Deterministic nonmonotone strategies for effective training of multilayer perceptrons.
We present deterministic nonmonotone learning strategies for multilayer perceptrons (MLPs), i.e., deterministic training algorithms in which error function values are allowed to increase at some epochs. To this end, we argue that the current error function value must satisfy a nonmonotone criterion with respect to the maximum error function value of the M previous epochs, and we propose a subprocedure to dynamically compute M. The nonmonotone strategy can be incorporated in any batch training algorithm and provides fast, stable, and reliable learning. Experimental results in different classes of problems show that this approach improves the convergence speed and success percentage of first-order training algorithms and alleviates the need for fine-tuning problem-depended heuristic parameters.


Cytokine gene expression in neoplastic B cells from human mantle cell, follicular, and marginal zone lymphomas and in their postulated normal counterparts.
Cytokines may promote tumor growth by paracrine and/or autocrine pathways. Little information is available because malignant cells differ from their normal counterparts for the cytokine repertoire they express. Here we have investigated by reverse transcription-PCR the expression of 22 cytokine genes in neoplastic B lymphocytes from six patients with mantle cell lymphoma, 10 with follicular lymphoma, and 5 with marginal zone lymphoma and in their normal counterparts, i.e., naive, germinal center, and memory B cells, purified from tonsils. The overall profiles of cytokine gene expression in neoplastic B cells and in the corresponding normal B-cell subsets were similar, but some "holes" in the repertoire of malignant versus normal B lymphocytes were detected. Different "hole" combinations were identified consistently in mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma, thus representing molecular fingerprints of each individual lymphoma entity.


Gender, smoking, body size, and aneurysm geometry influence the biomechanical rupture risk of abdominal aortic aneurysms as estimated by finite element analysis.
Finite element analysis (FEA) has been suggested to be superior to maximal diameter measurements in predicting rupture of abdominal aortic aneurysms (AAAs). Our objective was to investigate to what extent previously described rupture risk factors were associated with FEA-estimated rupture risk. One hundred forty-six patients with an asymptomatic AAA of a 40- to 60-mm diameter were retrospectively identified and consecutively included. The patients' computed tomography angiograms were analyzed by FEA without (neutral) and with (specific) input of patient-specific mean arterial pressure (MAP), gender, family history, and age. The maximal wall stress/wall strength ratio was described as a rupture risk equivalent diameter (RRED), which translated this ratio into an average aneurysm diameter of corresponding rupture risk. In multivariate linear regression, RREDneutral increased with female gender (3.7 mm; 95% confidence interval [CI], 0.13-7.3) and correlated with patient height (0.27 mm/cm; 95% CI, 0.11-0.43) and body surface area (BSA, 16 mm/m2; 95% CI, 8.3-24) and inversely with body mass index (BMI, -0.40 mm/kg m-2; 95% CI, -0.75 to -0.054) in a wall stress-dependent manner. Wall stress-adjusted RREDneutral was raised if the patient was currently smoking (1.1 mm; 95% CI, 0.21-1.9). Age, MAP, family history, and patient weight were unrelated to RREDneutral. In specific FEA, RREDspecific increased with female gender, MAP, family history positive for AAA, height, and BSA, whereas it was inversely related to BMI. All results were independent of aneurysm diameter. Peak wall stress and RRED correlated with aneurysm diameter and lumen volume. Female gender, current smoking, increased patient height and BSA, and low BMI were found to increase the mechanical rupture risk of AAAs. Previously described rupture risk factors may in part be explained by patient characteristic-dependent variations in aneurysm biomechanics.


Analgesic studies in osteo-arthritis.
Two studies on a total of 45 patients with chronic osteoarthritis using fenoprofen calcium are presented. Different methods using only subjective criteria (pain intensity scores and pain relief scores) are applied. Measurable analgesic qualities were demonstrated for fenoprofen, which is seen as a valuable addition to the drug therapy of osteo-arthritis.


[Retroperitoneal laparoscopic nephrectomy with autotransplantation for severe iatrogenic ureteral injury].
To evaluate the safety and efficacy of retroperitoneal laparoscopic nephrectomy with autotransplantation in cases of severe iatrogenic proximal ureteral damage. From July 2011 to March 2015, two patients, aged 44 (female) and 54 years (male), underwent retroperitoneal laparoscopic nephrectomy and autotransplantation for treatment of severe iatrogenic proximal ureteral injuries. Both injuries were proximal ureteral avulsion during ureterolithotomy with the holmium laser for ureteral calculi. computed tomography angiography (CTA) and computed tomography urography (CTU) was performed in both patients before operation. A 3-port retroperitoneal technique was used for the patients placed in a lateral decubitus position. A retroperitoneal laparoscopic nephrectomy with autotransplantation approach was used in both the patients, and the kidneys were removed to the right iliac fossa. Case 1's kidney was removed through the right Gibson incision, while Case 2's kidney was removed through the left lumbar incision. The renal artery and renal vein were ligated using the Hem-o-lok. The kidneys were taken out quickly from the patients and infused with 4 °C kidney preserving fluid immediately. The retroperitoneal laparoscopic nephrectomy with autotransplantations was performed 4 hours in Case 1 and 2 years in Case 2 after atrogenic proximal ureteral injuries. Case 2 was associated with dense perinephric and perihilar fibrosis. The procedures were successful, with immediate return of renal function in both the patients. After ex vivo graft preparation, ureteral and vessel length and quality were adequate for transplantation in both the cases. A direct ureterovesical anastomosis was performed in both patients. In the 2 patients, the warm ischemia time was 3 and 5 minutes, the total operation time 185 and 246 minutes, and the estimated blood loss 70 and 200 mL, respectively. No perioperative complications occurred. At the end of the follow-up, the transplanted kidneys were functional, and the patients had returned to their normal activity. Retroperitoneal laparoscopic nephrectomy with autotransplantation is an excellent alternative to nephrectomyor bowel interposition in patients with proximal ureteral loss. This procedure is associated with acceptable morbidity and preserves the renal function. This report supports the safety and efficacy of retroperotoneal laparoscopic nephrectomy with autotransplantation in experienced hands.


Impact of an after-hours on-call emergency physician on ambulance transports from a county jail.
The authors sought to determine if the availability of an after-hours on-call emergency physician by telephone for consultation to the staff at a county jail would safely reduce ambulance emergency department (ED) transport of inmates in the community. The authors conducted a prospective comparison study during the first ten months of an emergency physician on-call program for the county jail in which prospective data were collected on all consultations, including reason for call and disposition (ambulance, deputy, or no ED transport of inmate). They compared this time with a similar period a year before the program in terms of total ambulance transports from the jail. They also reviewed all hospital and jail medical records to assess for any adverse consequences within one month, or subsequent ambulance transport within 24 hours as a result of inmate care after the consultation call. Total after-hours ambulance transports from the jail decreased significantly from 30.3 transports/month (95% confidence interval [CI], 21.0-39.6) to 9.1 transports/month (95% CI, 4.1-14.0) (p < 0.05). The most common reasons for consultation calls were chest pain (16%), trauma (15%), and abnormal laboratory or radiology results (14%). Of all calls, only 30% resulted in ambulance transport to the ED. On review of records, no adverse outcome or subsequent ambulance transport was identified. The initiation of an on-call emergency physician program for after-hours consultation to jail nursing and law enforcement staff safely reduced ambulance transports from a county jail with no adverse outcomes identified.


Mortality from childhood stroke in England and Wales, 1921-2000.
Stroke is an important but under-recognised cause of childhood mortality. The authors aimed to describe the trends in mortality from childhood stroke in England and Wales between 1921 and 2000. The study searched the Office for National Statistics mortality database for the years 1921-2000 using appropriate, previously validated International Classification of Diseases codes. Mortality rates were analysed by period of death, gender, age at death, birth cohort and stroke subtype. 6029 deaths from childhood stroke were found between 1921 and 2000. Analysis by period of death demonstrated an initial decline in mortality followed by a steep rise in the 1940s. Subsequently, rates declined from the late 1960s onwards. At all time points males had a higher mortality rate than females. Infants had a relatively high mortality rate (24.5 per million person years) but rates fell steeply in early childhood (2.5 per million person years at age 5-9 years) before rising again in late adolescence (7.5 per million person years at age 15-19 years). An increased rate was found for males at all ages (RR = 1.24, p<0.0001) but was greatest in infancy (RR = 1.45, p<0.0001). Haemorrhagic stroke accounted for 71% of stroke deaths. Birth cohort analysis showed a trend of declining mortality with each successive generation since the 1950s. This study describes characteristics and temporal changes in childhood stroke mortality in the 20(th) century. In particular, the higher mortality rates in males and infants, the importance of deaths from haemorrhagic stroke and the finding of a decline in birth cohort mortality since the 1950s provide aetiological insights.


Factors That Influence Sustained Release from Hot-Melt Extrudates.
Hot-melt extrusion is a well-established tool in the pharmaceutical industry, mostly implemented to increase the solubility of poorly soluble drugs. A less frequent application of this technique is to obtain formulations with extended release. This study investigated the influence of polymer choice, drug loading, milling and hydrodynamics on the release of a model drug, flurbiprofen, from sustained-release hot-melt extrudates with Eudragit polymers. The choice of polymer and degree of particle size reduction of the extrudate by milling were the two key influences on the release profile: the percentage release after 12 h varied from 6% (2 mm threads) to 84% (particle size <125 µm) for Eudragit RL extrudates vs. 4.5 to 62% for the corresponding Eudragit RS extrudates. By contrast, the release profile was largely independent of drug loading and robust to hydrodynamics in the dissolution vessel. Thus, hot-melt extrusion offers the ability to tailor the release of the API to the therapeutic indication through a combination of particle size and polymer choice while providing robustness over a wide range of hydrodynamic conditions.


