A cost-effectiveness analysis of diagnostic strategies for symptomatic patients with ileal pouch-anal anastomosis.
Pouchitis is often diagnosed based on symptoms and empirically treated with antibiotics (treat-first strategy). However, symptom assessment alone is not reliable for diagnosis, and an initial evaluation with pouch endoscopy (test-first strategy) has been shown to be more accurate. Cost-effectiveness of these strategies has not been compared. The aim of this study was to compare cost-effectiveness of different clinical approaches for patients with symptoms suggestive of pouchitis. Pouchitis was defined as pouchitis disease activity index scores > or =7. The frequency of pouchitis in symptomatic patients with ileal pouch was estimated to be 51%; the efficacy for initial therapy with metronidazole (MTZ) and ciprofloxacin (CIP) was 75% and 85%, respectively. Cost estimates were obtained from Medicare reimbursement data. Six competing strategies (MTZ trial, CIP trial, MTZ-then-CIP trial, CIP-then-MTZ trial, pouch endoscopy with biopsy, and pouch endoscopy without biopsy) were modeled in a decision tree. Costs per correct diagnosis with appropriate treatment were $194 for MTZ trial, $279 for CIP trial, $208 for MTZ-then-CIP trial, $261 for CIP-then-MTZ trial, $352 for pouch endoscopy with biopsy, and $243 for pouch endoscopy without biopsy. Of the two strategies with the lowest cost, the pouch endoscopy without biopsy strategy costs $50 more per patient than the MTZ trial strategy but results in an additional 15 days for early diagnosis and thus initiation of appropriate treatment (incremental cost-effectiveness ratio $3 per additional day gained). The results of base-case analysis were robust in sensitivity analyses. Although the MTZ-trial strategy had the lowest cost, the pouch endoscopy without biopsy strategy was most cost-effective. Therefore, based on its relatively low cost and the avoidance of both diagnostic delay and adverse effects associated with unnecessary antibiotics, pouch endoscopy without biopsy is the recommended strategy among those tested for the diagnosis of pouchitis.


Could Fidicina mannifera (Hemiptera: Cicadoidea: Fidicinini) promote a resource pulse in two Brazilian Cerrado vegetation classes?
Cicadas are usually studied regarding their importance in agriculture. However, the possibility of this group to represent a pulse of nutrients can also imply on the success of a given species in the biome. The aim of this study was to assess the level of total soluble proteins and lipids of Fidicina mannifera (Fabricius, 1803), and to determine whether the species can promote a pulse of nutrients in two vegetation classes of the Brazilian Cerrado. To assess the pulse of nutrients, it was concluded the determination of total soluble proteins and lipids from samples of males and adult females of F. mannifera, and the spatial distribution of exuviae of this species was also calculated in two vegetation classes of the Brazilian Cerrado. The amount of protein provided by each individual did not differ between males and females (p = 0.66) but females had 40% more lipids than males (p = 0.05). Regarding F. mannifera the gallery forest offered 11.75 g/ha of protein, 3.91 g/ha of lipids, and the Cerrado stricto sensu offered 4.25 g/ha of protein, and 1.41 g/ha of lipid. The male cicadas have a hollow abdomen, which houses a resonance chamber for sound production in order to attract females to mate, and females store larger amounts of lipids, mainly located in the abdominal cavity, where the body fat is directly linked to the reproductive system for the development of the ovaries and egg production after emergence. The mass occurrence of F. mannifera in the Brazilian Cerrado and the fast availability of proteins and lipids make this species a food resource that can directly impact the diet of secondary consumers and scavengers, although the amount of nutrients available by F. mannifera does not promote a pulse of nutrients in the study site.


Non-small cell lung cancer in young adults: presentation and survival in the English National Lung Cancer Audit.
Non-small cell lung cancer (NSCLC) in young adults is a rare but devastating illness with significant socioeconomic implications, and studies of this patient subgroup are limited. This study employed the National Lung Cancer Audit to compare the clinical features and survival of young adults with NSCLC with the older age groups. A retrospective cohort review using a validated national audit dataset. Data were analysed for the period between 1 January 2004 and 31 December 2011. Young adults were defined as between 18 and 39 years, and all others were divided into decade age groups, up to the 80 years and above group. We performed logistic and Cox regression analyses to assess clinical outcomes. Of a total of 1 46 422 patients, 651 (0.5%) were young adults, of whom a higher proportion had adenocarcinoma (48%) than in any other age group. Stage distribution of NSCLC was similar across the age groups and 71% of young patients had stage IIIb/IV. Performance status (PS) was 0-1 for 85%. Young adults were more likely to have surgery and chemotherapy compared with the older age groups and had better overall and post-operative survival. The proportion with adenocarcinoma, better PS and that receiving surgery or chemotherapy diminished progressively with advancing decade age groups. In our cohort of young adults with NSCLC, the majority had good PS despite the same late-stage disease as older patients. They were more likely to have treatment and survive longer than older patients.


Prediction of treatment outcomes in psychiatry--where do we stand ?
Psychiatric treatment relies on a solid armamentarium of pharmacologic and nonpharmacologic treatment modalities that perform reasonably well for many patients but leave others in a state of chronic disability or troubled by problematic side effects. Treatment planning in psychiatry remains an art that depends on considerable trial and error. Thus, there is an urgent need for better tools that will provide a means for matching individual patients with the most effective treatments while minimizing the risk of adverse events. This review will consider the current state of the science in predicting treatment outcomes in psychiatry. Genetic and other biomarkers will be considered alongside clinical diagnostic, and family history data. Problems inherent in prediction medicine will also be discussed, along with recent developments that support the hope that psychiatry can do a better job in quickly identifying the best treatments for each patient.


Alcohol withdrawal syndrome: how to predict, prevent, diagnose and treat it.
(1) When people who are physically dependent on alcohol stop drinking, they experience an alcohol withdrawal syndrome. The symptoms generally resolve spontaneously within a week, but more severe forms may be associated with generalised seizures, hallucinations and delirium tremens, which can be fatal. (2) We carried out a literature review in order to obtain answers to the following questions: how to predict or rapidly diagnose a severe alcohol withdrawal syndrome; how to prevent and treat this syndrome; how to manage severe forms; and how to deal with the risk of vitamin B1 deficiency. (3) The main risk factors for severe withdrawal syndrome are: chronic heavy drinking; a history of generalised seizures; and a history of delirium tremens. (4) Anxiety, agitation, tremor, excessive sweating, altered consciousness and hallucinations are signs of a severe withdrawal syndrome. (5) Individual support and effective communication seem to reduce the risk of severe withdrawal syndrome. (6) Oral benzodiazepines are the best-assessed drugs for preventing a severe alcohol withdrawal syndrome, particularly the risk of seizures. When given for a maximum of 7 days, the adverse effects are usually mild. (7) Clinical trials of other antiepileptics suggest they are less effective than benzodiazepines, and their addition to benzodiazepine therapy offers no tangible advantage. (8) Betablockers increase the risk of hallucinations, and clonidine increases the risk of nightmares, and the efficacy of these two drugs is not well documented. Neuroleptics increase the risk of seizures. There are no convincing data to support the use of magnesium sulphate or meprobamate (the latter carries a risk of serious adverse effects). Acamprosate, naltrexone and disulfiram are not beneficial in alcohol withdrawal. (9) Gradual withdrawal, i.e. ingestion of decreasing amounts of alcohol, has not been compared with other methods but is generally not recommended. (10) There are no specific recommendations on hydration. Note that excessive water-sodium intake carries a risk of pulmonary oedema in patients with heart disease. (11) As vitamin B1 deficiency is frequent and can lead to serious complications in alcohol-dependent patients, oral vitamin B1 supplementation is widely recommended, despite the absence of comparative trials. High doses must be used to compensate for poor absorption. Intravenous administration is best if patients have very poor nutritional status or severe complications such as Gayet-Wernicke encephalopathy (a medical emergency), even though rare anaphylactic reactions have been reported after vitamin B1 injection. (12) Planned alcohol withdrawal in specialised hospital units has been extensively studied. Outpatient withdrawal may be more appropriate for patients who are at low risk of developing severe withdrawal syndrome. (13) A large proportion of alcohol-dependent patients were excluded from trials of withdrawal strategies. These include elderly patients, patients with serious psychiatric or somatic disorders, and patients who are also dependent on other substances. (14) An oral benzodiazepine is the best-assessed treatment for a single episode of generalised seizures or hallucinations during alcohol withdrawal. (15) In randomised comparative trials benzodiazepines were more effective than neuroleptics in preventing delirium-related mortality. Currently, with appropriate fluid-electrolyte support, continuous monitoring of vital signs, and respiratory support if necessary, the mortality rate for delirium tremens is under 3%. (16) In practice, patients who are attempting to stop drinking alcohol need close personal support and communication, and a reassuring environment, as well as regular monitoring for early signs of a withdrawal syndrome; the latter may require benzodiazepine therapy.


Aneurysms of the ascending aorta and arch: the role of imaging in diagnosis and surgical management.
Thoracic aortic aneurysms tend to be asymptomatic and were previously often diagnosed only after a complication such as dissection or rupture occurred. Better imaging techniques and an increase in the use of cross-sectional imaging has led to an increase in the diagnosis of aortic aneurysms, which has allowed for elective treatment prior to the development of a complication. The location, size and etiology of an aneurysm all impact the clinical outcomes and these factors are used to determine the appropriate timing of surgical replacement. Surgeons often rely on the information obtained from preoperative imaging to determine when to intervene and what type of procedure will be necessary, making it important for the radiologist to understand these issues in order to provide the necessary information. Postoperative imaging after surgical replacement of the aorta is also important, as there are some common findings that occur in this patient population that can impact how they are treated. The purpose of this article is to review the etiology and associated findings of aneurysms of the ascending aorta and arch, with a focus on how computed tomography angiography and magnetic resonance angiography findings are used to determine the appropriate timing for elective replacement and the type of surgical procedure, as well as the role of follow-up imaging. This will include a review of the most commonly performed types of surgical procedures, to provide an understanding of how the findings of preoperative imaging studies impact what the surgeon does in the operating room, as well as the expected findings of postoperative imaging studies.


