Electrical characteristics of the beta-cells in pancreatic islets.
1. The electrical activity of beta-cells is characterized by a regular burst pattern. 2. The bursts occur in a potential range which is not dependent on external glucose concentration. However, there is a clear dose-response relationship between spike frequency or plateau duration and the glucose concentration. 3. There is a striking biphasic pattern of the electrical activity in response to a sudden and sustained stimulation with glucose. 4. These findings agree well with corresponding investigations on insulin release and strongly support the view that insulin release and electrical activity are directly correlated. 5. Concerning the mechanism of the electrical activity, there is evidence that an electrogenic pump plays an important role in the regulation of the burst pattern and presumably in the regulation of insulin release.


SYNTHESIS, ANTI-HEPATITIS B AND C VIRUS ACTIVITY AND ANTITUMOR SCREENING OF NOVEL THIAZOLO[4,5-D]-PYRIMIDINE DERIVATIVES.
The paper describes the synthesis, antivirus and antitumor evaluation of novel thiazolo[4,5-d]pyrim- idine derivatives. The target compounds 3a-h were synthesized by cyclocondensation of 4-amino-N'-(phenyl- methylidene)-3-phenyl-2-thioxo-2,3-dihydrothiazole-5-carbohydrazides 2a-d with aromatic aldehydes. The structures of new compounds were determined by IR, ¹H-NMR and elemental analysis. Thiazolopyrimidines 3a and 3d-h were screened by the National Institute of Allergy and Infectious Diseases against various viruses. Four compounds 3e-h showed in vitro anti-HCV activity. One (3e) demonstrated significant activity against HBV and was submitted to an anti-HBV in vivo assay but had a low bioavailability. As a result of antitumor study, compound 3h was found to be most potent against leukemia SR.


[Lyme disease and facial paralysis in children].
Lyme disease is one of the most common cause of acute peripheral facial palsy in children. Overall nervous system involvement is also the predominant manifestation of Lyme disease in children, chiefly as facial palsy and/or aseptic meningitis. The medical records of ten patients with discharge diagnosis of facial palsy associated to borreliosis were retrospectively reviewed. The diagnostic criteria for borreliosis included acute peripheral facial palsy associated with erythema migrans (1/10) and/or positive Lyme serology in serum (10/10) or CSF (6/10). Facial palsy was associated with a high rate (9/10) of occult meningitis. Cerebrospinal fluid findings showed lymphocytic pleocytosis associated to moderate increased protein level. PCR assays displayed a very low sensitivity. All patients with meningitis were treated with intravenous ceftriaxone for 3 weeks and received their treatment as outpatients with an heparinised venous catheter. Our study confirm that borreliosis should be considered in every case of peripheral facial palsy and based on the high rate of occult meningitis, we also advocate to perform a lumbar puncture. Although long term prognosis of facial palsy associated with Lyme disease in children appears excellent, current treatment recommendations advocate prolonged antibiotic therapy.


Expression of AR, 5αR1 and 5αR2 in bladder urothelial carcinoma and relationship to clinicopathological factors.
Bladder urothelial carcinoma is increasing in incidence with age and its prognosis could become worse when accompanied with metastasis. Effective treatment of these advanced patients is required and it becomes important to understand its underlying biology of this neoplasm, especially with regard to its biological pathways. A potential proposed pathway is androgen receptor (AR)-mediated intracellular signaling but the details have remained relatively unexplored. The expression of AR, 5α-reductase type1 (5αR1) and 5α-reductase type2 (5αR2) were examined in the bladder cancer cell line T24 and surgical pathology specimens. We also evaluated the status of androgen related cell proliferation and migration using the potent, non-aromatizable androgen agonist 5α-dihydrotestosterone (DHT). DHT treatment significantly increased AR mRNA expression level, but not those of 5αR1 and 5αR2 in T24 cells. DHT also suppressed cellular migration with weaker and opposite effects on cell proliferation. A significant inverse correlation was detected between pT stage and AR, 5αR1 and 5αR2 immunoreactivity. Inverse correlations detected between tumor grade and AR/androgen metabolizing enzyme also suggested that the loss of AR and androgen-producing enzymes could be associated with tumor progression. Effects of DHT on cells also suggest that androgens may regulate cellular behavior.


Glomerular diseases in human renal allograft.
A total of 64 renal graft biopsies performed on 44 transplant patients from among 116 transplants (12 from living donors, 104 from cadavers) were analyzed during the period from July 1983 to December 1990. The frequency of allograft glomerular disease was 22.7% (10/44). Membranous glomerulonephritis (MGN) was detected in five patients; focal segmental glomerulosclerosis (FSGS), in two; transplant glomerulopathy, in two; and IgA nephropathy, in one. Nephrotic syndrome occurred in nine of the ten patients. Progressive deterioration of graft function developed in four patients associated with chronic rejection, and two of them later lost the graft. The remaining six patients had no chronic rejection and retained a stable renal condition with one exception, a patient who suffered from acute total occlusion of the right internal iliac artery and who eventually lost the graft. It is concluded that MGN is the most common allograft glomerular disease, but the outcome of the graft is probably related to the coexistent chronic rejection.


Chromosome elimination in trisomics of Coix aquatica Roxb.
Somatic chromosome elimination was identified and its patterns studied in a trisomic (2n=11) with marker genes in Coix aquatica Roxb. In a cross between a recessive trisomic with green base and white style (ccc ii ss) and a dominant disomic having purple base and purple style (CC II SS), all the F(1) seedling progeny were purple based because of the presence of C, I and S. For C. to be expressed in seedling base, either I should be absent or S should be present with I. In style colour, however, irrespective of the presence of I and S, C produces purple phenotype.In one trisomic (Ccc ii ss) plant (designated as 4-15) of the F(1) progeny, a part of the seedling base was green. All the tillers coming up from the green side of the main tiller also had green base, and those arising on the purple side were purple based. Similarly, the pistillate spikelets on the green side of the main culm and on the tillers with green base were white styled, and the male spikes showed 10 chromosomes. Female spikelets on the purple side of the main tiller and on the tillers with purple base were mostly purple styled and the male spikes had 11 chromosomes. In some of the purple based tillers, however, there were both 11 and 10 chromosomes in different regions or different inflorescence clusters on the tiller. In these tillers, where the chromosome number was 11, style colour was purple, and white style occurred when there were 10 chromosomes. In one tiller, the style colour was purple but the chromosome number was 10.The recessive phenotype of the style in the trisomic conceivably resulted from an elimination of the extra chromosome carrying the dominant allele C. On the basis of the morphological features of the extra chromosome, such as length, centromere position and distribution pattern of the hetero and eupycnotic regions, it was identified as chromosome No. 2 in the complement. It was therefore possible to place with certainty the gene c on this chromosome. Sometimes, however, the extra chromosome carrying c also was eliminated giving 10 chromosomes and purple style.In the other trisomic plants of the F(1) progeny, one plant showed 11 chromosomes but in a tiller there were only 10 chromosomes and white styles. In two other plants, although the chromosome number was 11 throughout, white style was present in a single cluster of inflorescences in one plant, and in one pistillate spikelet in the other. In the latter two cases, white style was believed to have arisen as a result of a mutation from C to c or somatic crossing over, giving the genotype ccc in the affected regions. In a single plant, chromosome elimination was observed in only one cell.Apparently the 10-chromosome sectors arose from the 11-chromosome condition by selective elimination of the extra chromosome during mitosis in the primordium giving rise to these sectors. In the affected plants, elimination did not obviously occur at the same stage but at different times in their ontogeny. Instability is probably governed by one or a few major genes, associated with a number of modifiers, exhibiting incomplete penetrance and variable expression. Chromosome elimination did not apparently follow any particular pattern but was erratic. Probably some intracellular environment is necessary to trigger the mechanism governing the elimination into action. The unstable system, occurring in combination with other favourable features like the functional nature of the aneuploid gametes, sexual reproduction, monoecious condition favouring cross pollination and tolerance of extra chromosomes by the sporophyte, could be an important factor in the cytogenetic evolution of the species.


Are We Ready for Migrastatics?
Metastasis accounts for the highest mortality rates in solid tumor cancer patients. However, research and development have neglected this most lethal characteristic and, instead, have concentrated on the hallmarks of cancer that make tumor cells highly proliferative and distinctive from nonmalignant cells. The concentration on invasion and metastasis can be one of the most meaningful advancements in cancer investigation. Importantly, metastasis-free survival (MFS) was recently approved by the Food and Drug Administration (FDA) as a novel primary endpoint in clinical trials and has been used to evaluate the prognosis of patients with nonmetastatic castration-resistant prostate cancer and soft tissue sarcoma. This new definition enables to shift the focus of research and development in cancer therapeutics toward metastasis and to change the emphasis from using tumor shrinkage as a benchmark for indicating the efficacy of treatment to using MFS as a more representative endpoint for antimetastatic drugs. This perspective outlines the possibility to use this novel endpoint in other solid cancers, and examples of large clinical trials are given in which MFS is defined as an endpoint and/or in which antimetastatic strategies are being examined. These advances now open the door for the rapid development of antimetastatic therapies, which could be used in combination with standard cytotoxic cancer therapies. With pioneer research on metastasis prevention on the rise and the underlying biomechanisms of tumor cell motility and invasion explored further than ever before, we believe an intensified focus on antimetastatic properties will shape this era of cancer translational research.


Intracranial pressure modulates distortion product otoacoustic emissions: a proof-of-principle study.
There is an important need to develop a noninvasive method for assessing intracranial pressure (ICP). We report a novel approach for monitoring ICP using cochlear-derived distortion product otoacoustic emissions (DPOAEs), which are affected by ICP. We hypothesized that changes in ICP may be reflected by altered DPOAE responses via an associated change in perilymphatic pressure. We measured the ICP and DPOAEs (magnitude and phase angle) during opening and closing in 20 patients undergoing lumbar puncture. We collected data on 18 patients and grouped them based on small (<4 mm Hg), medium (5-11 mm Hg), or large (≥15 mm Hg) ICP changes. A permutation test was applied in each group to determine whether changes in DPOAEs differed from zero when ICP changed. We report significant changes in the DPOAE magnitudes and angles, respectively, for the group with the largest ICP changes and no changes for the group with the smallest changes; the group with medium changes had variable DPOAE changes. We report, for the first time, systematic changes in DPOAE magnitudes and phase in response to acute ICP changes. Future studies are warranted to further develop this new approach. DPOAE, distortion product otoacoustic emissionICP, intracranial pressureIIH, idiopathic intracranial hypertensionLP, lumbar punctureTBI, traumatic brain injury.


