Evolving nonapeptide mechanisms of gregariousness and social diversity in birds.
Of the major vertebrate taxa, Class Aves is the most extensively studied in relation to the evolution of social systems and behavior, largely because birds exhibit an incomparable balance of tractability, diversity, and cognitive complexity. In addition, like humans, most bird species are socially monogamous, exhibit biparental care, and conduct most of their social interactions through auditory and visual modalities. These qualities make birds attractive as research subjects, and also make them valuable for comparative studies of neuroendocrine mechanisms. This value has become increasingly apparent as more and more evidence shows that social behavior circuits of the basal forebrain and midbrain are deeply conserved (from an evolutionary perspective), and particularly similar in birds and mammals. Among the strongest similarities are the basic structures and functions of avian and mammalian nonapeptide systems, which include mesotocin (MT) and arginine vasotocin (VT) systems in birds, and the homologous oxytocin (OT) and vasopressin (VP) systems, respectively, in mammals. We here summarize these basic properties, and then describe a research program that has leveraged the social diversity of estrildid finches to gain insights into the nonapeptide mechanisms of grouping, a behavioral dimension that is not experimentally tractable in most other taxa. These studies have used five monogamous, biparental finch species that exhibit group sizes ranging from territorial male-female pairs to large flocks containing hundreds or thousands of birds. The results provide novel insights into the history of nonapeptide functions in amniote vertebrates, and yield remarkable clarity on the nonapeptide biology of dinosaurs and ancient mammals. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.


Development of a music perception test for adult hearing-aid users.
The purpose of this research was twofold: firstly, to develop a music perception test (MPT) for hearing-aid users, and secondly, to evaluate the influence of non-linear frequency compression (NFC) on music perception with the use of the self-compiled test. This article focuses on the description of the development and validation of the MPT. To date, the main direction in frequency-lowering hearing-aid studies has been in relation to speech perception abilities. As hearing-aid technology has improved, interest has grown in musical perception as a dimension that could improve hearing-aid users' quality of life. The MPT was designed to evaluate different aspects of rhythm, timbre, pitch and melody. The development of the MPT could be described as design-based. Phase 1 of the study included test development and recording, while phase 2 entailed presentation of stimuli to normal hearing listeners (n = 15) and hearing-aid users (n = 4). Based on the findings of phase 2, item analysis was performed to eliminate or change stimuli that resulted in high error rates. During phase 3 the adapted version of the test was performed on a smaller group of normal hearing listeners (n = 4) and 20 hearing-aid users. Results proved that adults with normal hearing as well as adults using hearing aids were able to complete all the sub-tests of the MPT, although hearing-aid users scored lower on the various sub-tests than normal hearing listeners. For the rhythm section of the MPT normal hearing listeners scored on average 93.8% versus 75.5% of hearing-aid users; for the timbre section the scores were 83% versus 62.3% respectively. Normal hearing listeners obtained an average score of 86.3% for the pitch section and 88.2% for the melody section, compared with the 70.8% and 61.9% respectively obtained by hearing-aid users. This implies that the MPT can be used successfully for assessment of music perception in hearing-aid users within the South African context and may therefore result in more effective hearing-aid fittings taking place. The test can be used as a counselling tool to assist audiologists and patients in understanding the problems they experience regarding music perception, and might be used for future musical training in areas where participants experience problems in customising individual fittings.


Bicuspid aortic valve: evolving knowledge and new questions.
Bicuspid aortic valve (BAV), a common congenital anomaly with various morphological phenotypes, is also characterised by marked heterogeneity in clinical presentations including clinically silent condition with mild valvulo-aortopathy, progressive valvulopathy and complex valvulo-aortopathy with shorter life expectancy. The clinical importance of using a general and unified nosology for BAV is well-accepted by opinion leaders and an international consensus statement has been recently published, which will serve as an important scientific platform for BAV. This review describes the current knowledge of BAV based on clinical studies, addresses several unresolved issues requiring investigators' attention and highlights the necessity of prospective studies with a very long follow-up duration for better appreciation of BAV-associated valvulo-aortopathy. In addition, the progression of valvular calcification in patients with BAV and its potential contribution to development of valvulopathy will be discussed.


Radioiodine therapy in differentiated thyroid cancer: the first targeted therapy in oncology.
Iodide uptake across the membranes of thyroid follicular cells and cancer cells occurs through an active transport process mediated by the sodium-iodide symporter (NIS). The rat and human NIS-coding genes were cloned and identified in 1996. Evaluation of NIS gene and protein expression is critical for the management of thyroid cancer, and several approaches to increase NIS levels have been tried. Identification of the NIS gene has provided a means of expanding its role in radionuclide therapy and molecular target-specific theragnosis (therapy and diagnosis using the same molecular target). In this article, we describe the relationship between NIS expression and the thyroid carcinoma treatment using I-131 and alternative therapeutic approaches.


Regional calcium accumulation and cation shifts in rat brain by kainate.
Following local application of kainic acid, changes in the contents of Na+, K+, Ca2+, and Mg2+ of the striatum, cerebellum, and hippocampus of the rat were observed at various times after surgery. Within 1 h the levels of K+ decreased 20% whereas the levels of Na+ and Ca2+ increased at least 50% and 20%, respectively. These changes persisted for more than 8 weeks. Ca2+ levels rose further, to more than 10-fold during 8 weeks. The Mg2+ levels were slightly and only transiently decreased. Unilateral injections of kainate into the striatum affected the contents of these cations not only in this area, but also in the overlying cerebral cortex, the olfactory tubercle, and the ipsilateral substantia nigra. The Ca2+ increases were less when rats were kept on a diet deficient in Ca2+ and vitamin D. 45Ca2+, intravenously administered, accumulated significantly more in the kainate-lesioned striatum and substantia nigra than in the homotopic contralateral areas. Electron microscopic examination of the localization of Ca2+ with the oxalate-pyroantimonate technique showed the appearance of extracellularly located deposits and the accumulation of Ca2+ in (possibly degenerating) myelinated axons in kainate-lesioned striata. This study provides evidence that calcification of cerebral tissue is closely associated with neurodegenerative processes and shows that kainate may serve as a tool to elucidate the mechanism of brain calcification. The results are discussed in relation to idiopathic calcinosis (striopallidodentate calcinosis, Fahr's disease).


Predictors of completion axillary lymph node dissection in patients with positive sentinel lymph nodes.
Completion axillary lymph node dissection (CALND) is routinely performed in breast cancer patients with positive sentinel lymph nodes (SLN). We sought to determine the sociodemographic, pathologic, and therapeutic variables that were associated with CALND. From 7/1997 to 7/2003, 1,470 patients with invasive breast cancer were SLN positive by intraoperative frozen section or final pathologic exam by hematoxylin-eosin and/or immunohistochemistry (IHC). A comorbidity score was assigned using Adult Comorbidity Evaluation-27 system. Fisher's exact, Wilcoxon tests, and multivariate logistic regression analysis were used. CALND was performed less often in patients with age >or= 70 years compared with age < 70 years, moderate or severe comorbidities compared with no or mild, IHC-only positive SLN and breast conservation therapy (BCT compared with mastectomy. Patients who did not undergo CALND were less likely than CALND patients to have grade III disease, lymphovascular invasion multifocal disease, tumor size > 2 cm or to receive adjuvant chemotherapy. However, they were more likely to undergo axillary radiotherapy (RT). On multivariate analysis, age >or= 70 years [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.26-0.63], IHC-only positive SLN (OR 0.13, 95%CI 0.09-0.19), presence of moderate to severe comorbidities (OR 0.64, 95%CI 0.41-0.99), tumor size <or= 2 cm (OR 0.44, 95%CI 0.29-0.66), axillary RT (OR 0.39, 95%CI 0.20-0.78), and BCT (OR 0.54, 95%CI 0.37-0.79) were all independently associated with lower odds of CALND. The decision to perform CALND following positive SLN biopsy was multifactorial. Patient factors were a primary determinant for the use of CALND in our study. The decreased use of CALND in the BCT patients probably reflects reliance on the radiotherapy tangents to maintain local control in the axilla.


Extreme ultraviolet spectrometer for the Shenguang III laser facility.
An extreme ultraviolet spectrometer has been developed for high-energy density physics experiments at the Shenguang-III (SG-III) laser facility. Alternative use of two different varied-line-spacing gratings covers a wavelength range of 10-260 Å. A newly developed x-ray framing camera with single wide strip line is designed to record time-gated spectra with ~70 ps temporal resolution and 20 lp/mm spatial resolution. The width of the strip line is up to 20 mm, enhancing the capability of the spatial resolving measurements. All components of the x-ray framing camera are roomed in an aluminum air box. The whole spectrometer is mounted on a diagnostic instrument manipulator at the SG-III laser facility for the first time. A new alignment method for the spectrometer based on the superimposition of two laser focal spots is developed. The approaches of the alignment including offline and online two steps are described. A carbon spectrum and an aluminum spectrum have been successfully recorded by the spectrometer using 2400 l/mm and 1200 l/mm gratings, respectively. The experimental spectral lines show that the spectral resolution of the spectrometer is about 0.2 Å and 1 Å for the 2400 l/mm and 1200 l/mm gratings, respectively. A theoretical calculation was carried out to estimate the maximum resolving power of the spectrometer.


Tumor Marker B7-H6 Bound to the Coiled Coil Peptide-Polymer Conjugate Enables Targeted Therapy by Activating Human Natural Killer Cells.
Targeted cancer immunotherapy is a promising tool for restoring immune surveillance and eradicating cancer cells. Hydrophilic polymers modified with coiled coil peptide tags can be used as universal carriers designed for cell-specific delivery of such biologically active proteins. Here, we describe the preparation of pHPMA-based copolymer conjugated with immunologically active protein B7-H6 via complementary coiled coil VAALEKE (peptide E) and VAALKEK (peptide K) sequences. Receptor B7-H6 was described as a binding partner of NKp30, and its expression has been proven for various tumor cell lines. The binding of B7-H6 to NKp30 activates NK cells and results in Fas ligand or granzyme-mediated apoptosis of target tumor cells. In this work, we optimized the expression of coiled coil tagged B7-H6, its ability to bind activating receptor NKp30 has been confirmed by isothermal titration calorimetry, and the binding stoichiometry of prepared chimeric biopolymer has been characterized by analytical ultracentrifugation. Furthermore, this coiled coil B7-H6-loaded polymer conjugate activates NK cells in vitro and, in combination with coiled coil scFv, enables their targeting towards a model tumor cell line. Prepared chimeric biopolymer represents a promising precursor for targeted cancer immunotherapy by activating the cytotoxic activity of natural killer cells.