The pineal gland: anatomy, physiology, and clinical significance.
Since the discovery of melatonin approximately 25 years ago, there has been intense study regarding the details of the structure and function of the pineal gland. This work is reviewed, with particular emphasis on those aspects of importance to human physiology and disease.


Associations between adolescent socioeducational status and use of snus and smoking.
Findings from studies on the association between smoking and socioeconomic status are mixed. While adolescent smoking is reduced in many countries, use of smokeless tobacco seems to increase. Associations between socioeducational status and smoking as well as use of snus (smokeless tobacco), and to what extent these associations had changed significantly from 2004 to 2007 (a period of relatively abrupt changes in tobacco use in Norway), were examined. Data from two national representative cross-sectional studies of Norwegian 16-20 year olds, where participants were asked questions allowing us to construct indicators of socioeducational status, was used. Information was also collected about the adolescents' smoking and use of snus, as well as their intentions with regard to future use of these products. Adolescents with a lower socioeducational status had much higher odds for smoking compared to those with higher socioeducational status (ORs ranged from 2.9 to 3.8). There was no similar association between socioeducational status and snus use (ORs ranged from 0.6 to 1.2). No support was found for a change in the socioeducational status-smoking/snus use association from 2004 to 2007. Adolescents' socioeducational status was associated with smoking for boys and girls, while there was no similar association with snus use. This may indicate that snus truly deviates from how smoking is distributed across social strata or that snus is at a much earlier stage in the social diffusion process.


Tamoxifen forms DNA adducts in human colon after administration of a single [14C]-labeled therapeutic dose.
Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [(14)C]-labeled therapeutic (20 mg) dose, approximately 18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N(2)-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/10(9) nucleotides. No [(14)C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to alpha-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifen-induced damage displayed a degree of interindividual variability, when present, it was approximately 10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo[4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.


Pharmacokinetic disposition and tissue distribution of bisphenol A in rats after intravenous administration.
This study examined the dose-linearity pharmacokinetics of bisphenol A, a U.S. Environmental Protection Agency (EPA) classified endocrine disruptor, in rats following iv administration. Upon iv injection of 0.2, 0.5, 1, or 2 mg/kg, serum levels of bisphenol A declined biexponentially, with mean initial distribution and elimination half-life ranges of 4-8.2 min and 38.6-62.2 min, respectively. There were no significant alterations in the systemic clearance rate (mean range 90.1-123.6 ml/min/kg) and the steady-state volume of distribution (mean range 4.6-6.0 L/kg) as a function of the administered dose. In addition, the area under the serum concentration-time curve linearly rose as the dose was increased. In a second study, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state, and levels were measured in serum and various organs. When expressed in concentration terms (e.g., amount accumulated per gram organ weight), bisphenol A was found predominantly in the lung, followed by kidneys, thyroid, stomach, heart, spleen, testes, liver, and brain. Ratios of the organ to serum bisphenol A concentrations exceeded unity for all the organs examined (ratio range 2.0-5.8) except for brain (ratio 0.75). Given the high systemic clearance and short elimination half-life, bisphenol A is unlikely to accumulate significantly in the rat.


Cyclosporine-induced pseudo-graft-versus-host disease in the early post-cyclosporine period.
Cyclosporine-induced pseudo-graft-versus-host disease (CIPGVHD) in syngeneic or autologous rat marrow chimeras has clinical and histologic features closely resembling classic graft-versus-host disease in the allogeneic chimera. We describe here the pathology and immunopathology of the usual target tissues in CIPGVHD developing in the first week following CsA (early group). The findings are constrasted to the CIPGVHD developing during the second week post-CsA (later group). Six of 9 rats in the early group had acute-type CIPGVHD in the tongue, skin, liver, intestines, and mainstem bronchi. In general, the lymphocytic infiltrates in these tissues were in intimate contact with injured epithelial cells. The intestines had multiple apoptotic lesions. Class II antigen was prominent in the tongue mucosa, but only patchy expression was evident in 2 skin biopsies. All of the lymphocytes infiltrating the mucosa were CD8+(OX-8)/CD4-(W3/25) T cells (OX-19+). Most of the lymphocytes in the lamina propria expressed CD4 as well as CD8 markers, suggesting coexpression. In the later group, 6 of 7 rats had chronic-type CIPGVHD (1 with acute and chronic) while 1 rat had no GVHD (P = .02, Fisher's exact test compared with the early group). These animals had features characteristic of established chronic GVHD in the skin, tongue, liver, intestines, and salivary glands. Fibrosis of the dermis and lamina propria was prominent in the skin and tongue. Submucosal fibrosis was increased in the small intestine. The salivary glands had an interstitial infiltrate and fibrosis with loss of ducts and glands. Class II antigen was prominent in the epidermis of the tongue and skin of all rats. The number of lymphocytes infiltrating the mucosa of the tongue was considerably smaller than seen in the early group. More than 90% of these cells were T cells, as detected by OX-19, and expressed both CD4 and CD8 markers. While most lamina propria lymphocytes expressed the CD4 antigen, there were significantly fewer CD8+ cells, consistent with increased numbers of CD8-/CD4+ helper-phenotype cells. The observations indicate that immediately post-CsA, the CIPGVHD is primarily acute, with epithelial infiltrates of CD8+/CD4- T cells and lamina propria infiltrates that include double-labeled cells consistent with immature thymocytes. There is a rapid transition to established chronic-type CIPGVHD by the second week. The residual mucosal infiltrate is now dominated by double-labeled T cells or thymocytes while the lamina propria infiltrate has more mature helper-phenotype T cells. Induced RT1.B/D antigen could be important in the pathogenesis of the peripheral tissue manifestations.


Coarticulation in fluent fingerspelling.
In speech, the phenomenon of coarticulation (differentiation of phoneme production depending on the preceding or following phonemes) suggests an organization of movement sequences that is not strictly serial. In the skeletal motor system, however, evidence for comparable fluency has been lacking. Thus the present study was designed to quantify coarticulation in the hand movement sequences of sign language interpreters engaged in fingerspelling. Records of 17 measured joint angles were subjected to discriminant and correlation analyses to determine to what extent and in what manner the hand shape for a particular letter was influenced by the hand shapes for the preceding or the following letters. Substantial evidence of coarticulation was found, revealing both forward and reverse influences across letters. These influences could be further categorized as assimilation (tending to reduce the differences between sequential hand shapes) or dissimilation (tending to emphasize the differences between sequential hand shapes). The proximal interphalangeal (PIP) joints of the index and middle fingers tended to show dissimilation, whereas at the same time (i.e., during the spelling of the same letters) the joints of the wrist and thumb tended to show assimilation. The index and middle finger PIP joints have been shown previously to be among the most important joints for computer recognition of the 26 letter shapes, and therefore the dissimilation may have served to enhance visual discrimination. The simultaneous occurrence of dissimilation in some joints and assimilation in others demonstrates an unprecedented level of parallel control of individual joint rotations in an essentially serial task.


High dose trivalent influenza vaccine compared to standard dose vaccine in patients with rheumatoid arthritis receiving TNF-alpha inhibitor therapy and healthy controls: Results of the DMID 10-0076 randomized clinical trial.
Subjects with rheumatoid arthritis (RA) receiving tumor necrosis factor-inhibiting (TNFi) therapies are at risk for severe influenza, and may respond less well to influenza vaccine. We examined the safety and immunogenicity of high dose influenza vaccine (HD) compared to standard dose vaccine (SD) in participants with RA receiving stable TNFi. A randomized, double-blinded, Phase II study was conducted in adults with RA receiving TNFi, and healthy, gender and age-matched control subjects. Participants were immunized with HD (Sanofi Pasteur Fluzone High Dose [60 mcg × 3 strains]) or SD (Sanofi Pasteur Fluzone® [15 mcg × 3 strains]) intramuscularly (IM). A self-administered memory aid recorded temperature and systemic and local adverse events (AEs) for 8 days, and safety was evaluated and serum obtained to measure HAI activity on days 7, 21 and 180 days following vaccination. A greater proportion of RA subjects who received HD seroconverted at day 21 compared to SD, although this was not statistically significant. GMT antibody responses in RA subjects who received HD compared to SD were greater for all strains on day 21, and this was significant for H1N1. Seroconversion rates and GMT values were not different between RA subjects and control subjects. There were no safety concerns for HD or SD in RA subjects, and RA-related symptoms did not differ between SD and HD recipients by a RA-symptom questionnaire (RAPID 3). TNF-inhibitor therapy in people with RA did not appear to influence the immunogenicity of either SD or HD. Influenza seroconversion and GMT values were higher among RA subjects receiving HD compared to SD; however, differences were small and a larger study is needed to validate these findings. Given the apparent risk of increased influenza-related morbidity and mortality among immune compromised subjects, the higher GMT values generated by HD may be beneficial.


Evidence for multiple photosystems in jellyfish.
Cnidarians are often used as model animals in studies of eye and photopigment evolution. Most cnidarians display photosensitivity at some point in their lifecycle ranging from extraocular photoreception to image formation in camera-type eyes. The available information strongly suggests that some cnidarians even possess multiple photosystems. The evidence is strongest within Cubomedusae where all known species posses 24 eyes of four morphological types. Physiological experiments show that each cubomedusan eye type likely constitutes a separate photosystem controlling separate visually guided behaviors. Further, the visual system of cubomedusae also includes extraocular photoreception. The evidence is supported by immunocytochemical and molecular data indicating multiple photopigments in cubomedusae as well as in other cnidarians. Taken together, available data suggest that multiple photosystems had evolved already in early eumetazoans and that their original level of organization was discrete sets of special-purpose eyes and/or photosensory cells.


Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion.
We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point.


The presence of a defective LEU2 gene on 2 mu DNA recombinant plasmids of Saccharomyces cerevisiae is responsible for curing and high copy number.
The copy number of 2 mu DNA-derived plasmids in CIR+ Saccharomyces cerevisiae transformants is determined by its selective marker and is usually much lower than that of the endogenous plasmid. Only plasmids containing the leu2 allele of pJDB219, designated as leu2-d, under selective conditions displayed a higher copy number than did endogenous 2 mu DNA and by displacement generated cured cells. Spontaneous loss of 2 mu DNA occurred with a frequency of about 0.02% per generation. Curing plasmids, like pMP78, have copy numbers of 35; noncuring plasmids, like pDB248 or YEp6, have copy numbers of 4 to 8. The 2 mu DNA copy number in strains AH22 and YNN27 were determined to be 40 and 100, respectively. The high copy number of leu2-d-containing plasmids can be explained by its weak expression of less than 5% that of the wild-type LEU2 gene. The leu2-d allele has a deletion of the 5'-end sequence starting from 29 base pairs before the ATG initiation codon, but surprisingly, its expression is still regulated. On YRp7, which contains the chromosomal autonomic replication sequence ARS1, the defective leu2-d allele could not complement a leu2 host strain. This suggests a more stringent control of replication of ARS1-containing plasmids than of 2 mu-containing plasmids.


Idiopathic nasal bone osteitis: A preliminary report on a recently recognized entity.
Osteitis of the nasal bones is a rare disease; when it occurs, it usually has a known etiology. To the best of our knowledge, idiopathic nasal bone osteitis (NBO) has not been described before. We conducted a study to analyze the behavior of idiopathic NBO and its outcome and to determine a cutoff level for diagnosis using technetium-99m-methylene-diphosphonate (Tc-MDP) bone scanning. This retrospective, controlled analysis involved 9 women (mean age: 44 yr) who had been admitted to an otolaryngology department in Israel with idiopathic NBO over a 5-year period. Clinical evaluation, isotopic evaluation, and computed tomography were done. A lesion-to-nonlesion ratio was calculated between an area of interest on the nasal bone and a reference point (L/R ratio). The same ratio was calculated for a control group of 20 subjects. All the Tc-MDP scans in the study group were suggestive of osteitis. Intravenous antibiotic treatment was effective in all cases. A high degree of accuracy was achieved with cutoff L/R ratios of 2.05 for planar views and 2.34 for single-photon emission computed tomography views.


Carbidopa/levodopa dose elevation and safety concerns in Parkinson's patients: a cross-sectional and cohort design.
Sinemet, a combination drug containing carbidopa and levodopa is considered the gold standard therapy for the treatment of Parkinson's disease (PD). When approved by the Food and Drug Administration (FDA) in 1988, a maximum daily dosage limit of 800 mg (eight tablets) of the 25/100 carbidopa/levodopa formulation was introduced. Overall, the FDA approval was a historic success; however, the pill limit has been hardcoded into many online medical record systems. This study investigates the 800 mg threshold by using a prospectively collected database of patient information. A retrospective cohort study: (Part I) cross-sectional, (Part II) longitudinal. PD patients at a Movement Disorders Center in a large academic, tertiary medical setting. An analysis was performed using carbidopa/levodopa at dosages below and above the 800 mg threshold. A secondary analysis was then performed using two consecutive clinic visits to determine the effects of crossing the 800 mg threshold. Comparisons were made on standardised scales. There was no significant difference in motor, mood and quality-of-life scores in patients consuming below and above the 800 mg carbidopa/levodopa threshold, though a mild worsening in dyskinesia duration was noted without worsening in dyskinesia pain and disability. In PD patients who crossed the 800 mg threshold between two consecutive clinic visits, a significant improvement in depressive symptoms and quality-of-life measures was demonstrated, and in these patients there was no worsening of motor fluctuations or dyskinesia. The data suggest that PD patients have the potential for enhanced clinical benefits when eclipsing the 800 mg carbidopa/levodopa threshold. Many patients will likely need to eclipse the 800 mg threshold and pharmacies and insurance companies should be aware of the requirements that may extend beyond approval limits.


Use of chloroprocaine in orthopedic day surgery: a brief report in a cohort of patients undergoing knee arthroscopy.
Spinal anesthesia with local anesthetics is a viable alternative to general anesthesia in orthopedic surgery, and it is currently considered the standard of care for knee arthroscopy. The use of chloroprocaine may offer several potential advantages over other local anesthetics, including, above all, its rapid onset and short duration of action. The aim of the present retrospective study is to evaluate the post-surgical outcomes of patients who underwent knee arthroscopy using spinal anesthesia with chloroprocaine in an outpatient orthopedic setting. Data from patients who underwent elective knee arthroscopy between January 2022 and December 2022 were collected for the present study. Spinal anesthesia with chloroprocaine 10 mg/mL was administered in the designated subarachnoid space (L3-L4 in the majority of patients). A dosage of 40 mg was used to obtain a satisfactory sensory and motor block. A total number of 302 patients met the inclusion criteria. No complications were reported during surgery in the present series of patients. None of the patients required bladder catheterization. In 84% of cases, the PADSS (Post-Anesthetic Discharge Scoring System) score at discharge was 10, whereas in 16% of cases, the PADSS score was 9. The mean time from anesthesia induction to first urination was 75±9.4 minutes, while the mean time from the anesthesia induction to the discharge from the hospital was 152±18.5 minutes. Spinal chloroprocaine for knee arthroscopy demonstrated a short motor block duration, resulting in a fast time to discharge. These limited data show that chloroprocaine may be safely and effectively applied in outpatient knee arthroscopy procedures. However, more studies, possibly with a randomized design, are required to confirm these findings.


Inhibitory plasticity dictates the sign of plasticity at excitatory synapses.
The broad connectivity of inhibitory interneurons and the capacity of inhibitory synapses to be plastic make them ideal regulators of the level of excitability of many neurons simultaneously. Whether inhibitory synaptic plasticity may also contribute to the selective regulation of single neurons and local microcircuits activity has not been investigated. Here we demonstrate that in rat primary visual cortex inhibitory synaptic plasticity is connection specific and depends on the activation of postsynaptic GABAB-Gi/o protein signaling. Through the activation of this intracellular signaling pathway, inhibitory plasticity can alter the state of a single postsynaptic neuron and directly affect the induction of plasticity at its glutamatergic inputs. This interaction is modulated by sensory experience. Our data demonstrate that in recurrent circuits, excitatory and inhibitory forms of synaptic plasticity are not integrated as independent events, but interact to cooperatively drive the activity-dependent rewiring of local microcircuits.


3D MRI of the Hip Joint: Technical Considerations, Advantages, Applications, and Current Perspectives.
Magnetic resonance imaging (MRI) is a common choice among various imaging modalities for the evaluation of hip conditions. Conventional MRI with two-dimensional acquisitions requires a significant amount of time and is limited by partial-volume artifacts and suboptimal fluid-to-cartilage contrast. Recent hardware and software advances have resulted in development of novel isotropic three-dimensional (3D) single-acquisition protocols that cover the volume of the entire hip and can be reconstructed in arbitrary planes for submillimeter assessment of bony and labro-cartilaginous structures in their planes of orientation. This technique facilitates superior identification of small labral tears and other hip lesions with better correlations with arthroscopy. In this review, we discuss technical details related to 3D MRI of the hip, its advantages, and its role in commonly encountered painful conditions that can be evaluated with great precision using this technology. The entities described are femoroacetabular impingement with acetabular labral tears, acetabular dysplasia, avascular necrosis, regional tendinopathies and tendon tears, bursitis, and other conditions.


Simulation of photoacoustic imaging of microcracks in silicon wafers using a structure-changeable multilayered thermal diffusion model.
The detection characteristics for photoacoustic imaging of microcracks in silicon wafers were theoretically and quantitatively investigated using a numerical simulation. The simulation is based on a one-dimensional multilayered thermal diffusion model coupled with the thermal-wave impedance of each layer, the layer structures of which are constructed along the wafer surface and are variable according to the scanning position of the point heat source. As the modulation frequency was reduced, the spatial resolution of the temperature amplitude profile at the cracks decreased, showing good agreement with the experimentally obtained photoacoustic amplitude images. At a modulation frequency of 200 kHz, for cracks with narrow air gaps of up to 20 nm, which is much smaller than both the beam spot size of 1.5 microm and the thermal diffusion length of 12 microm, the temperature amplitude is twice that of regions without cracks, and the temperature contrast increased with an increase in the modulation frequency. These calculation results suggest the effectiveness of using a high modulation frequency, making it possible to detect microcracks of the order of 10 nm.


[A method of determining the anti-, de- and fibrin-polymerization activity of the blood plasma].
The suggested method is based on measuring the changed level of polymerized fibrin monomer and nonstabilized fibrin under the effects of agents enhancing or inhibiting fibrin monomer polymerization. This method permits measurement of plasma specific activity influencing fibrin monomer and unstabilized fibrin polymerization in human and animal blood plasma in health and various diseases involving disorders of hemostasis system, as well as in various drug exposures.


The high prevalence of hypertension in rural-dwelling Tanzanian older adults and the disparity between detection, treatment and control: a rule of sixths?
There are limited, reliable data on the prevalence of hypertension in East African populations. The aim of this study was to document the prevalence of hypertension in the rural Hai district of Tanzania. All consenting individuals aged 70 years and over who were living in 12 randomly-selected villages in the district underwent three consecutive sitting blood pressure (BP) measurements. An average of the last two measurements was taken. Prior diagnosis of, and treatment for, hypertension was recorded. Of the 2223 subjects, 1553 (69.9%, 95% CI 68.0-71.8) had hypertension (BP ≥140/90). Of those with hypertension 733 (47.2%) had isolated systolic hypertension. Only 586 (37.7%) hypertensives had been previously diagnosed, 94 (6.1%) were currently treated and 14 (0.9%) were adequately controlled. This is the first large-scale prevalence study of hypertension in the elderly in sub-Saharan Africa (SSA). Our results approximate to a 'rule of sixths'; 2/6 of hypertensives were previously detected, 1/6 of those previously detected were on treatment and 1/6 of those on treatment were adequately controlled. Hypertension is a large problem in the elderly population in SSA, and there are a growing number of elderly who are at risk of hypertensive sequelae owing to lack of detection and treatment.


