In 60 of 63 women studied, the PSA concentration in serum was less than 0.2 microgram/L. The increase in PSA in serum of asymptomatic men 51 years old or older, as compared with that for younger subjects, was possibly a result of "occult" prostatic hyperplasia. Most of the patients with prostatic hyperplasia or prostatic cancer had higher PSA concentrations than did subjects of ages less than 50 years or asymptomatic age-matched healthy subjects. Results compared favorably with those by an established technique relying on the use of radioactive label. Our method for measuring PSA in human serum is convenient, inexpensive, and well compatible with present clinical practice.


Transformation by integration in Aspergillus nidulans.
DNA-mediated genetic transformation of Aspergillus nidulans has been achieved by incubating protoplasts from a strain of A. nidulans carrying a deletion in the acetamidase structural gene with DNA of derivatives of plasmid pBR322 containing the cloned structural gene for acetamidase [Hynes et al., Mol. Cell. Biol. 3 (1983) 1430-1439; p3SR2] in the presence of polyethylene glycol and CaCl2. The highest frequency obtained was 25 transformants per microgram of DNA. No enhancement of the transformation frequency was observed when DNAs of plasmids carrying either a fragment of the A. nidulans ribosomal repeat (p3SR2rr) or a fragment containing a possible A. nidulans mitochondrial origin of replication (p3SR2mo) in addition to the acetamidase gene were used. Both pBR322 and acetamidase gene sequences become integrated into the genome of A. nidulans in transformant strains. Integration events into the residual sequences adjacent to the deletion in the acetamidase gene, and probably (for p3SR2rr and p3SR2mo) into the ribosomal repeat unit are described.


Allele-specific virulence attenuation of the Pseudomonas syringae HopZ1a type III effector via the Arabidopsis ZAR1 resistance protein.
Plant resistance (R) proteins provide a robust surveillance system to defend against potential pathogens. Despite their importance in plant innate immunity, relatively few of the approximately 170 R proteins in Arabidopsis have well-characterized resistance specificity. In order to identify the R protein responsible for recognition of the Pseudomonas syringae type III secreted effector (T3SE) HopZ1a, we assembled an Arabidopsis R gene T-DNA Insertion Collection (ARTIC) from publicly available Arabidopsis thaliana insertion lines and screened it for plants lacking HopZ1a-induced immunity. This reverse genetic screen revealed that the Arabidopsis R protein HOPZ-activated resistance 1 (ZAR1; At3g50950) is required for recognition of HopZ1a in Arabidopsis. ZAR1 belongs to the coiled-coil (CC) class of nucleotide binding site and leucine-rich repeat (NBS-LRR) containing R proteins; however, the ZAR1 CC domain phylogenetically clusters in a clade distinct from other related Arabidopsis R proteins. ZAR1-mediated immunity is independent of several genes required by other R protein signaling pathways, including NDR1 and RAR1, suggesting that ZAR1 possesses distinct signaling requirements. The closely-related T3SE protein, HopZ1b, is still recognized by zar1 Arabidopsis plants indicating that Arabidopsis has evolved at least two independent R proteins to recognize the HopZ T3SE family. Also, in Arabidopsis zar1 plants HopZ1a promotes P. syringae growth indicative of an ancestral virulence function for this T3SE prior to the evolution of recognition by the host resistance protein ZAR1. Our results demonstrate that the Arabidopsis resistance protein ZAR1 confers allele-specific recognition and virulence attenuation of the Pseudomonas syringae T3SE protein HopZ1a.


Linear stability analysis in a liquid layer with a surface velocity gradient.
A case of combined planar Couette-Poiseuille flow corresponding to vanishing horizontal flux has been generalized by the introduction of a model for the surface velocity gradient. A relation corresponding to the Orr-Sommerfeld equation has been derived for this model. The critical value of the surface velocity gradient has been obtained. At the critical point, the corresponding critical Reynolds number equals infinity. Using an approximated method we estimated the behavior of the critical Reynolds number for a slightly overcritical surface velocity gradient.