Understanding specific and nonspecific toxicities: a requirement for the development of dendrimer-based pharmaceuticals.
Dendrimer conjugates for pharmaceutical development are capable of enhancing the local delivery of cytotoxic drugs. The ability to conjugate different targeting ligands to the dendrimer allows for the cytotoxic drug to be focused at the intended target cell while minimizing collateral damage in normal cells. Dendrimers offer several advantages over other polymer conjugates by creating a better defined, more monodisperse therapeutic scaffold. Toxicity from the dendrimer, targeted and nonspecific, is not only dependent upon the number of targeting and therapeutic ligands conjugated, but can be influenced by the repeating building blocks that grow the dendrimer, the dendrimer generation, as well as the surface termination.


Quantitative cerebral blood flow with optical coherence tomography.
Absolute measurements of cerebral blood flow (CBF) are an important endpoint in studies of cerebral pathophysiology. Currently no accepted method exists for in vivo longitudinal monitoring of CBF with high resolution in rats and mice. Using three-dimensional Doppler Optical Coherence Tomography and cranial window preparations, we present methods and algorithms for regional CBF measurements in the rat cortex. Towards this end, we develop and validate a quantitative statistical model to describe the effect of static tissue on velocity sensitivity. This model is used to design scanning protocols and algorithms for sensitive 3D flow measurements and angiography of the cortex. We also introduce a method of absolute flow calculation that does not require explicit knowledge of vessel angles. We show that OCT estimates of absolute CBF values in rats agree with prior measures by autoradiography, suggesting that Doppler OCT can perform absolute flow measurements in animal models.


Distribution of anticancer activity in higher plants.
The systematic distribution in higher plants of general anticancer activity, high-interest anticancer activity, and high-interest compounds is presented. Special emphasis is placed on those taxonomic groups offering, by virtue of their high-interest activity and/or compounds, the greatest potential as sources of useful anticancer agents.


Neuropsychological Outcomes of Children 1 Year After Pediatric Cardiac Arrest: Secondary Analysis of 2 Randomized Clinical Trials.
Little is known about neuropsychological outcomes of children who survived pediatric cardiac arrest (CA). To describe the neuropsychological outcomes of CA survivors enrolled in the Therapeutic Hypothermia After Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) and Out-of-Hospital (THAPCA-OH) trials and compare the results with the primary outcome measure for these trials. Secondary analysis of 222 CA survivors aged 1 to 18 years who received chest compressions for 2 minutes or more, remained comatose and required mechanical ventilation after return of circulation, and were enrolled in targeted temperature-management trials from 41 pediatric intensive care units. Data were collected from September 3, 2009, to February 3, 2016, and analyzed from March 10, 2017, to April 20, 2018. The Vineland Adaptive Behavior Scales, Second Edition (VABS-II), a standardized measure of neurobehavioral functioning based on caregiver report (age-corrected mean [SD] scores = 100 [15]), was used to evaluate pre-CA functioning within 24 hours after enrollment; VABS-II<70 indicated significant developmental delays; VABS-II and neuropsychological testing were completed 1 year after CA. Neuropsychological testing included the Mullen Scales of Early Learning (Mullen) for children younger than 6 years and the Wechsler Abbreviated Scale of Intelligence (WASI) and neuropsychological measures of attention, memory, processing speed, and executive functioning for older children. Of 160 participants who completed neuropsychological testing, 96 (60.0%) were male; the median (interquartile range [IQR]) age was 2.5 years (1.3-6.1 years). Ninety-six (60.0%) were white, 41 (25.6%) were black, and 23 (14.4%) were of other/unknown race; 343 (21.2%) were Hispanic or Latino; 119 (74.4%) were non-Hispanic or Latino; and 7 (4.4%) were of unknown ethnicity. One hundred fourteen participants (71.2%) were classified as having favorable outcomes (VABS-II ≥70). Impairments (>2 SD below the mean for age) across neuropsychological measures ranged from 7% to 61%. Correlations between global cognitive and VABS-II scores were strong for younger children (Mullen, r = 0.69-0.87) but moderate for older children (r = 0.21-0.54 for the WASI). Of 111 children with favorable outcomes on VABS-II, 25.2% had global cognitive impairment and 30 of 35 older children (85.7%) had selective neuropsychological deficits. In this prospectively evaluated cohort of pediatric CA survivors who were initially comatose, although 71.2% were classified as having favorable outcomes, significant neuropsychological deficits were identified in pediatric CA survivors who were classified as having favorable outcomes. The findings provide clinicians with a greater understanding of the spectrum of neuropsychological outcomes of pediatric CA survivors and the complex relationship between standardized caregiver-reported functional outcome measures incorporated in clinical trials and performance-based neuropsychological assessments.


The Simplified Nutritional Appetite Questionnaire (SNAQ) as a Screening Tool for Risk of Malnutrition: Optimal Cutoff, Factor Structure, and Validation in Healthy Community-Dwelling Older Adults.
Malnutrition is an independent marker of adverse outcomes in older adults. While the Simplified Nutritional Appetite Questionnaire (SNAQ) for anorexia has been validated as a nutritional screening tool, its optimal cutoff and validity in healthy older adults is unclear. This study aims to determine the optimal cutoff for SNAQ in healthy community-dwelling older adults, and to examine its factor structure and validity. We studied 230 community-dwelling older adults (mean age 67.2 years) who were nonfrail (defined by Fatigue, Resistance, Ambulation, Illnesses & Loss (FRAIL) criteria). When compared against the risk of malnutrition using the Mini Nutritional Assessment (MNA), the optimal cutoff for SNAQ was ≤15 (area under receiver operating characteristic (ROC) curve: 0.706, sensitivity: 69.2%, specificity: 61.3%). Using exploratory factor analysis, we found a two-factor structure (Factor 1: Appetite Perception; Factor 2: Satiety and Intake) which accounted for 61.5% variance. SNAQ showed good convergent, discriminant and concurrent validity. In logistic regression adjusted for age, gender, education and MNA, SNAQ ≤15 was significantly associated with social frailty, unlike SNAQ ≤4 (odds ratio (OR) 1.99, p = 0.025 vs. OR 1.05, p = 0.890). Our study validates a higher cutoff of ≤15 to increase sensitivity of SNAQ for anorexia detection as a marker of malnutrition risk in healthy community-dwelling older adults, and explicates a novel two-factor structure which warrants further research.


Anterior surgery in trauma of the cervical spine.
The study reports a series of 37 traumatic lesions of the cervical spine treated surgically by anterior approach. The series includes two IInd type fractures of the odontoid, treated by direct screwing, 32 recent fractures or fracture-dislocations of the lower cervical spine treated by decompression and anterior arthrodesis with a plate, 3 inveterate dislocations treated by anterior-posterior osteotomy in 2 cases, and decompression-arthrodesis in the third. One amyelic fracture of the odontoid healed in 4 months, the other patient, with Frankel C spinal cord lesion improved to D, but died 4 months later as a result of bronchial pneumonia ab ingestis. In all of the recent lower cervical lesions fusion was obtained in 3-12 months (mean 4.5 months). Eight incomplete spinal cord lesions improved by 2 Frankel classes in 3 cases and by 1 in 5. Six nerve root lesions healed with complete recovery. Three cases with no neurologic deficit remained unchanged as did 15 complete spinal cord lesions. In the 3 inveterate cases we obtained healing of a slow-developing myelopathy (Frankel D) after osteotomy, no improvement after osteotomy in the second case (Frankel B). In the case submitted to decompression and anterior fusion we obtained recovery from Frankel B to E in three months, but the patient then died as a result of pulmonary complications. Direct screwing of the odontoid allows us to obtain healing of the type II fractures without blocking C1-C2 movement with a posterior fusion. Anterior surgery in traumas of the lower cervical spine allows for anatomical decompression of the spinal cord and bone reconstruction with good results, avoiding the risk of neurologic progression caused by dragging of the disc material in the spinal canal, that may take place at the time of non-surgical reduction or by posterior approach of the dislocations. In our series complications included 2 infections, 1 that healed without sequelae and the other with kyphosis, and a fistula of the hypopharynx caused by fibrobronchoscopy 1 year after osteosynthesis, that healed after primary repair. For this latter complication anterior surgery can, at most, be considered a contributing cause, because of the deep scar.


Epidemics of meningococcal meningitis in Northern Nigeria focus on preventive measures.
Throughout the past 200 years, epidemics of meningococcal infection have been noted in Northern Nigeria. Consequently, control of meningococcal meningitis is one of the major priorities in infection control in the region. The proportions of cases of invasive meningococcal disease (IMD) caused by the five common serotypes (A, B, C, Y, and W135) vary among different regions and within specific geographic locations. Hence, effective and comprehensive disease control can only be achieved with the use of vaccines that target all of these disease-causing serotypes. Vaccines for the majority of meningococcal serogroups implicated in causing IMD are available in developed countries and have proven effective in reducing the disease incidence. However, the overall success of a vaccine depends on its coverage of the at-risk population as well as safety and effectiveness of the vaccine at preventing disease. Therefore, maximizing the global impact of these vaccines requires having them made available in regions with the high incidence of the disease, like Northern Nigeria, where rates of meningococcal disease are several times higher than in industrialized nations, and the reported mortality is usually high.


Volume of blood removed for analytical purposes during hospitalization of low-birthweight infants.
Iatrogenic hazards may be induced by blood sampling in very-low-birthweight neonates. We report the number and types of analyses performed on 20 neonates with a birthweight below 1500 g during their first four weeks of hospitalization. Blood was sampled one to 13 times per infant per day on 382 of the 435 total days of hospitalization. The average blood loss was 7 to 51 mL per kilogram of body weight per four weeks--that is, from 5 to 45% of the calculated total blood volume. Of the blood removed, about 25% was in excess of the need for analytical procedures. Of the analyses, 40% were for acid-base, sodium, and potassium analyses--analyses for which transcutaneous methodology has been or is being developed. We conclude that because of the risks for low-birthweight neonates, procedures for blood sampling and analysis should periodically be reviewed, so as to minimize the number of samplings and the amount of blood removed.