Advertising in dentistry.
Due to a rapid increase of unemployment among dentists in many countries, the interest in advertising as a means of stimulating the demand for dental care is increasing. In some countries (i.e. USA, Canada, Finland and Holland) campaigns have been organized and the results have been published. In order to give as complete a picture as possible of all promotional activities in the field of dentistry, the member organizations of the FDI have been asked to answer the following questions: (1) Are individual dentists in your country allowed to solicit new patients by means of advertisements? (2) Do you, as an organization, have guidelines for your members in this respect? (3) Have there been any joint promotional activities by dentists in your country aimed at increasing the demand for dental care? (a) If so, in what form (e.g. advertisements, television or radio commercials)? (b) How much money was invested in such activities? (c) What were the results achieved? The results are presented. The effectiveness of specific methods used in stimulating the demand for dental care are analysed. Moreover, a comparison is made between studies on the attitudes of dentists toward advertising in Holland and the United States.


Candesartan cilexetil in cardiovascular disease.
Hypertension is a major cardiovascular risk factor, but most patients remain asymptomatic for many years. Successful therapy not only needs to be effective, it also needs to be well tolerated. Angiotensin receptor blockers have emerged as a major therapeutic class because they meet both of these requirements. Numerous studies indicate that all approved angiotensin receptor blockers are highly selective for angiotensin-1 receptors, lower blood pressure as monotherapies, and work well in combination with other drugs - particularly diuretics. The side-effect profile of angiotensin receptor blockers is similar to that of placebo and they have not been associated with known side effects of angiotensin-converting enzyme inhibitors such as cough and angioneurotic edema. Candesartan cilexetil is an angiotensin receptor blocker with insurmountable binding properties to the angiotensin-1 receptor, long duration of action and improved efficacy. In patients with hypertension, candesartan monotherapy has been shown to be safe and effective. Comparative data have shown similar or better results to other monotherapies in blood-pressure control, and in combination with hydrochlorothiazide it has been shown to have additive or synergistic effects. More recent data demonstrate that candesartan cilexetil is useful in the treatment of patients with heart failure and may protect against diabetic nephropathy. Studies have also shown protection from stroke, particularly in patients with isolated systolic hypertension.


An isoform-specific mutation in the protein 4.1 gene results in hereditary elliptocytosis and complete deficiency of protein 4.1 in erythrocytes but not in nonerythroid cells.
Multiple protein 4.1 isoforms are expressed in a variety of tissues through complex alternative pre-mRNA splicing events, one function of which is to regulate use of two alternative translation initiation signals. Late erythroid cells express mainly the downstream initiation site for synthesis of prototypical 80-kD isoforms; nonerythroid cells in addition use an upstream site to encode higher molecular mass isoform(s). In this study, we examined the effects of a 5' gene rearrangement in a family with hereditary elliptocytosis and complete deficiency of erythrocyte 4.1 protein on 4.1 isoform expression in erythroid vs. nonerythroid cells. Patient 4.1 mRNAs from reticulocytes, fibroblasts, and B lymphocytes were amplified by reverse transcriptase/polymerase chain reaction techniques and shown to exhibit a 318-nucleotide deletion that encompasses the downstream AUG, but leaves intact the upstream AUG. Immunoblot analysis revealed a total deficiency of 4.1 in patient red cells and a selective deficiency of 80-kD isoform(s) but not high molecular weight 4.1 in patient nonerythroid cells. Thus, the 4.1 gene mutation in this family produces an isoform-specific deficiency that is manifested clinically in tissue-specific fashion, such that red cells are affected but other cell types are unaffected because of tissue-specific differences in RNA splicing and translation initiation.


Functional consequences of NR2 subunit composition in single recombinant N-methyl-D-aspartate receptors.
Single-channel recordings were obtained from Chinese hamster ovary cells transfected with the N-methyl-D-aspartate (NMDA) receptor subunit NR1 in combination with NR2A, NR2B, NR2C, or NR2A/NR2B. NMDA-activated currents were recorded under control conditions and in the presence of a thiol reductant (DTT), an oxidant (5, 5'-dithio-bis[2-nitrobenzoic acid], DTNB), or the noncompetitive antagonist CP101,606 (CP). For all subunit combinations, DTT increased the frequency of channel opening when compared with DTNB. In addition, channels obtained from NR1/NR2A-transfected cells also exhibited a pronounced difference in mean open dwell-time between redox conditions. CP dramatically reduced both the open dwell-time and frequency of channel opening of NR1/NR2B-containing receptors, but only modestly inhibited NR1/NR2A and NR1/NR2C channel activity. A small number of patches obtained from cells transfected with NR1/NR2A/NR2B had channels with properties intermediate to NR1/NR2A and NR1/NR2B receptors, including insensitivity to CP block but redox properties similar to NR1/NR2B, consistent with the coassembly of NR2A with NR2B. Hence, NMDA receptors containing multiple types of NR2 subunits can have functionally distinguishable attributes.


Effects of breath-hold and cardiac cycle on the MRI appearance of the aorta and inferior vena cava in t2 abdominal imaging.
The purpose of this article is to review the MR principles of blood signal and normal flow-related phenomena seen in the aorta and inferior vena cava (IVC) on T2-weighted images of the abdomen and to discuss the physiologic and physical basis of signal alterations with breath-hold imaging. We define time-of-flight (TOF) loss and list the factors that affect it; explain the physiologic effects of breath-hold imaging on both aortic and IVC waveforms and velocity; state which abdominal T2 imaging techniques are most susceptible to variable TOF effects and explain why based on physiologic effects and MR principles; and describe three trouble-shooting techniques to confirm that unexpected signal does not reflect pathology. T2 images customarily result in TOF loss and dark blood signal. Abdominal MRI relies extensively on breath-hold imaging techniques that may alter markedly the flow velocity in normal vessels. This marked flow change results in signal heterogeneity and variable TOF loss especially with faster sequences filling k-space in shorter time frames. Breath-hold imaging decreases k-space fill time, and of the breath-hold T2 techniques, single-shot fast spin-echo decreases k-space fill time the most. Atypical blood signal during breath-hold imaging may mimic pathology, but abnormal findings can be verified by review of other sequences and planes of imaging.


Depicting the battle between nectarine and Monilinia laxa: the fruit developmental stage dictates the effectiveness of the host defenses and the pathogen's infection strategies.
Infections by the fungus Monilinia laxa, the main cause of brown rot in Europe, result in considerable losses of stone fruit. Herein, we present a comprehensive transcriptomic approach to unravel strategies deployed by nectarine fruit and M. laxa during their interaction. We used M. laxa-inoculated immature and mature fruit, which was resistant and susceptible to brown rot, respectively, to perform a dual RNA-Seq analysis. In immature fruit, host responses, pathogen biomass, and pathogen transcriptional activity peaked at 14-24 h post inoculation (hpi), at which point M. laxa appeared to switch its transcriptional response to either quiescence or death. Mature fruit experienced an exponential increase in host and pathogen activity beginning at 6 hpi. Functional analyses in both host and pathogen highlighted differences in stage-dependent strategies. For example, in immature fruit, M. laxa unsuccessfully employed carbohydrate-active enzymes (CAZymes) for penetration, which the fruit was able to combat with tightly regulated hormone responses and an oxidative burst that challenged the pathogen's survival at later time points. In contrast, in mature fruit, M. laxa was more dependent on proteolytic effectors than CAZymes, and was able to invest in filamentous growth early during the interaction. Hormone analyses of mature fruit infected with M. laxa indicated that, while jasmonic acid activity was likely useful for defense, high ethylene activity may have promoted susceptibility through the induction of ripening processes. Lastly, we identified M. laxa genes that were highly induced in both quiescent and active infections and may serve as targets for control of brown rot.


A parallel approximate string matching under Levenshtein distance on graphics processing units using warp-shuffle operations.
Approximate string matching with k-differences has a number of practical applications, ranging from pattern recognition to computational biology. This paper proposes an efficient memory-access algorithm for parallel approximate string matching with k-differences on Graphics Processing Units (GPUs). In the proposed algorithm, all threads in the same GPUs warp share data using warp-shuffle operation instead of accessing the shared memory. Moreover, we implement the proposed algorithm by exploiting the memory structure of GPUs to optimize its performance. Experiment results for real DNA packages revealed that the performance of the proposed algorithm and its implementation archived up to 122.64 and 1.53 times compared to that of sequential algorithm on CPU and previous parallel approximate string matching algorithm on GPUs, respectively.


Preventive home therapy for symptomatic patients affected by COVID-19 and followed by teleconsultations.
In this paper we present our experience on the treatment at home of Covid+ symptomatic patients. One hundred and eighty-two subjects (111 men and 71 women) aged from 32 to 71 years have been consecutively followed at home in telemedicine from 1st September to 24th December 2020. We were informed almost twice daily in morning and evening about body temperature, symptoms (cough, shortness of breath or difficulty breathing, fatigue, muscle of body aches, headache, loss of taste or smell, sore throat, congestion or runny nose, nausea and vomiting, diarrhea), oxygen saturation measured by digital pulse oximetry and blood pressure. Our protocol of treatment was based on early use of prednisone (25 mg in the morning and 12.5 mg in the afternoon) and low molecular weight heparin (4000 UI one or two times daily) initiated just after the positivity of molecular nasopharyngeal test (about 3-4 days as mean time after initiation of symptomatology and not after 7-8 days as suggested by other protocols) and oxygen therapy when necessary. Antibiotics such as azithromycin for six days was added. It is always recommended to associate lansoprazole 30 mg to prevent gastric hemorrhages and potassium and magnesium supplements. This treatment scheme was able to reduce the risk of hospitalization as only 4 patients needed to be admitted to the Hospital, and only two in subintensive department. After negativeness of molecular nasopharyngeal test, patients were invited for a thoracic computerized tomography and laboratory evaluation of d-dimer and other data of inflammation to show eventual lung interstitial involvement characteristic of COVID-19.


