Mapping of truncated O-glycans in cancers of epithelial and non-epithelial origin.
Novel immunotherapies targeting cancer-associated truncated O-glycans Tn (GalNAcα-Ser/Thr) and STn (Neu5Acα2-6GalNacα-Ser/Thr) are promising strategies for cancer treatment. However, no comprehensive, antibody-based mapping of truncated O-glycans in tumours exist to guide drug development. We used monoclonal antibodies to map the expression of truncated O-glycans in >700 tissue cores representing healthy and tumour tissues originating from breast, colon, lung, pancreas, skin, CNS and mesenchymal tissue. Patient-derived xenografts were used to evaluate Tn expression upon tumour engraftment. The Tn-antigen was highly expressed in breast (57%, n = 64), colorectal (51%, n = 140) and pancreatic (53%, n = 108) tumours, while STn was mainly observed in colorectal (80%, n = 140) and pancreatic (56%, n = 108) tumours. We observed no truncated O-glycans in mesenchymal tumours (n = 32) and low expression of Tn (5%, n = 87) and STn (1%, n = 75) in CNS tumours. No Tn-antigen was found in normal tissue (n = 124) while STn was occasionally observed in healthy gastrointestinal tissue. Surface expression of Tn-antigen was identified across several cancers. Tn and STn expression decreased with tumour grade, but not with cancer stage. Numerous xenografts maintained Tn expression. Surface expression of truncated O-glycans is limited to cancers of epithelial origin, making Tn and STn attractive immunological targets in the treatment of human carcinomas.


Autogenous onlay bone grafts fixed with screw implants for the treatment of severely resorbed maxillae. Radiographic evaluation of preoperative bone dimensions, postoperative bone loss, and changes in soft-tissue profile.
Thirty patients with severely resorbed edentulous maxillae underwent combined treatment of iliac bone onlay graft and titanium implants. The patients were followed for 3 years. They were radiographically examined before surgery to evaluate the bone volume at the intended implant sites. Only 13/156 implant sites were suitable for implant insertion. The bone level at the implant surfaces was evaluated after 6 months and 1, 2, and 3 years, respectively. There was a continuing decrease of the bone level throughout the follow-up period with a mean loss of 4.9 mm after 3 years and with no difference between sexes. Twenty-six implants were radiographically examined before removal, and only three of these implant sites showed radiographic signs of failure. The soft-tissue profile was analyzed cephalometrically by the subtraction technique. The upper lip generally moved inward and the apex of the nose and the columella downward and inward. The anterior facial height increased in most of the patients, resulting in a downward and inward change of the lower lip, the mentolabial sulcus, the soft-tissue pogonion, and the soft-tissue gnathion.


Evaluating the effectiveness of teeth and dorsal fin spines for non-lethal age estimation of a tropical reef fish, coral trout Plectropomus leopardus.
This study investigated whether teeth and dorsal fin spines could be used as non-lethal methods of age estimation for a vulnerable and highly valued tropical fisheries species, coral trout Plectropomus leopardus. Age estimation of individuals from 2 to 9 years old revealed that dorsal spines represent an accurate ageing method (90% agreement with otoliths) that was more precise [average per cent error (APE) = 4·1, coefficient of variation (c.v.) = 5·8%] than otoliths (APE = 6·2, c.v. = 8·7%). Of the three methods for age estimation (otoliths, dorsal spines and teeth), spines were the most time and cost efficient. An aquarium-based study also found that removing a dorsal spine or tooth did not affect survivorship or growth of P. leopardus. No annuli were visible in teeth despite taking transverse and longitudinal sections throughout the tooth and trialling several different laboratory methods. Although teeth may not be suitable for estimating age of P. leopardus, dorsal spines appear to be an acceptably accurate, precise and efficient method for non-lethal ageing of individuals from 2 to 9 years old in this tropical species.


Nicotinic acetylcholine receptors of muscles and nerves: comparison of their structures, functional roles, and vulnerability to pathology.
There are fetal and adult subtypes of muscle nicotinic receptors (AChRs), whose structures and functional roles are reasonably well known. Mutations of their subunits cause congenital myasthenic syndromes. An autoimmune response to them causes myasthenia gravis (MG). The main immunogenic region (MIR) on muscle AChRs accounts for many aspects of the pathological mechanisms by which the autoimmune response impairs neuromuscular transmission. There are many other AChR subtypes, each defined by a different combination of subunits, some of which are transiently expressed in muscle during development, others of which are expressed in keratinocytes, vascular and bronchial epithelia, and other nonneuronal cells, as well as in a wide variety of neurons. Their varied structures and functional roles are much less well known. Mutations in subunits of some of these AChRs have thus far been associated with rare forms of epilepsy and dysautonomia, but other genetic diseases associated with them probably remain to be discovered. Autoimmune responses to some of these subunits are associated with rare dysautonomias and a skin disease. The pathological mechanisms by which these autoimmune responses impair function are much less well known than in the case of MG. AChRs may provide useful drug targets in several neurological diseases. By far, the biggest direct medical impact of AChRs is addiction to tobacco, which is mediated by nicotine acting on a variety of neuronal AChRs.


Alkaline air: changing perspectives on nitrogen and air pollution in an ammonia-rich world.
Ammonia and ammonium have received less attention than other forms of air pollution, with limited progress in controlling emissions at UK, European and global scales. By contrast, these compounds have been of significant past interest to science and society, the recollection of which can inform future strategies. Sal ammoniac (nūshādir, nao sha) is found to have been extremely valuable in long-distance trade (ca AD 600-1150) from Egypt and China, where 6-8 kg N could purchase a human life, while air pollution associated with nūshādir collection was attributed to this nitrogen form. Ammonia was one of the keys to alchemy-seen as an early experimental mesocosm to understand the world-and later became of interest as 'alkaline air' within the eighteenth century development of pneumatic chemistry. The same economic, chemical and environmental properties are found to make ammonia and ammonium of huge relevance today. Successful control of acidifying SO2 and NOx emissions leaves atmospheric NH3 in excess in many areas, contributing to particulate matter (PM2.5) formation, while leading to a new significance of alkaline air, with adverse impacts on natural ecosystems. Investigations of epiphytic lichens and bog ecosystems show how the alkalinity effect of NH3 may explain its having three to five times the adverse effect of ammonium and nitrate, respectively. It is concluded that future air pollution policy should no longer neglect ammonia. Progress is likely to be mobilized by emphasizing the lost economic value of global N emissions ($200 billion yr-1), as part of developing the circular economy for sustainable nitrogen management. This article is part of a discussion meeting issue 'Air quality, past present and future'.


Immunoglobulin gene rearrangements in hairy cell leukemia.
Studies of hairy cell leukemia have yielded conflicting data about the cell of origin in this disease. To investigate this issue, we have examined the state of immunoglobulin genes in the cells of 11 randomly selected spleens showing histologic involvement with hairy cell leukemia. DNA was extracted from splenic tissue samples and digested with restriction endonucleases. Following agarose gel electrophoresis and transfer to nitrocellulose filters or activated nylon membranes, splenic DNA was hybridized with radiolabeled DNA fragment probes specific for the constant regions of the immunoglobulin heavy chain and kappa and lambda light chain genes. Autoradiograms of the hybridized DNA in each case revealed rearrangements of a heavy chain gene and at least one light chain gene. In addition, immunophenotyping of cellular immunoglobulin polypeptides was carried out on frozen tissue sections from all but one case. In each case in which an immunoglobulin polypeptide could be detected, a rearrangement was present in the DNA of the corresponding immunoglobulin gene. These studies offer strong evidence for endogenous immunoglobulin synthesis in hairy cells and for the B lymphocytic character of this leukemia.


A Golden Age for Motor Skill Learning? Learning of an Unfamiliar Motor Task in 10-Year-Olds, Young Adults, and Adults, When Starting From Similar Baselines.
It is often argued within sports circles that the age span of around 6-12 years is a golden age for motor skill learning, and this period is often described as sensitive, or even critical, for learning such skills. Consequently, skill development programmes target this age span for teaching technical and coordinative skills. In the scientific literature, however, the term golden age is scarcely seen, and few studies have even attempted to test this hypothesis. When comparing motor learning between children and adults, studies have typically found little difference or differences favoring adults. Studies that have reported precocious learning within the golden age seem not to have controlled all relevant variables. Typically, the different age groups have not started from similar baselines and have tested tasks that have not been scaled according to physical differences between individuals belonging to the various groups. The present study tested 10-year-olds, 18-year-olds, and 40-year-olds on dart throwing with their non-dominant hands. They each completed 200 throws over 2 days, with 1 day in between. All participants performed at similar levels at the pre-test, and the task was scaled according to each participant's individual size. No difference was found between the groups after practice in terms of change in absolute error, or with respect to the slopes of their learning curves. The 10-year-olds' learning curves were more variable compared with the other groups. Thus, the present study found no evidence that the 10-year-olds belonged to a golden age for motor learning, and we would argue that previous findings of differences might well be artefacts due to lack of control of relevant variables.


Nitrogen, tillage, and crop rotation effects on nitrous oxide emissions from irrigated cropping systems.
We evaluated the effects of irrigated crop management practices on nitrous oxide (N(2)O) emissions from soil. Emissions were monitored from several irrigated cropping systems receiving N fertilizer rates ranging from 0 to 246 kg N ha(-1) during the 2005 and 2006 growing seasons. Cropping systems included conventional-till (CT) continuous corn (Zea mays L.), no-till (NT) continuous corn, NT corn-dry bean (Phaseolus vulgaris L.) (NT-CDb), and NT corn-barley (Hordeum distichon L.) (NT-CB). In 2005, half the N was subsurface band applied as urea-ammonium nitrate (UAN) at planting to all corn plots, with the rest of the N applied surface broadcast as a polymer-coated urea (PCU) in mid-June. The entire N rate was applied as UAN at barley and dry bean planting in the NT-CB and NT-CDb plots in 2005. All plots were in corn in 2006, with PCU being applied at half the N rate at corn emergence and a second N application as dry urea in mid-June followed by irrigation, both banded on the soil surface in the corn row. Nitrous oxide fluxes were measured during the growing season using static, vented chambers (1-3 times wk(-1)) and a gas chromatograph analyzer. Linear increases in N(2)O emissions were observed with increasing N-fertilizer rate, but emission amounts varied with growing season. Growing season N(2)O emissions were greater from the NT-CDb system during the corn phase of the rotation than from the other cropping systems. Crop rotation and N rate had more effect than tillage system on N(2)O emissions. Nitrous oxide emissions from N application ranged from 0.30 to 0.75% of N applied. Spikes in N(2)O emissions after N fertilizer application were greater with UAN and urea than with PCU fertilizer. The PCU showed potential for reducing N(2)O emissions from irrigated cropping systems.


Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1.
The signal transducer and activator of transcription 5 (Stat5) plays a pivotal role in the proliferation, secretory differentiation, and survival of mammary epithelial cells. However, there is little information about Stat5 target genes that facilitate these biological processes. We provide here experimental evidence that the prolactin-mediated phosphorylation of Stat5 regulates the transcriptional activation of the Akt1 gene. Stat5 binds to consensus sequences within the Akt1 locus in a growth factor-dependent manner to initiate transcription of a unique Akt1 mRNA from a distinct promoter, which is only active in the mammary gland. Elevating the levels of active Akt1 restores the expression of cyclin D1 and proliferation of Jak2-deficient mammary epithelial cells, which provides evidence that Akt1 acts downstream of Jak/Stat signaling. The ligand-inducible expression of Stat5 in transgenic females mediates a sustained upregulation of Akt1 in mammary epithelial cells during the onset of postlactational involution. Stat5-expressing mammary glands exhibit a delay in involution despite induction of proapoptotic signaling events. Collectively, the results of the present study elucidate an underlying mechanism by which active Stat5 mediates evasion from apoptosis and self-sufficiency in growth signals.


Quantification of isomerically summed hydrocarbon contributions to crude oil by carbon number, double bond equivalent, and aromaticity using gas chromatography with tunable vacuum ultraviolet ionization.
The ability to structurally characterize and isomerically quantify crude oil hydrocarbons relevant to refined fuels such as motor oil, diesel, and gasoline represents an extreme challenge for chromatographic and mass spectrometric techniques. This work incorporates two-dimensional gas chromatography coupled to a tunable vacuum ultraviolet soft photoionization source, the Chemical Dynamics Beamline 9.0.2 of the Advanced Light Source at the Lawrence Berkeley National Laboratory, with a time-of-flight mass spectrometer (GC × GC-VUV-TOF) to directly characterize and isomerically sum the contributions of aromatic and aliphatic species to hydrocarbon classes of four crude oils. When the VUV beam is tuned to 10.5 ± 0.2 eV, both aromatic and aliphatic crude oil hydrocarbons are ionized to reveal the complete chemical abundance of C9-C30 hydrocarbons. When the VUV beam is tuned to 9.0 ± 0.2 eV only aromatic hydrocarbons are ionized, allowing separation of the aliphatic and aromatic fractions of the crude oil hydrocarbon chemical classes in an efficient manner while maintaining isomeric quantification. This technique provides an effective tool to determine the isomerically summed aromatic and aliphatic hydrocarbon compositions of crude oil, providing information that goes beyond typical GC × GC separations of the most dominant hydrocarbon isomers.


Studies on the beta-oxidative metabolism of delta 1- and delta 6-tetrahydrocannabinol in the mouse. The in vivo biotransformation of metabolites oxidized in the side chain.
The metabolism of 5"-hydroxy-delta 1-tetrahydrocannabinol (THC), 5"-hydroxy-[5",5"-2H2]delta 1-THC, delta 1-THC-5"-oic acid, and delta 6-THC-5"-oic acid was examined by combined gas chromatography and mass spectrometry in the mouse after intraperitoneal administration of the compounds. Metabolic profiles from all three derivatives of delta 1-THC were similar and showed extensive metabolism by the beta-oxidation pathway. Nine metabolites were identified, seven of which contained a C3 side chain. The major metabolite from the delta 1-THC derivatives was 7-hydroxy-4",5"-bis,nor-delta 1-THC-3"-oic acid. Similar metabolites were found with delta 6-THC-5"-oic acid. No metabolites were found with even numbers of carbon atoms in the side chain although these have been reported to be produced in vivo by THC and several other cannabinoids in several species. Thus, the beta-oxidation route, after initial hydroxylation at C-5", appears to be directly responsible for formation of side chain-degraded cannabinoid metabolites containing odd numbers of carbon atoms in the chain but not initially for those metabolites containing an even number of carbon atoms. These are presumed to be formed by initial alpha-oxidation to give a C4 side chain which can then undergo beta-oxidation to the cannabinoids with C2 side chains. The extensive beta-oxidation observed in these experiments, coupled with the absence of corresponding cannabinoids from delta 1-THC itself in the mouse, suggests that 5"-hydroxylation is the rate-determining step in the formation of these compounds.


Maternal Trauma Exposure and Childhood Anxiety Outcomes: Examining Psychosocial Mechanisms of Risk.
The current study aimed to explore the relationship between maternal exposure to various types of trauma and child anxiety outcomes, and to investigate maternal depression and parenting quality as potential mediators of these relationships. Aims were examined within a sample of 185 mother-child dyads who participated in a longitudinal study assessing maternal trauma history, maternal depression, and parenting quality at preschool age (ages 2.5 to 5.5 years), and for whom maternal and secondary caregiver reports of child anxiety were obtained at school age (ages 6 to 11 years). Hypotheses were that (1) maternal exposure to trauma would be positively associated with anxiety levels in offspring and that (2) parenting quality and maternal depression would mediate the relationship between maternal exposure to trauma and child anxiety. Results suggest a direct association between maternal trauma history and child anxiety, as well as indirect associations through parenting quality and maternal depression. These findings are discussed with regard to their implications for the prevention of child anxiety, as well as their implications for the advancement of the literature on intergenerational effects of trauma.


Effect of age on the efficacy of blood pressure treatment strategies.
To study whether the proportion of excess cardiovascular events attributable to various levels of systolic blood pressure varies with age, we calculated the population-attributable risk of all-cause mortality, fatal and nonfatal cardiovascular events (stroke, coronary heart disease, angina, congestive heart failure, and peripheral vascular disease), and stroke incidence due to systolic blood pressure in men and women 45 years of age or older in the United States during 1980. Our estimates are based on US census counts, blood pressure prevalence distributions from the second National Health and Nutrition Examination Survey, and the annual risk of cardiovascular complications during 18 years of follow-up in the Framingham cohort. We then determined the impact of age on the relative efficacy of mass treatment and case-finding strategies in preventing systolic blood pressure-related events. At 45-54 years of age, only 30-40% of systolic blood pressure-related excess events occur in hypertensive individuals (systolic blood pressure greater than or equal to 160 mm Hg). With increasing age, however, the percentage of systolic blood pressure-related events that occur in hypertensive individuals rose substantially; in the older age group (greater than or equal to 75 years), 65-70% of fatal and nonfatal cardiovascular disease events occur in hypertensive persons. The pattern is similar for men and women. The potential impact of a mass treatment strategy designed to shift the distribution of blood pressure downward by a small amount is greater in younger than in older groups, whereas an opposite trend is seen for a high-risk, hypertensive case-finding and treatment approach.(ABSTRACT TRUNCATED AT 250 WORDS)


Complications of Neurofibromatosis 1 (NF1) in an Adult With Multiple Comorbidities.
Neurofibromatosis (NF) is an autosomal genetic disorder with three types, including NF1, NF2, and schwannomatosis. It is characterized by bulging and deforming masses arising from multiple nerves involving skin folds and connective tissues. Prompt diagnosis and provision of care for NF1 patients by clinicians aware of the diverse clinical features of this disorder are needed for optimum patient care and management. A 65-year-old African American female with a past medical history significant for multiple neurofibromas covering more than 95% of her total body surface area (TBSA), presented to a primary care clinic with an enlarged ulcerated neurofibroma of the right elbow. She reported associated pulsating, sharp pain, which was radiating to her entire right upper extremity. For most of her adult life, the lesion has been present and began as the rest of the neurofibromas on her body but gradually enlarged with eventual ulceration three months before the visit. The patient reported a failed surgical resection for the same neurofibroma several years ago. She also reported diffuse tenderness of the lesion, which severely impaired her daily living activities and limited her sleep ability. She acknowledged using multiple over-the-counter analgesics, prescription hydrocodone/acetaminophen 5/325 mg as needed, and gabapentin 300 mg orally twice daily but denied significant symptom alleviation. The patient was started on oral clindamycin hydrochloride 300 mg every six hours for 10 days and a topical mupirocin ointment 2% three times daily for five days. Subsequent visits showed no improvement of the ulcer, which necessitated a referral to wound care. After multiple wound care visits without progress, the patient was referred to a plastic surgeon for evaluation for repeat ulcer resection. NF1 patients develop multiple tumors (neurofibromas); approximately 8%-15% percent of them present with malignant peripheral nerve sheath tumors (MPNST) within the patient's lifetime. Tumor ulceration is a rare but possible complication of NF1. Due to the acute ulcerated fibromas' complications, previous unsuccessful cosmetic management, and ambiguity about NF1 disorder, the patient's quality of life was impaired. The physical and emotional pain the patient experienced impacted her activities of daily living and likely contributed to or exacerbated her diagnoses of substance use disorder and major depressive disorder. NF1 is incurable and can be associated with complications that deteriorate the quality of life, depending on symptom severity. The condition impacts patients' bodies, minds, and spirits, as seen in this patient who had diagnoses of substance use disorder and major depressive disorder, as well as a history of suicidal ideation and suicide attempts. The treatment of conditions related to NF1 is best managed in centers equipped with doctors experienced in treating patients with NF1. A multidisciplinary management approach is ideal. Preferably, for the management of chronic pain and beyond, the osteopathic holistic approach, targeting the body, mind, and spirit, in combination with other innovative non-pharmacotherapies and pharmacotherapy methods, would be beneficial.