Development of reverse genetics systems for bluetongue virus: recovery of infectious virus from synthetic RNA transcripts.
Bluetongue virus (BTV), an insect-vectored emerging pathogen of both wild ruminants and livestock, has had a severe economic impact in agriculture in many parts of the world. The investigation of BTV replication and pathogenesis has been hampered by the lack of a reverse genetics system. Recovery of infectious BTV is possible by the transfection of permissive cells with the complete set of 10 purified viral mRNAs derived in vitro from transcribing cores (M. Boyce and P. Roy, J. Virol. 81:2179-2186, 2007). Here, we report that in vitro synthesized T7 transcripts, derived from cDNA clones, can be introduced into the genome of BTV using a mixture of T7 transcripts and core-derived mRNAs. The replacement of genome segment 10 and the simultaneous replacement of segments 2 and 5 encoding the two immunologically important outer capsid proteins, VP2 and VP5, are described. Further, we demonstrate the recovery of infectious BTV entirely from T7 transcripts, proving that synthetic transcripts synthesized in the presence of cap analogue can functionally substitute for viral transcripts at all stages of the BTV replication cycle. The generation of BTV with a fully defined genome permits the recovery of mutations in a defined genetic background. The ability to generate specific mutants provides a new tool to investigate the BTV replication cycle as well as permitting the generation of designer vaccine strains, which are greatly needed in many countries.


Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.
A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.


How difficult is difficult? Speech perception in noise in the elderly hearing impaired.
Perception of speech in the presence of competing multitalker noise is difficult for most individuals with sensory hearing loss, and in particular, for the elderly hearing impaired. Elderly people frequently report that these difficulties are poorly compensated for by hearing aids, albeit the algorithms and technologies aiming to improve speech perception in noise. The aim of the current study was therefore to assess competing speech signals processing by measuring the amount of signal to noise ratio (SNR) loss experienced by elderly hearing impaired individuals and their performance in dichotic listening tests. Speech in multitalker babble noise and dichotic listening were assessed in older hearing impaired individuals and in young normal-hearing adults. The average dichotic scores in the elderly group were substantially and significantly lower compared with the scores of the younger group with a significant right ear advantage (higher accuracy in reporting words arriving at the right ear than words arriving at the left ear) in the elderly group. Speech identification in noise in the older group was significantly poorer than in the younger group (SNR loss: 10 dB). The poor performance in the elderly hearing impaired group highlights the difficulties faced by hearing impaired older adults in demanding listening environments. Our results suggest that it may be unreasonable to expect that elderly hearing impaired individuals may fully understand speech in multitalker environments even when hearing aids are used.


Electrochemical nitric oxide sensors for physiological measurements.
The important biological roles of nitric oxide (NO) have prompted the development of analytical techniques capable of sensitive and selective detection of NO. Electrochemical sensing, more than any other NO detection method, embodies the parameters necessary for quantifying NO in challenging physiological environments such as blood and the brain. In this tutorial review, we provide a broad overview of the field of electrochemical NO sensors, including design, fabrication, and analytical performance characteristics. Both electrochemical sensors and biological applications are detailed.


Dietary Diversity and All-Cause and Cause-Specific Mortality in Japanese Community-Dwelling Older Adults.
We examined associations between dietary diversity and all-cause and cause-specific mortality in 386 men and 413 women (age range, 60-79 years at baseline) who took part in the National Institute for Longevity Sciences-Longitudinal Study of Aging study from 1997 to 2000. Dietary intake was assessed using three-day dietary records and photographs. The Quantitative Index for Dietary Diversity was used to determine the dietary diversity among thirteen food groups. Dietary diversity score and each food intake were examined by sex-stratified tertiles, and hazard ratios (HR) were calculated to compare the risk for all-cause and cause-specific deaths across tertiles, after controlling for age, sex, body mass index, alcohol intake, smoking status, education, physical activity, and disease history. During a mean follow-up of 15.7 years, 289 subjects (36.2%) died. Compared to the subjects in the lowest tertile, the multivariate-adjusted HR for all-cause and cancer mortality was 0.69 (95% confidence interval (CI): 0.51-0.94) and 0.57 (95% CI: 0.33-0.98), respectively (trend p < 0.05), in subjects in the highest tertile of dietary diversity. There were no significant associations between dietary diversity score and death from cardiovascular or cerebrovascular disease. Eating a variety of foods might contribute to longevity in older Japanese community dwellers.


Efficacy of Quichua healers as psychiatric diagnosticians.
Traditional healers' practices are widespread around the world, yet their diagnostic skills have rarely been investigated. This exploratory study examines whether yachactaitas (Quichua healers) in the Andes identify cases of psychiatric illness in their communities. For over 18 months, ten yachactaitas participated in the identification of 50 individuals with the condition known as llaqui. Medical and psychiatric evaluation indicated that most of those so diagnosed had a DSM-III-R mental disorder. None of the participants with llaqui was considered healthy in biomedical or psychiatric terms. It is suggested that yachactaitas might indeed identify general psychiatric cases in their communities, and that this might be useful for screening purposes.


Equilibration of Micelle-Polyelectrolyte Complexes: Mechanistic Differences between Static and Annealed Charge Distributions.
The role of charge density and charge annealing in polyelectrolyte complexation was investigated through systematic comparison of two micelle-polyelectrolyte systems. First, poly(dimethylaminoethyl methacrylate)-block-poly(styrene) (PDMAEMA-b-PS) micelles were complexed with poly(styrenesulfonate) (PSS) at pH values above and below the pKa of PDMAEMA to investigate the role of charge annealing in the complexation process. Second, complexes of poly(DMAEMA-stat-oligo(ethylene glycol) methyl ether methacrylate)-block-poly(styrene) (P(DMAEMA-stat-OEGMA)-b-PS) micelles with the same PSS at low pH were used to investigate how the complexation process differs when the charged sites are in fixed positions along the polymer chains. Characterization by turbidimetric titration, dynamic light scattering, and cryogenic transmission electron microscopy reveals that whether or not the charge distribution can rearrange during the complexation process significantly affects the structure and stability of the complexes. In complexes of PDMAEMA-b-PS micelles at elevated pH, in which the charge distributions can anneal, the charge sites redistribute along the corona chains upon complexation to favor more fully ion-paired configurations. This promotes rapid rearrangement to single-micelle species when the micelles are in excess but traps complexes formed with PSS in excess. In complexes with static charge distributions introduced by copolymerization of DMAEMA with neutral OEGMA monomers, on the other hand, the opposite is true: in this case, reducing the charge density promotes rearrangement to single-micelle complexes only when the polyanion is in excess. Molecular dynamics simulations show that disruption of the charge density in the corona brush reduces the barrier to rearrangement of individual ion pairs, suggesting that the inability of the brush to rearrange to form fully ion-paired complexes fundamentally alters the kinetics of complex formation and equilibration.


Acute Effect of Brace Use on Upper-Extremity Functionality in Adolescent Individuals With Idiopathic Scoliosis: A Cross-Sectional Study.
It is well known that scoliosis adversely affects the functions of the upper extremities. However, the acute effect of rigid braces, which are widely used in the conservative treatment of scoliosis, on upper-extremity functionality remains unknown. The aim of this study was to investigate the acute effect of a rigid thoracolumbosacral brace use on upper-extremity functionality in individuals with adolescent idiopathic scoliosis (AIS). Thirty-eight individuals diagnosed with AIS participated in this cross-sectional study, with a mean age of 14.55 ± 1.90 years and a range of 10-18 years. The upper-extremity functionality was assessed using the Nine-Hole Peg Test and handgrip strength, with assessments conducted under both in-brace (with their own braces) and out-of-brace conditions. Nine-Hole Peg Test durations of the AIS patients for the nondominant side were significantly lower for in-brace conditions compared with out-of-brace conditions (p = .049, effect size = 0.136). The grip strength of the nondominant side was significantly higher for in-brace conditions compared with out-of-brace conditions (p = .025, effect size = 0.365). A weak negative correlation was found between the degree of curvature and the grip strength of the dominant side for in-brace conditions (r = -.323, p = .048). It was concluded that the brace had a positive effect on upper-extremity functionality on the nondominant side by both shortening the Nine-Hole Peg Test duration and increasing grip strength. In AIS patients, the brace may positively affect daily living by improving the functionality of the nondominant extremity.


Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation.
Mitogen-activated protein kinase (MAPK) signaling pathways are implicated in inflammatory and apoptotic processes of cerebral ischemia and reperfusion (I/R) injury. Hence, MAPK pathways represent a promising therapeutic target. Exploring the full potential of inhibitors of MAPK pathways is a useful therapeutic strategy for ischemic stroke. Bilobalide, a predominant sesquiterpene trilactone constituent of Ginkgo biloba leaves, has been shown to exert powerful neuroprotective properties, which are closely related to both anti-inflammatory and anti-apoptotic pathways. We investigated the neuroprotective roles of bilobalide in the models of middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reoxygenation (OGD/R) of cerebral I/R injury. Moreover, we attempted to confirm the hypothesis that its protection effect is via modulation of pro-inflammatory mediators and MAPK pathways. Male Sprague-Dawley rats were subjected to MCAO for 2 h followed by reperfusion for 24 h. Bilobalide was administered intraperitoneally 60 min before induction of middle cerebral artery occlusion (MCAO). After reperfusion, neurological deficit scores, infarct volume, infarct weight, and brain edema were assessed. Ischemic penumbrae of the cerebral cortex were harvested to determine superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide, TNF-α, interleukin 1β (IL-1β), p-ERK1/2, p-JNK1/2, and p-p38 MAPK concentration. Similarly, the influence of bilobalide on the expression of nitric oxide, TNF-α, IL-1β, p-ERK1/2, p-JNK1/2, and p-p38 MAPK was also observed in an OGD/R in vitro model of I/R injury. Pretreatment with bilobalide (5, 10 mg/kg) significantly decreased neurological deficit scores, infarct volume, infarct weight, brain edema, and concentrations of MDA, nitric oxide, TNF-α, IL-1β, and increased SOD activity. Furthermore, bilobalide (5, 10 mg/kg) pretreatment significantly down-regulated both p-JNK1/2 and p-p38 MAPK expression, whereas they had no effect on p-ERK1/2 expression in the ischemic penumbra. Supporting these observations in vivo, pretreatment with bilobalide (50, 100 μM) significantly down-regulated nitric oxide, TNF-α, IL-1β, p-JNK1/2, and p-p38 MAPK expression, but did not change p-ERK1/2 expression in rat cortical neurons after OGD/R injury. These data indicate that the neuroprotective effects of bilobalide on cerebral I/R injury are associated with its inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation.