Use of height-specific weigh tapes to estimate the bodyweight of horses.
Two thousand horses of different ages, heights and breeds were divided into two height groups of up to 14.2 hands high (hh) and more than 14.2 hh, and weighed on a weighbridge; each horse then had its weight estimated by three weigh tapes, one height specific (tape 1 or 2, depending on the animal's height) and two for general use (tapes 3 and 4). For horses up to 14.2 hh, weigh tape 1 provided the most accurate estimate of mean (sd) bodyweight (100.5 [6.2] per cent), and weigh tapes 3 and 4 were 112 (6.8) and 97-0 (6.1) per cent accurate, respectively. For horses more than 14.2 hh, weigh tape 2 provided the most accurate estimate of bodyweight (98.6 [18.4] per cent), with weigh tapes 3 and 4 being 102.6 (17.4) and 90.8 (15.2) per cent accurate, respectively.


The mental state and risk factors of Chinese medical staff and medical students in early stages of the COVID-19 epidemic.
This study aimed to investigate the mental state of medical staff and medical students in the early stages of the SARS-CoV-2 outbreak, as well as analyze the risk factors of serious mental illness (SMI), so as to provide a scientific basis for further psychological intervention and management. A cross-sectional survey was conducted from February 2-7, 2020. The Kessler 6 Psychological Distress Scale and a general information questionnaire were administered on-line to a convenience sample of 548 medical staff and medical students in China. Multivariate binary logistic regression analysis was used to screen the risk factors of SMI in medical staff and medical students. Of the 505 respondents in the final analysis, 188 (37.23%) were at high risk of SMI. Respondents were at significantly higher risk of SMI if they had been suspected of being infected with the SARS-CoV-2 (OR = 7.00, 95% CI: 1.19-41.14), had relatives suspected of being infected with the SARS-CoV-2 (OR = 23.60, 95% CI: 1.11-501.30), felt concerned towards media coverage of outbreak-related information (OR = 11.95, 95% CI: 3.07-46.57), recently dreamed related to SARS-CoV-2 (OR = 4.21, 95% CI: 2.22-8.01), experienced difficulty in controlling emotions during SARS-CoV-2 epidemic (OR = 3.25, 95% CI: 1.66-6.37), or spent hours watching outbreaks per day (OR = 1.29, 95% CI: 1.13-1.46). Our findings highlight that medical staff and medical students were vulnerable to SMI during the early stages of the SARS-CoV-2 outbreak and identify the factors associated with SMI which can be used to formulate psychological interventions to improve the mental health. The independent risk factors for SMI among them are suspicion that they or relatives were infected with the SARS-CoV-2, greater interest in media reports about the epidemic, frequency of recent dreams related to SARS-CoV-2, difficulty in controlling emotions during the epidemic, and hours spent watching outbreaks per day.


Right Aortic Arch Associated with Left Internal Carotid Artery Agenesis.
We report the rare case of a right aortic arch associated with agenesis of the left internal carotid artery. A 75-year-old woman with a medical history of tetralogy of Fallot presented with dizziness. Magnetic resonance angiography revealed agenesis of the left internal carotid artery in addition to a previously diagnosed right aortic arch. The left common carotid artery was present, but it was thin. Computed tomography showed the absence of the left carotid canal. The left anterior cerebral artery was fed via the anterior communicating artery. The left middle cerebral artery was fed via a thickened posterior communicating artery originating from the left posterior cerebral artery. Although a right aortic arch and agenesis of the internal carotid artery are both very rare, association of the two conditions may occur. Both anomalies depend on the abnormal regression of the dorsal aorta during embryonic development. In such a situation, the presence of other anomalies in the cardiac or central nervous system should be taken into consideration.


Estrogen suppresses epileptiform activity by enhancing Kv4.2-mediated transient outward potassium currents in primary hippocampal neurons.
Catamenial epilepsy is a common phenomenon in female epileptic patients that is, in part, influenced by the 17-β-estradiol level during the menstrual cycle, which modulates the strength of the epileptic seizures. However, the underlying mechanism(s) for catamenial epilepsy remains unknown. In the present study, the effect of 17‑β‑estradiol on modulating epileptiform activities was investigated in cultured hippocampal neurons by focusing on the transient outward potassium current. Using the patch clamp technique, 17‑β‑estradiol was demonstrated to have a dose‑dependent U‑shape effect on epileptiform bursting activities in cultured hippocampal neurons; only the low dose (~0.1 ng/ml) of 17‑β‑estradiol had a suppressive effect on the epileptiform activities. The blockade effect of the low dose 17‑β‑estradiol could be suppressed by phrixotoxin2 (PaTx2), a selective channel blocker for voltage‑gated potassium channel type 4.2 (Kv4.2), which mediates the transient outward potassium current. Furthermore, the 17‑β‑estradiol bell‑shape‑like dose‑dependently enhanced the transient outward potassium current, which was inhibited by the estrogen receptor antagonist ICI 182,780. In conclusion, these results indicate that reduced activation of the transient outward potassium current by a high (or none) 17‑β‑estradiol level may enhance the epileptiform bursting activities in neurons, which may be one of the triggering causes for catamenial epilepsy, and therefore, maintaining a certain low 17‑β‑estradiol level may aid in the control of catamenial epilepsy.


High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition.
The acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril to healthy subjects transiently increases 5.5-fold the plasma levels of a natural stem-cell regulator, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The aim of this study was to measure plasma Ac-SDKP levels during chronic treatment with all types of ACE inhibitors and to assess its relevance as a marker of ACE inhibition. Plasma levels of Ac-SDKP were blindly determined in age- and sex-matched hypertensive patients either treated (ACEI group, n=27) or not (non-ACEI group, n=23) with an ACE inhibitor for more than 1 month. Geometric mean [range] of plasma Ac-SDKP levels were significantly higher in the ACEI group (3.78 [1.48 to 14.5] pmol/mL) than in the non-ACEI group, with no overlap between the groups (0.75 [0.36 to 1.22] pmol/mL, P<.0001). The measurement of Ac-SDKP in plasma discriminated all the patients of the ACEI group, whereas the simultaneous determination of either in vitro (using hippuryl-histidine-leucine as substrate) or in vivo (angiotensin II/angiotensin I ratio) ACE activity failed to identify nine and five cases, respectively. We conclude that Ac-SDKP accumulates in plasma during chronic ACE inhibitor treatment. The long-term consequences of Ac-SDKP accumulation are unknown. The reliability of plasma Ac-SDKP measurement makes it the best marker of chronic ACE inhibition, which can help to verify patients' compliance to ACE inhibitor treatment.


Fractures of the femur and blood transfusions.
Blood loss estimation after trauma (i.e. physical injury) and early identification of potential sources of bleeding are important for planning of investigation and management of trauma. Long bone fractures have been reported to be associated with substantial volumes of blood loss requiring blood transfusion. The aim of this study was to assess rates and amounts of blood transfusion in the setting of isolated extra capsular femur fractures and to determine variables associated with the need for transfusion within the first 48 h of admission. A retrospective cohort study was conducted of patients in The Alfred Trauma Registry with isolated extra capsular femur fractures over a 7-year period. We compared patients with a femoral shaft fracture (FSF) to patients with either distal femur or proximal femur fractures (i.e. extremity fracture). We collected data potentially associated with blood transfusion within 48 h as well as operation details and patient outcomes. There were 293 patients included, of which 121 had FSF and 172 extremity fracture. 105 (36%) patients received a blood transfusion during their admission. Admission haemoglobin (AOR 0.92; 95%CI 0.89-0.94, p < 0.01) was the only independently associated variable with blood transfusion within the first 48 h of hospital admission. Volume of blood transfused to patients with extra-capsular femoral fractures was low and usually in the post-operative period. FSF, compared to femoral extremity fractures, were not more likely to receive blood transfusion within the first 48 h of admission, and did not receive a higher volume of blood overall. In the setting of major trauma with haemorrhagic shock, alternate sources of bleeding should be sought.


Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice.
Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.


Use of cis- and trans-acting viral regulatory sequences to improve expression of human immunodeficiency virus vectors in human lymphocytes.
We compared the efficiency of human immunodeficiency virus (HIV-1) vectors that express a marker gene (chloramphenicol acetyltransferase, CAT) using different promoter elements. In one vector, CAT was expressed under the control of an internal murine leukemia virus (MuLV) long terminal repeat (LTR). In other vectors, CAT production was regulated by the HIV-1 LTR; these vectors also contained the HIV-1 tat gene and pol sequences reported to exert cis-acting positive effects on reverse transcription or gene expression. Vectors employing the Tat-driven HIV-1 LTR exhibited up to 500-fold greater CAT expression in Jurkat lymphocytes or human peripheral blood mononuclear cells compared with vectors using the internal MuLV LTR element as a promoter. This difference was not due to improved packaging of the vector RNA into virions, but to an improved level of gene expression in the target cells. Target cell CAT expression was two- to threefold higher for the vector containing the pol sequences and was only slightly less than that seen for a trans-complemented envdeleted provirus. These results indicate that defective HIV-1 vectors with efficiencies of gene transfer and expression comparable with that of HIV-1 itself are feasible.


Voluntary activation and variability during maximal dynamic contractions with aging.
Whether reduced supraspinal activation contributes to age-related reductions in maximal torque during dynamic contractions is not known. The purpose was to determine whether there are age differences in voluntary activation and its variability when assessed with stimulation at the motor cortex and the muscle during maximal isometric, concentric, and eccentric contractions. Thirty young (23.6 ± 4.1 years) and 31 old (69.0 ± 5.2 years) adults performed maximal isometric, shortening (concentric) and lengthening (eccentric) contractions with the elbow flexor muscles. Maximal isometric contractions were performed at 90° elbow flexion and dynamic contractions at a velocity of 60°/s. Voluntary activation was assessed by superimposing an evoked contraction with transcranial magnetic stimulation (TMS) or with electrical stimulation over the muscle during maximal voluntary contractions (MVCs). Old adults had lower MVC torque during isometric (- 17.9%), concentric (- 19.7%), and eccentric (- 9.9%) contractions than young adults, with less of an age difference for eccentric contractions. Voluntary activation was similar between the three contraction types when assessed with TMS and electrical stimulation, with no age group differences. Old adults, however, were more variable in voluntary activation than young (standard deviation 0.99 ± 0.47% vs. 0.73 ± 0.43%, respectively) to both the motor cortex and muscle, and had greater coactivation of the antagonist muscles during dynamic contractions. Thus, the average voluntary activation to the motor cortex and muscle did not differ with aging; however, supraspinal activation was more variable during maximal dynamic and isometric contractions in the old adults. Lower predictability of voluntary activation may indicate subclinical changes in the central nervous system with advanced aging.