Reliability of Visual Field Testing in a Telehealth Setting Using a Head-Mounted Device: A Pilot Study.
Monitoring visual fields via virtual reality device proved to have good inter-test and test-retest reliability as well as easy usability when self-administered by individuals with and without visual field defects in a remote setting. To assess the reliability of remote, self-administered visual field monitoring using a virtual reality visual field (VRVF) device in individuals without ocular disease and with stable visual field defects. Individuals without ocular disease and with stable defects were recruited. All participants had a baseline standard automated perimetry (SAP) test. Participants tested remotely on a VRVF device for four weeks (exams V1, V2, V3, V4), with the last three unassisted. The mean sensitivities of VRVF results were compared to each other and to SAP results for reliability. A total of 42 eyes from 21 participants were tested on the VRVF device. Participants tested consistently although external factors impacted outcomes. VRVF results were in reasonable agreement with the baseline SAP. Exams performed by the cohort with stable defects evinced better agreement with SAP exams (V2, P = 0.79; V3, P = 0.39; V4, P = 0.35) than those reported by the cohort without ocular disease (V2, P = 0.02; V3, P = 0.15; V4, P = 0.22), where the null hypothesis is that the instruments agree. Fixation losses were high and variable in VRVF exams compared to those of SAP, particularly in certain test-takers. Participants considered the device comfortable and easy to use. Self-administered, remote VF tests on a VRVF device showed satisfactory test-retest reliability, good inter-test agreement with SAP, and acceptability by its users. External factors may impact at-home testing and age and visual impairment may hinder fixation. Future studies to expand the sample size and understand inconsistencies in fixation losses are recommended.


Photon pair source based on parametric fluorescence in periodically poled twin-hole silica fiber.
We present observations of quasi-phase matched parametric fluorescence in a periodically poled twin-hole silica fiber. The phase matching condition in the fiber enables the generation of a degenerate signal field in the fiber-optic communication band centered on 1556 nm. We performed coincidence measurements and a Hong-Ou-Mandel experiment to validate that the signal arises from photon pairs. A coincidence peak with a signal to noise ratio (SNR) of 4 using 43 mW of pump power and a Hong-Ou-Mandel dip showing 40% net visibility were measured. Moreover, the experiments were performed with standard single mode fibers spliced at both ends of the poled section, which makes this source easy to integrate in fiber-optic quantum communication applications.


[Features to improve health care in "dietology" profile in Voronezh Region].
Recent years, restructuring of the health care to the population, including a complex of measures to improve the human resources policy in health, spurring the practice of the disciplines to public health care, turning, organizing 3-tier health care system, including the profile "nutrition" is carried out in Voronezh region. Analysis of security by dietitians, dietary nurses and hi-tech medical equipment is carried out. Set of measures to developing interaction between health care institutions (accordingly Health Ministry order N 474 from 24.06.2010) was worked up. Implementation of order of medical care in "Dietology" profile, high-quality dietitians work at all stages of 3-tier system of organization of medical care will make an unconditional contribution to the overall development strategy of the national health care.


Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling.
Glutamatergic neurotransmission is controlled by presynaptic metabotropic glutamate receptors (mGluRs). A subdomain in the intracellular carboxyl-terminal tail of group III mGluRs binds calmodulin and heterotrimeric guanosine triphosphate-binding protein (G protein) betagamma subunits in a mutually exclusive manner. Mutations interfering with calmodulin binding and calmodulin antagonists inhibit G protein-mediated modulation of ionic currents by mGluR 7. Calmodulin antagonists also prevent inhibition of excitatory neurotransmission via presynaptic mGluRs. These results reveal a novel mechanism of presynaptic modulation in which Ca(2+)-calmodulin is required to release G protein betagamma subunits from the C-tail of group III mGluRs in order to mediate glutamatergic autoinhibition.


Complete pathological response (ypT0N0M0) after preoperative chemotherapy alone for stage IV rectal cancer.
Complete pathological response occurs in 10-20% of patients with rectal cancer who are treated with neoadjuvant chemoradiation therapy prior to pelvic surgery. The possibility that complete pathological response of rectal cancer can also occur with neoadjuvant chemotherapy alone (without radiation) is an intriguing hypothesis. A 66-year old man presented an adenocarcinoma of the rectum with nine liver metastases (T3N1M1). He was included in a reverse treatment, aiming at first downsizing the liver metastases by chemotherapy, and subsequently performing the liver surgery prior to the rectum resection. The neoadjuvant chemotherapy consisted in a combination of oxaliplatin, 5-FU, irinotecan, leucovorin and bevacizumab (OCFL-B). After a right portal embolization, an extended right liver lobectomy was performed. On the final histopathological analysis, all lesions were fibrotic, devoid of any viable cancer cells. One month after liver surgery, the rectoscopic examination showed a near-total response of the primary rectal adenocarcinoma, which convinced the colorectal surgeon to perform the low anterior resection without preoperative radiation therapy. Macroscopically, a fibrous scar was observed at the level of the previously documented tumour, and the histological examination of the surgical specimen did not reveal any malignant cells in the rectal wall as well as in the mesorectum. All 15 resected lymph nodes were free of tumour, and the final tumour stage was ypT0N0M0. Clinical outcome was excellent, and the patient is currently alive 5 years after the first surgery without evidence of recurrence. The presented patient with stage IV rectal cancer and liver metastases was in a unique situation linked to its inclusion in a reversed treatment and the use of neoadjuvant chemotherapy alone. The observed achievement of a complete pathological response after chemotherapy should promote the design of prospective randomized studies to evaluate the benefits of chemotherapy alone in patients with stages II-III rectal adenocarcinoma (without metastasis).


Membrane-associated insulin-like growth factor-binding protein-3 inhibits insulin-like growth factor-I-induced insulin-like growth factor-I receptor signaling in ishikawa endometrial cancer cells.
The function of cell surface-associated insulin-like growth factor-binding proteins (IGFBPs) is controversial. Both inhibition and facilitation of IGF action as well as IGF-independent effects have been reported. We examined the influence of endogenous cell surface-associated IGFBPs on IGF-I receptor (IGF-IR) function in Ishikawa endometrial cancer cells by comparing the effects of IGF-I and its truncated analog des-(1-3)-IGF-I on several components of the IGF-IR signal transduction pathway in the absence of significant amounts of soluble IGFBPs. IGF-I and des-(1-3)-IGF-I are known to have similar affinities for IGF-IR, although the affinity of des-(1-3)-IGF-I for IGFBPs is greatly reduced. Here we show that the two ligands were equipotent not only in IGF-IR binding but also in receptor activation in NIH 3T3 cells overexpressing IGF-IR and possessing a relatively small number of cell surface-associated IGFBPs. In contrast, des-(1-3)-IGF-I manifested a remarkably higher potency as compared with IGF-I in inducing short and middle term cellular responses in IGF-IR-transfected Ishikawa endometrial cancer cells possessing a high number of both the receptor and the cell membrane-bound IGFBP-3. Thus, this difference in the effects of IGF-I and des-(1-3)-IGF-I can be attributed to the attenuation of IGF-I-mediated IGF-IR signaling by membrane-bound IGFBP-3.


An automated tool for detecting medication overuse based on the electronic health records.
Medication overuse is a serious concern in healthcare as it leads to increased expenditures, side effects, and morbidities. Identifying overuse is only possible through excluding appropriate indications that are primarily mentioned in unstructured notes. We developed a framework for automatic identification of medication overuse and applied it to proton pump inhibitors (PPIs). We first created an indications knowledge base using data from drug labels, clinical guidelines, expert opinion, and other sources. We also obtained the list of current problems for 200 randomly selected inpatients who received PPIs using a natural language processing system and the discharge summaries of those patients. These problems were checked against the indications knowledge base to identify overuse candidates. Two gastroenterologists manually reviewed the notes and identified cases of overuse. Results from the automated framework were compared with the manual review. Reviewers had high interrater reliability in finding indications (agreement = 92.1%, Cohen's κ = 0.773). In 137 notes included in the final analysis, our system identified indications with a sensitivity of 74% (95%CI = 59-86) and specificity of 95% (95%CI = 87-98). In cases of appropriate use where the automated system also found one or more indications, it always included the correct indication. We created an automated system that can identify established indications of medication use in electronic health records with high accuracy. It can provide clinical decision support for identifying potential overuse of PPIs and could be useful for reducing overuse and encouraging better documentation of indications.


Use of oral mucoperiosteal and pterygo-masseteric muscle flaps as interposition material in surgery of temporomandibular joint ankylosis: a comparative study.
The most common complication of surgery for the release of temporomandibular joint (TMJ) ankylosis is relapse of the ankylosis. To prevent re-ankylosis, a variety of interpositional materials have been used. The aim was to compare the surgical outcome of oral mucoperiosteal flap, not hitherto used as interpositional material, with pterygo-masseteric muscles flap after surgical release of TMJ ankylosis. This was a prospective randomized study of all consecutive patients treated for the release of complete TMJ bony ankylosis, from January 2003 to December 2012, at the Oral and Maxillofacial unit of our institution. The patients were randomized into two groups: The pterygo-masseteric group comprises 22 patients while the oral mucoperiosteal group had 23 patients. Information on demographics, clinical characteristics, and postoperative complications over a 5 year follow-up period were obtained, and analyzed using the statistical package for social sciences (Statistical Package for the Social Sciences version 13, Chicago, IL, USA). A P < 0.05 was considered significant. The age of the patients ranged from 15 to 28 mean 20.3 (3.35) years while the duration of ankylosis ranged from 2 to 16 mean 5.1 (3.4) years. The baseline demographic (gender; P = 0.92; side; P = 0.58) and clinical characteristics in terms of etiology (P = 0.60) and age (P = 0.52) were comparable in both treatment groups. All the patients presented with complete bony TMJ ankylosis with a preoperative inter-incisal distance of <0.5 cm. The intraoperative mouth opening achieved ranged from 4 cm to 5 cm, mean 4.6 (0.27) cm and this was not different for either group (P = 0.51). The patients were followed up postoperatively for a period ranging from 3 to 5 years, mean 3.4 (0.62) years. The mouth opening decreased, over the period of postoperative review, from the initial range of 4-5 cm to 2.9-3.6 cm, and this was not different in both groups (P = 0.18). This study suggests that oral mucoperiosteal flap could be an option in the choice of interpositional materials in surgery of TMJ ankylosis.