The contribution of the cortical shell to pedicle screw fixation.
A pedicle screw insertion technique known as "hubbing" involves the removal of cortical bone around the screw insertion with the aim of improving fixation and decreasing screw loosening. However, the efficacy of this procedure relative to bone density and early loading have not been fully explored. The purpose of this study is to establish the contribution of the cortical layer (hubbing), cancellous density, early loading (toggling) in an idealised model. This is an in vitro laboratory study. Synthetic bone blocks with cancellous bulk and a simulated cortical shell were implanted with 6.5 mm pedicle screws. Three key variables were evaluated in this study; density of the simulated bone (10-20 lb/ft3), toggling (±0.5 mm for 10,000 cycles), and the presence or absence of the surrounding cortex (hubbing). Pullout testing after toggling was performed to determine maximum load, stiffness and energy. Results were analyzed to assess interaction and main effects. Removal of the cortex decreased the pullout loads by approximately 1,100 N after toggling. Toggling in the presence of the cortical shell had no effect. However, once the cortical shell is removed damage to the weaker cancellous bone accumulates and further compromises the fixation. The addition of a cortical layer in the Sawbone model is significant and provides a more realistic model of load sharing. The cortex plays a considerable role in the protection of underlying cancellous bone as well as contributing to initial pullout strength. The results of this study demonstrate a negative synergistic effect when both toggling and hubbing are applied to the weaker bone.


Left Temporal Pole Encephalocele With Independent Hippocampal Seizures: Surgical Strategy and Relevance of Epileptic Biomarkers.
Temporal pole encephalocele (TE) is an increasingly recognized surgically treatable subtype of refractory temporal lobe epilepsy that rarely shows hippocampal involvement. A 27-year-old patient presented with medically intractable epilepsy because of a left temporal pole encephalocele with a normal hippocampus on MRI. Extraoperative electrocorticography showed independent seizure onset with distinct morphology of seizure onset pattern from the temporal pole encephalocele and hippocampus. Additional analysis of ictal and interictal fast ripples revealed different electrophysiological fast ripple profiles in the two seizure onset zones. The patient underwent temporopolar disconnection, eliminating the need for large dural repair and multiple hippocampal transections that helped preserve the intrahippocampal and extrahippocampal memory pathways. Herein, the authors report that independent hippocampal seizures can be observed in patients with temporal pole encephalocele. Features of the ictal and interictal fast ripples can differ depending on the morphology of the seizure onset pattern. The authors suggest that, the interpretation of fast ripples in clinical practice should take seizure onset patterns into consideration.


Melting of monolayer plasma crystals.
Melting of a monolayer plasma crystal in a radio-frequency discharge with no particles suspended above or below is studied. The experimental data are compared with results of molecular dynamics simulations and theory. It is shown that the melting is caused by the resonance coupling between the longitudinal and the transverse dust-lattice wave modes, due to the interaction of particles with the plasma wakes.


Population screening for abdominal aortic aneurysm: do the benefits outweigh the costs?
To prevent the high mortality rate associated with ruptured abdominal aortic aneurysm (AAA), population screening at or soon after retirement age has been advocated, with elective operations being performed on patients with the appropriate indications. There is considerable pressure on some health authorities to fund such programmes even though there is substantial uncertainty about the consequent benefits. The ultrasound screening test is acceptable and accurate. Also, other health problems may be detected in the same screen. However, screening would lead to a questionable increase in surgery, as most patients with AAA die from other causes and not from a ruptured aneurysm. In addition, there is an elective operative mortality of around 5 per cent. Furthermore, as many of those who have a positive result on screening would never have known that they harbour an aneurysm, there is the possibility of unnecessary anxiety arising from the test. An economic analysis has been conducted for two identical, hypothetical cohorts of men using the best available data. One cohort was assumed to undergo screening and a number of men were indicated for immediate elective aneurysm repair or for follow-up, and surgery if their aneurysms become large. The other cohort was assumed not to be screened and would thereby face the possibility of rupture with its adverse outcome. The survival prospects of the two cohorts were calculated as life expectancies and in terms of life-years: the incremental life-years gained were compared with the incremental costs of the programme. Although there are considerable uncertainties in the analysis parameters, the base-line result and sensitivity analysis indicate that, on the basis of current knowledge, population screening should not be introduced.