Borderline personality disorder and recovery.
Recovery focuses on the broader concept of having a good life with mental health problems than remission. This review aims to deliver up-to-date information on the concept of recovery in borderline personality disorder. A computerized database search was conducted in PubMed and Web of Science sites, using various combinations of keywords for the period between January 1990 and April 2020. According to current findings, a full remission or complete disappearance of symptoms of a borderline personality disorder usually does not occur soon after the initiation of treatment, but recovery is an achievable goal. A precondition for recovery is the patient's responsibility for their health. Apart from psychotherapy and psychosocial rehabilitation, pharmacotherapy can help individuals with BPD improve their quality of life and can provide significant aid on their path to recovery.


[MODERN TRENDS IN IMMUNOPROPHYLAXIS (ANALYSIS OF FOREIGN EXPERIENCE)].
Currently, immunoporphylaxis reaches the population through information support, mass vaccination sites and the system of monitoring warning. The capabilities of information technologies have made it possible to monitor the patient's health at all stages of life, regardless of the place of medical care delivery (including vaccination). The use of mathematical modeling technologies coupled with the queueing theory made it possible to develop an optimum location scheme of vaccination sites. Organization of the work of vaccination centers considered the need to optimize travel arrangements of the recipients and operating costs. The integration with geographic information systems contributes to the adequate distribution of vaccination centers in densely populated areas. The availability of information support made it possible to create the following innovative vaccination solutions: "get a vaccine without ever leaving your car" (with prior registration on the website), vaccination at pharmacies (with the subsequent data transfer to the cloud storage), deployment of vaccination sites at sports and religious facilities. Compact mobile vaccination sites have proven their effectiveness in both sparsely populated areas and in places with a high throughput. Effective performance of mass vaccination centers is impossible without the use of effective information and communication technologies. The systems ensure interaction between the patient, medical professionals and software that allows you to write, read or update in real time the database located in the data storage center. The information technologies of vaccination have made it possible to create a system for continuous support of immunoprophylaxis.


[Rabbit syndrome due to olanzapine].
Rabbit syndrome (RS) is a rare extrapyramidal side effect of antipsychotic treatment. It is characterized by involuntary, rhythmic dyskinesias of mouth and lips excluding the tongue, and is most common under typical neuroleptics. There are also several reports of the syndrome in patients with the atypical antipsychotics risperidone and aripiprazole. We report a 74 year-old patient suffering from a bipolar affective disorder, who developed a rabbit syndrome following the intake of 20 mg/d olanzapine. To our knowledge this is the first case report of a RS due to olanzapine.


Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.
Fibroblast growth factor receptor 4 (FGFR4) polymorphisms are positively correlated with tumor progression in numerous malignant tumors. However, the association between FGFR4 genetic variants and the risk of hepatocellular carcinoma (HCC) has not yet been determined. In this study, we investigated the potential associations of FGFR4 single nucleotide polymorphisms (SNPs) with HCC susceptibility and its clinicopathological characteristics. Four SNPs in FGFR4 (rs1966265, rs351855, rs2011077, and rs7708357) were analyzed among 884 participants, including 595 controls and 289 patients with HCC. The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of HCC, and the impact of these SNPs on the susceptibility and clinicopathological characteristics of HCC. After adjusting for other covariants, HCC patients who carrying at least one A genotype (GA and AA) at rs351855 were observed to have a higher risk of liver cirrhosis compared with those carrying the wild-type genotype (GG) (OR: 2.113, 95% CI: 1.188-3.831). Moreover, the patients with at least one A genotype were particularly showed a high level of alpha-fetoprotein (AFP). Our findings suggest that genetic polymorphism in FGFR4 rs351855 may be associated with the risk of HCC coupled with liver cirrhosis and may markedly increase the AFP level in Taiwanese patients with HCC. In addition, this is the first study that evaluated the risk factors associated with FGFR4 polymorphism variants in Taiwanese patients with HCC.


Hubs in the human fetal brain network.
Advances in neuroimaging and network analyses have lead to discovery of highly connected regions, or hubs, in the connectional architecture of the human brain. Whether these hubs emerge in utero, has yet to be examined. The current study addresses this question and aims to determine the location of neural hubs in human fetuses. Fetal resting-state fMRI data (N = 105) was used to construct connectivity matrices for 197 discrete brain regions. We discovered that within the connectional functional organization of the human fetal brain key hubs are emerging. Consistent with prior reports in infants, visual and motor regions were identified as emerging hub areas, specifically in cerebellar areas. We also found evidence for network hubs in association cortex, including areas remarkably close to the adult fusiform facial and Wernicke areas. Functional significance of hub structure was confirmed by computationally deleting hub versus random nodes and observing that global efficiency decreased significantly more when hubs were removed (p < .001). Taken together, we conclude that both primary and association brain regions demonstrate centrality in network organization before birth. While fetal hubs may be important for facilitating network communication, they may also form potential points of vulnerability in fetal brain development.


ZCCHC17 is a master regulator of synaptic gene expression in Alzheimer's disease.
In an effort to better understand the molecular drivers of synaptic and neurophysiologic dysfunction in Alzheimer's disease (AD), we analyzed neuronal gene expression data from human AD brain tissue to identify master regulators of synaptic gene expression. Master regulator analysis identifies ZCCHC17 as normally supporting the expression of a network of synaptic genes, and predicts that ZCCHC17 dysfunction in AD leads to lower expression of these genes. We demonstrate that ZCCHC17 is normally expressed in neurons and is reduced early in the course of AD pathology. We show that ZCCHC17 loss in rat neurons leads to lower expression of the majority of the predicted synaptic targets and that ZCCHC17 drives the expression of a similar gene network in humans and rats. These findings support a conserved function for ZCCHC17 between species and identify ZCCHC17 loss as an important early driver of lower synaptic gene expression in AD. Matlab and R scripts used in this paper are available at https://github.com/afteich/AD_ZCC. email@example.com. Supplementary data are available at Bioinformatics online.


A randomized controlled trial of venlafaxine XR for major depressive disorder after spinal cord injury: Methods and lessons learned.
We describe the rationale, design, methods, and lessons learned conducting a treatment trial for major depressive disorder (MDD) or dysthymia in people with spinal cord injury (SCI). A multi-site, double-blind, randomized (1:1) placebo controlled trial of venlafaxine XR for MDD or dysthymia. Subjects were block randomized and stratified by site, lifetime history of substance dependence, and prior history of MDD. Six SCI centers throughout the United States. Across participating centers, 2536 subjects were screened and 133 were enrolled into the trial. Subjects were 18-64 years old and at least 1 month post-SCI. Interventions Twelve-week trial of venlafaxine XR versus placebo using a flexible titration schedule. The primary outcome was improvement in depression severity at 12 weeks. The secondary outcome was improvement in pain. This article includes study methods, modifications prompted by a formative review process, preliminary data on the study sample and lessons learned. We describe common methodological and operational challenges conducting multi-site trials and how we addressed them. Challenges included study organization and decision making, staff training, obtaining human subjects approval, standardization of measurement and treatment, data and safety monitoring, subject screening and recruitment, unblinding and continuity of care, database management, and data analysis. The methodological and operational challenges we faced and the lessons we learned may provide useful information for researchers who aim to conduct clinical trials, especially in the area of medical treatment of depression in people with SCI.


Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1.
Treatment of human monocytes with vascular endothelial growth factor (VEGF) isolated from tumor cell supernatants was reported to induce monocyte activation and migration. In this study we show that recombinant human VEGF165, and VEGF121 had a maximal effect on human monocyte migration at 65 to 250 pmol/L. Chemotactic activity of VEGF165 was inhibited by a specific antiserum against VEGF, by heat treatment of VEGF165, and by protein kinase inhibitors. In addition, we could show that VEGF-stimulated monocyte migration is mediated by a pertussis toxin-sensitive GTP-binding protein. Placenta growth factor (PlGF152), a heparin-binding growth factor related to VEGF, was also chemotactic for monocytes at concentrations between 2.5 and 25 pmol/L. In accordance with these findings, human monocytes showed specific and saturable binding for 125I-VEGF165 (half-maximal binding at 1 to 1.5 nmol/L). Using Northern blot analysis, we further could show that human monocytes express only the gene for the VEGF receptor type, flt-1, but not for the second known VEGF receptor, KDR. Resting monocytes expressed low levels of flt-1 gene only. Brief exposure (2 to 4 hours) of human monocytes to lipopolysaccharide, a prototypic monocyte activator, led to a significant upregulation of the flt-1 mRNA level. The results presented here suggest that monocyte chemotaxis in response to VEGF and most likely to PlGF152 is mediated by flt-1 and thus show a possible function for the VEGF-receptor flt-1.


[Unilateral paralysis of the vocal fold: correlation between laryngoscopy and electromyography].
From a clinical point of view, unilateral vocal fold paresis means that one of the vocal folds shows reduced mobility. Etiology may be mechanical or supranuclear, but in most cases it is a partial peripheral neurogenic lesion in the muscles innervated by one of the recurrent laryngeal nerves. On the one hand, a retrospective analysis was made of 71 cases with laryngoscopically reduced mobility of one vocal fold: 58 patients had electromyographic signs of partial denervation; 13 had normal electromyographic activity. Possible explanations are mechanical factors, paradoxical reinnervation, or central neurological pathology. On the other hand we reviewed 179 cases with an electromyographic diagnosis of unilateral partial peripheral neurogenic lesion in the muscles innervated by one of the recurrent laryngeal nerves: 119 patients showed a clinically immobile vocal fold, 2 a normally moving vocal fold and 58 a paretic vocal fold. A lot of immobile vocal folds are thus partial denervations. Insufficient amount of functional motor units and paradoxical reinnervation provide possible explanations.