Communication strategies to improve drug use evaluation.
Successful examples of teams and drug use evaluations explore communication strategies to enhance quality improvement of medication use. Topics highlighted include establishing contacts within key departments, creating committee connections, fostering physician and nurse participation, and increasing visibility and maintaining awareness. Multidisciplinary collaboration and linkage between the hospital and the managed care pharmacy are also reviewed. Medication use can be improved by integrating these communication tactics.


Development and implementation of an advanced model predictive control system into continuous pharmaceutical tablet compaction process.
In the context of continuous pharmaceutical oral dosage manufacturing, a control system is essential to ensure that the critical quality attributes (CQAs) are maintained within the regulatory constraints by mitigating variations generated in upstream operations. Such a system is essential to the Quality by Design (QbD) paradigm shift, which can ensure that predefined end quality attributes are achieved within an optimal economic and time bracket. In this work, an advanced model predictive control (MPC) architecture integrated with a novel real-time tablet weight measurement method has been development and implemented into a continuous direct compaction tablet manufacturing pilot-plant. The proposed control architecture has the potential to control tablet weight and tablet breaking force simultaneously by systematically decoupling and cascading the control loops. The model predictive control algorithm was experimentally found to be superior to the PID (proportional, integral and derivative) controller and thus, can be utilized for a wide range of applications to improve the quality of pharmaceutical products in continuous manufacturing. The MPC was used to control main compression force and pre compression force using main compression height and fill depth respectively as the actuators. The introduction of this methodology leads to new ways of developing MPC models, tablet weight measurement methods and control strategies that enhance the manufacturability and quality of pharmaceutical tablets.


Fucosyltransferase gene expression in goat endometrium during the estrous cycle and early pregnancy.
Regulation of the expression of the alpha(1,2)fucosyltransferase (FUT) genes and their enzymatic products, including the H-type 1 antigen (HT1), on the luminal surface of the uterus is believed to be critical for establishment of pregnancy in mammals. The FUT1 gene is a marker for conception rates in dairy cows and HT1 is a marker for uterine receptivity in rodents. To determine the spatiotemporal expression patterns of FUT1 and FUT2 genes in goats, endometrial tissues were obtained on six days spanning the estrous cycle (Days 5, 11, 13, 15, 17 and 19) and seven days spanning early pregnancy (Days 5, 11, 13, 15, 17, 19 and 25). In all data, we found no effect of status (cyclic or pregnant; P > 0.1) and pooled data where appropriate. We cloned FUT1 cDNA from goat endometrium and made probes from it for Northern and slot blot analyses. The analyses indicated that FUT1 gene expression was high until Day 13, and then declined. In situ hybridization revealed a change in the cell-specificity of FUT1 gene expression over the estrous cycle and early pregnancy. In situ hybridization signal intensity scores indicated that FUT1 expression by uterine epithelium was high on Day 5, moderate on Day 11, and minimal on subsequent days. In situ hybridization signals in uterine glandular epithelial cells remained high from Day 5 to Day 13, with weaker signals thereafter. Quantitative reverse transcription-PCR (RT-qPCR) assays were used for quantitation of FUT1 and FUT2 mRNAs. Quantitative RT-qPCR data were generated from endometrium collected from cyclic and pregnant animals on Days 5, 11 and 17. Relative levels of FUT1 mRNA were high on Days 5 and 11, but then fell 5-fold by Day 17 (P < 0.01). FUT2 mRNA concentrations were below the accurate detectable limit of the assay. High levels of HT1 were observed on the apical surface of uterine luminal epithelia on Days 5, 15, 17 and 19, with much lower levels on Days 11 and 13. Thus, data suggests that FUT1 is the primary enzyme responsible for the high levels of HT1 antigen present on the uterine luminal epithelium between Days 5 and 11 of the estrous cycle and early pregnancy. But changes in the expression of the FUT1 gene does not directly correlate to HT1 staining, which increased from Day 13-15. Future studies are required to understand the regulation of the HT1 antigen on the luminal surface of endometrium.


(2Z)-2-Benzyl-idene-4-(prop-2-yn-1-yl)-2H-1,4-benzo-thia-zin-3(4H)-one.
The mol-ecule of the title compound, C18H13NOS, is build up from two fused six-membered rings, with the heterocyclic component linked to a benzyl-idene group and to a prop-2-yn-1-yl chain. The six-membered heterocycle adopts a distorted screw-boat conformation. The prop-2-yn-1-yl chain is almost perpendicular to the mean plane through benzo-thia-zine as indicated by the C-N-C-C torsion angle of 86.5 (2)°. The dihedral angle between the benzene rings is 47.53 (12)°. There are no specific inter-molecular inter-actions in the crystal packing.


Minimally invasive treatment of calcaneal fracture by percutaneous leverage, anatomical plate, and compression bolts--the clinical evaluation of cohort of 156 patients.
To introduce a minimally invasive procedure and investigate its clinical significance in the treatment of displaced intra-articular calcaneal fractures. This minimally invasive procedure consists of percutaneous leverage, manual compression, and fixation with anatomic plates and compression bolts through small lateral incisions. Two hundred ten feet with calcaneal fractures from 156 patients were managed by this minimally invasive procedure. According to Sanders classification, the fracture patterns in our study include 132 type II, 60 type III, and 18 type IV fractures. The Böhler's and Gissan's angle as well as the width, height, and length of the calcaneum were measured on pre- and postoperative radiographs. The anatomic plates were removed from 3 months to 12 months after operation for all patients. The Maryland hindfoot score system was applied to evaluate the postoperative function of the hindfoot. All patients were followed up for an average of 9.7 months (range, 4.5-12 months). The reduction of the posterior articular facet was graded as nearly anatomic with articular displacement of < 3 mm in 159 fractures (75.7%). The reduction was measured radiologically by the change in the width, height, length of the calcaneum, and Böhler's and Gissan's angle, which have seen significant improvement in all patients. Based on the Maryland hindfoot score, 90 (43%) fractures was assessed as excellent, 90 (43%) good, 18 (8%) fair, and 12 (6%) poor. One hundred thirty-two patients (84.6%) were able to return to their original occupation at a mean time of 5.2 months (4.0-10.6 months) after operation. No patient sustained lateral impingement syndrome or soft tissue complications. Up to date, 20 patients (9.5%) sustained mild-to-moderate subtalar osteoarthritis, evidented radiologically as the narrowing of the joint space and subchondral sclerosis, but pain in the subtalar joint was present only in four patients (1.9%). No subtalar arthrodesis has been performed because of patients' unwillingness to undergo second procedure to relieve the pain that is well tolerable. This minimal invasive procedure featured percutaneous leverage, manual compression, and the application of the anatomic plates and compression bolts through lateral approach is proved to be an effective treatment for displaced intra-articular calcaneal fracture, offering the combination of fewer soft tissue complications and good reduction. With < 3-mm displacement of the posterior facet after reduction, the restoration of the calcaneal width and height can be very important to achieve satisfactory radiologic and functional outcomes.


Transcriptome profiling identifies genes/pathways associated with experimental resistance to paromomycin in Leishmania donovani.
Widespread resistance towards antimony and reports of relapses following miltefosine treatment has severely affected the management of visceral leishmaniasis (VL) in the Indian subcontinent. Paromomycin (PMM), an aminoglycoside antibiotic, has been licensed for VL treatment in India in 2007. Although its use is still restricted in the field, unraveling the molecular mechanism of resistance towards PMM is the key to preserve the drug. In this study, PMM resistant lines were selected up to 100 μM of PMM in three distinct field isolates of Leishmania donovani at promastigote stage. The resistance induced at promastigote level was also evident in amastigotes which showed 6 fold decreases in PMM susceptibility. Comparative transcriptome profiling of PMM resistant (PMM-R) and the corresponding PMM sensitive (PMM-S) parasites revealed modulated expression of 500 genes (1.5 fold cut off) in PMM-R parasites. Selected genes were validated for their modulated expression by quantitative real-time PCR. Functional classification and pathway analysis of modulated genes indicated probable adaptations in drug resistant lines which included a) reduced oxidative phosphorylation; b) increased glycosomal succinate fermentation and substrate level phosphorylation; c) dependency on lipids and amino acids for energy generation; d) reduced DNA synthesis and increased DNA damage repair and e) decreased protein synthesis and degradation. Interestingly, PMM-R parasites showed a marked increase in PMM susceptibility in presence of verapamil and amlodipine, antagonists of Ca2+ channel that are also modulators of ABC transporters. Moreover, infection of macrophages by PMM-R parasites led to modulated nitric oxide (NO) levels while reactive oxygen species (ROS) level remained unaltered. The present study highlights the putative mechanisms of PMM resistance in Leishmania.


Carbon sink strength of nodules but not other organs modulates photosynthesis of faba bean (Vicia faba) grown under elevated [CO2 ] and different water supply.
Photosynthetic stimulation by elevated [CO2 ] (e[CO2 ]) may be limited by the capacity of sink organs to use photosynthates. In many legumes, N2 -fixing symbionts in root nodules provide an additional sink, so that legumes may be better able to profit from e[CO2 ]. However, drought not only constrains photosynthesis but also the size and activity of sinks, and little is known about the interaction of e[CO2 ] and drought on carbon sink strength of nodules and other organs. To compare carbon sink strength, faba bean was grown under ambient (400 ppm) or elevated (700 ppm) atmospheric [CO2 ] and subjected to well-watered or drought treatments, and then exposed to 13 C pulse-labelling using custom-built chambers to track the fate of new photosynthates. Drought decreased 13 C uptake and nodule sink strength, and this effect was even greater under e[CO2 ], and was associated with an accumulation of amino acids in nodules. This resulted in decreased N2 fixation, and increased accumulation of new photosynthates (13 C/sugars) in leaves, which in turn can feed back on photosynthesis. Our study suggests that nodule C sink activity is key to avoid sink limitation in legumes under e[CO2 ], and legumes may only be able to achieve greater C gain if nodule activity is maintained.