Identification of kinetically hot residues in proteins.
A number of recent studies called attention to the presence of kinetically important residues underlying the formation and stabilization of folding nuclei in proteins, and to the possible existence of a correlation between conserved residues and those participating in the folding nuclei. Here, we use the Gaussian network model (GNM), which recently proved useful in describing the dynamic characteristics of proteins for identifying the kinetically hot residues in folded structures. These are the residues involved in the highest frequency fluctuations near the native state coordinates. Their high frequency is a manifestation of the steepness of the energy landscape near their native state positions. The theory is applied to a series of proteins whose kinetically important residues have been extensively explored: chymotrypsin inhibitor 2, cytochrome c, and related C2 proteins. Most of the residues previously pointed out to underlie the folding process of these proteins, and to be critically important for the stabilization of the tertiary fold, are correctly identified, indicating a correlation between the kinetic hot spots and the early forming structural elements in proteins. Additionally, a strong correlation between kinetically hot residues and loci of conserved residues is observed. Finally, residues that may be important for the stability of the tertiary structure of CheY are proposed.


Is ground cover vegetation an effective biological control enhancement strategy against olive pests?
Ground cover vegetation is often added or allowed to generate to promote conservation biological control, especially in perennial crops. Nevertheless, there is inconsistent evidence of its effectiveness, with studies reporting positive, nil or negative effects on pest control. This might arise from differences between studies at the local scale (e.g. orchard management and land use history), the landscape context (e.g. presence of patches of natural or semi-natural vegetation near the focal orchard), or regional factors, particularly climate in the year of the study. Here we present the findings from a long-term regional monitoring program conducted on four pest species (Bactrocera oleae, Prays oleae, Euphyllura olivina, Saissetia oleae) in 2,528 olive groves in Andalusia (Spain) from 2006 to 2012. Generalized linear mixed effect models were used to analyze the effect of ground cover on different response variables related to pest abundance, while accounting for variability at the local, landscape and regional scales. There were small and inconsistent effects of ground cover on the abundance of pests whilst local, landscape and regional variability explained a large proportion of the variability in pest response variables. This highlights the importance of local and landscape-related variables in biological control and the potential effects that might emerge from their interaction with practices, such as groundcover vegetation, implemented to promote natural enemy activity. The study points to perennial vegetation close to the focal crop as a promising alternative strategy for conservation biological control that should receive more attention.


Spectral and angular shaping of infrared radiation in a polymer resonator with molecular vibrational modes.
We present a comprehensive approach for tailoring the spectral and angular properties of infrared thermal radiation by using a polymer resonator with molecular vibrational modes, consisting of a polymer thin film on a back-reflective substrate. To precisely design the resonator, we derived the infrared dielectric function of a poly(methyl methacrylate) (PMMA) thin film from the measured reflectance spectrum by fitting it with a Gaussian-convoluted Drude-Lorentz model while accounting for the inhomogeneous broadening caused by the disordered structure of polymers. Our experimental and numerical characterization confirms that the polymer resonator exhibits spectral shaping from quasi-broadband to narrowband due to the intrinsic molecular vibrational absorption of the polymer. The frequency-isolated and strong molecular vibrational absorption of the carbonyl stretching mode at 1730 cm-1 enables the narrowband shaping of the PMMA resonator. In addition, we confirm that the angular-shaping characteristics of this polymer resonator can be tuned, from omnidirectional to strongly angular selective, by changing its polymer film thickness. Modal dispersion analysis reveals that the angle-selectivity of the polymer resonator at an angle of incidence of 80° comes from coupling between the molecular vibrational mode and leaky mode. The proposed infrared radiation management strategy based on molecular vibrational modes of polymers is cost-effective, scalable, and works well with terrestrial matter, including organic compounds and gas molecules, showing promise for applications such as optical gas sensing and radiative thermal management.


The V2 Protein from the Geminivirus Tomato Yellow Leaf Curl Virus Largely Associates to the Endoplasmic Reticulum and Promotes the Accumulation of the Viral C4 Protein in a Silencing Suppression-Independent Manner.
Viruses are strict intracellular parasites that rely on the proteins encoded in their genomes for the effective manipulation of the infected cell that ultimately enables a successful infection. Viral proteins have to be produced during the cell invasion and takeover in sufficient amounts and in a timely manner. Silencing suppressor proteins evolved by plant viruses can boost the production of viral proteins; although, additional mechanisms for the regulation of viral protein production likely exist. The strongest silencing suppressor encoded by the geminivirus tomato yellow leaf curl virus (TYLCV) is V2: V2 suppresses both post-transcriptional and transcriptional gene silencing (PTGS and TGS), activities that are associated with its localization in punctate cytoplasmic structures and in the nucleus, respectively. However, V2 has been previously described to largely localize in the endoplasmic reticulum (ER), although the biological relevance of this distribution remains mysterious. Here, we confirm the association of V2 to the ER in Nicotiana benthamiana and assess the silencing suppression activity-independent impact of V2 on protein accumulation. Our results indicate that V2 has no obvious influence on the localization of ER-synthesized receptor-like kinases (RLKs) or ER quality control (ERQC)/ER-associated degradation (ERAD), but dramatically enhances the accumulation of the viral C4 protein, which is co-translationally myristoylated, possibly in proximity to the ER. By using the previously described V2C84S/86S mutant, in which the silencing suppression activity is abolished, we uncouple RNA silencing from the observed effect. Therefore, this work uncovers a novel function of V2, independent of its capacity to suppress silencing, in the promotion of the accumulation of another crucial viral protein.


Impaired Isometric, Concentric, and Eccentric Rate of Torque Development at the Hip and Knee in Patellofemoral Pain.
Ferreira, AS, de Oliveira Silva, D, Barton, CJ, Briani, RV, Taborda, B, Pazzinatto, MF, and de Azevedo, FM. Impaired isometric, concentric, and eccentric rate of torque development at the hip and knee in patellofemoral pain. J Strength Cond Res 35(9): 2492-2497, 2021-The aims of this study were to compare maximal muscle strength and rate of torque development (RTD) of knee extensor and hip abductor during isometric, concentric, and eccentric contractions between women with and without patellofemoral pain (PFP). Thirty-eight women with PFP (PFPG) and 38 pain-free women (CG) participated in this study. Isometric, concentric, and eccentric maximal torque and RTD of knee extensor and hip abductor were assessed using an isokinetic dynamometer. Rate of torque development was calculated as the change in torque over the change in time from torque onset to 30, 60, and 90% of the maximal torque (RTD30%, RTD60%, and RTD90%) during isometric, concentric, and eccentric contractions. PFPG had lower isometric, concentric, and eccentric knee extensor maximal torque (29.9, 28.3, and 26.7%) compared with the CG. For knee extensor RTD, PFPG had slower isometric RTD30% (17.8%), RTD60% (21.5%), and RTD90% (23.4%); slower concentric RTD30% (35.7%), RTD60% (29.3%), and RTD90% (28.2%); and slower eccentric RTD30% (20.5%), RTD60% (25.2%), and RTD90% (22.5%) compared with the CG. PFPG had lower isometric, concentric, and eccentric hip abductor maximal torque (28.3, 21.8, and 17%) compared with the CG. For hip abductor RTD, PFPG had slower isometric RTD30% (32.6%), RTD60% (31.1%), and RTD90% (25.4%); slower concentric RTD90% (11.5%); and slower eccentric RTD30% (19.8%), RTD60% (26.4%), and RTD90% (24%) compared with the CG. In conclusion, women with PFP presented deficits in both maximal strength and RTD of knee extensor and hip abductor during isometric, concentric, and eccentric contractions, which highlight the potential importance of addressing different aspects of muscle function through exercise therapy.


Targeted re-sequencing confirms the importance of chemosensory genes in aphid host race differentiation.
Host-associated races of phytophagous insects provide a model for understanding how adaptation to a new environment can lead to reproductive isolation and speciation, ultimately enabling us to connect barriers to gene flow to adaptive causes of divergence. The pea aphid (Acyrthosiphon pisum) comprises host races specializing on legume species and provides a unique system for examining the early stages of diversification along a gradient of genetic and associated adaptive divergence. As host choice produces assortative mating, understanding the underlying mechanisms of choice will contribute directly to understanding of speciation. As host choice in the pea aphid is likely mediated by smell and taste, we use capture sequencing and SNP genotyping to test for the role of chemosensory genes in the divergence between eight host plant species across the continuum of differentiation and sampled at multiple locations across western Europe. We show high differentiation of chemosensory loci relative to control loci in a broad set of pea aphid races and localities, using a model-free approach based on principal component analysis. Olfactory and gustatory receptors form the majority of highly differentiated genes and include loci that were already identified as outliers in a previous study focusing on the three most closely related host races. Consistent indications that chemosensory genes may be good candidates for local adaptation and barriers to gene flow in the pea aphid open the way to further investigations aiming to understand their impact on gene flow and to determine their precise functions in response to host plant metabolites.