Newly designed ergonomic surgical binocular telescope with angulated optic axis.
Magnification by surgical loupes has the distinct merits of agility and nimbleness in observation, a wide stereo base effectuating superior depth sensation, and light augmentation by an objective lens that is larger than the pupil. However, continuous use of these loupes causes neck strain for surgeons as a result of flexion posture and fatigue. To minimize the strain and fatigue and maximize the advantages and performance of binocular telescopes, we have developed a novel optical design. To allow observation of the operative field with the surgeon's neck and eye in a straight position, the light path of the telescopes was angulated downward with roof prisms. For maximum image quality, Keplerian real-image optics were adopted. The optics, finishing of the lens, and assembly were perfected through practical trials of more than 500 procedures over a period of 3 years. The new ergonomically designed optics provide excellent image quality comparable to standing microscopes in the low to medium range of magnification, while effectively reducing the neck flexion of surgeons working in the operative field below and relieving the surgeon's fatigue during hours of continuous use.


[Drug-induced mania and hypomania: analysis of a case of lamotrigine-induced mania].
Lamotrigine is an antiepileptic medication approved as a mood stabilizer for the prevention of depressive episodes in bipolar disorder. Among its adverse reactions, it may present maniac symptoms, despite being an idiosyncratic adverse effect and low incidence. We present the case of a 58-year-old patient, diagnosed with bipolar disorder since her youth and who has required multiple therapeutic schemes. After a pharmacological change from lithium to lamotrigine in progressive ascending doses, she presented a mania decompensation, temporally consistent with the initiation of lamotrigine, and that was accentuated with increasing dose. The symptoms disappear when lamotrigine is withdrawn and a pharmacological approach is carried out. When evaluating the case according to the causality criteria of Naranjo et al, we found a possible result. Although lamotrigine-induced manifest symptoms have been previously documented, it is important to take this adverse effect into account, given the affective and behavioral repercussions. Further studies are needed to understand the bilateral relationship of this effect from a clinical and neurobiological point of view.


A phase I trial of high-dose paclitaxel, cyclophosphamide and mitoxantrone with autologous blood stem cell support for the treatment of metastatic breast cancer.
The aim of this phase I study was to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and efficacy of a new combination of cyclophosphamide (6 g/m2), mitoxantrone (70 mg/m2), with dose escalation of paclitaxel (TaxolR) at a starting dose of 250 mg/m2 given intravenously over 3 h in a transplantation setting. Patients with metastatic breast cancer and chemosensitive disease were eligible. The autologous blood stem cell re-infusion and subsequent recovery occurred in an out-patient setting. 50 patients were enrolled, but 10 withdrew. 40 completed the entire protocol. At 400 mg/m2 paclitaxel administered over 3 h, 3 of 6 patients experienced serious adverse events: approximately 20-40 min after completion of infusion, diaphoresis, bradycardia mild hypotension and diarrhoea occurred; 2 patients lost consciousness for a few minutes. An extended infusion schedule delivering 400 mg/m2 paclitaxel over 6 h rather than 3 h was initiated at this level without patients experiencing this DLT. At the next dose of 450 mg/m2 paclitaxel over 6 h, the same DLT was seen as at 400 mg/m2 paclitaxel over 3 h and, therefore, MTD was reached. Time to recovery for the absolute neutrophil count > or = 0.5 x 10(9)/l was 10-19 days (median 12 days); and for platelets > or = 20 x 10(9)/l was 18-20 days (median 11.5 days). 21 patients developed neutropenic fever that required intravenous antibiotics and re-admission; the transfusion frequency for packed red blood cell was 0-5 units (median 2 units) and for platelets, 1-5 encounters (median 2). 13 complete responses, 1 patient with no evidence of disease and 19 partial remissions were documented. The dose of 400 mg/m2 at an infusion rate of 6 h will be used for the ongoing phase II study to evaluate efficacy and toxicity further.


Differential misclassification of exposure in case-crossover studies.
The aim of this study is to examine 2 types of differential misclassification of exposure in case-crossover studies. The first is the outcome-dependent misclassification of exposure, meaning that if an event has occurred, it could affect the reporting of exposure. The second is differential misclassification of exposure as a result of fading memory over time, which arises if the length of the recall period for case and control windows differs. We use empirical data from a case-crossover study of triggers of attacks in Ménière's disease. The study applied the matched-pair interval control window sampling approach. We examined misclassification in relation to 2 different types of exposures: emotional stress and salty food intake. The study covered repeated events reported by the same patients and involved the sampling of many control windows. Because some of these windows were related to case events and some unrelated, we were able to conduct both case-crossover and control-crossover analyses. Although this group of Ménière patients are well aware of their disease, and many of them have definite ideas regarding what triggers attacks, neither outcome-dependent misclassification nor differential misclassification of exposure resulting from fading memory over time seemed to be a major problem.


Effect of hydration state and storage media on corneal biomechanical response from in vitro inflation tests.
To evaluate corneal deformation with varying intraocular pressure and the dependency of the biomechanical response on the corneal hydration state, modulated by the storage solutions or postmortem period. Thirty fresh enucleated porcine eyes were used for in vitro whole eye globe inflation experiments. The eyes were separated into five groups and treated with different solutions: 20% dextran, 8% dextran, 0.125% riboflavin-20% dextran, Optisol-GS (Bausch & Lomb, Rochester, NY), and one control group of virgin (untreated) eyes. Intraocular pressure was increased (from 15 to 55 mm Hg) and decreased (to 15 mm Hg) in 5-mm Hg steps and Scheimpflug images were taken at each step. Measurements were repeated after 24 hours. Thickness and curvature changes were analyzed as a function of intraocular pressure. Corneal deformation differed across conditions and hydration states. Dehydration by any dextran solution increased the hysteresis after the inflation/deflation cycle (14.29 vs 22.07 to 41.75 μm), whereas overnight hydration did not lead to a significant difference. Compared to control corneas, corneas treated with Optisol-GS showed the most similar behavior. Corneas treated with 0.125% riboflavin-20% dextran deformed most (Δthickness(max) = 38.27 μm), indicating a softening of the corneal tissue compared to control corneas (23.18 μm) and corneas treated with 8% dextran (21.01 μm) and 20% dextran (29.07 μm). Dextran instillation decreased corneal thickness on average to 56.5% at 0 hours and 72.7% at 24 hours. Corneal hydration and tissue preservation changed corneal biomechanics, in particular its relaxation over a period of 24 hours.


Using support vector regression coupled with the genetic algorithm for predicting acute toxicity to the fathead minnow.
The potential toxicity of chemicals may present adverse effects to the environment and human health. The quantitative structure-activity relationship (QSAR) provides a useful method for hazard assessment. In this study, we constructed a QSAR model based on a highly heterogeneous data set of 571 compounds from the US Environmental Protection Agency, for predicting acute toxicity to the fathead minnow (Pimephales promelas). An approach coupling support vector regression (SVR) with the genetic algorithm (GA) was developed to build the model. The generated QSAR model showed excellent data fitting and prediction abilities: the squared correlation coefficients (r(2)) for the training set and the test set were 0.826 and 0.802, respectively. Only eight critical descriptors, most of which are closely related to the toxicity mechanism, were chosen by GA-SVR, making the derived model readily interpretable. In summary, the successful case reported here highlights that our GA-SVR approach can be used as a general machine learning method for toxicity prediction.


Role of the proteolytic hierarchy between cathepsin L, cathepsin D and caspase-3 in regulation of cellular susceptibility to apoptosis and autophagy.
The present investigation was undertaken to measure the relative abilities of pro-death versus pro-survival proteases in degrading each other and to determine how this might influence cellular susceptibility to death. For this, we first carried out in vitro experiments in which recombinant pro-death proteases (caspase-3 or cathepsin D) were incubated with the pro-survival protease (cathepsin L) in their respective optimal conditions and determined the effects of these reactions on enzyme integrity and activity. The results indicated that cathepsin L was able to degrade cathepsin D, which in turn cleaves caspase-3, however the later enzyme was unable to degrade any of the cathepsins. The consequences of this proteolytic sequence on cellular ability to undergo apoptosis or other types of cell death were studied in cells subjected to treatment with a specific inhibitor of cathepsin L or the corresponding siRNA. Both treatments resulted in suppression of cellular proliferation and the induction of a cell death with no detectable caspase-3 activation or DNA fragmentation, however, it was associated with increased accumulation of cathepsin D, cellular vaculolization, expression of the mannose-6-phosphate receptor, and the autophagy marker LC3-II, all of which are believed to be associated with autophagy. Genetic manipulations leading either to the gain or loss of cathepsin D expression implicated this enzyme as a key player in the switch from apoptosis to autophagy. Overall, these findings suggest that a hierarchy between pro-survival and pro-death proteases may have important consequences on cell fate.


The sphenopetroclival venous gulf: a microanatomical study.
The sphenopetroclival area is the border zone between the middle and posterior cranial fossa. Several authors have studied the microsurgical anatomy of this region and have furnished sometimes contradictory descriptions of this area, which still represents a great challenge for the neurosurgeon. On the basis of previous anatomical data reported in the literature, the authors undertook a new microanatomical analysis of the sphenopetroclival region and report their findings. Twenty human cadaveric heads were used to reproduce, in the laboratory, different skull base approaches to expose the petroclival area. Measurements were taken in 40 specimens. From this study has emerged the finding that the sphenopetroclival area is a venous space, which the authors have named the "sphenopetroclival venous gulf" (SPCVG). The SPCVG is filled anteriorly by blood from the cavernous sinus (lateral sellar compartment [LSC], medially by blood from the basilar plexus, and laterally by blood from the superior petrosal sinus; this venous gulf is drained by the inferior petrosal sinus. The SPCVG is comparable in shape to an irregular hedron figure. It contains the Dorello canal, the venous segment of the abducent nerve, and the superior sphenopetrosal (Gruber) ligament, the fibers of which are in anatomical continuity with those of the inferior sphenopetrosal (petrolingual) ligament, forming a "falciform ligament." The structures defining the posterior surface of the SPCVG may represent a helpful surgical corridor through which it is possible to approach the LSC via the posterior fossa. This conceptualization of the SPCVG is an attempt to define univocally the microanatomy of the sphenopetroclival region in its entirety.