Within-season variation in sexual selection in a fish with dynamic sex roles.
The strength of sexual selection may vary between species, among populations and within populations over time. While there is growing evidence that sexual selection may vary between years, less is known about variation in sexual selection within a season. Here, we investigate within-season variation in sexual selection in male two-spotted gobies (Gobiusculus flavescens). This marine fish experiences a seasonal change in the operational sex ratio from male- to female-biased, resulting in a dramatic decrease in male mating competition over the breeding season. We therefore expected stronger sexual selection on males early in the season. We sampled nests and nest-holding males early and late in the breeding season and used microsatellite markers to determine male mating and reproductive success. We first analysed sexual selection associated with the acquisition of nests by comparing nest-holding males to population samples. Among nest-holders, we calculated the potential strength of sexual selection and selection on phenotypic traits. We found remarkable within-season variation in sexual selection. Selection on male body size related to nest acquisition changed from positive to negative over the season. The opportunity for sexual selection among nest-holders was significantly greater early in the season rather than late in the season, partly due to more unmated males. Overall, our study documents a within-season change in sexual selection that corresponds with a predictable change in the operational sex ratio. We suggest that many species may experience within-season changes in sexual selection and that such dynamics are important for understanding how sexual selection operates in the wild.


Oral inflammatory process and general health. Part 1: The focal infection and the oral inflammatory lesion.
A focal infection is a localized or generalized infection caused by the dissemination of microorganisms or toxic products from a focus of infection in various organic districts, including the oral district. In the Part 1 of this two-part review article, after historical signs, the Authors describe the current pathogenic concepts like the "immuno-allergic theory" and the formation of auto-antibodies in human body, contributing to the genesis of autoimmune illnesses sustained by individual reactivity linked to eredo-constitutionality. Some theories suppose a focal origin even for general pathology such as cancer, sarcoidosis, multiple sclerosis, amyotrophic lateral sclerosis, autism, Guillain-Barré syndrome, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS), Tourette's syndrome, myasthenia gravis, polycystic kidney disease, obesity, Alzheimer's disease and diabetes mellitus. Laboratory analyses (leucocytic formula, protein electrophoresis, C-reactive protein, REUMA test VES, TAS, etc.) are suggestive of the presence of an inflammatory process or of the presence of an aspecific answer to an inflammatory situation. The DNA-Polymerase Chain Reaction method (PCR) is fundamental for the diagnosis of bacterial and viral infections, particularly for those that have non-culturable microorganisms or in cases where are present but in extremely small number in the sample to be analyzed. A positive result confirms the diagnosis, but negative result is not indicator of the absence of illness. Even for oral inflammatory lesions, different basic mechanisms concerning the possible association with systemic diseases exist. They concern local spread, metastatic spread or immunologic cross-reactivity. In this case we assume that most of the ailments come from dental or periodontal foci, as in the bacterial endocarditis, but instead of considering them as possible pathogenetic mechanism of an immune nature, we consider them as originated by the body's response to the presence of bacterial antigens through the formation of specific antibodies. Much researche, sometimes contrasting, has evaluated periodontal pathogens in atheromatous plaques isolated from patients with chronic periodontitis. Oral inflammatory lesions have been shown unequivocally to contribute to elevated systemic inflammatory responses. In some researches intensive periodontal therapy showed a significant reduction of lymphocyte formula, of CRP levels, of interleukin-6 (IL-6) and of LDL cholesterol after two months.


Germinal GLT8D1, GATAD2A and SLC25A39 mutations in a patient with a glomangiopericytal tumor and five different sarcomas over a 10-year period.
Soft tissue sarcoma represents about 1% of all adult cancers. Occurrence of multiple sarcomas in a same individual cannot be fortuitous. A 72-year-old patient had between 2007 and 2016 a glomangiopericytal tumor of the right forearm and a succession of sarcomas of the extremities: a leiomyosarcoma of the left buttock, a myxofibrosarcoma (MFS) of the right forearm, a MFS of the left scapula, a left latero-thoracic MFS and two undifferentiated sarcomas on the left forearm. Pathological examination of the six locations was not in favor of disease with local/distant recurrences but could not confirm different diseases. An extensive molecular analysis including DNA-array, RNA-sequencing and DNA-Sanger-sequencing, was thus performed to determine the link between them. The genomic profile of the glomangiopericytal tumor and the six sarcomas revealed that five sarcomas were different diseases and one was the local recurrence of the glomangiopericytal tumor. While the chromosomal alterations in the six tumors were different, a common somatic CDKN2A/CDKN2B deletion was identified. RNA-sequencing of five tumors identified mutations in GLT8D1, GATAD2A and SLC25A39 in all samples. The germline origin of these mutations was confirmed by Sanger-sequencing. Innovative molecular analysis methods have made possible a better understanding of the complex tumorigenesis of multiple sarcomas.


Rapid HIV-1 genotyping assay for the detection of capsid mutations.
Human immunodeficiency virus (HIV) capsid is one of the most recent viral proteins successfully targeted for the development of antiretrovirals. Lenacapavir is a first in class HIV-1 capsid inhibitor that was recently approved for the treatment of highly treatment-experienced people with HIV in combination with other anti-HIV drugs. Owing to the novelty of the viral target, methods to characterize the potential resistance-associated mutations present in capsid upon treatment failure have not been fully established yet. Here, we describe a rapid and simple method to amplify capsid fragments and to determine their sequence from various clinical samples including diverse HIV-1 subtypes. These methods could easily be implemented in laboratories, including hospital laboratories often caring for this patient population.


Apoptosis and T cell hyporesponsiveness in pulmonary tuberculosis.
Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-gamma remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-gamma and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-gamma, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.


Lymphoid expression and TATAA binding of a human protein containing an Antennapedia homeodomain.
In an effort to identify human proteins that bind to the TATAA box, a lambda gt-11 expression library was screened with a radiolabeled DNA probe containing 12 copies of the TATAA sequence. A cDNA encoding a specific TATAA binding protein was isolated and found to contain a homeobox domain identical at 59 of 60 residues to the Drosophila Antennapedia (Antp) homeodomain, as well as another conserved motif found in homeotic genes, the homeo-specific pentapeptide. Although this and other Antp-like homeobox proteins have been described previously in neuronal cells and fibroblasts, we report the expression of this gene in lymphoid cells. This cDNA, isolated from a B-cell library, hybridizes to a 1.6-kb messenger RNA in several T- and B-cell lines, and the expected protein was identified in Jurkat T-lymphoid cells by Western blot analysis. The DNA binding specificity of this human Antp clone was analyzed using single-base mutations of the TATAA sequence. The first thymidine, as well as the last three bases (TAA), were important for homeobox binding. Finally, the function of the highly conserved homeospecific pentapeptide protein region was investigated in both the human and Drosophila Antp proteins. The homeospecific pentapeptide region was not required for DNA binding, and Drosophila Antp proteins mutated in the pentapeptide region were able to transactivate the Ubx promoter in Schneider L2 cells, in contrast to a homeodomain mutation, suggesting an alternative function for the homeospecific pentapeptide in homeotic genes. Because the human Antp TATAA binding protein is expressed in both lymphoid and non-lymphoid cells, we suggest that this homeobox gene has evolved a more general transcriptional regulatory function in higher eukaryotic cells.


Drugs versus placebo for dysthymia.
Dysthymia is a depressive disorder of chronic nature but of less severity than major depression, which depressive symptoms are more or less continuous for at least two years. The aim of this review was to conduct a systematic review of all RCTs comparing drugs and placebo for dysthymia. Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from the pharmaceutical industry; book chapters on the treatment of depression. The inclusion criteria for all randomised controlled trials were that they should focus on the use of drugs versus placebo for dysthymic patients. Exclusion criteria were: non randomised, mixed major depression/ dysthymia (trials not providing separate data) and depression secondary to other disorders (e.g. substance abuse). The reviewers extracted the data independently. In order to achieve an intention-to-treat analysis, when trials failed to report it was assumed that people who died or dropped out had no improvement. Authors of relevant trials were contacted for additional and missing data. Absence of treatment response as defined by authors was the main measure of outcome used. Relative Risks (RR) and 95% confidence intervals (CI) of dichotomous data were calculated with the Random Effects Model. Where possible, number needed to treat (NNT) and number needed to harm (NNH) were estimated, taking the reciprocal of the absolute risk reduction. Currently the review includes 15 trials. Similar results were obtained in terms of efficacy for different groups of drugs, such as tricyclic (TCA), selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI) and other drugs (sulpiride, amineptine, and ritanserin). The pooled RR for absence of treatment response was 0.68 (95% CI 0.59-0.78) for TCA and the NNT was 4.3 (95% CI 3.2-6.5). SSRIs showed similar RR for this outcome: 0.64 (95% CI 0.55-0.74), the NNT being 4.7 (95% CI 3.5-6.9). Concerning MAOIs, the RR was 0.59 (95% CI 0.48-0.71) and the NNT was 2.9 (95% CI 2.2-4.3). Other drugs (amisulpride, amineptine and ritanserin) showed similar results in terms of absence of treatment response. Using more stringent criteria for improvement - full remission - the results were unchanged. Patients treated on TCA were more likely to report adverse events, compared with placebo. Drugs are effective in the treatment of dysthymia with no differences between and within class of drugs. Tricyclic antidepressants are more likely to cause adverse events and dropouts. As dysthymia is a chronic condition, there remains little information on quality of life and medium or long-term outcome.