Effects of seasonal changes in cotton plants on the evolution of resistance to pyramided cotton producing the Bt toxins Cry1Ac and Cry1F in Helicoverpa zea.
In pests with inherently low susceptibility to Bacillus thuringiensis (Bt) toxins, seasonal declines in the concentration of Bt toxins in transgenic crops could accelerate evolution of resistance by increasing the dominance of resistance. Here, we evaluated Helicoverpa zea survival on young and old cotton plants that produced the Bt toxins Cry1Ac and Cry1F or did not produce Bt toxins. Using a strain selected for resistance to Cry1Ac in the laboratory, its parent strain that was not selected in the laboratory, and their F1 progeny, we showed that resistance to Cry1Ac + Cry1F cotton was partially dominant on young and old plants. On Cry1Ac + Cry1F cotton, redundant killing was incomplete on young plants but nearly complete on old plants. No significant fitness costs on non-Bt cotton occurred on young plants, but large recessive costs affected survival on old plants. Simulation models incorporating the empirical data showed that the seasonal changes in fitness could delay resistance to Cry1Ac + Cry1F cotton by inducing low equilibrium frequencies of resistance alleles when refuges are sufficiently large. Our results suggest that including effects of seasonal changes in fitness of pests on Bt crops and refuge plants can enhance resistance risk assessment and resistance management. © 2017 Society of Chemical Industry.


Extended Oral Antibiotic Prophylaxis in High-Risk Patients Substantially Reduces Primary Total Hip and Knee Arthroplasty 90-Day Infection Rate.
Total joint arthroplasty (TJA) episodic payment models shift risk and cost of periprosthetic joint infection (PJI) to surgeons and hospitals, causing some to avoid treating high-risk patients. Furthermore, there are little data to support optimization of host factors preoperatively to decrease PJI, and recent literature supports using extended antibiotic prophylaxis following reimplantation TJA. The purpose of this study was to evaluate whether extended oral antibiotic prophylaxis minimized PJI after primary TJA in high-risk patients. A retrospective cohort study was performed of 2,181 primary total knee arthroplasties (TKAs) and primary total hip arthroplasties (THAs) carried out from 2011 through 2016 at a suburban academic hospital with modern perioperative and infection-prevention protocols. Beginning in January 2015, extended oral antibiotic prophylaxis for 7 days after discharge was implemented for patients at high risk for PJI. The percentages of patients diagnosed with PJI within 90 days were identified and compared between groups that did and did not receive extended oral antibiotic prophylaxis, with p ≤ 0.05 indicating significance. The 90-day infection rates were 1.0% and 2.2% after the TKAs and THAs, respectively. High-risk patients without extended antibiotic prophylaxis were 4.9 (p = 0.009) and 4.0 (p = 0.037) times more likely to develop PJI after TKA and THA, respectively, than high-risk patients with extended antibiotic prophylaxis. Extended postoperative antibiotic prophylaxis led to a statistically significant and clinically meaningful reduction in the 90-day infection rate of selected patients at high risk for infection. We encourage further study and deliberation prior to adoption of a protocol involving extended oral antibiotic prophylaxis after high-risk TJA, with the benefits weighed appropriately against potential adverse consequences such as increasing the development of antimicrobial resistance. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Structurally dynamic hydrogels derived from 1,2-dithiolanes.
The design and generation of adaptable materials derived from structurally dynamic polymers provides a strategy for generating smart materials that can respond to environmental stimuli or exhibit self-healing behavior. Herein we report an expedient organocatalytic ring-opening polymerization of cyclic carbonates containing pendant dithiolanes (trimethylene carbonate/dithiolane, TMCDT) from poly(ethylene oxide) diols to generate water-soluble triblock (ABA) copolymers containing a central poly(ethylene oxide) block and terminal dithiolane blocks. Hydrogels generated from the triblock copolymers and a cross-linking dithiol exhibited dynamic behavior as a result of the reversible ring opening of the pendant 1,2-dithiolanes. These materials exhibit self-healing behavior, can be injected through a syringe, and rapidly recover their mechanical properties after a severe strain deformation. The dynamic properties of these gels can be modulated with the number of dithiolane units, pH, and temperature.


Head and Neck Tuberculosis: Scenario in a Tertiary Care Hospital of North Eastern India.
Tuberculosis has affected mankind since time immemorial and with emergence of AIDS both extrapulmonary and pulmonary tuberculosis presents increased morbidity and mortality along with an increased financial burden upon the developing nations. The study is a hospital based observational study of one year duration carried out in the Department of ENT in a tertiary care hospital of North Eastern India. Total of 63 cases were detected. Females comprised 60.3% of the study population as against 39.7% males. Most commonly affected age group were of 15 to 24 years age (57.1%). Cervical tubercular lymphadenitis was the most common lesion 90.5% (57 cases) followed by laryngeal tuberculosis 7.9% (5 cases) and tubercular otitis media with mastoiditis 1.6% (1 case). Level II lymph node was mostly affected either single or in groups (75.4%) followed by level III node (57.9%). Successful outcome of the treatment with Category I regimen was achieved in 96.8% of the cases. Head and neck tuberculosis is not an uncommon disease and though cervical lymphadenitis is the most common presentation, isolated involvement of the larynx, ear and other subsites are not an entirely unknown entity. The clinical presentation of tuberculosis of the head and neck region can be varied and often misleading. It is therefore important for the clinician to be aware of the condition and consider it in their differential diagnosis.


Molecular cloning of a cDNA encoding a potential water-borne pheromonal attractant released during Aplysia egg laying.
Recently deposited egg cordons are a source of water-borne pheromones that attract the marine mollusk Aplysia into breeding aggregations and coordinate male and female reproductive behavior within the aggregation. A potential pheromonal attractant has been isolated from egg cordon eluates and the peptide partially characterized [S.D. Painter, B. Clough, X. Fan, G.T. Nagle, Soc. Neurosci. Abstr., Vol. 22 (1996) 837]. Using this information, we have cloned an Aplysia albumen gland cDNA that encodes a precursor protein containing a single copy of the full-length peptide, and demonstrated that there are abundant levels of pheromone mRNA transcripts (0.8 and 2.5 kb) in the albumen gland. This is consistent with the reported function of the gland (i.e. packaging the eggs into a cordon for deposition), with behavioral studies showing that the albumen gland is a potential source of attractants, and more recent biochemical studies in which the full-length peptide has been isolated from the albumen gland. This is the first candidate peptide pheromone in mollusks and the first in invertebrates. The pheromonal regulatory system in Aplysia may provide a model system for examining the structural characteristics of peptide pheromones.


Hypoxia-inducible factor-1 (HIF-1).
Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1beta and an oxygen-regulated subunit HIF-1alpha (or its paralogs HIF-2alpha and HIF-3alpha). The stability and activity of the alpha subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1alpha trigger its association with pVHL E3 ligase complex, leading to HIF-1alpha degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1alpha subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.


Trust, variability in relationship evaluations, and relationship processes.
Little is known about why some people experience greater temporal fluctuations of relationship perceptions over short periods of time, or how these fluctuations within individuals are associated with relational processes that can destabilize relationships. Two studies were conducted to address these questions. In Study 1, long-term dating partners completed a 14-day diary study that assessed each partner's daily partner and relationship perceptions. Following the diary phase, each couple was videotaped trying to resolve the most important unresolved problem from the diary period. As predicted, (a) individuals who trusted their partners less reported greater variability in perceptions of relationship quality across the diary period; (b) they also perceived daily relationship-based conflict as a relatively more negative experience; and (c) greater variability in relationship perceptions predicted greater self-reported distress, more negative behavior, and less positive behavior during a postdiary conflict resolution task (rated by observers). The diary results were conceptually replicated in Study 2a, in which older cohabiting couples completed a 21-day diary. These same participants also took part in a reaction-time decision-making study (Study 2b), which revealed that individuals tend to compartmentalize positive and negative features of their partners if they (individuals) experienced greater variability in relationship quality during the 21-day diary period and were involved in higher quality relationships. These findings advance researchers' understanding of trust in intimate relationships and provide some insight into how temporal fluctuations in relationship quality may undermine relationships.


A penicillin-resistant Streptococcus pneumoniae; case report.
A strain of Streptococcus pneumoniae has been isolated from a five-month-old child with persistent otitis media. The minimum inhibitory concentration (MIC) detected was 4 micrograms/ml penicillin. This strain was possibly selected out by inadequate penicillin V therapy.


What do gay men know about human papillomavirus? Australian gay men's knowledge and experience of anal cancer screening and human papillomavirus.
The objective of this study was to determine levels of experience and knowledge concerning anal dysplasia, anal Pap smear tests, and human papillomavirus (HPV) among gay and other homosexually active men. Three hundred eighty-four men attending a large gay community event in Melbourne completed a short survey. Ninety-two percent identified as gay and 4.8% as bisexual. A total of 6.4% were HIV-positive and a further 3.5% did not know their HIV status. On a range of measures, it was clear that the men knew very little about anal cancer (19% scored zero on a 12-point knowledge scale) and virtually nothing about HPV (47% scored zero on an 8-point knowledge scale). A total of 55.1% had never heard of an anal Pap smear and 44.8% had ever heard of HPV; 56.4% did not know whether it affected men and/or women. The test for anal dysplasia is still largely unknown among Australian gay men and they currently have poor sense of personal susceptibility to the disease. Health education strategies are suggested to improve this situation.