Relationship Between Fatigability and Perceived Fatigue Measured Using the Neurological Fatigue Index in People with Multiple Sclerosis.
Understanding the relationship between perceived fatigue and performance fatigability could lead to more effective interventions to manage multiple sclerosis (MS)-related fatigue. However, the relationship between self-perceived fatigue measured using the Neurological Fatigue Index (NFI-MS) and performance fatigability in people with MS is unknown. We sought to explore the relationship between the NFI-MS and performance fatigability in people with MS. Fifty-two participants (mean ± SD age, 46.8 ± 10.1 years) completed the study. Three measures of performance fatigability were used: percent change in meters walked from first to last minute of the 6-Minute Walk Test, percent change in force exerted from first to last trial on a repetitive maximal hand grip test, and response speed variability on the Continuous Performance Test. Perceived physical and cognitive fatigue were measured using the NFI-MS. The state level of fatigue was examined immediately before and after performing the fatigability measures using a one-item visual analogue fatigue scale. Of the three performance fatigability measures, only the attentional task (response speed variability) was significantly associated with NFI-MS physical (r = 0.326, P = .020) and cognitive (r = 0.276, P = .050) domain scores. Participants demonstrated significantly higher state levels of fatigue after performing all performance fatigability measures (P ≤ .001). The NFI-MS and the performance fatigability measures used in this study are easy to administer. We encourage wider use of these measures in clinical and research settings for comprehensive assessment of MS-related fatigue.


[Unilateral polyposis: evaluation of preoperative tests].
The aim of this paper is to study a group of patients with occupancy of a nasal fossal, apparently by polyps, and being the other side of the nose normal. Evaluating on the one hand the true incidence of unspecific polyposis and, of other diagnosis, and on the other hand to compare the preoperative radiological findings with those seen during surgery. A prospective study of 23 consecutive patients was carried out over a period of 30 months at the ENT Department of the Dr. Peset Hospital, in Valencia. A CT scan and preoperative biopsy was performed in all cases, the results of these being later compared with the surgical findings and the final histopathologic diagnosis. A discrepancy between the preoperative biopsy and final diagnosis was found in 26% of the patients. The incidence of polyposis was 52%, inverted papilloma 26%, malignant tumours 13% and other diagnosis 8.6%. There is a good correlation between preoperative CT scans and surgical findings in those cases of polyposis and inverted papilloma, but not in those of malignant tumours as CT scans often underestimated these lesions.


Insight into motor control and motor impairment from stroke and beta oscillations.
Beta oscillations are associated with motor function and are thought to play a role in movement impairment. In a recent magnetoencephalography (MEG) study, Rossiter et al. (J Neurophysiol 112: 2053-2058, 2014) found a disruption in the modulation of movement-related beta oscillations in stroke patients that correlated with motor impairment. We discuss how beta oscillatory measures characterize motor impairment, the implications of stroke variability, and the potential role of GABA in modulating oscillations following stroke and during stroke recovery.


[Characteristics of the epizootic process in hemorrhagic fever with renal syndrome].
For the first time in the study of epizootology of hemorrhagic fever with the renal syndrome (HFRS) in wild animals data are presented indicating certain relationship between true infection rate of bank voles with HFRS virus and the content of the circulating antigen of HFRS virus and antibody to this virus in these animals. Different age groups of animal populations were shown to have different intensity of immunity: it was more marked in animals of older age groups, and less in young animals. On the contrary, live virus was most frequently found in young animals. It has been shown that for successful isolation of the virus from bank voles it is necessary to take into consideration the characteristics of acute infection in rodents: the presence of HFRS virus antigen in their lung tissue and the lack of antibody to the virus in the blood.


Why the "sugars" in traditional Unani formulations are a pivotal component: A viewpoint perspective.
Traditional medicine systems around the globe, like Unani, Ayurveda and traditional Chinese medicine, include a number of sugar-based formulations, which contain a large amount of saccharide-containing sweetener, such as honey, sucrose or jaggery. With pervasive lifestyle disorders throughout the world, there have been discussions to consider alternative sweetening agents. Here, from the perspective of Unani medicine, we discuss how the saccharide-based sweeteners may be an essential component of these traditional preparations, like electuaries, which may be deprived of their bioactivities without these saccharides. With contemporary researches, it is known that apart from their own therapeutic effects, saccharides also form deep eutectic solvents which help in enhancing the bioactivity of other ingredients present in crude drugs. In addition, they provide energy for fermentation which is essential for biotransformation of compounds. Interestingly, the sugars also increase the shelf-life of these compound drugs and act as natural preservatives. On the basis of this review, we strongly believe that saccharide-based sweeteners are an essential component of traditional medicines and not merely an excipient.


[HMG1 domains: the victims of circumstance].
The method of circular dichroism (CD) was used to compare DNA behavior during its interaction with linker histone H1 and with non-histone chromosomal protein HMG1 at different ionic strength and at different protein content in the system. The role of negatively charged C-terminal fragment of HMG1 was analyzed using recombinant protein HMG1-(A + B), which lacks the C terminal amino acid sequence. The psi-type CD spectra were common for DNA interaction with histone H1, but no spectra of this type were observed in HMG1-DNA systems even at high ionic strength. The CD spectrum of the truncated recombinant protein at high salt concentration somewhat resembled the psi-type spectrum. Two very intense positive bands were located near 215 nm and near 273 nm, and the whole CD spectrum was positive. The role of C-terminal tail of HMG1 in formation of the ordered DNA-protein complexes is discussed.


Effects of a potent platelet-activating factor antagonist, SR27417A, on allergen-induced asthmatic responses.
Platelet-activating factor (PAF) is a lipid-derived mediator that has been implicated in the pathophysiology of airway inflammation in asthma. Its actions include chemotaxis and activation of inflammatory cells, particularly eosinophils. Inhaled PAF causes bronchoconstriction and increased airway responsiveness in human subjects. However, PAF antagonists have so far failed to show benefits in allergen challenge or in the treatment of chronic asthma. SR27417A is a novel PAF antagonist with increased potency compared with previously tested compounds. Twelve asthmatic subjects received treatment with either SR27417A or placebo for 1 wk in a double-blind crossover study. After treatment each subject underwent allergen challenge. Effects were assessed in terms of early and late asthmatic responses and allergen-induced effects on airway responsiveness. Baseline lung function and airway responsiveness were also examined. Treatment with SR27417A significantly attenuated the late asthmatic response (AUC LAR4-10h: 107 +/- 24 after placebo, 79 +/- 17 after SR27417A, p < 0.05; mean maximal percent fall in FEV1 LAR: 29 +/- 6% after placebo, 23.5 +/- 5.4% after SR27417A, p < 0.05). There were no effects on early asthmatic responses, allergen-induced airway responsiveness, or baseline lung measurements. SR27417A is the most potent PAF antagonist to date, and it has a modest inhibitory effect on the late asthmatic response. This suggests that PAF has a small role in allergic inflammation.


A Novel Fatigue Driving State Recognition and Warning Method Based on EEG and EOG Signals.
Traffic accidents are easily caused by tired driving. If the fatigue state of the driver can be identified in time and a corresponding early warning can be provided, then the occurrence of traffic accidents could be avoided to a large extent. At present, the recognition of fatigue driving states is mostly based on recognition accuracy. Fatigue state is currently recognized by combining different features, such as facial expressions, electroencephalogram (EEG) signals, yawning, and the percentage of eyelid closure over the pupil over time (PERCLoS). The combination of these features increases the recognition time and lacks real-time performance. In addition, some features will increase error in the recognition result, such as yawning frequently with the onset of a cold or frequent blinking with dry eyes. On the premise of ensuring the recognition accuracy and improving the realistic feasibility and real-time recognition performance of fatigue driving states, a fast support vector machine (FSVM) algorithm based on EEGs and electrooculograms (EOGs) is proposed to recognize fatigue driving states. First, the collected EEG and EOG modal data are preprocessed. Second, multiple features are extracted from the preprocessed EEGs and EOGs. Finally, FSVM is used to classify and recognize the data features to obtain the recognition result of the fatigue state. Based on the recognition results, this paper designs a fatigue driving early warning system based on Internet of Things (IoT) technology. When the driver shows symptoms of fatigue, the system not only sends a warning signal to the driver but also informs other nearby vehicles using this system through IoT technology and manages the operation background.


Epidermoid cyst mimicry: report of seven cases and review of the literature.
Cysts are entities encountered frequently in dermatological clinics. Various types of cysts have been described and include trichilemmal cysts, epidermoid cysts, steatocystomas, and the myriad of developmental cysts (branchial cleft cyst, thyroglossal duct cysts, bronchogenic cysts). Moreover, not all lesions that appear clinically as cystic structures are, in fact, cysts. Increased awareness of these mimickers and a systematic approach to the evaluation of these cases is essential. The authors report seven cases, over the course of six years, presenting to their dermatology department, all of which were originally clinically diagnosed as "cysts" and referred to the authors for management. In this article, the authors review seven cyst mimickers and describe important aspects of these diagnoses to increase awareness of the importance of a preoperative biopsy and evaluation. It is important to have a thorough understanding of the wide differential diagnosis of cutaneous nodules and to consider other causes of lesions that appear to be cysts, particularly in the anatomical locations described.