Structure of KOH-soluble polysaccharides from сoniferous greens of Norway spruce (Picea abies): The pectin-xylan-AGPs complex. Part 2.
Polymers containing arabinoglucuronoxylan, fucogalactoxyglucan, pectin and arabinogalactan proteins were obtained from PAK isolated from Norway spruce with 7 % KOH. The pectin core of PAK-I2-F-1 and PAK-I2-F-2 was dominated by RG-I, as treatment with 1,4-α-D-polygalacturonase resulted in almost complete removal of homogalacturonan. Interestingly, the above has not affected the co-fractionation of arabinoglucuronoxylan (AGX), arabinogalactan proteins and rhamnogalacturonan I (RG-I). Since pectin was mainly represented by RG-I, we concluded that xylan is specifically associated with RG-I. Correlations in the HMBC spectrum demonstrate intermolecular interactions between the α-L-Rhap (RG-I) and the Xyl (xylan), indicating a covalently bound AGX:RG-I complex via the Xyl-(1→4)-Rha bond: …→2)-[(2,4-β-D-Xylp)-(1→4)]-[(α-D-GalpA-(1→2)]-α-L-Rhap-(1→4)-α-D-GalpA-(1→…. In PAK-H1-1-F-1 and PAK-H1-1-F-2, parts of RG-I and xylan were removed by enzymolysis. Part of the xylan was probably attached to the above-mentioned RG-I blocks. The removal of part of RG-I, xylan and the disappearance of the signal in the HMBC spectrum indicating the bond between RG-I and xylan confirms that part of the arabinoglucuronoxylan is covalently bound to RG-I. The observed glycosidic linkage contradicts the dominant PCW model in which pectin and hemicellulose polysaccharide networks are considered as independent components. It can be concluded that alkali-soluble xylan from Norway spruce was detected both in the free state and covalently bound to pectin.


Mineral elements and essential oil contents of Scutellaria luteo-caerulea Bornm. & Snit.
Scutellaria luteo-caerulea Bornm. & Snit. is one of the species of genus Scutellaria, within the family of the Lamiaceae, that is used for immune system stimulation and antibacterial effects in traditional medicine in Iran. The aims of this study were to analyze essential oils and mineral element contents of leaves of S. luteo-caerulea in flowering stage of development. The essential oils were obtained by hydrodistillation of the leaves of S. luteo-caerulea and were analyzed by gas chromatography mass spectrometry (GC/MS). Moreover, microwave digestion with atomic absorption spectrophotometry were used for the mineral elements assay. Ninety-seven constituents were detected. Between them, the major components were trans-caryophyllene (25.4%), D-germacrene (7.9%), and linalool (7.4%). Determination of mineral elements showed that the highest minerals were Ca(2+) (65.14±1.95 µg/ml) and K(+) (64.67±3.10 µg/ml). Presence of different essential oils and rich sources of Ca(2+) and K(+) candidate this plant as an auxiliary medication in different diseases, but more complementary researches are needed about its potency and side effects.


Quality of care for decompensated heart failure: comparable performance between academic hospitalists and non-hospitalists.
Hospitalists improve efficiency, but little information exists regarding whether they impact quality of care. To determine hospitalists' effect on the quality of acute congestive heart failure care. Using data from the Multicenter Hospitalist Study, we retrospectively evaluated quality of care in patients admitted with congestive heart failure who were assigned to hospitalists (n = 120) or non-hospitalists (n = 252) among six academic hospitals. Quality measures included the percentage of patients who had ejection fraction (EF) measurement, received appropriate medications [i.e., angiotensin-converting enzyme inhibitor (ACE-I) or beta-blockers] at discharge, measures of care coordination (e.g., follow-up within 30 days), testing for cardiac ischemia (e.g., cardiac catheterization), as well as hospital length of stay, cost, and combined 30-day readmissions and mortality. Compared to non-hospitalist physicians, hospitalists' patients had similar rates of EF measurement (85.3% vs. 87.5%; P = 0.57), ACE-I (91.5% vs. 88.0%; P = 0.52), or beta-blocker (46.9% vs. 42.1%; P = 0.57) prescriptions. Multivariable adjustment did not change these findings. Hospitalists' patients had higher odds of 30-day follow-up (adjusted OR = 1.83, 95% CI, 1.44 - 2.93). There were no significant differences between the groups' frequency of cardiac testing, length of stay, costs, or risk for readmission or death by 30-days. Academic hospitalists and non-hospitalists provide similar quality of care for heart failure patients, although hospitalists are paying more attention to longitudinal care. Future efforts to improve quality of care in decompensated heart failure may require attention towards system-level factors.


Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer.
Tumor suppressor p53 protein (p53) plays a vital role throughout the body to conserve DNA stability and prevent cancer. Normally, wild-type p53 protein (wtp53) is either degraded or bound to a negative regulator and is inactive. When damage to DNA occurs within a cell, p53 protein is induced and causes cell cycle arrest. This gives cells a chance to repair, but if damage is too severe, cells undergo apoptosis and are rejected. Mutations in the p53 gene (mtp53) are associated with a variety of cancers and occur in 70-80% of cases of triple-negative breast cancer (TNBC). Importantly, many mutations occur in the DNA binding domain of p53 gene and the altered mutant p53 protein (mtp53) is subsequently not degraded. High levels of mtp53 protein accumulate within the cell, leading to the development of tumors. Therefore, converting mtp53 protein back into its functional wild-type conformation is a promising means by which to prevent or reverse tumor development. Herein we will briefly examine how tumor suppressor wtp53 exerts its effects, the mechanisms involved in protecting cells that undergo DNA damage and ways in which wtp53 prevents tumorigenesis. Using TNBC as an example, we will describe the use of specific compounds to reactivate mtp53 protein function by reconfiguring its structure and outline the potential benefits of mtp53 protein reactivation. We will also briefly discuss current clinical trials aimed at reactivating mtp53 protein in order to cure certain cancers. Finally, we make the recommendation that greater emphasis should be placed on testing naturally occurring compounds that are generally non-toxic to re-activate mtp53 protein and control progression of TNBC.


The patient with severe traumatic brain injury: clinical decision-making: the first 60 min and beyond.
There is an urgent need to discuss the uncertainties and paradoxes in clinical decision-making after severe traumatic brain injury (s-TBI). This could improve transparency, reduce variability of practice and enhance shared decision-making with proxies. Clinical decision-making on initiation, continuation and discontinuation of medical treatment may encompass substantial consequences as well as lead to presumed patient benefits. Such decisions, unfortunately, often lack transparency and may be controversial in nature. The very process of decision-making is frequently characterized by both a lack of objective criteria and the absence of validated prognostic models that could predict relevant outcome measures, such as long-term quality and satisfaction with life. In practice, while treatment-limiting decisions are often made in patients during the acute phase immediately after s-TBI, other such severely injured TBI patients have been managed with continued aggressive medical care, and surgical or other procedural interventions have been undertaken in the context of pursuing a more favorable patient outcome. Given this spectrum of care offered to identical patient cohorts, there is clearly a need to identify and decrease existing selectivity, and better ascertain the objective criteria helpful towards more consistent decision-making and thereby reduce the impact of subjective valuations of predicted patient outcome. Recent efforts by multiple medical groups have contributed to reduce uncertainty and to improve care and outcome along the entire chain of care. Although an unlimited endeavor for sustaining life seems unrealistic, treatment-limiting decisions should not deprive patients of a chance on achieving an outcome they would have considered acceptable.


Triterpenoid saponins from Stauntonia chinensis ameliorate insulin resistance via the AMP-activated protein kinase and IR/IRS-1/PI3K/Akt pathways in insulin-resistant HepG2 cells.
Inflammation and oxidative stress play crucial roles in the etiology of type 2 diabetes mellitus. In this study, we examined the anti-diabetic effects of triterpenoid saponins extracted from Stauntonia chinensis on stimulating glucose uptake by insulin-resistant human HepG2 cells. The results showed that saponin 6 significantly increased glucose uptake and glucose catabolism. Saponin 6 also enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and activated the insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Therefore, our results suggest that saponins from S. chinensis improve glucose uptake and catabolism in hepatic cells by stimulating the AMPK and the IR/IRS-1/PI3K/Akt signaling pathways. The results also imply that saponins from S. chinensis can enhance glucose uptake and insulin sensitivity, representing a promising treatment for type 2 diabetes mellitus.


Dancing to a different tune: changing reproductive seasonality in an introduced chital deer population.
Male and female reproductive behaviour is typically synchronised. In species such as those in the family Cervidae, reproductive timing is often cued by photoperiod, although in females, it can be dependent on body condition. When a species is introduced to a novel environment, the environment changes, or responses of the sexes to such cues differ, asynchronous reproductive behaviour between males and females may occur. We investigated the seasonality of reproductive behaviour in introduced chital deer in northern Queensland by examining male antler phase in relation to female conception rates. We then analysed the influence of different variables likely to affect the timing of male and female reproductive physiology. The lowest percentage of chital in hard antler in any 1 month in this study was 35% (Fig. 1), but the average value was closer to 50%, thus there was a seasonal peak in antler phase linked with photoperiod. Females conceived at any time of year, but were strongly influenced by the amount of rainfall 3 months prior to conception. This resulted in varying conception peaks year-to-year that often did not correspond to the male's peak in hard antler. In this system, a proportion of males and females were physiologically and behaviourally ready to mate at any time of the year. We predict that differences in the timing of the peaks between the males and females will lead to increased reproductive skew (variation in reproductive success among individual males). This pattern may select for different mating strategies or physiological mechanisms to increase reproductive success. Fig. 1 The average percentage of male chital deer in hard antler by month from 2014 to 2019 in north Queensland. Values above the bars indicate the total number of males that were sampled in each month and the error bars indicate the standard error. In the month with the lowest % males in hard antler in the entire study (November, 2017), 35% of males were in hard antler.


Factors involved in the systemic transport of plant RNA viruses: the emerging role of the nucleus.
Compatible virus-host interactions depend on a suitable milieu in the host cells permitting viral gene expression, replication, and spread. During pathogenesis, viruses hijack the plant cellular machinery to access molecules, subcellular structures, and host transport pathways needed for infection. Vascular trafficking of virus transport forms (VTF) within the phloem is a crucial step in setting-up virus infection within the entire plant. Moreover, vascular trafficking is an essential step for the further transmission of the viruses by their natural vectors as movement of the viruses to the distant parts of the plant from the initial site of infection guarantees accessibility of the virus particle for vector transmission. With the recent advances in the field of plant virology several emerging themes of viral systemic movement occur linking the role of virus-mediated transcriptional reprogramming and nuclear factors in vascular trafficking. Recent studies have uncovered host factors involved in virus vascular trafficking. Surprisingly, it appears that the role of the nucleus and nuclear factors in virus movement is still under-appreciated. This review describes how these new themes started to emerge by using two contrasting modes of virus vascular trafficking. It is argued that the translocation of viral movement proteins into the nuclei is, in many cases, an essential step in promoting virus systemic infection.