Iron oxide cluster induced barrier-free conversion of nitric oxide to ammonia.
Nitrogen oxide (NO) conversion to ammonia (NH3) over iron oxide clusters is investigated using density functional theory calculations. The introduction of NO and H2 over gas-phase Fe4O2 results in the formation of NH3 and H2O without activation barriers. The key reaction is barrier free conversion of NO to N and H2O where the physical origin rests on negative-negative repulsion of NO over iron oxide clusters. The by-product H2O can be a hydrogen source due to electrolysis or re-visiting Fe4O2 and hence, the reaction is self-sustainable. Furthermore, the above reactions are performed by depositing Fe4O2 clusters on graphene/Cu(111) where the barrier free conversion of NO to NH3 is also observed, predicting that such reaction can be applicable. Thus, low temperature conversion of NO to NH3 over Fe4O2 can be predicted. The detailed reaction pathway and mechanism are presented.


Lifestyles of men in barren couples and their relationships to sperm quality.
This study is based on a questionnaire which focused on the possible association between lifestyle factors and male fertility in a group of 252 men attending our laboratory in connection with a fertility investigation. Their answers were correlated to sperm quality. No association could be documented between sperm quality and smoking habits, coffee drinking, a moderate alcohol intake, exposure to heat (sauna, hot baths, type of underwear, sedentary activities) or physical activities in their leisure time. In contrast, the reported average ejaculation frequency was significantly positively correlated to the motility of the sperm (% progressive) but inversely related to the proportion of sperm with abnormal morphology and semen volume. This indicates that the lifestyle of the subject has little, if any, impact on semen quality, at least within the limits recorded in the present study.


Reducing anxiety by pre-operative education: make the future familiar.
Pre-operative education is widely used by occupational therapists all over the world to help patients prepare for their impending surgery and post-operative needs. The purpose of this research was to gain understanding of how the pre-operative education process is beneficial in reducing anxiety for patients awaiting a total hip replacement provided in one National Health Service Trust in England. The participants in this study were a convenient sample of health care professionals who presented information on pre-operative education during a nine-month data collection period, and a sample of patients who attended the programme. Data were collected from observing five pre-operative education programmes, 26 written patient evaluations, 16 interviews with seven presenters of the education, observation of three team meetings, 20 interviews with 10 patients, and documentation pertaining to the programme. From the results it seems that patient education can reduce anxiety by making the unknown familiar. Such familiarity can be achieved in three ways by: providing an understanding of the experiences patients will encounter during and after surgery; giving an opportunity to meet the staff that will be caring for them; and familiarizing patients with the environments they will meet when in hospital. Major limitations of the study were not being able to control for researcher bias and not providing a standardized instrument to collect data. It is recommended that further research be carried out to understand the dynamics between patient education and the reduction of anxiety among patients undergoing hip replacements.


Role of anti-oncomirs miR-143 and -145 in human colorectal tumors.
We examined the expression levels of microRNAs (miRNAs (miRs)) in colorectal tumors (63 cancer specimens and 65 adenoma specimens) and paired non-tumorous tissues. Decreased expression of miR-143 and -145 was frequently observed in the adenomas and cancers tested, compared with miR-34a downregulation and miR-21 upregulation. Expression profiles of miR-143 and -145 were not associated with any clinical features. As the downregulation of miR-143 and -145 was observed even in the early phase of adenoma formation, the decreased expression of both miRs would appear to contribute mainly to the initiation step of tumorigenesis, not to the progression stage, and not to clinical prognostic factors. For clinical application, we changed the sequences of the passenger strand in the miR-143 duplex and performed chemical modification at the 3'-overhang portion of miR-143, leading to greater activity and stability to nuclease. The cell growth inhibitory effect of the chemically modified synthetic miR-143 in vitro was greater than that of endogenous miR-143. The miR-143 showed a significant tumor-suppressive effect on xenografted tumors of DLD-1 human colorectal cancer cells. These findings suggest that miR-143 and -145 are important onco-related genes for the initiation step of colorectal tumor development and that the chemically modified synthetic miR-143 may be a hopeful candidate as an RNA medicine for the treatment of colorectal tumors.


Development and psychometric evaluation of the FACE-Q Aging Appraisal Scale and Patient-Perceived Age Visual Analog Scale.
The primary outcome measures for patients who undergo aesthetic facial procedures are quality of life and satisfaction with appearance. The FACE-Q, a new patient-reported outcome (PRO) instrument composed of independently functioning scales, is designed to measure a broad range of important outcomes in patients who undergo cosmetic surgical and/or nonsurgical facial procedures. The authors describe the development and psychometric evaluation of the FACE-Q Aging Appraisal Scale and the FACE-Q Patient-Perceived Age Visual Analog Scale (VAS). International guidelines for creating PRO instruments were strictly observed throughout development of the FACE-Q scales. Qualitative methods were used to identify the concepts most important to patients who received aesthetic facial procedures. These were turned into "items"-and the resultant FACE-Q Aging Appraisal Scale was field tested, along with the Patient-Perceived Age VAS, in 288 patients who underwent cosmetic surgical and/or nonsurgical facial procedures. Rasch measurement theory and traditional psychometric methods confirmed the reliability and validity of the scales. The FACE-Q Aging Appraisal Scale and Patient-Perceived Age VAS are psychometrically sound, condition-specific PRO instruments with excellent reliability and validity. They enable accurate outcome assessments in patients who undergo aesthetic facial procedures.


Menstrual and reproductive factors in relation to ovarian cancer risk.
We assessed menstrual and reproductive factors in relation to ovarian cancer risk in a large, population-based, case-control study. 563 cases in Massachusetts and New Hampshire were ascertained from hospitals and statewide tumour registries; control women (n = 523) were selected through random digit dialing and matched to case women by age and telephone sampling unit. We used multivariate logistic regression to evaluate factors in relation to risk of ovarian cancer and the major tumour histologic subtypes. Ovarian cancer risk was reduced among parous women, relative to nulliparous women (OR = 0.4; 95% CI = 0.3-0.6). Among parous women, higher parity (P = 0.0006), increased age at first (P = 0.03) or last (P = 0.05) birth, and time since last birth (P = 0.04) were associated with reduced risk. Early pregnancy losses, abortions, and stillbirths were unrelated to risk, but preterm, term, and twin births were protective. Risk was lower among women who had breast-fed, relative to those who had not (OR = 0.7; 95% CI = 0.5-1.0), but the average duration of breast-feeding per child was unrelated to risk (P for trend = 0.21). Age at menarche and age at menopause were unrelated to risk overall, although increasing menarcheal age was protective among premenopausal women (P = 0.02). Menstrual cycle characteristics and symptoms were generally unrelated to risk, although cycle-related insomnia was associated with decreased risk (OR = 0.5; 95% CI = 0.3-0.8). We found no association between the type of sanitary product used during menstruation and ovarian cancer risk. In analyses by histologic subtype, reproductive and menstrual factors had most effect on risk of endometrioid/clear cell tumours, and least influential with regard to risk of mucinous tumours. Overall, our findings offer some support to current hypotheses of ovarian pathogenesis, and show aetiologic differences among the tumour subtypes.


Emotions and personality traits as high-level factors in visual attention: a review.
The visual sense has outstanding significance for human perception and behavior, and visual attention plays a central role in the processing of the sensory input. Thereby, multiple low- and high-level factors contribute to the guidance of attention. The present review focuses on two neglected high-level factors: emotion and personality. The review starts with an overview of different models of attention, providing a conceptual framework and illustrating the nature of low- and high-level factors in visual attention. Then, the ambiguous concept of emotion is described, and recommendations are made for the experimental practice. In the following, we present several studies showing the influence of emotion on overt attention, whereby the distinction between internally and externally located emotional impacts are emphasized. We also provide evidence showing that emotional stimuli influence perceptual processing outside of the focus of attention, whereby results in this field are mixed. Then, we present some detached studies showing the reversed causal effect: attention can also affect emotional responses. The final section on emotion-attention interactions addresses the interplay on the neuronal level, which has been neglected for a long time in neuroscience. In this context, several conceptual recommendations for future research are made. Finally, based on findings showing inter-individual differences in human sensitivity to emotional items, we introduce the wide range of time-independent personality traits that also influence attention, and in this context we try to raise awareness of the consideration of inter-individual differences in the field of neuroscience.


Model Selection in a Composite Likelihood Framework Based on Density Power Divergence.
This paper presents a model selection criterion in a composite likelihood framework based on density power divergence measures and in the composite minimum density power divergence estimators, which depends on an tuning parameter α . After introducing such a criterion, some asymptotic properties are established. We present a simulation study and two numerical examples in order to point out the robustness properties of the introduced model selection criterion.


Efficiency of repair of an abasic site within DNA clustered damage sites by mammalian cell nuclear extracts.
Ionizing radiation induces clustered DNA damage sites which have been shown to challenge the repair mechanism(s) of the cell. Evidence demonstrating that base excision repair is compromised during the repair of an abasic (AP) site present within a clustered damage site is presented. Simple bistranded clustered damage sites, comprised of either an AP-site and 8-oxoG or two AP-sites, one or five bases 3' or 5' to each other, were synthesized in oligonucleotides, and repair was carried out in xrs5 nuclear extracts. The rate of repair of an AP-site when present opposite 8-oxoG is reduced by up to 2-fold relative to that when an AP-site is present as an isolated lesion. The mechanism of repair of the AP-site shows asymmetry, depending on its position relative to 8-oxoG on the opposite strand. The AP-site is rejoined by short-patch base excision repair when the lesions are 5' to each other, whereas when the lesions are 3' to one another, rejoining of the AP-site occurs by both long-patch and short-patch repair processes. The major stalling of repair occurs at the DNA ligase step. 8-OxoG and an AP-site present within a cluster are processed sequentially, limiting the formation of double-strand breaks to <4%. In contrast, when two AP-sites are contained within the clustered DNA damage site, both AP-sites are incised simultaneously, giving rise to double-strand breaks. This study provides new insight into understanding the processes that lead to the biological consequences of radiation-induced DNA damage and ultimately tumorigenesis.