Effects of intracerebral ventricular administration of gastrin-releasing peptide and its receptor antagonist RC-3095 on learned fear responses in the rat.
Several lines of evidence have implicated bombesin and its mammalian analogue, gastrin-releasing peptide (GRP), in the mediation and/or modulation of the stress response. However, the physiological role of GRP in mediating conditioned fear responses remains to be elucidated. The objective of the present study was to characterize the role(s) of GRP and its receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) BB((6-14)) (RC-3095) in fear-related responses using two animal models of conditioned fear. To this end, the effects of intracerebroventricular (i.c.v.) administration of GRP (0.062, 0.30, 3.0 nmol) and RC-3095 (0.3, 3.0 and 9.0 nmol) were assessed in the conditioned emotional response (CER) and the fear-potentiated startle (FPS) paradigms. In the CER paradigm, i.c.v. administration of GRP dose-dependently (all doses) attenuated the expression of both contextual and cued fear as reflected by a reduction in freezing behavior to both the context (cage where shock was received) and cue (tone paired with shock). Conversely, pretreatment with RC-3095 (high dose), blocked the reduction of contextual and cued fear normally observed over time. Further, in the FPS paradigm, i.c.v. administration of GRP significantly attenuated the fear-potentiated startle response at medium and high doses without affecting basal startle amplitude. In contrast, pretreatment with RC-3095 at the highest dose (9.0 nmol) significantly increased the basal startle amplitude without affecting fear-potentiation, suggesting elevated fear at the onset of testing. These data provide further evidence that GRP is involved in conditioned fear responses.


Net clinical benefit of warfarin in individuals with atrial fibrillation across stroke risk and across primary and secondary care.
To investigate net clinical benefit (NCB) of warfarin in individuals with atrial fibrillation (AF) across stroke risk and across primary and secondary care. We conducted a linked electronic health record cohort study of 70 206 individuals with initial record of diagnosis of AF in primary (n=29 568) or secondary care (n=40 638) in England (1998-2010). We defined stroke risk according to the CHA2DS2-VASc score, and followed individuals over a median 2.2 years for 7005 ischaemic strokes (IS) and for 906 haemorrhagic strokes (HS). We calculated incidence rates (IRs) and 95% CIs per 100 person-years (PYs) (IR (95% CI)/100 PY) of IS and HS, with and without use of warfarin, and the NCB (ie, number of IS avoided) per 100 PYs of warfarin use (NCB (95% CI)/100 PY). Compared with individuals with initial record of diagnosis in secondary care, those in primary care had lower scores of IS risk (CHA2DS2-VASc≤2: 30.8% vs 20.6%), and lower overall incidence of IS (IR (95% CI)/100 PY: 2.3 (2.2 to 2.4) vs 4.3 (4.2 to 4.4), p value=0.00); however among individuals with CHA2DS2-VASc=0, 1 or 2 there were no differences in IS rate between those with initial record of diagnosis in primary care or secondary care (IR (95% CI)/100 PY: 0.2 (0.1 to 0.3) vs 0.3 (0.2 to 0.5), p value=0.16), (IR (95% CI)/100 PY: 0.6 (0.4 to 0.7) vs 0.7 (0.6 to 0.9), p value=0.08) and (IR (95% CI)/100 PY: 1.1 (1.00 to 1.3) vs 1.4 (1.2 to 1.6), p value=0.05), respectively. For CHA2DS2-VASc=0, 1 and 2, IRs of IS with versus without warfarin were (IR (95% CI)/100 PY: 0.4 (0.2 to 0.8) vs 0.2 (0.1 to 0.3), p value=0.16), (IR (95% CI)/100 PY: 0.4 (0.3 to 0.7) vs 0.7 (0.6 to 0.8), p value=0.03) and (IR (95% CI)/100 PY: 0.8 (0.7 to 1.0) vs 1.4 (1.3 to 1.6), p value=0.00), respectively. We found a significant positive NCB of warfarin from CHA2DS2-VASc≥2 in men (NCB (95% CI)/100 PY: 0.5 (0.1 to 0.9)) and from CHA2DS2-VASc≥3 in women (NCB (95% CI)/100 PY: 1.5 (1.1 to 1.9)). CHA2DS2-VASc accurately stratifies IS risk in individuals with AF across both primary and secondary care. However, the incidence rate of ischaemic stroke at CHA2DS2-VASc=1 are lower than previously reported, which may change the decision to start anticoagulation with warfarin in these individuals.


Vestibular Aqueduct Measurements in the 45° Oblique (Pöschl) Plane.
The 45° oblique (Pöschl) plane allows reliable depiction of the vestibular aqueduct, with virtually its entire length often visible on 1 CT image. We measured its midpoint width in this plane, aiming to determine normal measurement values based on this plane. We retrospectively evaluated temporal bone CT studies of 96 pediatric patients without sensorineural hearing loss. Midvestibular aqueduct widths were measured in the 45° oblique plane by 2 independent readers by visual assessment (subjective technique). The vestibular aqueducts in 4 human cadaver specimens were also measured in this plane. In addition, there was a specimen that had undergone CT scanning before sectioning, and measurements made on that CT scan and on the histologic section were compared. Measurements from the 96 patients' CT images were then repeated by using findings derived from the radiologic-histologic comparison (objective technique). All vestibular aqueducts were clearly identifiable on 45° oblique-plane CT images. The mean for subjective measurement was 0.526 ± 0.08 mm (range, 0.337-0.947 mm). The 97.5th percentile value was 0.702 mm. The mean for objective measurement was 0.537 ± 0.077 mm (range, 0.331-0.922 mm). The 97.5th percentile value was 0.717 mm. Measurements of the vestibular aqueduct can be performed reliably and accurately in the 45° oblique plane. The mean midpoint width was 0.5 mm, with a range of 0.3-0.9 mm. These may be considered normal measurement values for the vestibular aqueduct midpoint width when measured in the 45° oblique plane.


Mechanistic Studies of Palladium-Catalyzed Aminocarbonylation of Aryl Chlorides with Carbon Monoxide and Ammonia.
Mechanistic information on a reliable, palladium-catalyzed aminocarbonylation of aryl chlorides with ammonia is reported. The reaction occurs with ethylene complex 1 as catalyst, and mechanistic information was gained by isolation of catalytic intermediates and kinetic measurements, including the first mechanistic data on the oxidative addition of aryl chloride to a palladium(0) complex in the presence of CO. Arylpalladium and phenacylpalladium halide intermediates were synthesized, and kinetic measurements of the formation and reactions of these intermediates were undertaken to determine the mechanism of the oxidative addition of aryl bromides and chlorides to a Pd(0) dicarbonyl compound in the presence of CO and the mechanism of the reaction of ammonia with a Pd(II) phenacyl complex to form benzamide. The oxidative addition of aryl chlorides and aryl bromides was determined to occur with rate-limiting reaction of the haloarene with a three-coordinate Pd(0) species bearing a bidentate phosphine and one CO ligand. A primary 13C kinetic isotope effect suggested that this step involves cleavage of the carbon-halogen bond. Our data show that the formation of benzamide from the reaction of phenacylpalladium halide complexes with ammonia occurs by a pathway involving reversible displacement of chloride from a phenacylpalladium chloride complex by ammonia, deprotonation of the bound ammonia to form a phenacylpalladium amido complex, and reductive elimination to form the C-N bond. Consistent with this mechanism, the reaction of an aryl palladium amido complex with CO formed the corresponding primary benzamide. A catalyst deactivation pathway involving the formation of a Pd(I) dimer also was elucidated.


3D object localization using EIT measurements at two levels.
Electrical impedance tomography (EIT) is designed essentially for two-dimensional imaging, but current flow in the third dimension causes images to be formed for objects in 3D. The present work has shown that the image of an object is shifted in position towards the centre almost linearly with the 3D distance from the electrode plane and that the slope of this linear variation depends on the radial distance of the object. An empirical curve has been fitted to this dependence, based on which a method has been developed to locate 3D point objects from EIT measurements in only two planes. This will be useful in clinical and other applications in which 3D objects are few and widely separated. This new methodology may be the basis for 3D imaging in the future.


Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease.
Parkinson disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati et al. (23) found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant and gene regulatory activity of the DJ-1 protein. Because low levels of DJ-1 cause Parkinson, we reasoned that overexpression might stop the disease. We found that overexpression of DJ-1 improved tolerance to oxidative stress by selectively up-regulating the rate-limiting step in glutathione synthesis. When we imposed a different metabolic insult, A53T mutant α-synuclein, we found that DJ-1 turned on production of the chaperone protein Hsp-70 without affecting glutathione synthesis. After screening a number of small molecules, we have found that the histone deacetylase inhibitor phenylbutyrate increases DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant α-synuclein toxicity. In mice, phenylbutyrate treatment leads to a 260% increase in brain DJ-1 levels and protects dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduces α-synuclein aggregation in brain and prevents age-related deterioration in motor and cognitive function. We conclude that drugs that up-regulate DJ-1 gene expression may slow the progression of Parkinson disease by moderating oxidative stress and protein aggregation.


Predictors of clinical evolution of SARS-CoV-2 infection in hematological patients: A systematic review and meta-analysis.
Main aim of this systematic review is to quantify the risk and identify predictors of clinical evolution of SARS-CoV-2 in hematological patients compared to different control populations. Two independent reviewers screened the literature assessing clinical outcomes of SARS-CoV-2 infection in adult patients with active hematological malignancies published up to June 2021. Primary outcome was COVID-19 related mortality, secondary outcomes were hospital and intensive-care admission, mechanical ventilation (MV), and thromboembolic events. Variables related to study setting, baseline patients' demographic, comorbidities, underlying hematological disease, ongoing chemotherapy, COVID-19 presentation, and treatments were extracted. A total of 67 studies including 10,061 hematological patients and 111,143 controls were included. Most of the studies were retrospective cohorts (51 studies, 76%) and only 19 (13%) provided data for a control group. A significant increased risk of clinical progression in the hematological population compared to the controls was found in terms of COVID-19 related mortality (OR, 2.12; 95% CI, 1.77-2.54), hospitalization (OR, 1.98; 95% CI, 1.15-3.43), intensive-care admission (OR, 1.77; 95% CI, 1.38-2.26), and MV (OR, 2.17; 95% CI, 1.71-2.75). The risk remained significantly higher in the subgroup analysis comparing hematological patients versus solid cancer. Meta-regression analysis of uncontrolled studies showed that older age, male sex, and hypertension were significantly related to worse clinical outcomes of COVID-19 in hematological population. Older age and hypertension were found to be associated also to thromboembolic events. In conclusion, hematological patients have a higher risk of COVID-19 clinical progression compared to both the general population and to patients with solid cancer.