Assays for the detection of recent infections with human immunodeficiency virus type 1.
The Serological Testing Algorithm for Recent HIV Seroconversion (STARHS) is a generic term for several laboratory techniques that can be used to differentiate recent from long standing infections with human immunodeficiency virus-1 (HIV-1). There are several other approaches that identify acute seroconverters, but STARHS methods are distinguished by their ability to identify infections that occurred during an extended period of 4-6 months prior to sampling. While the STARHS techniques have been employed on an individual basis, their main usefulness lies in the potential of estimating the rate of acquisition of new HIV infection, or incidence, in a population by application to cross-sectional sero-surveys. This is substantially simpler and less expensive than cohort studies. As such, STARHS techniques facilitate the timely monitoring of the impact on HIV incidence of factors such as interventions, demographic factors and behavioural patterns. The major STARHS techniques currently available are described. Furthermore, the principles behind the methods used are discussed and the limitations of the current assays and the confounding factors that may affect assay specificity are described. A model algorithm for the application of a STARHS assay is shown. Finally, we outline recommendations for laboratory quality systems that will improve the efficiency of STARHS testing, reproducibility of results and reliability of incidence estimates.


Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility.
The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. To compare EMP numbers in stable COPD patients with those during and after exacerbation. We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41- MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p<0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation.


The effects of cholecystokinin on the in vivo release of newly synthesized [3H]dopamine from the nucleus accumbens of the rat.
It has been reported that in the medial nucleus accumbens (NAc) there are nerve terminals which contain either the neuropeptide cholecystokinin (CCK) or the catecholamine dopamine (DA), as well as terminals which contain both. In this study, we have examined the action of CCK-peptides on the basal and potassium-evoked release of [3H]DA within this structure. The in vivo release of [3H]DA, newly synthesized from [3H]tyrosine, was measured by using the push-pull cannula perfusion technique. It appeared that a large percentage of the [3H]DA released under resting conditions was dependent upon nerve impulse activity as it was found that tetrodotoxin, absence of extracellular Ca2+, and the inhibition of DA synthesis by alpha-methyl-p-tyrosine all decreased [3H]DA release by more than 50%. In addition, the potassium-evoked release of [3H]DA was found to be almost completely dependent upon extracellular Ca2+. When sulfated CCK-octapeptide was administered into the NAc, it was found to increase the basal levels of [3H]DA released at concentrations of 2 X 10(-8) and 2 X 10(-7) M. However, at 2 X 10(-6) M there was no longer an effect by this peptide. The unsulfated form was found to have no effect at a concentration which was maximally effective for the sulfated form. In contrast to its effects on the basal release of [3H]DA, sulfated CCK-octapeptide was found to attenuate the potassium-evoked release of [3H]DA from the NAc in a concentration-dependent fashion from 2 X 10(-9) to 2 X 10(-6) M. The unsulfated form of the octapeptide had no effect on evoked release. Our results suggest that CCK acts to modulate the release of DA within the NAc in vivo in a complex manner, as it appears that the action of CCK depends not only on the concentration tested but also on the excitation state of the tissue during the testing period.


Electrical stimulation of cranial nerves in cognition and disease.
The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.


Quantum key distribution session with 16-dimensional photonic states.
The secure transfer of information is an important problem in modern telecommunications. Quantum key distribution (QKD) provides a solution to this problem by using individual quantum systems to generate correlated bits between remote parties, that can be used to extract a secret key. QKD with D-dimensional quantum channels provides security advantages that grow with increasing D. However, the vast majority of QKD implementations has been restricted to two dimensions. Here we demonstrate the feasibility of using higher dimensions for real-world quantum cryptography by performing, for the first time, a fully automated QKD session based on the BB84 protocol with 16-dimensional quantum states. Information is encoded in the single-photon transverse momentum and the required states are dynamically generated with programmable spatial light modulators. Our setup paves the way for future developments in the field of experimental high-dimensional QKD.


Human squamous cell carcinoma of the tongue and colon undergoes apoptosis upon phagocytosis of Saccharomyces cerevisiae, the baker's yeast, in vitro.
The present study was carried out to evaluate the effect of phagocytosis of killed yeast on the induction of apoptosis in two human solid tumors of the gastrointestinal (GI): the squamous cell carcinomas of the tongue (SCCA) are (SCC-4 and SCC-9) and the adenocarcinomas of the colon (ADENOCA) are (Caco-2 and DLD-1). Cancer cells were cultured with heat killed Saccharomyces cerevisiae, baker's and brewer's yeast, at ratio of yeast to cancer cells = 10:1. The percentage of tumor cells that had attached/phagocytosed yeast and oxidative burst was determined by using oxidative sensitive dye (DCFH-DA) and flow cytometry. SCC-4 and colon Caco-2 cells demonstrated initial high levels of phagocytosis that peaked (35.8-52.8%) at 2 hr. The oral SCC-9 and colon DLD-1 cells demonstrated low phagocytic activity (7-12%). Phagocytosis was not associated with oxidative burst. Upon phagocytosis of yeast, cancer cells underwent apoptosis that was maximized at 4 hr. Yeast-induced apoptosis was significant in SCC-4 (45%), as compared with SCC-9 cells (17%), and Caco-2 (76%), as compared with DLD cells (12%). Apoptosis in cancer cells was inhibited by caspase inhibitor, Z-VAD-FMK; this suggests that caspases may be involved in apoptosis of the GI cancers. This data may have clinical implications for the treatment of solid tumors.


A metabolomics investigation into the effects of HIV protease inhibitors on HPV16 E6 expressing cervical carcinoma cells.
Recently, it has been reported that anti-viral drugs, such as indinavir and lopinavir (originally targeted for HIV), also inhibit E6-mediated proteasomal degradation of mutant p53 in E6-transfected C33A cells. In order to understand more about the mode-of-action(s) of these drugs the metabolome of HPV16 E6 expressing cervical carcinoma cell lines was investigated using mass spectrometry (MS)-based metabolic profiling. The metabolite profiling of C33A parent and E6-transfected cells exposed to these two anti-viral drugs was performed by ultra performance liquid chromatography (UPLC)-MS and gas chromatography (GC)-time of flight (TOF)-MS. Using a combination of univariate and multivariate analyses, these metabolic profiles were investigated for analytical and biological reproducibility and to discover key metabolite differences elicited during anti-viral drug challenge. This approach revealed both distinct and common effects of these two drugs on the metabolome of two different cell lines. Finally, intracellular drug levels were quantified, which suggested in the case of lopinavir that increased activity of membrane transporters may contribute to the drug sensitivity of HPV infected cells.


[Investigation of the presence of Blastocystis spp. in stool samples with microscopic, culture and molecular methods].
Blastocystis species are enteric protozoa frequently detected in human and animals. Seventeen subtypes (STs) have now been identified, nine of them isolating from humans. The pleomorphic structure and genetic diversity of Blastocystis spp. and the absence of standardized diagnostic methods complicate the evaluation of current data. Microscopic methods such as native-lugol and trichrome staining are most frequently used methods in routine diagnosis, while culture and molecular methods are preferred for research purposes. The aims of this study were to investigate the presence of Blastocystis spp. in the stool samples of patients with gastrointestinal complaints by microscopic and culture methods, and to detect the subtypes of isolates by polymerase chain reaction (PCR). A total of 350 stool samples collected from patients with diarrhea (n= 157) and without diarrhea (n= 193) were included in the study. Presence of Blastocystis spp. in the samples were investigated by native-lugol examination, trichrome staining and direct fluorescent antibody (DFA) methods. Ringer's solution containing 10% horse serum and 0.05% asparagine was used for cultivation. The cultures were evaluated after 3-4 days of incubation at 37°C by microscopic examination. The subtypes of Blastocystis spp. strains isolated from the cultures have been identified by PCR using sequence-tagged site primers. A total of 66 (19%) stool samples, of them 26 (16.6%) were from diarrheal and 40 (21%) from non-diarrheal cases, yielded Blastocystis sp. growth in culture. Among the evaluated samples, 12% (42/350) were found positive with native-lugol examination, 17% (58/350) with trichrome staining, and 19% (66/350) with DFA method. The agreement of culture and native-lugol method was estimated as strong (κ= 0.752), while it was very strong between culture with trichrome staining and DFA methods (κ= 0.922 and κ= 1.00, respectively). When the culture was accepted as reference method, the sensitivity and specificity rates of native-lugol method were 65% and 100%, trichrome staining method were 88% and 100%, and DFA method were 100% and 100%, respectively. Forty-three (65%) of Blastocystis spp. positive samples were subtyped by PCR, while 23 isolates could not be subtyped. The most frequent detected subtype was ST3 (12/43; 28%), followed by ST1 (6/43; 13.9%), ST4 (5/43; 11.6%) and ST7 (5/43; 11.6%), ST2 (3/43; 7%) and ST6 (1/43; 2.3%). ST5 was not detected in this study and 11 (25.6%) samples have been identified to have mixed subtypes. The differences of Blastocystis spp. positivity rates and the distribution of the subtypes between the patients with or without diarrhea were not found statistically significant (p> 0.05). In our study, ST3 was the most frequently identified Blastocystis spp. subtype, similar to the previous national studies, however ST6 and ST7 have been identified for the first time. In conclusion, as the sensitivity of native-lugol examination is low, culture is time-consuming and laborious and PCR methods are costly and non-standardized, rapid, practical and high sensitive DFA is considered as the favourable method in the diagnosis of Blastocystis spp. in routine laboratories.