Detection of the aerolysin gene in Aeromonas hydrophila by the polymerase chain reaction.
Synthetic oligonucleotide primers were used in a polymerase chain reaction (PCR) technique to detect the gene for aerolysin in strains of Aeromonas hydrophila and to screen for identical genes in A. caviae, A. sobria, and A. veronii isolated from patients with diarrheal disease. Primers targeted a 209-bp fragment of the aer gene coding for the beta-hemolysin and detected template DNA only in the PCR using nucleic acid (NA) from hemolytic strains of A. hydrophila which were also cytotoxic to Vero and CHO cells and enterotoxic in suckling-mouse assays. PCR amplification of NA from hemolytic A. sobria or nonhemolytic A. hydrophila and A. caviae strains was consistently negative. Primer specificity was determined in the PCR by using NA extracted from 56 strains of bacteria, including hemolytic Escherichia coli and Listeria monocytogenes as well as several recognized enteric pathogens defined in terms of their toxigenicity. The detection limit for the aerolysin gene by PCR amplification was 1 ng of total NA. The PCR clearly identified aerolysin-producing strains of A. hydrophila and may have application as a species-specific virulence test because other hemolytic Aeromonas species tested were negative.


Psychological distress among adolescents in Chengdu, Sichuan at 1 month after the 2008 Sichuan earthquake.
A devastating earthquake occurred on May 12, 2008 in Sichuan, China. This study investigated the prevalence and factors in association with psychological problems among secondary school students living in Chengdu (90 km away from the disaster epicenter) in June 2008. In a cross-sectional survey, 3,324 secondary students self-administered a structured questionnaire in classroom setting. Validated scales were used in this study. Among all respondents, 22.3% reported post-traumatic stress disorder (PTSD); 22.6% were probable depression cases; 10.6% reported suicidal ideation; and 14.1% would like to receive psychological counseling. No gender differences were found. While social/emotional support from teachers or peers (OR from 0.40 to 0.78) and exposure to positive news reports (OR from 0.59 to 0.62) were found protective, prior experience of severe mental distress (OR from 1.60 to 2.68) and corporal punishment (OR from 1.31 to 1.58), worry about future aftershocks (OR from 1.64 to 3.11), absence from school when it was not closed (OR from 1.38 to 1.48), exposures to scary or sorrowful disaster media coverage (OR from 1.39 to 2.07), post-disaster visits to affected sites (OR from 1.51 to 1.59), separation from parents (OR = 1.61), etc., were risk factors predictive of some of the aforementioned psychological problems. Negative mental health impacts were prevalent among the respondents. Teachers, parents, and the mass media are all important in maintaining good mental health among adolescents that are indirectly affected by the severe earthquake. The results have important implications for earthquake preparedness and relief work in the future.


Brief Arabic tobacco craving questionnaire: An investigation into craving and heavy smoking in Saudi Arabian males.
Research in the United States has shown that craving tobacco is associated with smoking, yet no investigation has been done into the relationship between craving and the use of tobacco in Saudi Arabian smokers. The aim of this cross-sectional study was to examine the craving of tobacco by Saudi males and its influence on daily smoking. Subjects were recruited under the auspices of the Tobacco Control Program in Jeddah City and Riyadh. The American English version of the tobacco craving questionnaire (TCQ-12) is a valid measure of four distinct aspects (factors) of tobacco craving. The TCQ-12 was translated into Arabic tobacco craving questionnaire (ATCQ-12) and administered to a sample of 322 male smokers. Predictive validity was determined by examining the relationship between the factors and the number of cigarettes smoked per day (CPD). In a general linear multivariate analysis of variance model, CPD increased significantly as either ATCQ-12 Factor 1 (emotionality) or Factor 3 (compulsiveness) increased. A significant Factor 1 by Factor 3 interaction indicated that Factor 1 was a better predictor of heavy smoking, but only when Factor 3 was low. Factor 3 was a better predictor of heavy smoking, but only when Factor 1 was low. The ATCQ-12 is a rapid measure of craving and valid predictor of CPD and heavy smoking. Craving in anticipation of smoking as relief from a negative mood (emotionality) is an indicator of psychological withdrawal symptoms, while craving in anticipation of the inability to control tobacco use (compulsiveness) is an indicator of physical dependence.


Case study: bipolar disorder after head injury.
A case of bipolar disorder subsequent to a mild head injury in a 15-year-old girl is reported. Review of the literature indicates that this is an extremely rare outcome. Lack of adequate follow-up studies makes it difficult to accurately predict type and severity of psychiatric outcome. Assessment and management involves ongoing consideration of both organic and psychosocial factors even after initial negative investigations.


The Precautionary Principle, epidemiology and the ethics of delay.
Ethics tells us: do good and do no harm and invokes the norms of justice, equity and respect for autonomy in protecting and promoting health and well-being. The Precautionary Principle, a contemporary re-definition of Bradford Hill's case for action, gives us a common sense rule for doing good by preventing harm to public health from delay: when in doubt about the presence of a hazard, there should be no doubt about its prevention or removal. It shifts the burden of proof from showing presence of risk to showing absence of risk, aims to do good by preventing harm, and subsumes the upstream strategies of the Driving Forces Pressure Stress Exposure Effect Action model and downstream strategies from molecular epidemiology for detection and prevention of risk. The Precautionary Principle has emerged because of the ethical import of delays in detection of risks to human health and the environment. Ethical principles, the Precautionary Principle, the DPSEEA model and molecular epidemiology all imply re-emphasizing epidemiology's classic role for early detection and prevention. Delays in recognizing risks from past exposures and acting on the findings (e.g., cigarette smoking and lung cancer, asbestos, organochlorines and endocrine disruption, radiofrequency, raised travel speeds) were examples of failures that were not only scientific, but ethical, since they resulted in preventable harm to exposed populations. These may delay results from, among other things, external and internal determinants of epidemiologic investigations of hazard and risk, including misuse of tests of statistical significance. Furthermore, applying the Precautionary Principle to ensure justice, equity, and respect for autonomy raises questions concerning the short-term costs of implementation to achieve long-term goals and the principles that guide compensation.


Enhanced induction of mitochondrial damage and apoptosis in human leukemia HL-60 cells due to electrolyzed-reduced water and glutathione.
Electrolzyed-reduced water (ERW) is a higher pH and lower oxidation-reduction potential water. In the present study, we examined the enhanced effect of ERW in the apoptosis of leukemia cells (HL-60) induced by glutathione (GSH). An enhanced inhibitory effect on the viability of the HL-60 cells was observed after treatment with a combination of ERW with various concentrations of GSH, whereas no cytotoxic effect in normal peripheral blood mononuclear cells was observed. The results of apoptotic related protein indicated that the induction of HL-60 cell death was caused by the induction of apoptosis through upregulation of Bax and downregulation of Bcl-2. The results of further investigation showed a diminution of intracellular GSH levels in ERW, and combination with GSH groups. These results suggest that ERW is an antioxidant, and that ERW, in combination with GSH, has an enhanced apoptosis-inducing effect on HL-60 cells, which might be mediated through the mitochondria-dependent pathway.


Development of glyburide fast-dissolving tablets based on the combined use of cyclodextrins and polymers.
Commercial tablets of glyburide exhibit unsatisfactory dissolution profiles and, consequently, problems of bioinequivalence and poor bioavailability. The aim of this work was to develop glyburide fast-dissolving tablets by exploiting the solubilizing effect of different cyclodextrins (CDs), alone or in combination with hydrophilic polymers. Drug-CD and drug-CD-polymer systems, prepared by different techniques, were characterized by differential scanning calorimetry (DSC), X-ray diffractometry, and Fourier transform infra-red (FT-IR) spectroscopy. Tablets containing binary and ternary systems were prepared by direct compression and evaluated for technological properties and dissolution behavior in comparison with a reference formulation containing the plain drug. A significant improvement of the drug dissolution profile was achieved from tablets containing drug-CD systems (coevaporated products doubled drug dissolution efficiency [DE]), but 100% drug dissolution was never reached. Better results were obtained with ternary systems. In particular, polyvinylpyrrolidone (PVP) emerged as the most effective polymer, and tablets with drug-PVP-hydroxypropyl-betaCD coevaporated products showed the best dissolution profiles, reaching 100% dissolved drug within only 15 min.


Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter's syndrome after long-term testosterone substitution.
Klinefelter's syndrome (KS) is a common sex chromosomal disorder associated with androgen deficiency and osteoporosis. Only few bone mineral density (BMD) and no quantitative ultrasound (QUS) data are available in these patients after long-term testosterone replacement therapy. We examined in a cross-sectional study 52 chromatin-positive KS patients aged 39.1 +/- 12.4 years (mean +/- SD). Patients had been treated with oral or parenteral androgens for 9.2 +/- 8.2 years (range 1-32 years). Areal BMD and bone mineral apparent density (BMAD, i.e., estimated volumetric BMD) at the lumbar spine, total hip and femoral neck were determined by dual-energy X-ray absorptiometry. BMD T-scores in the patient group were calculated based on three different North American reference databases. The QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the calcaneus using an ultrasound imaging device (UBIS 3000) and were compared with QUS results in a sex-, age- and height-matched control group. QUS T-scores were calculated based on the results of QUS measurements in 50 normal Dutch men between the ages of 20 and 30 years. QUS and BMD results in the KS patient group were compared. Overall, based on the three reference databases, 46% and 63% of the KS patients had a T-score between -1 and -2.5 and a further 10% and 14% had a T-score < or = -2.5 at the total hip and/or lumbar spine, as measured by areal BMD or BMAD, respectively. Thirty-nine percent of the KS patients had a T-score between -2.5 and -1, while 2% had a T-score < or = -2.5 for BUA and/or SOS. BUA (77.7 +/- 15.0 dB/MHz) and SOS (1518.8 +/- 36.5 m/s) were significantly lower in the KS patients than in age- and height-matched controls (87.1 +/- 17.8 dB/MHz, p < 0.005, and 1536.5 +/- 42.5 m/s, p < 0.05). Correlation coefficients between the QUS parameters and areal BMD (0.28 to 0.37) or BMAD (0.27 to 0.46) were modest. ROC analysis showed that discrimination of a BMD or BMAD T-score < or = -2.5 with either BUA or SOS was not statistically significant. Although a limitation of our study is that direct comparison of BMD and QUS T-scores is not possible because in the control group in which QUS parameters were determined no BMD measurements were performed, we conclude that despite long-term testosterone replacement therapy, a considerable percentage of patients with KS had a BMD T-score < -1 or even < or = -2.5, based on different North American reference databases. This percentage was even higher for BMAD. QUS parameters were also low in the KS patient group when compared with Dutch control subjects. QUS parameters cannot be used to predict BMD or BMAD in KS patients.