Functional domains of the RhlR transcriptional regulator of Pseudomonas aeruginosa.
The RhlR transcriptional regulator of Pseudomonas aeruginosa, along with its cognate autoinducer, N-butyryl homoserine lactone (C(4)-HSL), regulates gene expression in response to cell density. With an Escherichia coli LexA-based protein interaction system, we demonstrated that RhlR multimerized and that the degree of multimerization was dependent on the C(4)-HSL concentration. Studies with an E. coli lasB::lacZ lysogen demonstrated that RhlR multimerization was necessary for it to function as a transcriptional activator. Deletion analysis of RhlR indicated that the N-terminal domain of the protein is necessary for C(4)-HSL binding. Single amino acid substitutions in the C-terminal domain of RhlR generated mutant RhlR proteins that had the ability to bind C(4)-HSL and multimerize but were unable to activate lasB expression, demonstrating that the C-terminal domain is important for target gene activation. Single amino acid substitutions in both the N-terminal and C-terminal domains of RhlR demonstrated that both domains possess residues involved in multimerization. RhlR with a C-terminal deletion and an RhlR site-specific mutant form that possessed multimerization but not transcriptional activation capabilities were able to inhibit the ability of wild-type RhlR to activate rhlA expression in P. aeruginosa. We conclude that C(4)-HSL binding is necessary for RhlR multimerization and that RhlR functions as a multimer in P. aeruginosa.


Safety and Biodistribution Evaluation in CNGB3-Deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia.
Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice. Three groups of animals (n = 35 males and 35 females per group) received a subretinal injection in one eye of 1 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two dose concentrations (1 × 10(12) or 4.2 × 10(12) vg/ml) and were euthanized 4 or 13 weeks later. There were no test-article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated electroretinography (ERG) responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group and 31% of animals in the lower dose group. Rod-mediated ERG responses were reduced in the treated eye for all groups, with the greatest reduction in males given the higher dose of vector, but returned to normal by the end of the study. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in nonocular tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.


Nurses' attitude to patient education barriers in educational hospitals of Urmia University of Medical Sciences.
The purpose of this study was to explore nurses' attitudes to the barriers of patient education as a right for getting information based on work situation of nurses, educational facilities in hospitals, and patients' situation. The study was conducted using a cross-sectional design. The populations consisted of 240 nurses affiliated in the Educational Hospitals. The data were gathered by a questionnaire. Demographic variables and three domains were studied. Twenty questions were about their working situation, 4 questions about hospital educating facilities, and 12 questions were about patients' situation in hospital. The type and frequency of education barriers were evaluated, and variables associated with reporting an obstacle were analyzed. In our questionnaire, we used a Likert scale for determining severity of three domains as the barriers of patient education that ranged from 0 to 4. Generally, it was obvious that educational condition in our hospitals was not good and most of the nurses believed that patient education is not their duties, facilities in hospitals are not sufficient and shortness of time is the most important cause of insufficiency of patient education. The interactions of patient, physician and systemic factors have implications for the implementation of patient education. The failure of adequate patient education may be attributed to the lack of patient adherence, the failure of nurses' knowledge and skill level or the insufficient funding and organization of necessary programs in the current health care system.


Environmental Contamination and Hygienic Measures After Feline Calicivirus Field Strain Infections of Cats in a Research Facility.
Feline calicivirus (FCV) can cause painful oral ulcerations, salivation, gingivitis/stomatitis, fever and depression in infected cats; highly virulent virus variants can lead to fatal epizootic outbreaks. Viral transmission occurs directly or indirectly via fomites. The aim of this study was to investigate the presence and viability of FCV in the environment after sequential oronasal infections of specified pathogen-free cats with two FCV field strains in a research facility. Replicating virus was detected in saliva swabs from all ten cats after the first and in four out of ten cats after the second FCV exposure using virus isolation to identify FCV shedders. In the environment, where cleaning, but no disinfection took place, FCV viral RNA was detectable using RT-qPCR on all tested items and surfaces, including cat hair. However, only very limited evidence was found of replicating virus using virus isolation. Viral RNA remained demonstrable for at least 28 days after shedding had ceased in all cats. Disinfection with 5% sodium bicarbonate (and IncidinTM Plus) and barrier measures were effective in that no viral RNA was detectable outside the cat rooms. Our findings are important for any multicat environment to optimize hygienic measures against FCV infection.


Long-term fracture load of all-ceramic crowns: Effects of veneering ceramic thickness, application techniques, and cooling protocol.
To evaluate, in vitro, the effects of the cooling protocol, application technique, and veneering ceramic thickness on the fracture resistance of ceramic crowns with Y-TZP frameworks. 80 frameworks were made from zirconia by the CAD/CAM technique and divided into 8 groups (n = 10) according to the factors: "application technique" (stratified-L and pressed -P), "thickness" (1 mm and 2 mm), and "cooling protocol" (slow-S and fast-F) of the feldspathic veneering ceramic. After, all crowns were cemented over G10 preparations with resin cement (Panavia F, Kuraray), mechanically cycled (2x106 cycles, 200 N, 3Hz), and subjected to the axial compression resistance test (0.5 mm/min, 10 kN). The data (N) underwent descriptive statistical analysis by 3-way ANOVA and Tukey's test (5%). Fracture analysis was performed to determine the possible origin of failure. The factors "cooling protocol" (P=0.0058) and "application" technique (P=0.0001) influenced the fracture resistance of the crowns. For pressed veneer technique, the P2S (4608.9±464.5). A presented significantly higher results than that P2F(3621.1±523.0)BCD (Tukey's test). For the stratified technique, this difference was not observed (P>0.05). The thickness of the veneering ceramic was not significant regardless of the cooling protocol and technique (P>0.05). The predominant failure mode was chipping of the ceramic veneer originating in the subsurface. The pressed technique, used with a slow-cooling protocol, leads to the best outcome for the veneering of all-ceramic crowns. Key words:Zirconia, ceramics, cooling protocol, thickness, application technique.


Differential Impact According to Mission's Operational Intensity on Psychoactive Substance Use: A Retrospective Cohort of French Male Army Service Members.
Stressful deployments in combat areas are known to increase the risk of substance abuse in military personnel. The aim of the study was to compare deployment on stressful, high-intensity missions (HIMs) to deployment on low-intensity missions (LIMs) in order to understand factors associated with substance use variations across the mission. A retrospective cohort study based on a one-shot self-questionnaire was performed four months after their return on two samples of male French Army service members: one returning from an HIM and one from an LIM. The questionnaire focused on tobacco, alcohol, cannabis, cocaine, and psychoactive medication use at three times: before, during, and after the mission. During an HIM, the frequency of tobacco use increased, alcohol use remained stable - although 38% declared a decrease in consumption - and illicit drug use decreased. During an LIM, tobacco and alcohol use increased, cannabis use remained stable, and only cocaine and medication use decreased. After their return, use levels among both samples reverted to values similar to those reported before the mission, except for a decrease in tobacco use observed at return from an HIM. The main factors perceived as related to variations were stress in an HIM and low cost in an LIM. Conclusions/importance: The study suggests a differential impact of deployment on substance use according to the operational intensity of the mission. Variations in use are predominant during the mission with a washout effect after returning home.


Variations in biochemical and pharmacological properties of Indian cobra (Naja naja naja) venom due to geographical distribution.
Indian cobra (Naja naja naja) venom obtained from three different geographical regions was studied in terms of electrophoretic pattern, biochemical and pharmacological activities. SDS-PAGE banding pattern revealed significant variation in the protein constituents of the three regional venoms. The eastern venom showed highest indirect hemolysis and hyaluronidase activity. In contrast, western and southern venoms were rich in proteolytic activity. All the three regional venoms were devoid of p-tosyl-L-arginine methyl ester hydrolysing activity. The eastern venom was found to be most lethal among the three regional venoms. The lethal potency varied as eastern > western > southern regional venoms. In addition, all the three regional venoms showed marked variations in their ability to induce symptoms/signs of neurotoxicity, myotoxicity, edema and effect on plasma coagulation process. Polyclonal antiserum prepared against the venom of eastern region cross-reacted with both southern and western regional venoms, but varied in the extent of cross-reactivity by ouchterlony immunodiffusion and ELISA.


Renal alpha 2-adrenoceptors and the adenylate cyclase-cAMP system: biochemical and physiological interactions.
alpha 2-Adrenoceptors were first described pharmacologically ten years ago. Within three years their capacity to inhibit adenylate cyclase had been demonstrated in many tissues. They were demonstrated biochemically in the kidneys in 1981 even before any renal physiological effects of their activation were known. They predominate numerically over alpha 1-adrenoceptors in renal membranes and their density is increased in genetic forms of rat hypertension. alpha 1-Adrenoceptors normally mediate the vasoconstriction and sodium- and water-retaining effects of sympathetic neuronally released norepinephrine. Norepinephrine or epinephrine must be infused to activate alpha 2-adrenoceptors, suggesting that renal alpha 2-adrenoceptors are extrajunctional, whereas alpha 1-adrenoceptors are postjunctional. When alpha 1-adrenoceptors are chronically blocked, renal alpha 2-adrenoceptor density increases and they assume a location at postjunctional sites, the otherwise exclusive domain of alpha 1-adrenoceptors. Results from microdissection studies have established that alpha 2-adrenoceptors are present on most segments of the nephron and that their activation can suppress adenosine 3,'5'-cyclic monophosphate (cAMP) accumulation induced by most renal hormones. However, failure of alpha 2-adrenoceptor activation to suppress cAMP accumulation in some tubular segments induced by certain hormones suggests compartmentalization of adenylate cyclase regulation that is hormone-function specific. In view of the potent inhibitory effects of alpha 2-adrenoceptor stimulation on hormone activated cAMP accumulation in several discrete areas of the nephron, we suggest that alpha 2-adrenoceptors fulfill important regulatory role(s) in renal function. To date, alpha 2-adrenoceptor activation has been shown to reverse vasopressin-induced sodium and water retention, and arachidonic acid- and furosemide-induced cAMP, sodium, and water excretion in the isolated perfused kidney. Thus the effects are qualitatively and quantitatively dependent in these studies on the hormone being infused and are therefore hormone-function specific. Physiological effects of alpha 2-adrenoceptor activation of thyrocalcitonin and on parathyroid hormone-induced effects have not been studied. alpha 2-Adrenoceptor activation can inhibit renin release in some model systems and can activate a sodium-hydrogen antiporter system in proximal tubules. The physiological roles of these actions are unknown.