Regulation of BACE1 by miR-29a/b in a cellular model of Spinocerebellar Ataxia 17.
Polyglutamine diseases are a class of neurodegenerative disorders characterized by expansion of polyglutamine repeats, protein aggregation and neuronal cell death in specific regions of the brain. The expansion of a polyglutamine repeat in the TATA binding protein (TBP) causes a neurodegenerative disease, Spinocerebellar Ataxia 17 (SCA17). This disease is characterized by intranuclear protein aggregates and selective loss of cerebellar neurons, including Purkinje cells. MicroRNAs are small, endogenous, regulatory non-coding RNA molecules that bind to messenger RNAs with partial complementarity and interfere in their expression. Here, we used a cellular model of SCA17 where we expressed TBP with 16 (normal) or 59 (pathogenic) polyglutamines and found differential expression of several microRNAs. Specifically, we found two microRNAs, miR-29a/b, were down-regulated. With miR-29a/b down regulation, we found an increased expression of targets of miR-29a/b -beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), p53 upregulated modulator of apoptosis (PUMA) and BAK, increased cytochrome c release and apoptosis. Restoration of miR-29a/b in the pathogenic polyglutamine background reduced the BACE1expression. While, antagomiRs against miR-29a/b resulted in an increase in BACE1 levels and neuronal apoptosis. In spite of the elevation of BACE1 in Alzhemiers disease, its role in neuronal cell death has not been established. Here, we show that increased BACE1 expression is not sufficient to cause apoptosis. However restoring level of BACE1 to normal in polyglutamine cells partially reduced neuronal apoptosis. We show a role for the miR-29a/b-BACE1 regulatory interaction in SCA17, suggesting that this microRNA could be part of a common molecular mechanism leading to neuronal cell death in multiple neurodegenerative disorders. The identification of a common mechanism of microRNA mediated neurodegeneration not only improves our understanding of the process, but also provides promising and novel therapeutic targets.


Discriminatory miRNAs for the Management of Papillary Thyroid Carcinoma and Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features.
Papillary thyroid carcinoma (PTC) variants have several overlapping clinical and pathological features. The World Health Organization recently published a new classification of thyroid tumors containing significant revisions. Encapsulated papillary thyroid carcinoma (EPTC) has been recognized as a distinctive variant of PTC. The noninvasive encapsulated follicular variant of PTC has been reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Different neoplasms are associated with different outcomes and require different clinical management. The objective of this study was to explore the miRNA expression patterns specific for classic PTC (cPTC), EPTC, follicular variant of PTC, and NIFTP in order to identify biomarkers of diagnostic and prognostic utility aiming for better clinical decisions. The expression of 84 miRNAs was determined by quantitative real-time polymerase chain reaction in 113 thyroid tissues of PTC (classic, encapsulated, and follicular), NIFTP, and hyperplasia lesions. Expression of the same miRNAs was tested in pre- and postoperative whole-blood samples. Several miRNAs were differentially expressed in the different groups. Expression profile of miRNAs in the tissue was similarly reflected in the circulation. Receiver operating characteristic curve analysis showed that miR-7-5p, miR-222-3p, and miR-146b-5p can discriminate between the different groups with high sensitivity and specificity. Downregulation of miR-144-3p, miR-15a-5p, miR-20a-5p, miR-32-5p miR-142-5p, miR-143-3p, and miR-20b-5p is associated with aggressive behavior in cPTC. Circulating miR-146b-5p, miR-222-3p, miR-155-5p, and miR-378a-3p are potential diagnostic and follow up biomarkers for PTC. Downregulation of miR-7-5p discriminates NIFTP from hyperplasia. Upregulation of miR-222-3p discriminates follicular variant of PTC from NIFTP. High levels of miR-146b-5p distinctively characterize cPTC. These miRNAs are useful biomarkers in the diagnosis of PTC and NIFTP, and help to avoid unnecessary thyroidectomy and improve clinical management.


Discontinuation of direct oral anticoagulants among patients with atrial fibrillation according to gender and cohabitation status: a nationwide cohort study.
The aim of this study was to evaluate the risk of discontinuing treatment with direct oral anticoagulants (DOACs) among patients with atrial fibrillation (AF) according to cohabitation status and gender. Using the Danish national registers, we identified 32 364 patients with AF aged 40-90 years undergoing treatment with DOACs. The study period was from 2013 to 2017, and patients were followed for 2 years, or until death, outcome, or emigration. The main outcome was discontinuation of DOAC treatment for at least 30 days. The absolute 2-year risk of DOAC discontinuation was highest among men living alone [35.7%, 95% confidence interval (CI): 37.3-34.1%]. Men living alone had a 4.6% (95% CI: 6.4-2.8%) higher absolute risk of discontinuation and a 12% [hazard ratio (HR): 1.12, 95% CI: 1.04-1.20] higher relative risk of discontinuation compared with men living with a partner. Female patients living alone likewise had a higher absolute risk of DOAC discontinuation (2.6%, 95% CI: 4.4-0.09%) compared with female patients living with a partner, yet no statistically significant difference in relative risk. In an analysis evaluating gender, we found male gender to be associated with a significantly higher relative risk of DOAC discontinuation (HR: 1.33, 95% CI: 1.26-1.40) compared with female gender (P-value for interaction with cohabitant status = 0.5996). In this nationwide population study, male gender and living alone were associated with a higher risk of DOAC discontinuation among patients with AF.