EEG machine learning for accurate detection of cholinergic intervention and Alzheimer's disease.
Monitoring effects of disease or therapeutic intervention on brain function is increasingly important for clinical trials, albeit hampered by inter-individual variability and subtle effects. Here, we apply complementary biomarker algorithms to electroencephalography (EEG) recordings to capture the brain's multi-faceted signature of disease or pharmacological intervention and use machine learning to improve classification performance. Using data from healthy subjects receiving scopolamine we developed an index of the muscarinic acetylcholine receptor antagonist (mAChR) consisting of 14 EEG biomarkers. This mAChR index yielded higher classification performance than any single EEG biomarker with cross-validated accuracy, sensitivity, specificity and precision ranging from 88-92%. The mAChR index also discriminated healthy elderly from patients with Alzheimer's disease (AD); however, an index optimized for AD pathophysiology provided a better classification. We conclude that integrating multiple EEG biomarkers can enhance the accuracy of identifying disease or drug interventions, which is essential for clinical trials.


Methods to Generate Innovative Research Ideas and Improve Patient and Public Involvement in Modern Epidemiological Research: Review, Patient Viewpoint, and Guidelines for Implementation of a Digital Cohort Study.
Patient and public involvement (PPI) in research aims to increase the quality and relevance of research by incorporating the perspective of those ultimately affected by the research. Despite these potential benefits, PPI is rarely included in epidemiology protocols. The aim of this study is to provide an overview of methods used for PPI and offer practical recommendations for its efficient implementation in epidemiological research. We conducted a review on PPI methods. We mirrored it with a patient advocate's viewpoint about PPI. We then identified key steps to optimize PPI in epidemiological research based on our review and the viewpoint of the patient advocate, taking into account the identification of barriers to, and facilitators of, PPI. From these, we provided practical recommendations to launch a patient-centered cohort study. We used the implementation of a new digital cohort study as an exemplary use case. We analyzed data from 97 studies, of which 58 (60%) were performed in the United Kingdom. The most common methods were workshops (47/97, 48%); surveys (33/97, 34%); meetings, events, or conferences (28/97, 29%); focus groups (25/97, 26%); interviews (23/97, 24%); consensus techniques (8/97, 8%); James Lind Alliance consensus technique (7/97, 7%); social media analysis (6/97, 6%); and experience-based co-design (3/97, 3%). The viewpoint of a patient advocate showed a strong interest in participating in research. The most usual PPI modalities were research ideas (60/97, 62%), co-design (42/97, 43%), defining priorities (31/97, 32%), and participation in data analysis (25/97, 26%). We identified 9 general recommendations and 32 key PPI-related steps that can serve as guidelines to increase the relevance of epidemiological studies. PPI is a project within a project that contributes to improving knowledge and increasing the relevance of research. PPI methods are mainly used for idea generation. On the basis of our review and case study, we recommend that PPI be included at an early stage and throughout the research cycle and that methods be combined for generation of new ideas. For e-cohorts, the use of digital tools is essential to scale up PPI. We encourage investigators to rely on our practical recommendations to extend PPI in future epidemiological studies.


Autophoretic locomotion from geometric asymmetry.
Among the few methods which have been proposed to create small-scale swimmers, those relying on self-phoretic mechanisms present an interesting design challenge in that chemical gradients are required to generate net propulsion. Building on recent work, we propose that asymmetries in geometry are sufficient to induce chemical gradients and swimming. We illustrate this idea using two different calculations. We first calculate exactly the self-propulsion speed of a system composed of two spheres of unequal sizes but identically chemically homogeneous. We then consider arbitrary, small-amplitude, shape deformations of a chemically homogeneous sphere, and calculate asymptotically the self-propulsion velocity induced by the shape asymmetries. Our results demonstrate how geometric asymmetries can be tuned to induce large locomotion speeds without the need of chemical patterning.


Pinaverium Reduces Symptoms of Irritable Bowel Syndrome in a Multicenter, Randomized, Controlled Trial.
Pinaverium bromide (pinaverium) is an antispasmodic commonly used to treat irritable bowel syndrome (IBS), but there has been no convincing evidence for its effectiveness and safety. We evaluated these in a prospective, double-blind, placebo-controlled trial. Patients with IBS, based on Rome III criteria, were assigned randomly to groups given pinaverium (50 mg, 3 times/day; n = 218) or placebo (3 times/day; n = 209) at 4 hospitals in China, from August 2012 through December 2013. The primary end points were reductions in abdominal pain and Bristol stool score. Secondary end points were reductions in pain and stool frequencies and abdominal discomfort and its frequency. We also evaluated changes in IBS global symptom scores and the number of adverse effects. Based on an intention-to-treat analysis, a significantly larger proportion of patients receiving pinaverium met either of the primary end points (50.0% met an end point at week 2, and 77.5% met an end point at week 4), compared with placebo (P < .001). Pinaverium reduced at least 1 secondary end point in significantly more patients receiving pinaverium (76.1% had a reduction at week 2, and 91.7% had a reduction at week 4) than placebo (P < .001). Based on symptom scores, significantly higher percentages of patients receiving pinaverium believed that their IBS symptoms improved (60%) than in the placebo group (34%; P < .001); 29% of patients in the pinaverium group believed that their IBS symptoms stayed the same (29%) and 11% said they worsened. Pinaverium was not associated with severe adverse effects; common side effects included nausea (3.7%), dizziness (3.2%), increased blood pressure (2.3%), and abdominal discomfort (2.3%). Based on a controlled trial, pinaverium reduces symptoms of IBS. It can be considered a first-line treatment for IBS. NCT01641224 (www.ClinicalTrials.gov).


A new approach to the analysis of piezoelectric cladded acoustic fibers.
In this paper, a new effective analysis method is proposed for the piezoelectric cladded acoustic fiber of hexagonal crystal symmetry. Interpreting all quantities appearing in the boundary conditions as state variables, a first-order differential equations system is obtained to investigate the waves in cladded acoustic fiber of hexagonal symmetry. This approach makes possible the analysis of cladded fibers by the general transmission-matrix technique. By using this method, dispersion relations for all modes are easily obtained. Examples of several materials are given. This method can also be applied in the analysis of the multilayered cylindrical fiber for which the individual layers have hexagonal symmetric piezoelectrical material.


The inter- and intraexaminer reliability of the Gonstead pelvic marking system.
An investigation was undertaken to determine the inter- and intraexaminer reliability of the Gonstead pelvic radiographic marking system. This methodology analyzes the relative dimensions and spatial positions of the two innominate bones and sacrum and measures leg length inequality through an evaluation of femur head height. Two examiners marked 71 full spine radiographs twice to provide data from 284 analyses. Reliability was ascertained with the Pearson r, Spearman, intraclass correlation coefficient (ANOVA) and Kappa statistics. All results were statistically significant (less than 0.001) and indicated high levels of concordance. In every case, intraexaminer agreement was superior to interexaminer concordance.


NMR analysis of methyl groups at 100-500 kDa: model systems and Arp2/3 complex.
Large macromolecular machines are among the most important and challenging targets for structural and mechanistic analyses. Consequently, there is great interest in development of NMR methods for the study of multicomponent systems in the 50-500 kDa range. Biochemical methods also must be developed in concert to produce such systems in selectively labeled form. Here, we present (1)H/(13)C-HSQC spectra of protonated methyl groups in a model system that mimics molecular weights up to approximately 560 kDa. Signals from side chain methyl groups of Ile, Leu, and Val residues are clearly detectable at correlation times up to approximately 330 ns. We have also developed a biochemical procedure to produce the 240 kDa, heteroheptameric Arp2/3 actin nucleation complex selectively labeled at one subunit and obtained (1)H/(13)C-HSQC spectra of this assembly. Sensitivity in spectra of both the Arp2/3 complex and the model system indicate that methyl groups will be useful sources of information in nonsymmetric systems with molecular weights greater than 600 kDa at concentrations less than 100 microM. Methyl analyses will complement TROSY and CRINEPT analyses of amides in NMR studies of structure and molecular interactions of extremely large macromolecules and assemblies.


Economic evaluation of "pulse dose" radiofrequency in the treatment of occipital neuralgia headache.
Headache occipital neuralgia is an example of pain-disease for which treatment both pharmacological protocols and invasive methods are used. Among the latter, the RF (Radiofrequency) pulse-dose has been of interest for the prospects of analgesic efficacy, safety and patient compliance, although at the moment only data concerning the pulsed RF and not the RF pulse-dose, that represents its evolution, are discussed in scientific literature. The purpose of this study is a "simple" economic evaluation of this method in headache occipital neuralgia.


Complexes of polyriboguanylate with modified polyribocytidylate.
It was established minimal length of continuous poly(C) sequence of poly(G).poly(C) complex required for effective interferon induction by investigation poly(G).poly(C,A) with different molar ratios of C:A varying from 10:1 to 90:1. The minimum length of the double-stranded sequence of the macromolecule complex poly(G).poly(C) is equal to at least 90-100 nucleotides. The effect of 5-halogen-polyribocytidilates on the properties of the complexes has been also investigated.