Quantitative infrared photoanalysis of selected bacteria.
A technique to measure transmitted infrared radiation from minute biological systems is described. Infrared color film was exposed by radiation transmitted through bacterial colonies. The resultant photographic image was unique for each species of bacteria examined and spectral analysis of the image provided differential light emission patterns which could be quantitated. A formula for developing numerical comparisons among bacterial colonies was provided. The results of this numerical procedure gave quantitative relationships for the total infrared data from each microbial colony and made possible the differential identification of ten species of medically significant bacteria.


Political challenges to prioritizing gender in global health organisations.
Many global health organisations have adopted formal strategies to integrate gender in their programming. In practice, few prioritise the issue. Institutions with considerable global power therefore largely overlook fundamental drivers of adverse health outcomes: gender inequality and harmful gender norms. We analyse the factors shaping attention to gender in organisations involved in global health governance. Drawing on scholarship from the fields of organisational behavior and management, sociology, international relations and the policy process, we undertook a thematic analysis of peer-reviewed scholarship and organisational documents. We also conducted 20 semi-structured interviews over Skype with individuals working at the cross-section of gender and health. In seeking to reform the policies and practices of global health organisations, gender proponents confront patriarchal organisational cultures, hostile political environments and an issue that is difficult to address as it requires upsetting existing power structures. Proponents also face three linked challenges internal to their own networks. First, there is little cohesion among champions themselves, as they are fragmented into multiple networks. Second, proponents differ on the nature of the problem and solutions, including whether reducing gender inequality or addressing harmful gender norms is the primary goal, the role of men in gender initiatives, which health issues to prioritise, and even the value of proponent cohesion. Third, there are disagreements among proponents on how to convey the problem. Some advance an instrumental case, while others believe that it should be portrayed as a human rights issue and using any other argument undermines that fundamental justification. Prospects for building more gender-responsive global health organisations will depend in part on the ability of proponents to address these disagreements and develop strategies for negotiating difficult organisational cultures and political environments.


Circulating miRNAs as Noninvasive Biomarkers for PDAC Diagnosis and Prognosis in Mexico.
Among malignant neoplasms, pancreatic ductal adenocarcinoma (PDAC) has one of the highest fatality rates due to its late detection. Therefore, it is essential to discover a noninvasive, early, specific, and sensitive diagnostic method. MicroRNAs (miRNAs) are attractive biomarkers because they are accessible, highly specific, and sensitive. It is crucial to find miRNAs that could be used as possible biomarkers because PDAC is the eighth most common cause of cancer death in Mexico. With the help of microRNA microarrays, differentially expressed miRNAs (DEmiRNAs) were found in PDAC tissues. The presence of these DEmiRNAs in the plasma of Mexican patients with PDAC was determined using RT-qPCR. Receiver operating characteristic curve analysis was performed to determine the diagnostic capacity of these DEmiRNAs. Gene Expression Omnibus datasets (GEO) were employed to verify our results. The Prisma V8 statistical analysis program was used. Four DEmiRNAs in plasma from PDAC patients and microarray tissues were found. Serum samples from patients with PDAC were used to validate their overexpression in GEO databases. We discovered a new panel of the two miRNAs miR-222-3p and miR-221-3p that could be used to diagnose PDAC, and when miR-221-3p and miR-222-3p were overexpressed, survival rates decreased. Therefore, miR-222-3p and miR-221-3p might be employed as noninvasive indicators for the diagnosis and survival of PDAC in Mexican patients.


Dicobalt-μ-oxo polyoxometalate compound, [(α(2)-P2W17O61Co)2O](14-): a potent species for water oxidation, C-H bond activation, and oxygen transfer.
High-valent oxo compounds of transition metals are often implicated as active species in oxygenation of hydrocarbons through carbon-hydrogen bond activation or oxygen transfer and also in water oxidation. Recently, several examples of cobalt-catalyzed water oxidation have been reported, and cobalt(IV) species have been suggested as active intermediates. A reactive species, formally a dicobalt(IV)-μ-oxo polyoxometalate compound [(α2-P2W17O61Co)2O](14-), [(POMCo)2O], has now been isolated and characterized by the oxidation of a monomeric [α2-P2W17O61Co(II)(H2O)](8-), [POMCo(II)H2O], with ozone in water. The crystal structure shows a nearly linear Co-O-Co moiety with a Co-O bond length of ∼1.77 Å. In aqueous solution [(POMCo)2O] was identified by (31)P NMR, Raman, and UV-vis spectroscopy. Reactivity studies showed that [(POMCo)2O]2O] is an active compound for the oxidation of H2O to O2, direct oxygen transfer to water-soluble sulfoxides and phosphines, indirect epoxidation of alkenes via a Mn porphyrin, and the selective oxidation of alcohols by carbon-hydrogen bond activation. The latter appears to occur via a hydrogen atom transfer mechanism. Density functional and CASSCF calculations strongly indicate that the electronic structure of [(POMCo)2O]2O] is best defined as a compound having two cobalt(III) atoms with two oxidized oxygen atoms.


[Search for medical care and determinants of the health services utilization].
There are four different conceptual approaches to assess the factors that explain, condition and determine the use of health services. This article discusses the epidemiological, psychosocial, sociological and economical models. The stages and determinants of the health service use process are described and a cross study is made with each of the four models, using a contingency matrix. A holistic analysis is proposed, as a starting point, for the search of a model that will allow the identification of factors that determine the use of health services. This analysis should be used as a conceptual framework for future work on health services utilization.


Weak and habitat-dependent effects of nutrient pollution on macrofaunal communities of southeast Australian estuaries.
Among the impacts of coastal settlements to estuaries, nutrient pollution is often singled out as a leading cause of modification to the ecological communities of soft sediments. Through sampling of 48 sites, distributed among 16 estuaries of New South Wales, Australia, we tested the hypotheses that (1) anthropogenic nutrient loads would be a better predictor of macrofaunal communities than estuarine geomorphology or local sediment characteristics; and (2) local environmental context, as determined largely by sediment characteristics, would modify the relationship between nutrient loading and community composition. Contrary to the hypothesis, multivariate multiple regression analyses revealed that sediment grain size was the best predictor of macrofaunal assemblage composition. When samples were stratified according to median grain size, relationships between faunal communities and nitrogen loading and latitude emerged, but only among estuaries with sandier sediments. In these estuaries, capitellid and nereid polychaetes and chironomid larvae were the taxa that showed the strongest correlations with nutrient loading. Overall, this study failed to provide evidence of a differential relationship between diffuse nutrient enrichment and benthic macrofauna across a gradient of 7° of latitude and 4°C temperature. Nevertheless, as human population growth continues to place increasing pressure on southeast Australian estuaries, manipulative field studies examining when and where nutrient loading will lead to significant changes in estuarine community structure are needed.


Identification of an IS711 element interrupting the wboA gene of Brucella abortus vaccine strain RB51 and a PCR assay to distinguish strain RB51 from other Brucella species and strains.
Brucella abortus vaccine strain RB51 is a natural stable attenuated rough mutant derived from the virulent strain 2308. The genetic mutations that are responsible for the roughness and the attenuation of strain RB51 have not been identified until now. Also, except for an assay based on pulsed-field gel electrophoresis, no other simple method to differentiate strain RB51 from its parent strain 2308 is available. In the present study, we demonstrate that the wboA gene encoding a glycosyltransferase, an enzyme essential for the synthesis of O antigen, is disrupted by an IS711 element in B. abortus vaccine strain RB51. Exploiting this feature, we developed a PCR assay that distinguishes strain RB51 from all other Brucella species and strains tested.


Antioxidants, radiation and mutation as revealed by sperm abnormality in barn swallows from Chernobyl.
Reduced levels of antioxidants such as carotenoids and vitamins A and E can increase DNA damage caused by free radicals. Exposure to radiation has been proposed to reduce levels of antioxidants that are used for DNA repair and this reduction may be responsible for increased levels of mutation in radioactively contaminated areas. We test this hypothesis using field measures of antioxidants in blood, liver and eggs of the barn swallow Hirundo rustica while relating these to levels of mutation as reflected by the frequency of abnormal sperm. Antioxidant levels in blood, liver and eggs were reduced in Chernobyl, Ukraine, compared with an uncontaminated control area, and levels of antioxidants correlated negatively with levels of background radiation. The frequency of abnormal sperm was almost an order of magnitude higher in Chernobyl than in the control area and was negatively related to antioxidant levels in blood and liver. This is consistent with the hypothesis of a direct link between radiation and individual levels of antioxidants, suggesting that levels of mutation differ among individuals owing to individual differences in the abundance of antioxidants.