HIM-10 is required for kinetochore structure and function on Caenorhabditis elegans holocentric chromosomes.
Macromolecular structures called kinetochores attach and move chromosomes within the spindle during chromosome segregation. Using electron microscopy, we identified a structure on the holocentric mitotic and meiotic chromosomes of Caenorhabditis elegans that resembles the mammalian kinetochore. This structure faces the poles on mitotic chromosomes but encircles meiotic chromosomes. Worm kinetochores require the evolutionarily conserved HIM-10 protein for their structure and function. HIM-10 localizes to the kinetochores and mediates attachment of chromosomes to the spindle. Depletion of HIM-10 disrupts kinetochore structure, causes a failure of bipolar spindle attachment, and results in chromosome nondisjunction. HIM-10 is related to the Nuf2 kinetochore proteins conserved from yeast to humans. Thus, the extended kinetochores characteristic of C. elegans holocentric chromosomes provide a guide to the structure, molecular architecture, and function of conventional kinetochores.


Expression of cyclic ADP-ribose-synthetizing CD38 molecule on human platelet membrane.
CD38 is a cell surface molecule widely used as a marker for immature and activated lymphocytes. It has been recently shown that CD38 displays three enzymatic activities: hydrolysis of NAD+ to ADP-ribose, synthesis of cyclic ADP-ribose from NAD+, and hydrolysis of cyclic ADP-ribose to ADP-ribose. Thus, CD38 plays a key role in the synthesis of cyclic ADP-ribose, a calcium-mobilizing compound. We investigate here the expression and cellular localization of CD38 in human platelets using a specific monoclonal antibody. Results showed that CD38 is expressed by human platelet membranes. Moreover, we show that platelet CD38 possesses NAD glycohydrolase, ADP-ribose cyclase, and cyclic ADP-ribose hydrolase activities. This finding indicates that the calcium-mobilizing agent cyclic ADP-ribose can be synthetized by human platelets and raises the question about the possible role of CD38 expression and enzymatic activities in the signal transduction pathways leading to platelet activation.


The Penile Microbiota in Uncircumcised and Circumcised Men: Relationships With HIV and Human Papillomavirus Infections and Cervicovaginal Microbiota.
While the human microbiota especially that of the gut, cervix, and vagina continue to receive great attention, very little is currently known about the penile (glans, coronal sulcus, foreskin, and shaft) microbiota. The best evidences to date for the potential role of the penile microbiota in human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) acquisition have come from studies examining medical male circumcision. We are still at the foothills of identifying specific penile bacteria that could be associated with increased risk of STI/HIV acquisition. In this review, we summarize the available literature on the human penile microbiota and how it is impacted by circumcision. We also discuss the potential role of penile microbiota in STIs and its impact on cervicovaginal microbiota. Taken together, the findings from the penile microbiota studies coupled with observational studies on the effect of male circumcision for reduction of STI/HIV infection risk suggest that specific penile anaerobic bacteria such as Prevotella spp. potentially have a mechanistic role that increases the risk of genital infections and syndromes, including bacterial vaginosis in sexual partners. Although penile Corynebacterium and Staphylococcus have been associated with healthy cervicovaginal microbiota and have been found to increase following male circumcision, further investigations are warranted to ascertain the exact roles of these bacteria in the reproductive health of men and women. This review aims to address existing gaps and challenges and future prospects in the penile microbiota research. The information described here may have translational significance, thereby improving reproductive health and management of STI/HIV.


Corn silage management: effects of maturity, inoculation, and mechanical processing on pack density and aerobic stability.
Three experiments were conducted to evaluate the effects of inoculation, maturity, and mechanical processing of corn silage on aerobic stability and pack density. Corn silage was stored in 20-L mini silos for the three aerobic stability experiments. Corn silage was stored in 80-L mini silos for the three pack-density experiments. The wet pack density of corn silage tended to decrease as maturity advanced in all of the pack-density experiments, and processed corn silage had a greater wet pack density compared with unprocessed corn silage in two of the three 20-L mini silo experiments. Aerobic stability, measured as the number of hours to reach 1.7 degrees C above ambient, was greater for processed corn silage in two of the three 20-L mini silo experiments, and was greater for inoculated corn silage across the three 20-L mini silo experiments. Inoculation of corn silage with lactic acid producing bacteria tended to improve aerobic stability of corn silage more than maturity and mechanical processing.


Aberration Correction to Optimize the Performance of Two-Photon Fluorescence Microscopy Using the Genetic Algorithm.
Due to less light scattering and a better signal-to-noise ratio in deep imaging, two-photon fluorescence microscopy (TPFM) has been widely used in biomedical photonics since its advent. However, optical aberrations degrade the performance of TPFM in terms of the signal intensity and the imaging depth and therefore restrict its application. Here, we introduce adaptive optics based on the genetic algorithm to detect the distorted wavefront of the excitation laser beam and then perform aberration correction to optimize the performance of TPFM. By using a spatial light modulator as the wavefront controller, the correction phase is obtained through a signal feedback loop and a process of natural selection. The experimental results show that the signal intensity and imaging depth of TPFM are improved after aberration correction. Finally, the method was applied to two-photon fluorescence lifetime imaging, which helps to improve the signal-to-noise ratio and the accuracy of lifetime analysis. Furthermore, the method can also be implemented in other experiments, such as three-photon microscopy, light-sheet microscopy, and super-resolution microscopy.


Carcinoid tumor of the ileoanal pouch in a patient with ulcerative colitis.
Carcinoid tumors have been reported to occur in various locations, particularly in the gastrointestinal tract. The relationship between the development of carcinoids and ulcerative colitis has been an unclear and controversial one. The association of ulcerative colitis and the development of ileal-pouch carcinoids has not, however, been well documented. We report a case of carcinoid tumor arising in an ileoanal pouch and discuss its unique diagnostic and therapeutic considerations.


Invalidation of Hyperamoeba by transferring its species to other genera of Myxogastria.
The genus Hyperamoeba Alexeieff, 1923 was established to accommodate an aerobic amoeba exhibiting three life stages-amoeba, flagellate, and cyst. As more species/strains were isolated, it became increasingly evident from small subunit (SSU) gene phylogenies and ultrastructure that Hyperamoeba is polyphyletic and its species occupy different positions within the class Myxogastria. To pinpoint Hyperamoeba strains within other myxogastrid genera we aligned numerous myxogastrid sequences: whole small subunit ribosomal (SSU or 18S rRNA) gene for 50 dark-spored (i.e. Stemonitida and Physarida) Myxogastria (including a new "Hyperamoeba"/Didymium sequence) and a approximately 400-bp SSU fragment for 147 isolates assigned to 10 genera of the order Physarida. Phylogenetic analyses show unambiguously that the type species Hyperamoeba flagellata is a Physarum (Physarum flagellatum comb. nov.) as it nests among other Physarum species as robust sister to Physarum didermoides. Our trees also allow the following allocations: five Hyperamoeba strains to the genus Stemonitis; Hyperamoeba dachnaya, Pseudodidymium cryptomastigophorum, and three other Hyperamoeba strains to the genus Didymium; and two further Hyperamoeba strains to the family Physaridae. We therefore abandon the polyphyletic and redundant genus Hyperamoeba. We discuss the implications for the ecology and evolution of Myxogastria, whose amoeboflagellates are more widespread than previous inventories supposed, being now found in freshwater and even marine environments.


Biosynthesized Multivalent Lacritin Peptides Stimulate Exosome Production in Human Corneal Epithelium.
Lacripep is a therapeutic peptide derived from the human tear protein, Lacritin. Lacripep interacts with syndecan-1 and induces mitogenesis upon the removal of heparan sulfates (HS) that are attached at the extracellular domain of syndecan-1. The presence of HS is a prerequisite for the syndecan-1 clustering that stimulates exosome biogenesis and release. Therefore, syndecan-1-mediated mitogenesis versus HS-mediated exosome biogenesis are assumed to be mutually exclusive. This study introduces a biosynthesized fusion between Lacripep and an elastin-like polypeptide named LP-A96, and evaluates its activity on cell motility enhancement versus exosome biogenesis. LP-A96 activates both downstream pathways in a dose-dependent manner. HCE-T cells at high confluence treated with 1 μM LP-A96 enhanced cell motility equipotent to Lacripep. However, cells at low density treated with 1 μM LP-A96 generated a 210-fold higher number of exosomes compared to those treated at low density with Lacripep. As monovalent Lacripep is capable of enhancing cell motility but not exosome biogenesis, activation of exosome biogenesis by LP-A96 not only suggests its utility as a novel molecular tool to study the Lacritin biology in the corneal epithelium but also implies activity as a potential therapeutic peptide that can further improve ocular surface health through the induction of exosomes.


Diltiazem and renal hemodynamics: implications for renal protection.
During the past decade, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists (including diltiazem) do not affect the vasodilated isolated perfused kidney, but they do dramatically alter the response of this preparation to vasoconstrictor agents. Our recent studies using the isolated perfused hydronephrotic rat kidney model, which permits direct visualization of afferent and efferent arterioles, have demonstrated that the preferential augmentation of glomerular filtration rate induced by calcium antagonists in the isolated perfused kidney is attributable to preferential vasodilation of preglomerular vessels. Although the clinical implications of such observations have not been fully delineated, the results of recent studies indicate that calcium antagonists exert salutary effects on renal function in patients with impaired renal hemodynamics, such as radiocontrast-induced nephrotoxicity and transplant-associated acute renal insufficiency.


Dapsone poisoning.
Two cases of suicidal dapsone ingestion are reported. These patients presented with marked cyanosis and had significant methaemoglobinaemia on admission. One patient also had acute psychosis and haemolytic anaemia. Both patients responded to intravenous methylene blue therapy and nasal oxygen inhalation and recovered without any sequelae.