Humour as experienced by patients and nurses in aged nursing in Finland.
Humour is an integral part of everyday life and therefore a component of the care and treatment of elderly patients in the modern health care. This article deals with the role of humour in aged nursing from the perspective of the nursing home residents. It also describes some preliminary results of our study on the meaning of humour to professional nurses. The chief motivation for the study is to provide a deeper understanding of humour as a part of aged nursing and as a 'phenomenon', which should also help us in the continuing challenge to improve the quality of nursing care. In this study the qualitative approach was used because the focus of interest was on an issue that has received only little attention in earlier research. The research material consists of data from patients and nurses. The data were collected via interviews and essay-type responses. The data obtained were analysed using the qualitative method of content analysis. In the light of our findings here, humour can be described as a joie de vivre which manifests itself in human interaction in the form of fun, jocularity and laughter. The assumption is supported by earlier research results which indicated that humour is an individual and personal matter and, in aged nursing care it is also very much a context-bound phenomenon. Humour makes it easier for some of the elderly patients to experience a positive, human relationship with the nurse. According to the results it seems to us that research should be continued and intensified into the role and use of humour in elderly people's everyday life and particularly in gerontological nursing care.


Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals.
Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered as a main component of the treatment protocols for a variety of inflammation and immune-mediated diseases besides its use as adjuvant to several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies. The current work aimed at investigating the potential protective effect of CAPE against GIO in vivo with emphasis on the modulation of oxidative status and receptor activator of NF-kB ligand (RANKL)/osteoprotegrin (OPG) signaling. The results showed that CAPE opposed dexamethasone (DEX)-mediated alterations in bone histology and tartarate-resistant acid phosphatase (TRAP) activity. In addition, CAPE restored oxidative balance, Runt-related transcription factor 2 (RunX2) expression and reduced caspase-3 activity in femur tissues. Co-administration of CAPE with DEX normalized RANKL/OPG ratio and Akt activation indicating a reduction in DEX-osteoclastogenesis. In conclusion, concurrent treatment of CAPE with DEX exhibited promising effects in the protection against DEX-induced osteoporosis through opposing osteoclastogenesis and protecting osteoblasts. The potent antioxidant activity of CAPE is, at least in part, involved in its anti-apoptotic effects and modulation of RunX2 and RANKL/OPG signals. The use of CAPE-enriched propolis formulas is strongly recommended for patients on chronic glucocorticoid therapy to help in the attenuation of GIO.


Administration of recombinant human IL11 after supralethal radiation exposure promotes survival in mice: interactive effect with thrombopoietin.
In the present study, we evaluated the therapeutic potential of recombinant human IL11 in lethally irradiated C57BL6/J mice exposed to gamma rays. IL11 administered for 5 consecutive days beginning 2 h after total-body irradiation with 8 or 9 Gy 60Co gamma rays resulted in a significant increase in 30-day survival. When IL11 was administered, only a slight improvement in the hematopoietic status (both blood cell counts and progenitor cells) was observed after an 8-Gy exposure, and no improvement in hematopoietic reconstitution was observed after 9 Gy total-body irradiation. The enhancement of fibrinogen in the plasma of irradiated animals suggested the importance of infections in the death of animals. IL11 was able to limit the increase in fibrinogen levels. However, prevention of bacterial infections by antibiotic treatment, although it delayed death, was ineffective in promoting survival either in placebo-treated and IL11-treated mice. IL11 was administered along with thrombopoietin (TPO) or bone marrow transplantation to limit the hematopoietic syndrome, in addition to antibiotic treatment. When IL11 was combined with TPO, a potent stimulator of hematopoiesis, the survival of animals which had been irradiated with 10 Gy 137Cs gamma rays was increased significantly compared to those treated with IL11 or TPO alone. Furthermore, an interactive effect of TPO and IL11 on hematopoietic reconstitution was observed. Similarly, IL11 in combination with bone marrow transplantation enhanced survival after 15 Gy 137Cs gamma rays. These data suggest that the effect of IL11 on the hematopoietic system is only moderate when it is used alone in supralethally irradiated mice but that the effect is improved in the presence of a hematopoietic growth factor or bone marrow transplantation.


Effects of a Program for Improving Biomechanical Characteristics During Walking and Running in Children Who Are Obese.
To investigate the influence of a weight-reduction program with locomotion-emphasis on improving biomechanical characteristics of children who are obese (OW). Ten children who are OW participated in a 6-month multidisciplinary childhood obesity management program (GRP1); another 10 children who are OW participated in the same multidisciplinary childhood obesity management program with additional locomotion-emphasis exercises for improving biomechanical characteristics (GRP2); and 10 control children who are OW with no intervention program. Outcomes were anthropometric measurements and temporal and foot pressure parameters. GRP2 had significantly improved foot pressure in the different walking/running speeds compared with GRP1. In the temporal parameters, pretests by speed by group interactions were significantly improved for GRP2 compared with GRP1. We found evidence to support beneficial effects of combined dietary and physical activity/locomotion-emphasis exercises on the movement characteristics of children who are OW.


Carbon multicharged ion generation from laser-spark ion source.
Multicharged carbon ions are generated by using a laser-assisted spark-discharge ion source. A Q-switched Nd:YAG laser pulse (1064 nm, 7 ns, ≤ 4.5 × 109 W/cm2) focused onto the surface of a glassy carbon target results in its ablation. The spark-discharge (∼1.2 J energy, ∼1 µs duration) is initiated along the direction of the plume propagation between the target surface and a grounded mesh that is parallel to the target surface. Ions emitted from the laser-spark plasma are detected by their time-of-flight using a Faraday cup. The ion energy-to-charge ratio is analyzed by a three-mesh retarding field analyzer. In one set of experiments, the laser plasma is generated by target ablation using a 50 mJ laser pulse. In another set of experiments, ∼1.2 J spark-discharge energy is coupled to the expanding plasma to increase the plasma density and temperature that results in the generation of carbon multicharged ions up to C6+. A delay-generator is used to control the time delay between the laser pulse and the thyratron trigger. Ion generation from a laser pulse when a high DC voltage is applied to the target is compared to that when a spark-discharge with an equivalent pulsed voltage is applied to the target. The laser-coupled spark-discharge (7 kV peak voltage, 810 A peak current) increases the maximum detected ion charge state from C4+ to C6+, accompanied by an increase in the ion yield by a factor of ∼6 compared to applying 7.0 kV DC voltage to the target.


An improved source of spin-polarized electrons based on spin exchange in optically pumped rubidium vapor.
We have improved a polarized electron source in which unpolarized electrons undergo collisions with a mixture of buffer gas molecules and optically spin-polarized Rb atoms. With a nitrogen buffer gas, the source reliably provides spin polarization between 15% and 25% with beam currents >4 μA. Vacuum pump upgrades mitigate problems caused by denatured diffusion pump oil, leading to longer run times. A new differential pumping scheme allows the use of higher buffer gas pressures up to 800 mTorr. With a new optics layout, the Rb polarization is continuously monitored by a probe laser and improved pump laser power provides more constant high polarization. We have implemented an einzel lens to better control the energy of the electrons delivered to the target chamber and to preferentially select electron populations of higher polarization. The source is designed for studies of biologically relevant chiral molecule samples, which can poison photoemission-based GaAs polarized electron sources at very low partial pressures. It operates adjacent to a target chamber that rises to pressures as high as 10-4 Torr and has been implemented in a first experiment with chiral cysteine targets.


Prevalence And Characteristics Of Surprise Out-Of-Network Bills From Professionals In Ambulatory Surgery Centers.
Patients treated at in-network facilities can involuntarily receive services from out-of-network providers, which may result in "surprise bills." While several studies report the surprise billing prevalence in emergency department and inpatient settings, none document the prevalence in ambulatory surgery centers (ASCs). The extent to which health plans pay a portion or all of out-of-network providers' bills in these situations is also unexplored. We analyzed 4.2 million ASC-based episodes of care in 2014-17, involving 3.3 million patients enrolled in UnitedHealth Group, Humana, and Aetna commercial plans. One in ten ASC episodes involved out-of-network ancillary providers at in-network ASC facilities. Insurers paid providers' full billed charges in 24 percent of the cases, leaving no balance to bill patients. After we accounted for insurer payment, we found that there were potential surprise bills in 8 percent of the episodes at in-network ASCs. The average balance per episode increased by 81 percent, from $819 in 2014 to $1,483 in 2017. Anesthesiologists (44 percent), certified registered nurse anesthetists (25 percent), and independent laboratories (10 percent) generated most potential surprise bills. There is a need for federal policy to expand protection from surprise bills to patients enrolled in all commercial insurance plans.


Mycosis fungoides with unusual vitiligo-like presentation.
Mycosis fungoides (MF), the commonest variant of primary cutaneous T cell lymphoma (CTCL), is relatively uncommon among the Asians. Hypopigmented mycosis fungoides is a rare variant usually observed in dark-skinned individuals, especially children. Hypopigmented MF usually responds well to therapy, particularly to PUVA, and has a comparatively benign course. Mycosis fungoides in a 16-year-old boy, with extensive asymptomatic hypopigmented lesions developing gradually all over the body over eight years and vitiligo-like skin lesions developing for seven years, with no systemic features, is presented for its unusual clinical features and conspicuous histopathological findings of prominent epidermotropism. The case showed fairly good response to PUVASOL therapy.