Dynamic nature of the ligustilide complex.
Monomeric phthalides such as Z-ligustilide (1) and Z-butylidenephthalide (2) are major constituents of medicinal plants of the Apiaceae family. While 1 has been associated with a variety of observed biological effects, it is also known for its instability and rapid chemical degradation. For the purpose of isolating pure 1 and 2, a gentle and rapid two-step countercurrent isolation procedure was developed. From a supercritical CO2 fluid extract of Angelica sinensis roots, the phthalides were isolated with high GC-MS purities of 99.4% for 1 and 98.9% for 2 and consistently lower qHNMR purities of 98.1% and 96.4%, respectively. Taking advantage of molarity-based qHNMR methodology, a time-resolved study of the dynamic changes and residual complexity of pure 1 was conducted. GC-MS and (qH)NMR analysis of artificially degraded 1 provided evidence for the phthalide degradation pathways and optimized storing conditions. Parallel qHNMR analysis led to the recognition of variations in time- and process-dependent sample purity and has impact on the overall assessment of time-dependent changes in complex natural products systems. The study underscores the importance of independent quantitative monitoring as a prerequisite for the biological evaluation of labile natural products such as monomeric phthalides.


Clinical Validation of Fragile X Syndrome Screening by DNA Methylation Array.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. It is most frequently caused by an abnormal expansion of the CGG trinucleotide repeat (>200 repeats) located in the promoter of the fragile X mental retardation gene (FMR1), resulting in promoter DNA hypermethylation and gene silencing. Current clinical tests for FXS are technically challenging and labor intensive, and may involve use of hazardous chemicals or radioisotopes. We clinically validated the Illumina Infinium HumanMethylation450 DNA methylation array for FXS screening. We assessed genome-wide and FMR1-specific DNA methylation in 32 males previously diagnosed with FXS, including nine with mosaicism, as well as five females with full mutation, and premutation carrier males (n = 11) and females (n = 11), who were compared to 300 normal control DNA samples. Our findings demonstrate 100% sensitivity and specificity for detection of FXS in male patients, as well as the ability to differentiate patients with mosaic methylation defects. Full mutation and premutation carrier females did not show FMR1 methylation changes. We have clinically validated this genome-wide DNA methylation assay as a cost- and labor-effective alternative for sensitive and specific screening for FXS, while ruling out the most common differential diagnoses of FXS, Prader-Willi syndrome, and Sotos syndrome in the same assay.


Bovine colostrum: changes in lipid constituents in the first 5 days after parturition.
Despite the great interest paid to protein components in colostrum, fat also plays an important role in the supply of essential nutrients to provide energy, increase metabolism, and protect the newborn calf against microbial infections. This work aimed to elucidate levels of different fat components in colostrum, in particular fatty acid (FA), triglyceride (TG), cholesterol, and phospholipid contents. Colostrum samples from primiparous and multiparous (3-5 lactations) Holstein dams, fed the same ration indoors, were collected on the first 5d after parturition, analyzed, and compared with milk samples from the same cows collected at 5mo of lactation. Fat content during the first 5d of milking did not vary. However, the proportion of short-chain saturated FA increased and that of long-chain FA decreased. The concentration of n-3 FA was higher on the first day of calving than on the other days, with clear differences in the number and type of n-3 FA. Conjugated linoleic isomers and trans FA slowly increased from d 1 to 5, reaching a maximum at 5mo of lactation. Changes in the distribution profile of TG were observed as lactation progressed, with a shift from a prevalence of high-carbon-number TG (C48-50) on d 1 to a bimodal distribution (maxima at C38 and C50) on d 5, characteristic of mid-lactation milk. Cholesterol content was high in the first hours after calving and rapidly decreased within 48h. Colostrum sampled on d 1 also had a high content of phospholipids. Phosphatidylethanolamine and sphingomyelin were, respectively, lower and higher in the first 5d than in mid-lactation milk. The influence of lactation number on colostrum fat composition was also considered and significant results were obtained for all FA groups (except for polyunsaturated and n-6 FA) and TG content.


Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial.
To determine the efficacy of the thrombopoietin receptor agonist romiplostim for the prevention of temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma. In the PLATUM phase II open-label, multicenter, single-arm trial, patients diagnosed with Common Terminology Criteria for Adverse Events grade 3 or 4 thrombocytopenia during chemoradiotherapy received weekly subcutaneous romiplostim injections. PLATUM aimed at demonstrating that the percentage of thrombocytopenic patients treated with romiplostim able to complete 6 cycles of maintenance temozolomide chemotherapy exceeded 10% (p0 = 0.10; pA = 0.35). Using type I error equal to 0.05% and 95% power, 31 patients had to be recruited. According to a Fleming 2-step design with a preplanned interim analysis after recruitment of 20 patients (step 1), the trial was terminated early for success. Twenty patients were enrolled in step 1. Median age was 61 years (range 33-73). Twelve patients received 6 temozolomide cycles, corresponding to a success rate of 60% (95% confidence interval 36%-81%). Four patients discontinued temozolomide because they did not respond to romiplostim, 2 for progression, and 2 for adverse events unrelated to romiplostim. The thrombopoietin receptor agonist romiplostim improves exposure to chemotherapy in patients with glioblastoma experiencing temozolomide-induced thrombocytopenia. NCT02227576. This study provides Class IV evidence that for patients with glioblastoma and thrombocytopenia, romiplostim is effective for the secondary prophylaxis of temozolomide-induced thrombocytopenia.


Pelvic exenteration associated with future renal dysfunction.
This study aimed to clarify the long-term change in the renal function after pelvic exenteration (PE) and to evaluate the risk factors for any future dysfunction. This study comprised 40 patients. A greater than 25% decline in the estimated glomerular filtration rate (eGFR) at 3 years was defined as early renal function disorder (ERFD), possibly predicting future chronic kidney disease (CKD). In the entire cohort, the median eGFR decreased by 23% at 3 years, and CKD developed in 50%. The patients were divided into the ERFD (n = 16) and non-ERFD (n = 24) groups. In the ERFD group, the eGFR significantly decreased by 28% during the first 1.5 years and continued to decline after that, resulting in 81.3% of patients reaching CKD, whereas it was 4% and 37.5%, respectively, in the non-ERFD group. In a growth model analysis, late urinary tract complications (UTC) and small bowel obstruction were shown to be risk factors for ERFD. Although PE was associated with a high incidence of future CKD, ERFD could predict it. Close observation of the eGFR decline over 1.5 years might be beneficial to identify ERFD patients. High-risk patients with late UTC and small bowel obstruction should, therefore, be observed carefully.


Cytotoxic Engineered Induced Neural Stem Cells as an Intravenous Therapy for Primary Non-Small Cell Lung Cancer and Triple-Negative Breast Cancer.
Converting human fibroblasts into personalized induced neural stem cells (hiNSC) that actively seek out tumors and deliver cytotoxic agents is a promising approach for treating cancer. Herein, we provide the first evidence that intravenously-infused hiNSCs secreting cytotoxic agent home to and suppress the growth of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Migration of hiNSCs to NSCLC and TNBC in vitro was investigated using time-lapse motion analysis, which showed directional movement of hiNSCs to both tumor cell lines. In vivo, migration of intravenous hiNSCs to orthotopic NSCLC or TNBC tumors was determined using bioluminescent imaging (BLI) and immunofluorescent post-mortem tissue analysis, which indicated that hiNSCs colocalized with tumors within 3 days of intravenous administration and persisted through 14 days. In vitro, efficacy of hiNSCs releasing cytotoxic TRAIL (hiNSC-TRAIL) was monitored using kinetic imaging of co-cultures, in which hiNSC-TRAIL therapy induced rapid killing of both NSCLC and TNBC. Efficacy was determined in vivo by infusing hiNSC-TRAIL or control cells intravenously into mice bearing orthotopic NSCLC or TNBC and tracking changes in tumor volume using BLI. Mice treated with intravenous hiNSC-TRAIL showed a 70% or 72% reduction in NSCLC or TNBC tumor volume compared with controls within 14 or 21 days, respectively. Safety was assessed by hematology, blood chemistry, and histology, and no significant changes in these safety parameters was observed through 28 days. These results indicate that intravenous hiNSCs-TRAIL seek out and kill NSCLC and TNBC tumors, suggesting a potential new strategy for treating aggressive peripheral cancers.


Internal exposure rate conversion coefficients and absorbed fractions of mouse for 137Cs, 134Cs and 90Sr contamination in body.
The aim of this study was to determine parameters for estimating the internal exposure of all organs in mouse experiments from the radioactivity concentration in organs. The estimation of internal exposure rate conversion coefficients and absorbed fractions for 137Cs, 134Cs and 90Sr by the Particle and Heavy Ion Transport code System (PHITS) with a voxel-based mouse phantom is presented. The geometry of the voxel phantom is constructed from computer tomography images of a mouse 9 cm in length weighing 23.9 g. The voxel-based mouse phantom has the following organs: brain, skull, heart, lungs, liver, stomach, spleen, kidneys, bladder, testis and tissue (tissue and other organs). Gamma- and beta-rays from 137Cs, 134Cs and 90Sr sources in each source organ are generated and scored for every target organ. The internal exposure rate conversion coefficients and absorbed fractions are calculated from deposition energies in each target organ from each source organ and are used to generate an internal exposure rate conversion coefficient matrix and an absorbed fraction matrix. The absorbed fractions of beta-rays in the source organs are roughly 0.5-0.8 for 137Cs and 134Cs, and the absorbed fractions of gamma-rays are <0.04 for 137Cs and <0.03 for 134Cs. The internal exposure rate conversion coefficient matrix is defined using the absorbed fractions. The calculated internal exposure rate coefficient matrix is tested under a uniform radioactivity concentration of 1 Bq/kg for 137Cs, 134Cs and 90Sr. The estimated internal exposure rates in the mouse whole body for 137Cs, 134Cs and 90Sr are 3.28 × 10-3, 2.55 × 10-3 and 1.20 × 10-2 μGy/d, respectively. These values are very similar to those for an ellipsoid frog (31.4 g) and an ellipsoid crab egg mass (12.6 g) reported in ICRP Publication 108.