Theory of nonlinear pulse propagation in silicon-nanocrystal waveguides.
We develop a comprehensive theory of the nonlinear propagation of optical pulses through silica waveguides doped with highly nonlinear silicon nanocrystals. Our theory describes the dynamics of arbitrarily polarized pump and Stokes fields by a system of four generalized nonlinear Schrödinger equations for the slowly varying field amplitudes, coupled to the rate equation for the number density of free carriers. In deriving these equations, we use an analytic expression for the third-order effective susceptibility of the waveguide with randomly oriented nanocrystals, which takes into account both the weakening of the nonlinear optical response of silicon nanocrystals due to their embedment in fused silica and the change in the tensor properties of the response due to the modification of light interaction with electrons and phonons inside the silicon-nanocrystal waveguide. In order to facilitate the use of our theory by experimentalists, and for reasons of methodology, we provide a great deal of detail on the mathematical treatment throughout the paper, even though the derivation of the coupled-amplitude equations is quite straightforward. The developed theory can be applied for the solving of a wide variety of specific problems that require modeling of nonlinear optical phenomena in silicon-nanocrystal waveguides.


Strategy for treating motor neuron diseases using a fusion protein of botulinum toxin binding domain and streptavidin for viral vector access: work in progress.
Although advances in understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have suggested attractive treatment strategies, delivery of agents to motor neurons embedded within the spinal cord is problematic. We have designed a strategy based on the specificity of botulinum toxin, to direct entry of viral vectors carrying candidate therapeutic genes into motor neurons. We have engineered and expressed fusion proteins consisting of the binding domain of botulinum toxin type A fused to streptavidin (SAv). This fusion protein will direct biotinylated viral vectors carrying therapeutic genes into motor nerve terminals where they can enter the acidified endosomal compartments, be released and undergo retrograde transport, to deliver the genes to motor neurons. Both ends of the fusion proteins are shown to be functionally intact. The binding domain end binds to mammalian nerve terminals at neuromuscular junctions, ganglioside GT1b (a target of botulinum toxin), and a variety of neuronal cells including primary chick embryo motor neurons, N2A neuroblastoma cells, NG108-15 cells, but not to NG CR72 cells, which lack complex gangliosides. The streptavidin end binds to biotin, and to a biotinylated Alexa 488 fluorescent tag. Further studies are in progress to evaluate the delivery of genes to motor neurons in vivo, by the use of biotinylated viral vectors.


Male infertility and endocrinopathies in Kano, Northwestern Nigeria.
Endocrinologic disorders and infertility are common all over the world; the prevalence of infertility is high in sub-Saharan Africa. Several authors have suggested that the increased incidence of infertility in Africa is due to high prevalence of sexually transmitted diseases. To evaluate the contributions of endocrine abnormalities to infertility in the male in Kano, Northern Nigeria. A total of five hundred males, aged between 28 and 56 years were evaluated over a period of 4 years (2001-2004). The hormones were analyzed using electrochemiluminescene immunoassay technique. Hormonal abnormalities were detected in 22% oligospermic, 40.7% severe oligospermic, and 42.7% azoospermic subjects. Endocrine abnormalities are common in the infertile males. The reason for the observed endocrinopathies is not known, appropriate laboratory investigations are essential for effective patients management. Further study to ascertain the cause(s) of hormonal derangements is suggested.


Food marketing targeting children: unveiling the ethical perspectives in the discourse on self-regulation.
When it comes to food marketing, children are one of the major targets. Regulatory actions can play a strategic role in health protection. The objective of this research was to characterize the ethical perspective in the discourse against state regulatory actions on food marketing directed at children, aiming to understand the context of the discourse's production and how it creates meaning. The methodology adopted was qualitative, with documentary analysis and use of concepts and procedures from Discourse Analysis. The work of Hans Jonas, specifically his Responsibility Principle, and Garrafa and Port's Intervention Bioethics oriented the analysis. The self-regulation discourse analysis showed an ethical perspective in which relations of consumption predominate over the children´s vulnerability. The rhetorical excess is constant, as well as the use of resources like naturalization, untruthfulness, ideological dissimulation and euphemism. An erasure of social conflicts takes place, and an ahistorical perspective is present. The discourse does not align with Jonas´ Responsibility Principle, nor those of Intervention Bioethics. Lastly, the ethical perspective of the discourse represents a double paradox, because it is a business discourse that hides its competitive roots and metamorphoses into an ethical one.


Reversible diffusion-influenced reactions of an isolated pair on some two dimensional surfaces.
We investigate reversible diffusion-influenced reactions of an isolated pair in two dimensions. To this end, we employ convolution relations that permit deriving the survival probability of the reversible reaction directly in terms of the survival probability of the irreversible reaction. Furthermore, we make use of the mean reaction time approximation to write the irreversible survival probability in restricted spaces as a single exponential. In this way, we obtain exact and approximative expressions in the time domain for the reversible survival probability for three different two dimensional spatial domains: The infinite plane, the annular domain, and the surface of a sphere. Our obtained results should prove useful in the context of membrane-bound reversible diffusion-influenced reactions in cell biology.


Isolation and characterization of ftsZ alleles that affect septal morphology.
The ftsZ gene encodes an essential cell division protein that specifically localizes to the septum of dividing cells. In this study we characterized the effects of the ftsZ2(Rsa) mutation on cell physiology. We found that this mutation caused an altered cell morphology that included minicell formation and an increased average cell length. In addition, this mutation caused a temperature-dependent effect on cell lysis. During this investigation we fortuitously isolated a novel temperature-sensitive ftsZ mutation that consisted of a 6-codon insertion near the 5' end of the gene. This mutation, designated ftsZ26(Ts), caused an altered polar morphology at the permissive temperature and blocked cell division at the nonpermissive temperature. The altered polar morphology resulted from cell division and correlated with an altered geometry of the FtsZ ring. An intragenic cold-sensitive suppressor of ftsZ26(Ts) that caused cell lysis at the nonpermissive temperature was isolated. These results support the hypothesis that the FtsZ ring determines the division site and interacts with the septal biosynthetic machinery.


Influence of genetic variation on plasma protein levels in older adults using a multi-analyte panel.
Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p=2.44×10(-5)) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46×10(-60), accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29×10(-112). Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5×10(-8)). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results.


Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson's disease?
Patients with Parkinson's disease often complain of fatigue, and although cardiac sympathetic denervation is thought to be associated with fatigue, this link remains unclear. Previously, we detected cardiac sympathetic denervation in patients with Parkinson's disease using dobutamine, a selective beta-1 stimulant. To clarify the involvement of autonomic dysfunction in fatigue in Parkinson's disease, we conducted autonomic function tests on 33 patients with Parkinson's disease (mean age, 66.1 ± 5.6 years; 20 men, 13 women) and evaluated their relationships to fatigue. We divided patients into 2 groups, fatigued (n = 12) and nonfatigued (n = 21), based on an average score ≥ 3.3 on the Parkinson fatigue scale. Autonomic function tests included the coefficient of variation of R-R intervals, head-up tilt test, norepinephrine and dobutamine infusion tests, and cardiac (123) I-metaiodobenzylguanidine scintigraphy. The coefficient of variation of R-R intervals and the systolic blood pressure changes accompanying the head-up tilt test did not show significant differences between the 2 groups; however, the pressor responses in the norepinephrine and dobutamine infusion tests were significantly greater in the fatigued group than in the nonfatigued group. The (123) I-metaiodobenzylguanidine heart-to-mediastinal uptake ratio was lower in the fatigued group than in the nonfatigued group. Partial correlation analyses, using disease duration and Hoehn and Yahr stage as control variables, also demonstrated significant correlations between the Parkinson fatigue scale score and the results of the autonomic function tests and cardiac (123) I-metaiodobenzylguanidine uptake. Our results suggest that autonomic dysfunction, including cardiac sympathetic denervation, is associated with fatigue in patients with Parkinson's disease.


Short-term effects of high-dose khat on sperm parameters and reproductive hormonal levels in olive baboons (Papio anubis).
The biological effects of khat (Catha edulis) on reproduction and fertility are inadequately investigated and controversial, hence we determined the effects of oral administration of high-dose khat on sperm parameters and male hormonal levels in olive baboons. In this study, 6 male baboons received a high dose of khat (500 g/week) during 1 month. Electroejaculation for sperm studies (concentration, motility and chromatin integrity) and plasma collection for hormonal analysis (testosterone, prolactin and cortisol) were done weekly during 1 month before and 1 month during khat administration as well as 2 weeks after the last dose of khat administration. Administration of khat extract induced a significant reduction in sperm motility (p = 0.008), sperm count (p = 0.041), sperm chromatin integrity (p = 0.0003), testosterone levels (p = 0.035) and prolactin levels (p = 0.0115), but not in cortisol levels and sperm volume (p > 0.05). The results suggest that high-dose khat decreases sperm quality and testosterone and hence may contribute to male infertility.