Pressor response to vasopressin and impaired baroreflex function in DOC-salt hypertension.
Baroreflexes and pressor responses to intravenous arginine vasopressin (AVP) and phenylephrine (PE) were evaluated in conscious, less severely hypertensive desoxycorticosterone (DOC)-salt-treated rats, hypertensive DOC-salt-treated rats, and control rats (n = 6, each group). Pressor responses were retested after ganglionic blockade. In control rats pressor responses to AVP were augmented more than those to PE after ganglion blockade; thus AVP appeared uniquely to augment baroreflex buffering. In hypertensive DOC-salt-treated rats baroreflexes were impaired (P less than 0.05); pressor responsiveness to AVP was augmented compared with control rats (P less than 0.05). After ganglion blockade augumentation of pressor responses was similar for AVP and PE. In less severely hypertensive rats baroreflexes were normal; pressor responses to AVP and PE were like those in control rats before and after ganglion blockade. These results suggest that AVP augments baroreflex buffering, which imposes a restraint on pressor effects of AVP that is not evident with PE. In hypertensive DOC-salt-treated rats a defect in baroreflex buffering during infusion of AVP may contribute to augmented pressor effects of AVP.


Group membership moderates the process of making trust judgments based on facial cues.
Trust is a foundation of interpersonal communication. Faces have a significant impact on trust judgments, and separate research demonstrates that group membership also influences trust judgments. However, it remains unclear whether and how group membership moderates the effect of face trustworthiness on trust judgments and investment decisions. In the present research, two experiments were conducted to explore the moderating effect of group membership (i.e., in-group vs. out-group) on perceptions of facial trustworthiness and trust judgments. Results showed that participants invested significantly more money on trials with trustworthy faces than trials with untrustworthy faces. Additionally, there was a significant interaction between group membership and facial trustworthiness; the investment difference between trustworthy faces and untrustworthy faces was greater for trials with in-group member faces than out-group member faces. These findings indicate that top-down and bottom-up cues jointly influence behavioral decisions.


Metagenome-assembled genomes from High Arctic glaciers highlight the vulnerability of glacier-associated microbiota and their activities to habitat loss.
The rapid warming of the Arctic is threatening the demise of its glaciers and their associated ecosystems. Therefore, there is an urgent need to explore and understand the diversity of genomes resident within glacial ecosystems endangered by human-induced climate change. In this study we use genome-resolved metagenomics to explore the taxonomic and functional diversity of different habitats within glacier-occupied catchments. Comparing different habitats within such catchments offers a natural experiment for understanding the effects of changing habitat extent or even loss upon Arctic microbiota. Through binning and annotation of metagenome-assembled genomes (MAGs) we describe the spatial differences in taxon distribution and their implications for glacier-associated biogeochemical cycling. Multiple taxa associated with carbon cycling included organisms with the potential for carbon monoxide oxidation. Meanwhile, nitrogen fixation was mediated by a single taxon, although diverse taxa contribute to other nitrogen conversions. Genes for sulphur oxidation were prevalent within MAGs implying the potential capacity for sulphur cycling. Finally, we focused on cyanobacterial MAGs, and those within cryoconite, a biodiverse microbe-mineral granular aggregate responsible for darkening glacier surfaces. Although the metagenome-assembled genome of Phormidesmis priestleyi, the cyanobacterium responsible for forming Arctic cryoconite was represented with high coverage, evidence for the biosynthesis of multiple vitamins and co-factors was absent from its MAG. Our results indicate the potential for cross-feeding to sustain P. priestleyi within granular cryoconite. Taken together, genome-resolved metagenomics reveals the vulnerability of glacier-associated microbiota to the deletion of glacial habitats through the rapid warming of the Arctic.


Total synthesis of clavepictines A and B and pictamine.
[Structure: see text] A short route for assembling clavepictines A and B and pictamine is described, which features elaboration of its trisubstituted piperidine moiety via condensation of a beta-keto sulfone with an l-alanine-derived bromide and subsequent alkylative cyclization and construction of its quinolizidine skeleton via a diastereoselective intramolecular conjugate addition. The possible stereochemical course for this conjugate addition is discussed.


Stigma and its associations with medication adherence in major depressive disorder.
This study sought to evaluate internalized stigma (IS) and perceived stigma (PS), in persons (n = 522) living with major depressive disorder (MDD), with a view to analyzing the association of IS and PS with medication adherence in a cohort of participants with MDD in China. Perceived stigma is the awareness of societal negative views and attitudes towards depression, and IS is applying others' attitudes to oneself, both measured by the Depression Stigma Scale (DSS). Medication adherence was assessed using the Medication Adherence Rating Scale (MARS). We observed that 76.0 % of participants reported IS and 84.5 % reported PS. Factors associated with increased IS included older age, marital status, disease history, and a higher baseline Patient Health Questionnaire-9 (PHQ-9). Higher education level, family income, and scores on the Connor-Davidson Resilience Scale (CD-RISC) were associated with lower levels of IS. Higher education levels, Childhood Trauma Questionnaire (CTQ) scores, and living with others were also associated with higher PS, while engagement in exercise and higher number of prior episodes were associated with lower PS. IS had a negative association with medication adherence, whereas PS did not significantly associate with adherence. In conclusion, a testable hypothesis is derived from our data that strategies targeting IS amongst persons with MDD may improve overall rates of adherence to antidepressant treatment, a necessary prelude to improving recovery.


Integration and transcription of human papillomavirus type 16 and 18 sequences in cell lines derived from cervical carcinomas.
Five cell lines, SKG-I, SKG-II, SKG-IIIb, QG-U and QG-H derived from cervical carcinomas of Japanese patients, were examined for the presence of human papillomavirus (HPV) DNA and the expression of viral mRNA. The DNA of HPV type 16 was shown to be linked covalently with SKG-IIb, QG-U and QG-H cell DNA, and HPV 18 DNA with SKG-I and SKG-II cell DNA. Although different regions of the HPV genome were integrated in these cell lines, the non-coding region and an early region including the E6 and E7 open reading frames (ORFs) were conserved in all cell lines. The complete genome of HPV 16 was found in QG-H cells by digestion of the DNA with a single-cut restriction enzyme. The other early region ORFs E1, E2, E4 and E5 were interrupted by flanking host cell DNA, suggesting that the integration into host cell DNA occurs preferentially in this region. HPV-specific mRNA species were detected in all five cell lines. In the three cell lines containing the HPV 16 genome, mRNAs hybridized with the early region of the genome, covering the entire E6 and E7 ORFs and a minor part of the E1 ORF, although the amount and size of the major mRNAs varied in these cell lines. These mRNAs did not hybridize with the late region of the HPV genome containing the L1 and L2 ORFs. In SKG-II, SKG-IIIb and QG-H cells we also detected c-myc and c-Ha-ras mRNA expression at about nine times the level of that in normal cells.


Sarcomere length-joint angle relationships of seven frog hindlimb muscles.
The sarcomere length-joint angle relationship was measured in 7 different muscle-joint complexes (n = 43 muscles) of the frog hindlimb (Rana pipiens). Muscles studied included the cruralis, iliacus internus, gastrocnemius, gluteus magnus, gracilis major, semimembranosus and the semitendinosus. Muscle-joint complexes were mounted in a jig and submerged in chilled Ringer's solution. Joints were rotated throughout their range of motion, while sarcomere length was measured by laser diffraction. Muscles were then formalin fixed and architectural properties determined by microdissection of individual muscle fibers. Sarcomere length change per degree of joint rotation (dLs/d theta) ranged from a low of 3.7 nm/degree for the cruralis muscle acting at the knee to a high of 12.5 nm/degree for the semitendinosus muscle acting at the hip. Values for dLs/d theta were significantly different between all muscles (p < 0.001), and dLs/d theta values for muscles acting at the hip were significantly greater than those for muscles acting at the knee (p < 0.005). dLs/d theta was negatively correlated with fiber length, suggesting a balance between fiber length and moment arm in most muscle-joint systems. However, many exceptions to this generalization were noted. These data suggest that different muscle-joint systems are 'designed' for differential contribution of muscle force production to the joint torque profile. The low variability of these data also suggests that sarcomere number is tightly regulated in these muscle-joint systems but not simply as a result of the total in vivo muscle excursion.


Effects of ballistic training on preseason preparation of elite volleyball players.
The purpose of this study was to determine whether ballistic resistance training would increase the vertical jump (VJ) performance of already highly trained jump athletes. Sixteen male volleyball players from a NCAA Division I team participated in the study. A Vertec was used to measure standing vertical jump and reach (SJR) and jump and reach from a three-step approach (AJR). Several types of vertical jump tests were also performed on a Plyometric Power System and a forceplate to measure force, velocity, and power production during vertical jumping. The subjects completed the tests and were then randomly divided into two groups, control and treatment. All subjects completed the usual preseason volleyball on-court training combined with a resistance training program. In addition, the treatment group completed 8 wk of squat jump training while the control group completed squat and leg press exercises at a 6RM load. Both groups were retested at the completion of the training period. The treatment group produced a significant increase in both SJR and AJR of 5.9+/-3.1% and 6.3+/-5.1%. respectively. These increases were significantly greater than the pre- to postchanges produced by the control group, which were not significant for either jump. Analysis of the data from the various other jump tests suggested increased overall force output during jumping, and in particular increased rate of force development were the main contributors to the increased jump height. These results lend support to the effectiveness of ballistic resistance training for improving vertical jump performance in elite jump athletes.