Prognostic value of dobutamine-atropine stress (99m)Tc-tetrofosmin myocardial perfusion SPECT in patients with known or suspected coronary artery disease.
99mTc-Tetrofosmin is a recently introduced radioactive isotope for the assessment of myocardial perfusion. Data regarding the prognostic value of stress imaging using this isotope are scarce. The aim of this study was to assess the prognostic value of dobutamine-atropine (99m)Tc-tetrofosmin SPECT for the prediction of late cardiac events in patients with known or suspected coronary artery disease. A total of 721 consecutive patients with limited exercise capacity underwent dobutamine-atropine stress (99m)Tc-tetrofosmin SPECT. Follow-up was successful in 719 of 721 patients (99.7%). Twenty-eight patients who underwent early revascularization were excluded. Myocardial perfusion abnormalities were detected in 381 patients (55%) and included fixed defects in 190 patients (27%) and reversible defects 191 patients (28%). During a mean follow-up period of 37 +/- 17 mo, there were 150 deaths (22%), of which 62 (41%) were attributed to cardiac causes. Nonfatal myocardial infarction occurred in 23 patients (3%), and late (>3 mo) coronary revascularization was performed on 21 patients (3%). The cardiac death rate was 1%/y in patients with a normal scan and 5.1%/y in patients with an abnormal scan (P < 0.0001). In a multivariable Cox proportional-hazards model, the presence of abnormal perfusion was independently associated with an increased risk of cardiac death, after adjusting for clinical and stress test data (hazard ratio, 8.2; 95% confidence interval, 3.2-21). Dobutamine-atropine stress (99m)Tc-tetrofosmin SPECT is a useful imaging method for distinguishing patients at high and low risk of future cardiac events. The presence of perfusion abnormalities provides incremental prognostic information to clinical, stress electrocardiographic, and hemodynamic data.


Re-entry into the registered nursing work force: we did it!
Because the enrollment in nursing programs dropped in the late 1990s and healthcare agencies and education programs were seeking ways to increase the numbers of nurses, Bethel College in Mishawaka, Indiana, and Memorial Hospital in South Bend, Indiana, designed a plan to encourage nurses who had been out of nursing to re-enter the work force. This article details the steps used in this partnership and demonstrates a process for helping registered nurses to return to nursing. In the 6-credit, 8-week course, nurses were prepared to function on a medical-surgical unit by reviewing important concepts related to nursing practice, physical assessment, nursing process, nursing skills, pharmacology, and clinical nursing update. It was anticipated that receiving college credit for the course would be a motivator for returning to study at the registered nurse to bachelor of science in nursing level. With 2 full clinical days each week, the students could experience a normal work shift and the routine of a busy clinical unit.


Estimation of pitavastatin calcium in tablet dosage forms by column liquid chromatography and ultraviolet spectrophotometry.
Two simple and accurate methods for the determination of pitavastatin calcium (PIT) in tablet dosage forms were developed and validated using column liquid chromatography (LC) and UV spectrophotometry. The LC separation was achieved on a Phenomenex Luna C18 column (250 mm, 4.6 mm id, 5 microm) in the isocratic mode using acetonitrile-water-triethylamine (80 + 19.8 + 0.2, v/v/v), adjusted to pH 3.5 +/- 0.05 with orthophosphoric acid, as the mobile phase at a flow rate of 1.5 mL/min. The retention time was 5.70 min. Both the methods were performed at 238 nm, the wavelength of maximum absorbance of PIT in methanol. In the LC method, quantification was achieved with a photodiode array detector over the concentration range of 0.1-2.5 microg/mL with a mean recovery of 100.26 +/- 0.75%. In the UV method, quantification was achieved over the concentration range of 2-20 microg/mL with mean recovery of 99.65 +/- 1.24%. Both methods were validated, and the results were compared statistically. They were found to be simple, specific, accurate, and precise. The methods were successfully applied for the determination of PIT in tablet dosage form without any interference from common excipients.


Necessity of Quantifying Urbach Energy through Scanning Tunneling Spectroscopy.
In this Letter, we introduce scanning tunneling spectroscopy (STS) to quantify the Urbach energy (EU) in disordered semiconductors. The technique enabled us to gain precise information on the extending component of conduction and valence band-edges responsible for Urbach tailing, individually; such information has been obtained from the width of band-energy-histograms drawn from STS studies at many different points. STS, as a probing method at the microscopic scale to derive EU, is in contrast to commonly employed optical spectroscopy studies which provide information at the macroscopic scale. A comparison between Urbach energy values from optical studies and distribution of band-edges obtained from STS revealed the inherent inaccuracies involved in the optical characterization process. We have considered copper oxide (CuxO) thin films in this regard; we show that through STS and the associated density of state (DOS) spectra, we can derive accurate information on the band-edges' distribution leading to EU in different phases of the binary oxide thin films.


Quality control of iodine-131-labeled metaiodobenzylguanidine.
Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG) is used worldwide for the diagnosis and therapy of neuroendocrine tumors, particularly adrenal medullae tumors. After the synthesis and preparation of a radioiodinated MIBG drug formulation, quality control testing to determine its radiochemical purity (RCP) should be performed. European Pharmacopoeia 8.0 requires that the quality control include a test for RCP for the determination of [(131)I]mIBG. Previously reported procedures using reversed-phase conditions require long retention times. Our system enables the separation of [(131)I]mIBG within a few minutes. The aim of this work was to carry out RCP testing for [(131)I]mIBG without any type of sample pretreatment. RCP testing for ([(131)I]mIBG has been carried out using high-performance liquid chromatography and thin-layer chromatography methods. A simple and rapid reversed-phase isocratic system enables the HPLC investigation of RCP testing for [(131)I]mIBG used for therapy within a few minutes. From the point of view of radiation protection, this method is safer, especially for therapeutic amounts of [(131)I]mIBG.


The time dependent UV resonance Raman spectra, conformation, and biological activity of acetylcholine analogues upon binding to acetylcholine binding proteins.
In order to obtain quantitative data on the relation between the conformation of acetylcholine and its interaction with biologically significant proteins, a series of acetylcholine analogues with absorption bands in the region 200-300 nm have been synthesized or obtained commercially. Each of these compounds were assayed to measure its activity as an ion channel activator of the nicotinic acetylcholine receptor protein (AChR). In addition, the suitability of some of these compounds as substrates for hydrolysis by acetylcholine esterase (AChE) was determined. One of these analogues, dimethylthionocarbamylcholine (DMTC-Ch), has the ester carbonyl oxygen replaced by a thionyl sulfur. DMTC-Ch has been found to be quite active as an ion channel activator when bound to AChR and was found to react with the enzyme AChE as a suicide substrate. It forms a thionoester of the serine at the AChE active site by an ester exchange reaction that releases the choline as the first product. However, the second or acid product is not released even at pH 7.5 over a period of days. This acetylcholine analog has an absorption band at about 240 nm and exhibits very strong ultraviolet resonance Raman (UVRR) spectra using 239 nm excitation from a frequency modified Nd:YAG laser. This technique allows observation of both conformational changes of the ligand molecule that result in frequency changes as well as changes in the excited state electronic structure that results in changes in the relative intensity of the Raman bands. The time dependence of the UVRR spectrum of the ligand upon binding to both AChE and AChR has been studied from 0.1 msec to minutes. Some time dependence in the conformation of DMTC-Ch upon binding to AChE has been found for very short (0.1-0.5 msec) times. However, no change in the conformation of this neurotransmitter analog is found in the available time range upon binding to AChR. From these data it is concluded that a previous suggestion that acetylcholine has a conformational change upon binding to AChR may be incorrect since the solution behavior of the carbamyl cholines and acetylcholine are similar. Even if acetylcholine does change conformation upont binding to AChR, it is unlikely that such a conformational change plays a significant role in channel activation. We present strong evidence that acetylcholine and its analogues can be active in a variety of conformations.(ABSTRACT TRUNCATED AT 400 WORDS)


Experimental study of plane electrode thickness scaling for 3D vertical resistive random access memory.
The vertical scaling for the multi-layer stacked 3D vertical resistive random access memory (RRAM) cross-point array is investigated. The thickness of the multi-layer stack for a 3D RRAM is a key factor for determining the storage density. A vertical RRAM cell with plane electrode thickness (tm) scaled down to 5 nm, aiming to minimize 3D stack height, is experimentally demonstrated. An improvement factor of 5 in device density can be achieved as compared to a previous demonstration using a 22 nm thick plane electrode. It is projected that 37 layers can be stacked for a lithographic half-pitch (F) = 26 nm and total thickness of one stack (T) = 21 nm, delivering a bit density of 72.8 nm(2)/cell.


Statistical analysis of differential gene expression in colorectal cancer using CLEAR-test.
CLEAR test provides a novel method of analysis by combining inference for differential expression and variability. Frozen tumor specimens from 14 (3 coded Stage I, 5 Stage II, 2 Stage III and 4 Stage IV) colon cancer patients were obtained. Archived primary tumor samples were collected at the time of surgery and normal colon mucosae (controls specimens) were also collected. The studied transcriptomes were clustered using hierarchical agglomeration with Ward's method and Tchebychev distance. The separable groups of transcriptomes were classified as high clinical stage of adenocarcinoma (HCS; stages II-IV), low clinical stage of adenocarcinoma (LCS; stages I and 3 controls), and two normal colon mucosae (controls N1 and N2). The results of the CLEAR-test algorithm in normal colon specimens and adenocarcinoma specimens with low and high clinical stage showed 50 most and 50 least significant genes. The list of differential genes (p<0.01) in normal colon specimens and adenocarcinoma specimens with low and high clinical stage presented 58 genes.


Absence of interferon in sera of patients with Kawasaki syndrome.
We measured serum interferon concentrations in 42 patients with Kawasaki syndrome. The children ranged in age from 7 months to 6 years. All acute sera were obtained within 12 days of the onset of fever. Convalescent sera (illness day 19 to 56) were available from 25 of 42 patients. Sera were also obtained from 40 controls ranging in age from 2 months to 12 years. Control sera included healthy children (n = 14), children with bacterial infection (n = 10) and children with viral infection (n = 16). Sera were coded and interferon concentrations were measured blindly using human diploid fibroblast cell monolayers challenged with 10(4) plaque-forming units of vesicular stomatitis virus. Specimens from 10 of 16 patients with viral infection were positive for interferon. Three of 10 patients with bacterial infection had detectable serum interferon. No interferon was detected in specimens from the 14 healthy control children or the 42 children with Kawasaki syndrome. Despite the use of a sensitive assay we were unable to detect interferon in the sera of patients with Kawasaki syndrome.