Feasibility of spirography features for objective assessment of motor function in Parkinson's disease.
Parkinson's disease (PD) is currently incurable, however proper treatment can ease the symptoms and significantly improve the quality of life of patients. Since PD is a chronic disease, its efficient monitoring and management is very important. The objective of this paper was to investigate the feasibility of using the features and methodology of a spirography application, originally designed to detect early Parkinson's disease (PD) motoric symptoms, for automatically assessing motor symptoms of advanced PD patients experiencing motor fluctuations. More specifically, the aim was to objectively assess motor symptoms related to bradykinesias (slowness of movements occurring as a result of under-medication) and dyskinesias (involuntary movements occurring as a result of over-medication). This work combined spirography data and clinical assessments from a longitudinal clinical study in Sweden with the features and pre-processing methodology of a Slovenian spirography application. The study involved 65 advanced PD patients and over 30,000 spiral-drawing measurements over the course of three years. Machine learning methods were used to learn to predict the "cause" (bradykinesia or dyskinesia) of upper limb motor dysfunctions as assessed by a clinician who observed animated spirals in a web interface. The classification model was also tested for comprehensibility. For this purpose a visualisation technique was used to present visual clues to clinicians as to which parts of the spiral drawing (or its animation) are important for the given classification. Using the machine learning methods with feature descriptions and pre-processing from the Slovenian application resulted in 86% classification accuracy and over 0.90 AUC. The clinicians also rated the computer's visual explanations of its classifications as at least meaningful if not necessarily helpful in over 90% of the cases. The relatively high classification accuracy and AUC demonstrates the usefulness of this approach for objective monitoring of PD patients. The positive evaluation of computer's explanations suggests the potential use of this methodology in a decision support setting.


Repeated Neonatal Phencyclidine Treatment Impairs Performance of a Spatial Task in Juvenile Ratsa.
The present study was designed to determine whether repeated postnatal blockade of N-methyl-d-aspartate (NMDA) channel produces cognitive deficit in juvenile rats. Rats received phencyclidine (PCP) intraperitoneally (i.p.) from postnatal Day 5 and continued daily till Day 15. On Day 28, saline- and PCP-treated rats were trained in the Morris water maze task. PCP-treated rats performed as well as the saline-treated rats on the first day of testing, but on the second day of testing they did significantly poorly compared to saline-treated controls. These data suggest that chronic postnatal NMDA channel blockade by PCP impairs processes that enable rats to retain spatial information.


Deoxyfluorination of Carboxylic Acids via an In Situ Generated Trifluoromethoxide Salt.
An in situ generated pyridinium trifluoromethoxide salt (PyOCF3) is a highly effective deoxyfluorination reagent for the synthesis of acid fluorides. PyOCF3 is formed at room temperature from the reaction of 2,4-dinitro(trifluoromethoxy)benzene with 4-dimethylaminopyridine. PyOCF3 undergoes slow release of fluorophosgene and fluoride, which serve as the electrophile and nucleophile, respectively, for deoxyfluorination. A wide substrate scope and high functional group tolerance are demonstrated. Furthermore, the acid fluorides can be purified by filtration and telescoped to various known reactions.


Effect of caloric restriction on cardiac reactivity and beta-adrenoceptor concentration.
The effect of a 21-day program of caloric restriction on cardiac reactivity and beta-adrenoceptor number was investigated in male Sprague-Dawley rats. Rats on the restricted diet (Restricted) exhibited significant decreases in body weight, epididymal fat pad, and retroperitoneal fat pad weight as well as the percent of body fat represented by these adipose tissue depots when compared with rats fed ad libitum (Fed). Fed rats exhibited significantly increased total heart weight and total heart protein, but the percent cardiac protein and ratio of heart weight to body weight were similar in Fed and Restricted rats. Isolated atria from Fed and Restricted rats developed similar chronotropic and inotropic responses over a range of isoproterenol concentrations. Although total beta-adrenoceptor number (fmol/heart) was greater in Fed rats, the concentration of beta-adrenoceptors (fmol/mg protein) was remarkably similar regardless of the dietary regimen. Therefore, despite significant decreases in body weight, body fat, and heart weight, the myocardium of Restricted rats maintained the capability of responding to isoproterenol as that of Fed rats, the mechanism of which is at least partially mediated through maintenance of beta-adrenoceptor concentration.


Aberrant expression levels of MTA1 and RECK in nasopharyngeal carcinoma: association with metastasis, recurrence, and prognosis.
We investigated the expression and clinical value of MTA1 and RECK genes in patients with nasopharyngeal carcinoma (NPC). We examined MTA1 and RECK expression in nasopharyngeal tissue from patients with chronic nasopharyngitis, lymph nodes with metastasis of NPC, and primary NPC tumor tissue by means of in situ hybridization and analyzed their correlation with the clinicopathologic features of NPC. The positive expression of MTA1 in the NPC tissues and metastatic lymph nodes was significantly higher than that in the chronic nasopharyngitis tissues (p < 0.05). The positive expression of RECK in the NPC tissues and metastatic lymph nodes was significantly lower than that in the chronic nasopharyngitis tissues (p < 0.05). The RECK expression level was inversely correlated with the MTA1 expression level in the NPC tissues (p < 0.05). The increased MTA1 and decreased RECK expressions in the NPC tissues had no association with gender, age, T-stage, or clinical stage (p > 0.05). However, they had a positive correlation with cervical lymph node metastasis, tumor recurrence, and 5-year overall survival rate of the patients with NPC (p < 0.05). Moreover, multivariate analysis showed that MTA1 and RECK expressions were independent prognostic factors for survival (p < 0.05). The conversely abnormal expression levels of MTA1 and RECK may be collectively involved in progression of malignancies and may serve as molecular predictors for metastasis, recurrence, and prognosis of NPC.


Somatosensory and visual deprivation each decrease the density of parvalbumin neurons and their synapse terminals in the prefrontal cortex and hippocampus of mice.
In the phenomenon known as cross-modal plasticity, the loss of one sensory system is followed by improved functioning of other intact sensory systems. MRI and functional MRI studies suggested a role of the prefrontal cortex and the temporal lobe in cross-modal plasticity. We used a mouse model to examine the effects of sensory deprivation achieved by whisker trimming and visual deprivation achieved by dark rearing in neonatal mice on the appearance of parvalbumin (PV) neurons and the formation of glutamic acid decarboxylase 67 (GAD67)-positive puncta around pyramidal neurons in the prefrontal cortex and hippocampus. Whisker trimming, but not dark rearing, decreased the density of PV neurons in the hippocampus at postnatal day 28 (P28). In the prefrontal cortex, whisker trimming and dark rearing decreased the density of PV neurons in layer 5/6 (L5/6) at P28 and in L2/3 at P56, respectively, whereas dark rearing increased the density of PV neurons in L5/6 at P56. Whisker trimming decreased the density of GAD67-positive puncta in CA1 of the hippocampus at both P28 and P56 and in L5/6 of the prefrontal cortex at P28. Dark rearing decreased the density of GAD67-positive puncta in CA1 of the hippocampus and in both L2/3 and L5/6 of the prefrontal cortex at P28, and in L2/3 of the prefrontal cortex at P56. These results demonstrate that somatosensory or visual deprivation causes changes in the PV-interneuronal network in the mouse prefrontal cortex and hippocampus. The results also suggest that the alteration of the PV-interneuronal network, especially in the prefrontal cortex, may contribute to cross-modal plasticity.


Evaluating the effectiveness of a mnemonic to guide staff when providing patient education to autologous hematopoietic stem cell transplant patients.
Effective patient education can influence cost savings and improve patient outcomes (CCO, 2006). Nursing staff provide education to patients and families through the assessment of learning needs, incorporating the teach-back method to assess comprehension, and documenting the care provided. For this pilot study, an educational intervention was developed incorporating a mnemonic memory aid to support a consistent, standardized approach in delivering effective patient teaching. Forty-five hematology nurses from Hamilton Health Sciences participated in the study, of which 36 completed the follow-up assessments. The mnemonic aid "CARE", developed for this study, helped nurses to recall the steps involved in patient education. The improved knowledge and the use of the mnemonic aid in patient education was sustained over the three- to six-weeks follow-up period. While there was an increase in documentation of the patient education after the intervention, the changes did not reach the statistically significant level. Further research on the use of mnemonics in nursing education would complement this pilot study.


Functional annotation of intrinsically disordered domains by their amino acid content using IDD Navigator.
Function prediction of intrinsically disordered domains (IDDs) using sequence similarity methods is limited by their high mutability and prevalence of low complexity regions. We describe a novel method for identifying similar IDDs by a similarity metric based on amino acid composition and identify significantly overrepresented Gene Ontology (GO) and Pfam domain annotations within highly similar IDDs. Applications and extensions of the proposed method are discussed, in particular with respect to protein functional annotation. We test the predicted annotations in a large-scale survey of IDDs in mouse and find that the proposed method provides significantly greater protein coverage in terms of function prediction than traditional sequence alignment methods like BLAST. As a proof of concept we examined several disorder-containing proteins: GRA15 and ROP16, both encoded in the parasitic protozoa T. gondii; Cyclon, a mostly uncharacterized protein involved in the regulation of immune cell death; STIM1, a protein essential for regulating calcium levels in the endoplasmic reticulum. We show that the overrepresented GO terms are consistent with recently-reported biological functions. We implemented the method in the web server IDD Navigator. IDD Navigator is available at http://sysimm.ifrec.osaka-u.ac.jp/disorder/beta.php.


Basic and clinical studies on quantitative analysis of lymph node micrometastasis in oral cancer.
Metastasis to cervical lymph nodes (LN) is significantly associated with the outcome of patients with oral cancer. To provide a useful method for the detection of micrometastases, we analyzed 115 LNs from 10 patients with oral cancer using real-time quantitative polymerase chain reaction (PCR) based on the expression of squamous cell carcinoma antigen (SCCA) and cytokeratin 13 (CK13). The sensitivity and quantification of this method were assessed by means of limited dilution of cultured oral cancer cells and a model of cervical LN-metastasis established by inoculating green fluorescent protein (GFP)-expressing cells into the tongue of nude mice. In both investigations, a few cancer cells were detected by real-time quantitative PCR, but not by conventional reverse transcription-PCR (RT-PCR). SCCA mRNA was detected at high levels in metastatic LNs. In contrast, 26 of the 30 control cervical LNs did not express the gene at all, and the rest showed fairly low levels. Of 108 histologically metastasis-negative LNs, 19 (17.6%) expressed SCCA mRNA levels higher than the cut-off value (1.0: mean expression of control LNs + 2SD). CK13 mRNA is not a suitable marker for the real-time PCR since it was detected frequently even in the control LNs. These findings suggest that genetic diagnosis by real-time quantitative PCR based on SCCA mRNA expression may be clinically useful for detecting occult tumor cells in cervical LNs.