Two Myxozoans from the Urinary Tract of Topsmelt, Atherinops affinis.
Two myxozoan species were observed in the kidney of topsmelt, Atherinops affinis , during a survey of parasites of estuarine fishes in the Carpinteria Salt Marsh Reserve, California. Fish collected on 3 dates in 2012 and 2013 were sectioned and examined histologically. Large extrasporogonic stages occurred in the renal interstitium of several fish from the first 2 collections (5/8, 11/20, respectively) and, in some fish, these replaced over 80% of the kidney. In addition, presporogonic and polysporogonic stages occurred in the lumen of the renal tubules, collecting ducts, and mesonephric ducts. The latter contained subspherical spores with up to 4 polar capsules, consistent with the genus Chloromyxum. For the third collection (15 May 2013, n = 30), we portioned kidneys for examination by histology, wet mount, and DNA extraction for small subunit ribosomal (SSU rDNA) gene sequencing. Histology showed the large extrasporogonic forms in the kidney interstitium of 3 fish and showed 2 other fish with subspherical myxospores in the lumen of the renal tubules with smooth valves and 2 spherical polar capsules consistent with the genus Sphaerospora. Chloromyxum-type myxospores were observed in the renal tubules of 1 fish by wet mount. Sequencing of the kidney tissue from this fish yielded a partial SSU rDNA sequence of 1,769 base pairs (bp). Phylogenetic reconstruction suggested this organism to be a novel species of Chloromyxum, most similar to Chloromyxum careni (84% similarity). In addition, subspherical myxospores with smooth valves and 2 spherical polar capsules consistent with the genus Sphaerospora were observed in wet mounts of 2 fish. Sequencing of the kidney tissue from 1 fish yielded a partial SSU rDNA sequence of 1,937 bp. Phylogenetic reconstruction suggests this organism to be a novel species of Sphaerospora most closely related to Sphaerospora epinepheli (93%). We conclude that these organisms represent novel species of the genera Chloromyxum and Sphaerospora based on host, location, and SSU rDNA sequence. We further conclude that the formation of large, histozoic extrasporogonic stages in the renal interstitium represents developmental stages of Chloromyxum species for the following reasons: (1) Large extrasporogonic stages were only observed in fish with Chloromyxum-type spores developing within the renal tubules, (2) a DNA sequence consistent with the Chloromyxum sp. was only detected in fish with the large extrasporogonic stages, and (3) several Sphaerospora species have extrasporogonic forms, but they are considerably smaller and are composed of far fewer cells.


Marine-Derived Compounds with Anti-Alzheimer's Disease Activities.
Alzheimer's disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to perform simple tasks. As the aging population continues to increase exponentially, AD has become a big concern for society. Therefore, neuroprotective compounds are in the spotlight, as a means to tackle this problem. On the other hand, since it is believed-in many cultures-that marine organisms in an individual diet cannot only improve brain functioning, but also slow down its dysfunction, many researchers have focused on identifying neuroprotective compounds from marine resources. The fact that the marine environment is a rich source of structurally unique and biologically and pharmacologically active compounds, with unprecedented mechanisms of action, marine macroorganisms, such as tunicates, corals, sponges, algae, as well as microorganisms, such as marine-derived bacteria, actinomycetes, and fungi, have been the target sources of these compounds. Therefore, this literature review summarizes and categorizes various classes of marine-derived compounds that are able to inhibit key enzymes involved in AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE-1), and different kinases, together with the related pathways involved in the pathogenesis of AD. The compounds discussed herein are emerging as promising anti-AD activities for further in-depth in vitro and in vivo investigations, to gain more insight of their mechanisms of action and for the development of potential anti-AD drug leads.


Mechanisms that regulate peripheral immune responses to control organ-specific autoimmunity.
The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self-proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals, one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This paper will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T-cell effector responses and the development of organ-specific autoimmune diseases such as type 1 diabetes.


Effects of captopril and enalapril on sodium excretion and blood pressure in sodium-deficient dogs.
Inhibition of angiotensin I-converting enzyme (ACE) (kininase II) provides a powerful new method for evaluating the role of the renin-angiotensin-aldosterone and kallikrein-kinin systems in the control of aldosterone secretion, renal function, and arterial blood pressure. This study compares the effects of long-term administration of a sulfhydryl inhibitor, captopril, with a nonsulfhydryl inhibitor, enalapril (1-[N-[1-(ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline), in conscious sodium-deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (UNaV), arterial pressure (AP), blood kinins (BK), urinary kinins (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of ACE in sodium-deficient dogs. In response to captopril administration (20 mg/(kg . day], PAC decreased from 38.9 +/- 6.7 to 14.3 +/- 2.3 ng/dl, PRA increased from 3.58 +/- 0.53 to 13.7 +/- 1.6 ng/(ml . h), UNaV increased from 0.65 +/- 0.27 to 6.4 +/- 1.2 meq/day, AP decreased from 102 +/- 3 to 65 +/- 2 mm Hg, BK increased from 0.17 +/- 0.02 to 0.41 +/- 0.04 ng/ml, UK increased from 7.2 +/- 1.5 to 31.4 +/- 3.2 micrograms/day, and UKA decreased from 23.6 +/- 3.1 to 5.3 +/- 1.2 EU/day. Quantitatively similar changes in AP, UNaV, and PAC were observed in sodium-deficient dogs in response to long-term enalapril administration (4 mg/(kg X day]. In sodium-deficient dogs maintained on captopril or enalapril for several days, angiotensin II (AngII) infusion (3 ng/(kg X min] restored PAC, UNaV, and AP to levels observed in untreated sodium-deficient dogs. These data indicate that the long-term hypotensive and natriuretic actions of inhibitors of ACE are mediated by inhibition of AngII formation and that the renin-angiotensin system plays an essential role in regulating aldosterone secretion, renal function, and AP during sodium deficiency.


Midfrontal theta oscillation encodes haptic delay.
Haptic technologies aim to simulate tactile or kinesthetic interactions with a physical or virtual environment in order to enhance user experience and/or performance. However, due to stringent communication and computational needs, the user experience is influenced by delayed haptic feedback. While delayed feedback is well understood in the visual and auditory modalities, little research has systematically examined the neural correlates associated with delayed haptic feedback. In this paper, we used electroencephalography (EEG) to study sensory and cognitive neural correlates caused by haptic delay during passive and active tasks performed using a haptic device and a computer screen. Results revealed that theta power oscillation was significantly higher at the midfrontal cortex under the presence of haptic delay. Sensory correlates represented by beta rebound were found to be similar in the passive task and different in the active task under the delayed and synchronous conditions. Additionally, the event related potential (ERP) P200 component is modulated under the haptic delay condition during the passive task. The P200 amplitude significantly reduced in the last 20% of trials during the passive task and in the absence of haptic delay. Results suggest that haptic delay could be associated with increased cognitive control processes including multi-sensory divided attention followed by conflict detection and resolution with an earlier detection during the active task. Additionally, haptic delay tends to generate greater perceptual attention that does not significantly decay across trials during the passive task.


[Serological typing of HLA].
Micro-lymphocyte cytotoxicity test (LCT) have been developed by Dr. Terasaki at 1964 and usually used for serological typing up to date. HLA typing has been complicated by the extensive diversity of and the sequence homology among HLA alleles. However, it is need to match HLA types between donor and patient for hematopoietic stem/progenitor cell transplantation, therefore accurate HLA typing is required. Recently, it is able to perform accurate lymphocyte separation and HLA typing of much blood samples by using immunomagnetic beads and computer analysis, respectively.


Granulosa cell tumors of the ovary: the clinical value of serum inhibin A and B levels in a large single center cohort.
In patients with a granulosa cell tumor of the ovary, the value of serum inhibin A and B concentrations for the assessment of disease status was investigated. In 30 consecutive patients with a stage I-III granulosa cell tumor, inhibin A and B concentrations were measured in pre- and post-treatment serum samples. Clinical data concerning diagnosis, treatment and follow-up of these patients were related to serum inhibin A and B concentrations. Serum samples from 41 premenopausal females with cervical dysplasia served as controls. In 30 patients, 13 (43%) recurrences were observed during a median follow-up of 10 years (range 1-31 years). Serum inhibin A and B concentrations were elevated in respectively 67% and 89% of the patients at diagnosis, and in 58% and 85% at recurrence. Inhibin A and B concentrations were normal in all controls. Sensitivity of inhibin A testing for the diagnosis of granulosa cell tumor was 67% with a specificity of 100%, compared to 89% and 100% respectively for inhibin B (ns). Elevations in serum inhibin B concentrations predated recurrences by a median of 11 months. None of the patients in remission showed increased concentrations of inhibin A and B. Inhibin B seems to be the predominant form of inhibin secreted by granulosa cell tumors and appears to reflect disease status more accurately than inhibin A. Measurement of serum inhibin B concentrations may be preferred for the follow-up of granulosa cell tumors.


Laparoscopic vs. Transabdominal Treatment for Overflow Fecal Incontinence Due to Residual Aganglionosis or Transition Zone Pathology in Hirschsprung's Disease Reoperation.
Objective: The aim of this study was to describe the details of laparoscopic-assisted reoperative surgery for Hirschsprung's disease (HSCR) with overflow fecal incontinence, and to retrospectively compare laparoscopic-assisted surgery with transabdominal pull-through surgery. Methods: We retrospectively analyzed patients with HSCR with overflow fecal incontinence after the initial surgery in our center between January 2002 and December 2018. Pre-operative, peri-operative, and post-operative data were recorded for statistical analysis. Results: Thirty patients with overflow fecal incontinence after initial megacolon surgery [17 who underwent transanal pull-through (TA-PT) and 13 who underwent laparoscopic-assisted pull-through (LA-PT)] required a secondary surgery [reoperation with LA-PT (LAR-PT) (n = 16) or reoperation with transabdominal pull-through (TR-PT) (n = 14)]. Indications for reoperation were residual aganglionosis (RA) (7/30, 23.3%) or transition zone pathology (TZP) (23/17, 76.7%). Blood loss was significantly decreased in the LAR-PT group (75 ± 29.2 ml) compared to the TR-PT group (190 ± 51.4 ml) (P = 0.001). The length of hospital stay was significantly shorter in the LAR-PT group (10 ± 1.5 days) than that in the TR-PT group (13 ± 2.4 days). No significant differences were found between two groups in surgical methods, defecation function score, or post-operative complications except for wound infection (LAR-PT vs. TR-PT 0 vs. 28.6%, P < 0.05). Conclusions: It is necessary to make a comprehensive analysis of the causes of fecal incontinence after HSCR surgery and make an accurate judgment using appropriate methods. If a reoperation was inevitable for patients with overflow fecal incontinence due to RA or TZP, a comprehensive evaluation prior to the operation is required to maximize the benefit from reoperation. Although laparoscopic reoperation with heart-shaped anastomosis was safe and feasible for patients with failed initial Soave technique, unnecessary reoperation should be avoided as much as possible.