Amplicon sequencing of bacterial microbiota in abortion material from cattle.
Abortions in cattle have a significant economic impact on animal husbandry and require prompt diagnosis for surveillance of epizootic infectious agents. Since most abortions are not epizootic but sporadic with often undetected etiologies, this study examined the bacterial community present in the placenta (PL, n = 32) and fetal abomasal content (AC, n = 49) in 64 cases of bovine abortion by next generation sequencing (NGS) of the 16S rRNA gene. The PL and AC from three fetuses of dams that died from non-infectious reasons were included as controls. All samples were analyzed by bacterial culture, and 17 were examined by histopathology. We observed 922 OTUs overall and 267 taxa at the genus level. No detectable bacterial DNA was present in the control samples. The microbial profiles of the PL and AC differed significantly, both in their composition (PERMANOVA), species richness and Chao-1 (Mann-Whitney test). In both organs, Pseudomonas was the most abundant genus. The combination of NGS and culture identified opportunistic pathogens of interest in placentas with lesions, such as Vibrio metschnikovii, Streptococcus uberis, Lactococcus lactis and Escherichia coli. In placentas with lesions where culturing was unsuccessful, Pseudomonas and unidentified Aeromonadaceae were identified by NGS displaying high number of reads. Three cases with multiple possible etiologies and placentas presenting lesions were detected by NGS. Amplicon sequencing has the potential to uncover unknown etiological agents. These new insights on cattle abortion extend our focus to previously understudied opportunistic abortive bacteria.


Healing of duodenal ulcers is not impaired by indomethacin or rofecoxib, the selective COX-2 inhibitor, in rats.
Studies have demonstrated an important role for endogenous PG and NO in the healing of chronic gastric ulcers. We investigated the effects of COX and NOS inhibitors on the healing of duodenal ulcers, in comparison with gastric ulcers, in rats. Gastric and duodenal ulcers were induced by serosal application of acetic acid (0.1 ml of 100% acetic acid) for 60 and 20 s, respectively. Indomethacin (a nonselective COX inhibitor) or rofecoxib (a selective COX-2 inhibitor) was given p.o. once daily for 14 days from 3 days after ulcer induction, while N(G)-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor) or aminoguanidine (a relatively selective iNOS inhibitor) was given s.c. twice daily during this period. Both gastric and duodenal ulcers induced by acetic acid healed spontaneously within 17 days to a minimal size. Daily administration of indomethacin or rofecoxib significantly delayed the healing of gastric but not duodenal ulcers. In contrast, the healing of both gastric and duodenal ulcers was delayed by repeated administration of either L-NAME or aminoguanidine. Ulceration markedly increased the PGE(2) content of the ulcerated mucosa in both the stomach and duodenum, and the increased PG biosynthetic response was inhibited by either indomethacin or rofecoxib in both tissues. The expression of both COX-2 and iNOS mRNAs was upregulated in the ulcerated mucosa of the stomach and duodenum. These results suggest that COX-2/PG is actively involved in the healing of gastric but not duodenal ulcers, although the mRNA for COX-2 is expressed in the duodenal mucosa after ulceration, as potently as in the gastric mucosa. In contrast, NO produced by both cNOS and iNOS plays a role in the healing of both gastric and duodenal ulcers.


Outbreaks of diarrheal illness associated with cyanobacteria (blue-green algae)-like bodies--Chicago and Nepal, 1989 and 1990.
Recent reports have described the detection of cyanobacteria (blue-green algae)-like bodies (CLB) in the stools of persons with a prolonged syndrome of diarrhea, anorexia, and fatigue (1-3). In each of these reports, affected persons either were immunocompromised or had recently traveled to tropical countries. During 1989 and 1990, the first three reported outbreaks of this CLB-associated syndrome occurred in immunocompetent populations, affecting at least 150 persons. This report summarizes investigations of these outbreaks, which occurred in Chicago in 1990 and in Kathmandu, Nepal, in 1989 and 1990.


Domains of macrophage N(O) synthase have divergent roles in forming and stabilizing the active dimeric enzyme.
The cytokine-inducible NO synthase (iNOS) is a flavin-containing hemeprotein that must dimerize to generate NO. Trypsin cleaves the dimeric enzyme into an oxygenase domain fragment that remains dimeric, contains heme and H4biopterin, and binds L-arginine and a reductase domain fragment that is monomeric, binds NADPH, FAD, FMN, and catalyzes the reduction of cytochrome c [Ghosh, D. K. & Stuehr, D. J. (1995) Biochemistry 34, 801-807]. The current study investigates the isolated oxygenase and reductase domains of iNOS to understand how they form and stabilize the active dimeric enzyme. The dimeric oxygenase domain dissociated into folded, heme-containing monomers when incubated with 2-5 M urea, whereas the reductase domain unfolded under these conditions and lost its ability to catalyze NADPH-dependent cytochrome c reduction. Spectral analysis of the dissociation reaction showed that it caused structural changes within the oxygenase domain and exposed the distal side of the heme to solvent, enabling it to bind dithiothreitol as a sixth ligand. Importantly, the oxygenase domain monomers could reassociate into a dimeric form even in the absence of the reductase domain. The reaction required L-arginine and H4biopterin and completely reversed the structural changes in heme pocket and protein structure that occurred upon dissociating the original dimer. Together, this confirms that the oxygenase domain contains all of the determinants needed for subunit dimerization and indicates that the dimeric structure greatly affects the heme and protein environment in the oxygenase domain.


Proliferation kinetics of plasma cells and of normal haemopoietic cells in multiple myeloma.
DNA synthesis time (Ts) and 3H thymidine (TdR) labelling index (LI) of bone marrow (BM) myelomatous plasma cells (PC) and of the residual haemopoietic cell population (RHCP) were measured by in vitro quantitative 14C-TdR autoradiography in five patients with multiple myeloma (MM) in different phases of disease (three at presentation and two at relapse) and in one patient with solitary extra-osseous myeloma. One other patient with plasma cell leukaemia (PCL) was studied during an initial relapse phase and later during the leukaemic terminal phase. PC Ts was 18.8 +/- 3.7 (from 13.3 to 25.0) hr and PC LI was 2.5 +/- 1.8% (from 1.0 to 6.3%). In the case of PCL, circulating PC had a Ts of 14.4 hr and a LI of 3.1. From these experimental measurements, the fractional turnover rate (FTR-percentage of cells produced per unit time) and the potential doubling time (Td) of BMPC were calculated assuming that all BMPC were in a steady-state at the time of the study. BMPC FTR was 3.53 +/- 2.3% cells per day (from 1.2 to 6.72) and BMPC Td was 46.8 +/- 27.5 days (from 15.0 to 75.4). Comparison with results obtained in BM blasts of children with acute lymphoblastic leukaemia (ALL) indicated that BMPC had a lower proliferative activity (P less than 0.001), although BMPC Ts was not significantly different. In two patients a tumour doubling time of 6 and 13 months was determined by clinical follow up. Comparison of this parameter with Td showed a cell loss factor of more than 90% in both patients. Kinetic data relative to RHCP showed slight variations with respect to those found in normal subjects, with a general tendency towards a prolongation of Ts and a reduction of LI.


How are you feeling?: A personalized methodology for predicting mental states from temporally observable physical and behavioral information.
It is believed that anomalous mental states such as stress and anxiety not only cause suffering for the individuals, but also lead to tragedies in some extreme cases. The ability to predict the mental state of an individual at both current and future time periods could prove critical to healthcare practitioners. Currently, the practical way to predict an individual's mental state is through mental examinations that involve psychological experts performing the evaluations. However, such methods can be time and resource consuming, mitigating their broad applicability to a wide population. Furthermore, some individuals may also be unaware of their mental states or may feel uncomfortable to express themselves during the evaluations. Hence, their anomalous mental states could remain undetected for a prolonged period of time. The objective of this work is to demonstrate the ability of using advanced machine learning based approaches to generate mathematical models that predict current and future mental states of an individual. The problem of mental state prediction is transformed into the time series forecasting problem, where an individual is represented as a multivariate time series stream of monitored physical and behavioral attributes. A personalized mathematical model is then automatically generated to capture the dependencies among these attributes, which is used for prediction of mental states for each individual. In particular, we first illustrate the drawbacks of traditional multivariate time series forecasting methodologies such as vector autoregression. Then, we show that such issues could be mitigated by using machine learning regression techniques which are modified for capturing temporal dependencies in time series data. A case study using the data from 150 human participants illustrates that the proposed machine learning based forecasting methods are more suitable for high-dimensional psychological data than the traditional vector autoregressive model in terms of both magnitude of error and directional accuracy. These results not only present a successful usage of machine learning techniques in psychological studies, but also serve as a building block for multiple medical applications that could rely on an automated system to gauge individuals' mental states.


The use of chloroquine and hydroxychloroquine for non-infectious conditions other than rheumatoid arthritis or lupus: a critical review.
Chloroquine and hydrocychloroquine have been evaluated in 30 noninfectious disorders and conditions other than rheumatoid arthritis or lupus erythematosus; 12 of these have been subjected to well-designed controlled trials. It is concluded that chloroquines are safe and effective first line therapies for selected patients with porphyria cutanea tarda, cutaneous sarcoidosis, cutaneous manifestations of dermatomyositis, hyperlipidemias and thromboembolic prophylaxis for patients with antiphospholipid antibodies. Published experience with these and other diseases or syndromes are critically reviewed.


Plasma endothelin in essential hypertension and diabetes mellitus.
This study was designed to determine plasma endothelin-1 levels in patients with essential hypertension and diabetes mellitus. Endothelin immunoreactivity was measured in normal controls (n = 30), mild-moderate essential hypertensives (n = 25), Type II diabetic normotensives (n = 25) and hypertensive patients (n = 20). In addition, in ten patients of each group we investigated the relationships of endothelin with other vasoactive hormones. Plasma endothelin concentrations were similar in healthy controls, in essential hypertensives and in diabetic patients with or without hypertension, averaging 8.23 +/- 1.68 pg/ml, 7.7 +/- 1.1 pg/ml, 5.05 +/- 0.94 pg/ml, 7.88 +/- 1.41 pg/ml, respectively. No correlations were observed between endothelin and concentrations of plasma renin activity, aldosterone, catecholamines, atrial natriuretic peptide and arginine-vasopressin. The present study suggests that Type II diabetic patients with or without essential hypertension do not have demonstrably higher values of plasma endothelin than essential hypertensives or healthy subjects.