Adsorbed soluble [3H]elastin as substrate for proteinase activity. A new microassay technique.
A microassay for elastase activity has been designed. Microtubes are coated with soluble elastin substrate by passive adsorption to the tube walls. On contact with enzymes in test samples, radioactivity is released into the sample buffer, which is then transferred to vials containing scintillation fluid without further processing. Porcine pancreatic elastase (EC 22.214.171.124) is easily detected in concentrations down to 8 micrograms/litre. The interassay coefficient of variation (CV) was below 10% for values above 50 micrograms/litre. The assay is rapid, precise, economical and sensitive.


Neck pain among fighter pilots after the introduction of the JHMCS helmet and NVG in their environment.
Neck pain is a common complaint among fighter pilots. With implementation of the joint helmet mounted cuing system (JHMCS), the strain on the pilot's neck has increased. We surveyed 58 F-16 pilots from the Royal Danish Air Force by anonymous questionnaires. More than half of these pilots used JHMCS regularly. The response rate was 100%. Of the pilots, 97% experienced neck pain in flight or shortly after flying, 83% within the last year. Right side neck pain was significantly more frequent than left side, odds ratio 3.25. There was a strong tendency toward predominant right-sided shoulder pain. The pilots reported that combined rotation and extension movements were especially hazardous. Only 1 in 10 pilots moved his head independent of G-load. Neck pain influenced operational flying, especially the ability to perform a "check six" movement sufficiently, and affected flying with high G loads as occurs in basic fighter maneuvers and air combat maneuvering. To avoid neck problems the majority of pilots aim to avoid certain head movements and to fix their neck before exposing themselves to high +Gz loads. With the implementation of JHMCS, two conflicting goals are evident and working at cross-purposes. A pilot's head should remain stationary while exposed to high +Gz loads. However, maximizing the advantages of JHMCS encourages the pilot to move his head sharply while exposed to high +Gz loads. Training programs to help the pilots cope with these challenges are warranted.


Does the presence or absence of sonographically identified cardiac activity predict resuscitation outcomes of cardiac arrest patients?
This study evaluated the ability of cardiac sonography performed by emergency physicians to predict resuscitation outcomes of cardiac arrest patients. A convenience sample of cardiac arrest patients prospectively underwent bedside cardiac sonography at 4 emergency medicine residency-affiliated EDs as part of the Sonography Outcomes Assessment Program. Cardiac arrest patients in pulseless electrical activity (PEA) and asystole underwent transthoracic cardiac ultrasound B-mode examinations during their resuscitations to assess for the presence or absence of cardiac kinetic activity. Several end points were analyzed as potential predictors of resuscitations: presenting cardiac rhythms, the presence of sonographically detected cardiac activity, prehospital resuscitation time intervals, and ED resuscitation time intervals. Of 70 enrolled subjects, 36 were in asystole and 34 in PEA. Patients presenting without evidence of cardiac kinetic activity did not have return of spontaneous circulation (ROSC) regardless of their cardiac rhythm, asystole, or PEA. Of the 34 subjects presenting with PEA, 11 had sonographic evidence of cardiac kinetic activity, 8 had ROSC with subsequent admission to the hospital, and 1 had survived to hospital discharge with scores of 1 on the Glasgow-Pittsburgh Cerebral Performance scale and 1 in the Overall Performance category. The presence of sonographically identified cardiac kinetic motion was associated with ROSC. Time interval durations of cardiac resuscitative efforts in the prehospital environment and in the ED were not accurate predictors of ROSC for this cohort. Cardiac kinetic activity, or lack thereof, identified by transthoracic B-mode ultrasound may aid physicians' decision making regarding the care of cardiac arrest patients with PEA or asystole.


Effects of vagal blockade on the counterregulatory response to insulin-induced hypoglycemia in the dog.
Our aim was to determine whether vagal transmission is required for the hormonal response to insulin-induced hypoglycemia in 18-h-fasted conscious dogs. Hollow coils were placed around the vagus nerves, with animals under general anesthesia, 2 wk before an experiment. On the day of the study they were perfused with -15 degrees C ethanol for the purpose of blocking vagal transmission, either coincident with the onset of insulin-induced hypoglycemia or after 2 h of established hypoglycemia. In a separate study the coils were perfused with 37 degrees C ethanol in a sham cooling experiment. The following parameters were measured: heart rate, arterial plasma glucose, insulin, pancreatic polypeptide, glucagon, cortisol, epinephrine, norepinephrine, glycerol, free fatty acids, and endogenous glucose production. In response to insulin-induced hypoglycemia (42 mg/dl), plasma glucagon peaked at a level that was double the basal level, and plasma cortisol levels quadrupled. Plasma epinephrine and norepinephrine levels both rose considerably to 2,135 +/- 314 and 537 +/- 122 pg/ml, respectively, as did plasma glycerol (330 +/- 60%) and endogenous glucose production (150 +/- 20%). Plasma free fatty acids peaked at 150 +/- 20% and then returned to basal levels by the end of the study. The hypoglycemia-induced changes were not different when vagal cooling was initiated after the prior establishment of hypoglycemia. Similarly, when vagal cooling occurred concurrently with the initiation of insulin-induced hypoglycemia (46 mg/dl), there were no significant differences in any of the parameters measured compared with the control. Thus vagal blockade did not prevent the effect on either the hormonal or metabolic responses to low blood sugar. Functioning vagal afferent nerves are not required for a normal response to insulin-induced hypoglycemia.


BMP7 expression in mammalian cortical radial glial cells increases the length of the neurogenic period.
The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that BMP7 is expressed by increasing numbers of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, man). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas SHH signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.


Reproductive isolation between phylogeographic lineages scales with divergence.
Phylogeographic studies frequently reveal multiple morphologically cryptic lineages within species. What is not yet clear is whether such lineages represent nascent species or evolutionary ephemera. To address this question, we compare five contact zones, each of which occurs between ecomorphologically cryptic lineages of skinks from the rainforests of the Australian Wet Tropics. Although the contacts probably formed concurrently in response to Holocene expansion from glacial refugia, we estimate that the divergence times (τ) of the lineage pairs range from 3.1 to 11.5 Ma. Multi-locus analyses of the contact zones yielded estimates of reproductive isolation that are tightly correlated with divergence time and, for lineages with older divergence times (τ > 5 Myr), substantial. These results show that phylogeographic splits of increasing depth represent stages along the speciation continuum, even in the absence of overt change in ecologically relevant morphology.


Thyroid dysfunction and risk of cutaneous malignant melanoma: a bidirectional two-sample Mendelian randomization study.
Epidemiologic and observational data have found a risk association between thyroid dysfunction and cutaneous malignant melanoma (CMM), however, the cause and direction of these effects are yet unknown. By using a bidirectional two-sample Mendelian randomization (MR) methodology, we hoped to further investigate the causal link between thyroid dysfunction and CMM in this work. A genome-wide association study (GWAS) of 9,851,867 single nucleotide polymorphisms (SNPs) in a European population was used to develop genetic tools for thyroid dysfunction. Hypothyroidism was linked to 22,687 cases and 440,246 controls. For hyperthyroidism, there were 3545 cases and 459,388 controls. A total of 3751 cases and 372016 controls were included in the genetic data for CMM from UK Biobank (http://www.nealelab.is/uk-biobank) (the Dataset: ieu - b - 4969). Among them, inverse variance weighting (IVW) is the main MR Analysis method for causality assessment. MR-Egger method, MR Pleiotropic residual and outlier test (MR-PRESSO), and simple and weighted median (VM) were used to supplement the IVW method. Sensitivity analyses, mainly Cochran's Q test, leave-one-out analysis, and MR Egger intercept test were performed to assess the robustness of the outcomes. The two-sample MR Analysis results revealed a negative correlation between genetically predicted hypothyroidism and the probability of CMM (OR=0.987, 95%CI =0.075-0.999, p=0.041). The supplemental MR Analysis did not reveal any statistically significant differences, although the direction of the effect sizes for the other approaches was consistent with the IVW effect sizes. The results of the causal analysis were relatively robust, according to a sensitivity analysis. The risk of CMM was unaffected by hyperthyroidism (p>0.05). No correlation between CMM and thyroid dysfunction was seen in the reverse MR analysis. Although the magnitude of the causal association is weak and further investigation of the mechanism of this putative causal relationship is required, our findings imply that hypothyroidism may be a protective factor for CMM.


Iron and Non-Iron-Related Characteristics of Multiple Sclerosis and Neuromyelitis Optica Lesions at 7T MRI.
Characterization of iron deposition associated with demyelinating lesions of multiple sclerosis and neuromyelitis optica has not been well studied. Our aim was to investigate the potential of ultra-high-field MR imaging to distinguish MS from neuromyelitis optica and to characterize tissue injury associated with iron pathology within lesions. Twenty-one patients with MS and 21 patients with neuromyelitis optica underwent 7T high-resolution 2D-gradient-echo-T2* and 3D-susceptibility-weighted imaging. An in-house-developed algorithm was used to reconstruct quantitative susceptibility mapping from SWI. Lesions were classified as "iron-laden" if they demonstrated hypointensity on gradient-echo-T2*-weighted images and/or SWI and hyperintensity on quantitative susceptibility mapping. Lesions were considered "non-iron-laden" if they were hyperintense on gradient-echo-T2* and isointense or hyperintense on quantitative susceptibility mapping. Of 21 patients with MS, 19 (90.5%) demonstrated at least 1 quantitative susceptibility mapping-hyperintense lesion, and 11/21 (52.4%) had iron-laden lesions. No quantitative susceptibility mapping-hyperintense or iron-laden lesions were observed in any patients with neuromyelitis optica. Iron-laden and non-iron-laden lesions could each be further characterized into 2 distinct patterns based on lesion signal and morphology on gradient-echo-T2*/SWI and quantitative susceptibility mapping. In MS, most lesions (n = 262, 75.9% of all lesions) were hyperintense on gradient-echo T2* and isointense on quantitative susceptibility mapping (pattern A), while a small minority (n = 26, 7.5% of all lesions) were hyperintense on both gradient-echo-T2* and quantitative susceptibility mapping (pattern B). Iron-laden lesions (n = 57, 16.5% of all lesions) were further classified as nodular (n = 22, 6.4%, pattern C) or ringlike (n = 35, 10.1%, pattern D). Ultra-high-field MR imaging may be useful in distinguishing MS from neuromyelitis optica. Different patterns related to iron and noniron pathology may provide in vivo insight into the pathophysiology of lesions in MS.


Amino acid-selective segmental isotope labeling of multidomain proteins for structural biology.
Current solution NMR techniques enable structural investigations of proteins in molecular particles with sizes up to several hundred kDa. However, the large molecular weight of proteins in such systems results in increased numbers of NMR signals, and the resulting spectral overlap typically imposes limitations. For multidomain proteins, segmental isotope labeling of individual domains facilitates the spectral interpretation by reducing the number of signals, but for large domains with small signal dispersion, signal overlap can persist. To overcome limitations arising from spectral overlap, we present a strategy that combines cell-free expression and ligation of the expressed proteins to produce multidomain proteins with selective amino acid-type labeling in individual domains. The bottleneck of intrinsically low cell-free expression yields of precursor molecules was overcome by introducing new fusion constructs that allowed milligram production of ligation-competent domains labeled in one or multiple amino acid types. Ligation-competent unlabeled partner domains were produced in vivo, and subsequent domain ligation was achieved by using an on-column strategy. This approach is illustrated with two multidomain RNA-binding proteins, that is, the two C-terminal RNA-recognition motifs of the human polypyrimidine tract-binding protein, and two highly homologous helix-turn-helix domains of the human glutamyl-prolyl-tRNA synthetase.


Association of Hepatic Steatosis Index and Fatty Liver Index with Carotid Atherosclerosis in Type 2 Diabetes.
Background/aim: Previous studies have suggested that the hepatic steatosis index (HSI) and fatty liver index (FLI) can be used as a predictor of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to determine whether non-invasive indices of hepatic steatosis (HSI and FLI) are associated with carotid atherosclerosis in type 2 diabetes mellitus (T2DM). Methods: This was a cross-sectional study conducted in the T2DM patients (n=768). Carotid intima-media thickness (CIMT) was measured by the Color Doppler ultrasound. The HSI was calculated based on gender, body mass index (BMI), and transaminases level. The FLI was based on BMI, waist circumference (WC), triacylglycerols (TG) and g-glutamyl transferase (GGT). Results: Raised HSI and FLI levels was associated with increased CIMT levels in T2DM patients. Patients with greater CIMT had higher HSI (39.10 ± 5.70 vs 36.10 ± 4.18, P < 0.001) and FLI (46.35 (29.96, 65.54) vs 36.93 (18.7, 57.93), P < 0.001) than those with lower CIMT. Subjects with existing carotid plaque had higher HSI (38.28 ± 5.63 vs 35.69 ± 3.45 P < 0.001) and FLI (47.41 (27.77, 66.62) vs 37.19 (17.71, 51.78), P < 0.001) accordingly. HSI (r = 0.343, P < 0.001) and FLI (r = 0.184, P < 0.001) were positively related with the CIMT. In the linear regression, after full adjustment metabolic risk factors, smoking, and measures of insulin resistance, HSI and FLI were independently associated with CIMT (HSI: β = 0.011, FLI: β = 0.001, all P < 0.01). Further, logistic regression analyses showed that higher HSI and FLI had an impact on the risk for carotid atherosclerosis [HSI: OR (95%CI): 1.174 (1.123-1.228), FLI: OR (95%CI): 1.011(1.004-1.019), all P < 0.01]. Overall, increasing values of HSI and FLI were associated with CIMT (P < 0.05) significantly across different categories of age and hypertension. Conclusion: Current data suggest HSI and FLI are independently correlated with carotid atherosclerosis in T2DM. They may be a simple and useful marker for assessing the progression of diabetic macrovascular complications.


The interaction between implicit and explicit awareness in anosognosia: emergent awareness.
The dissociation between implicit and explicit forms of awareness has been described in various neurological diseases. The way in which these forms of awareness integrate in order to permit the necessary unitary experience of self remains unclear. Here, the hypothesis that a form of emergent awareness (i.e., the emergence of a verbal acknowledgment of deficits as a consequence of attempting to act) may represent a link between implicit and explicit components is proposed for discussion.


FDG-PET and amyloid-PET imaging: the diverging paths.
The availability of PET neuroimaging tools for the in-vivo assessment of metabolic dysfunction and amyloid burden in Alzheimer's disease has opened important methodological and practical issues in the diagnostic design and the conduct of new clinical trials. This review, addressing the different molecular information that the amyloid-PET and fluorodeoxyglucose-PET (FDG-PET) tools can provide, highlights their diverging paths in Alzheimer's disease and possible new perspectives in research and clinical applications. Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention and biomarkers for diagnostic in-vivo imaging agents. Alzheimer's disease is a slowly progressing disorder, in which pathophysiological abnormalities, detectable in vivo by PET biomarkers, precede clinical symptoms by many years to decades. The unitary view of Alzheimer's disease as a sequential pathological pathway, with beta-amyloid (Aβ) as the only initial and causal event (the 'amyloid cascade hypothesis'), is likely to be progressively replaced by a more complex picture, also on the basis of recent PET imaging findings showing that neuronal injury biomarkers and tau pathology can be independent of β-amyloid deposition. The different molecular paths that PET in-vivo biomarkers can reveal in the timeframe of Alzheimer's disease progression reflect the events leading to deposition of Aβ and phosphorylated tau, neuronal injury and neurodegeneration, which can run in parallel instead of in a sequential manner. The amyloid and neuronal injury paths may diverge along the Alzheimer's disease cascade and bear separate relationships with Alzheimer's disease symptoms and clinical phenotypes. All these evidences are crucial for the diagnosis and the development of new drugs aimed at slowing or preventing dementia.


Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2.
Breast cancer-susceptibility genes BRCA1 and BRCA2 have recently been identified on the human genome. Women who carry a mutation of one of these genes have a greatly increased chance of developing breast and ovarian cancer, and they usually develop the disease at a much younger age, compared with normal individuals. Women can be tested to see whether they are carriers. A woman who undergoes genetic counseling before testing can be told the probabilities that she is a carrier, given her family history. In this paper we develop a model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives. Of special importance are the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases. This information can be elicited during genetic counseling and prior to genetic testing. The carrier probabilities are obtained from Bayes's rule, by use of family history as the evidence and by use of the mutation prevalences as the prior distribution. In addressing an individual's carrier probabilities, we incorporate uncertainty about some of the key inputs of the model, such as the age-specific incidence of diseases and the overall prevalence of mutations. There is some evidence that other, undiscovered genes may be important in explaining familial breast cancer. Users of the current version of the model should be aware of this limitation. The methodology that we describe can be extended to more than two genes, should data become available about other genes.


Reliability of RT3 accelerometer for measuring mobility in people with multiple sclerosis: pilot study.
This pilot study investigated the test-retest reliability of an RT3 accelerometer (RT3) for measuring motion in people with multiple sclerosis (MS). Ten people with MS (mean age 49 yr; Extended Disability Status Scale mean +/- standard deviation = 3.4 +/- 1.3) and ten nondisabled people (mean age 40 yr) wore the RT3 while they performed three discrete mobility tasks on two occasions separated by 1 week. The intraclass correlation coefficients (ICCs) calculated from the RT3 motion data for the group with MS were 0.64 for the 5-minute walk test (p = 0.01), 0.50 for the timed up and go test (p = 0.05), and 0.76 for the stair-climbing task (p = 0.002). For the control group, these values were 0.65 (p = 0.01), -0.04 (p = 0.54), and 0.39 (p = 0.11), respectively. We found that the RT3 can potentially provide stable data when measuring walking, but a more robust, yet participant-friendly, method of attaching the RT3 is required. Both participant groups demonstrated inconsistencies in motor-task performance, highlighting a potential source of measurement error that would need to be addressed when future studies are designed. Based on the results of the 5-minute walk test in this study, a sample of 53 participants would be required to obtain an ICC value with a 95% confidence interval of width 0.2 using two repeat measurements.


Production of specific agglutinins for mycobacteria in peritoneal fluid of mice.
Specific agglutinins were produced in ascitic fluid of mice by intraperitoneal injection of certain mycobacteria suspended in Freund's incomplete adjuvant.