Breastfeeding peer counseling: from efficacy through scale-up.
An increasing number of publications have evaluated various breastfeeding peer counseling models. This article describes a systematic review of (a) the randomized trials assessing the effectiveness of breastfeeding peer counseling in improving rates of breastfeeding initiation, duration, exclusivity, and maternal and child health outcomes and (b) scientific literature describing the scale-up of breastfeeding peer counseling programs. Twenty-six peer-reviewed publications were included in this review. The overwhelming majority of evidence from randomized controlled trials evaluating breastfeeding peer counseling indicates that peer counselors effectively improve rates of breastfeeding initiation, duration, and exclusivity. Peer counseling interventions were also shown to significantly decrease the incidence of infant diarrhea and significantly increase the duration of lactational amenorrhea. Breastfeeding peer counseling initiatives are effective and can be scaled up in both developed and developing countries as part of well-coordinated national breastfeeding promotion or maternal-child health programs.


Repair of a large "coup de sabre" with soft-tissue expansion and artificial bone graft.
The authors present a case of a "coup de sabre"--a linear form of scleroderma--in an 18-year-old woman treated by means of an expanded forehead and scalp flap, a hydroxyapatite implant, and an autologous iliac bone graft. Hydroxyapatite was implanted to augment a depressive bony deformity. The nasal deformity was repaired with an expanded forehead flap and an autologous iliac bone graft. This is the first reported case in which a deformity of scleroderma was treated with a combination of an expanded skin flap and a hydroxyapatite implant.


Reduced statherin reactivity of human submandibular gland in diabetes.
Statherin is a salivary protein involved in the formation of enamel pellicle and in regulation of calcium homeostasis. Diabetes and other pathologies affect both salivary flow and protein secretion by salivary glands, causing increased susceptibility to mucosal infections, tooth demineralization, and caries. The purpose of this study was to compare the statherin expression in submandibular glands of healthy and diabetic subjects. Fragments of submandibular glands obtained from diabetic and non diabetic patients were fixed, dehydrated, embedded in Epon Resin and processed for the immunogold histochemistry. The results were statistically evaluated. Specific statherin labeling was demonstrated in secretory granules of acinar cells in both diabetic and normal samples. The staining was much more intense in the latter compared to those of diabetics. The labeling density was quantified by evaluating the number and spatial distribution of gold particles within the granules. The number of gold particles was significantly lower in glands from diabetics than in control glands. The results obtained suggest that a reduced statherin secretion by salivary glands might be partly responsible for a less effective protection of the oral tissues, resulting in an higher incidence of caries and oral infections associated with diabetes.


[Status of coronary venous blood flow in patients with ischemic heart disease in myocardial ischemia induced by the atrial stimulation test].
A total of 85 patients (68 with coronary heart disease in the presence of effort angina of various functional classes (a major group) and 17 with neurocirculatory++ dystonia and cardialgic syndrome (a control group)) were examined. Heart failure severity and blood flow distribution in the functioning myocardial areas were evaluated in transient ischemia induced by atrial pacing. Three levels of coronary venous blood flow were defined in patients with coronary heart disease. A relationship between the coronary blood flow, disease history duration, and coronary blood flow changes was examined in cardioselective exercise.


Bayesian geostatistical modelling of stunting in Rwanda: risk factors and spatially explicit residual stunting burden.
Stunting remains a significant public health issue in Rwanda and its prevalence exhibits considerable geographical variation. We apply Bayesian geostatistical modelling to study the spatial pattern of stunting in children less than five years considering anthropometric, socioeconomic and demographic risk factors in Rwanda. In addition, we predict the spatial residuals effects to quantify the burden of stunting not accounted for by our geostatistical model. We used the data from the 2015 Rwanda Demographic and Health Survey. We fitted two spatial logistic models with similar structures, only differentiated by the inclusion or exclusion of spatially structured random effects. The risk factors of stunting identified in the geostatistical model were being male (OR = 1.32, 95% CI: 1.16, 1.47), lower birthweight (kg) (OR = 0.96, 95% CI: 0.95, 0.97), non-exclusive breastfeeding (OR = 1.24, 95% CI: 1.04, 1.45), occurrence of diarrhoea in the last two weeks (OR = 1.18, 95% CI: 1.02, 1.37), a lower proportion of mothers with overweight (BMI ≥ 25) (OR = 0.82, 95% CI: 0.71, 0.95), a higher proportion of mothers with no or only primary education (OR = 1.14, 95% CI: 0.99, 1.36). Also, a higher probability of living in a house with poor flooring material (OR = 1.22, 95% CI: 1.06, 1.41), reliance on a non-improved water source (OR = 1.13, 95% CI: 1.00, 1.27), and a low wealth index were identified as risk factors of stunting. Mapping of the spatial residuals effects showed that, in particular, the Northern and Western regions, followed by the Southern region of Rwanda, still exhibit a higher risk of stunting even after accounting for all the covariates in the spatial model. Further studies are needed to identify the still unknown spatially explicit factors associated with higher risk of stunting. Finally, given the spatial heterogeneity of stunting, interventions to reduce stunting should be geographically targeted.


Compatibility between Physical Stimulus Size and Left-right Responses: Small is Left and Large is Right.
According to a theory of magnitude (ATOM, Walsh, 2003, 2015), the cognitive representations of quantity, time, and space share a general magnitude code. Interestingly though, research has largely ignored the relationship between physical (stimulus) size and spatial (response) location. We conducted two experiments investigating compatibility effects between physical stimulus size and left-right responses. In both experiments, right-handed participants responded to a small or a large square stimulus by pressing a left or a right key. In Experiment 1, size was the relevant stimulus feature and we varied the S-R mapping within participants. Results revealed a strong compatibility effect: Performance was better with the compatible mapping (small-left and large-right) than with the incompatible mapping (large-left and small-right). In Experiment 2, participants responded to stimulus color, which varied independently of stimulus size, by pressing a left or right key. Results showed a congruency effect that mirrored the compatibility effect of Experiment 1. The results of our experiments suggest a strong relationship between the cognitive representation of physical (stimulus) size and response location in right-handers. The findings support the notion of a general magnitude code, as proposed in ATOM.


Serum antibody response to active infection with Cryptococcus neoformans and its varieties in immunocompetent subjects.
Using a class-specific enzyme immunoassay IgG and IgA anticryptococcal antibody was measured in 400 serum specimens at 1 week to 11.7 years after diagnosis from 43 immunocompetent subjects with confirmed active cryptococcosis. The prevalence of IgG was 86% at diagnosis, rose to 100% by 2 weeks and remained high thereafter. IgA prevalence was 71% at diagnosis, rose to 75% at 2 weeks and then fell over 2 years. IgG and IgA prevalence in paediatric controls was 5% and 0%, respectively. Mean antibody levels showed the same pattern and neither levels nor prevalence were influenced by age, sex or site of infection. Patients with the variety gattii infection had a greater antibody response than those with the variety neoformans which was significant for IgA. Specific anticryptococcal antibody was regularly present in conjunction with cryptococcal antigen at diagnosis. IgG persists but IgA falls over 1-2 years. The assay described may be a useful tool to study the antibody response and seroepidemiology of infection with C. neoformans.


[A case of Swyer-James syndrome with interesting chest radiographs].
A 28-year-old man was admitted for further examination after overinflation of the right lung was observed on a screening chest radiograph. The chest radiograph on admission showed increased radiolucency of the left lung and overinflation of the right lung, associated with a shift of the mediastinum toward the midline on expiration. High-resolution CT on expiration showed air trapping in the left lung and in part of the right lower lobe. Pulmonary perfusion scintigraphy showed a markedly decreased perfusion in these areas. Pulmonary angiography revealed small left pulmonary arteries with diminished peripheral vascular branches. Bronchoscopy showed no abnormality of either bronchus. Swyer-James syndrome was diagnosed on the basis of these findings. Although bronchial damage due to the lower respiratory tract infection during childhood is considered a very important factor in the pathogenesis of this syndrome, many patients have no history of airway infection, as in this case. This is a rare case of Swyer-James syndrome presenting with marked overinflation of the unaffected lung in an asymptomatic adult. Progression of this compensative overinflation probably involved asymptomatic damage caused by the weakness of the affected lung.


Cardiac rehabilitation and mortality reduction after myocardial infarction: the emperor's new clothes? Evidence against cardiac rehabilitation.
No trial of cardiac rehabilitation (CR) following myocardial infarction (MI) (not even the WHO European collaborative) demonstrates significant reduction of mortality, as do trials of secondary prevention. There is potential conflict of interest when therapists report self-evaluations. Reviews of published reports exaggerate publication bias. Meta-analyses show no significant effect of CR on mortality in recent years - since 1990, 23 trials, 6527 patients, relative risk 1.01 (0.88-1.15). It does no service to MI patients - or rehabilitation therapists - to repeat claims derived from poolings of historic trials, undertaken before many significant advances in diagnosis, acute treatment and effective secondary prevention. While CR has a role in good medical/nursing practice and continuity of care, rehabilitation therapists could be more effective elsewhere in the NHS.


Assessing tomorrow's learners: in competency-based education only a radically different holistic method of assessment will work. Six things we could forget.
In this paper we are challenging six traditional notions about assessment that are unhelpful when designing 'assessment for learning'-programmes for competency-based education. We are arguing for the following: Reductionism is not the only way to assure rigour in high-stakes assessment; holistic judgements can be equally rigorous. Combining results of assessment parts only because they are of the same format (like different stations in an OSCE) is often not defensible; instead there must be a logically justifiable combination. Numbers describe the quality of the assessment. Therefore, manipulating the numbers is usually not the best way to improve its quality. Not every assessment moment needs to be a decision moment, disconnecting both makes combining summative and formative functions of assessment easier. Standardisation is not the only route to equity. Especially with diverse student groups tailoring is more equitable than standardisation. The most important element to standardise is the quality of the process and not the process itself. Finally, most assessment is too much focussed on detecting deficiencies and not on valuing individual student differences. In competency-based education--especially with a focus on learner orientation--this 'deficiency-model' is not as well aligned as a 'differences-model'.