Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects.
This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters.


Beneficial effects of Rifaximin in post-infectious irritable bowel syndrome mouse model beyond gut microbiota.
Rifaximin is a minimally absorbed antibiotic, which has shown efficacy in irritable bowel syndrome (IBS) patients. However, the mechanism on how it effects in IBS is still incompletely defined. In this study, Trichinella spiralis-infected post-infectious (PI) IBS mouse model was used, to assess the action of rifaximin on visceral hypersensitivity, barrier function, gut inflammation, and microbiota. Post-infectious IBS model was established by T. spiralis infection in mice. Rifaximin were administered to PI-IBS mice for seven consecutive days. The abdominal withdrawal reflex and threshold of colorectal distention were employed to evaluate visceral sensitivity. Smooth muscle contractile response was recorded in the organ bath. Intestinal permeability was measured by Ussing chamber. Expression of tight junction protein and cytokines were measured by Western blotting. Ilumina miseq platform was used to analyze bacterial 16S ribosomal RNA. Post-infectious IBS mice treated with rifaximin exhibited decreased abdominal withdrawal reflex score, increased threshold, reduced contractile response, and intestinal permeability. Rifaximin also suppressed the expression of interleukin-12 and interleukin-17 and promoted the expression of the major tight junction protein occludin. Furthermore, rifaximin did not change the composition and diversity, and the study reavealed that rifaximin had a tiny effect on the relative abundance of Lactobacillus and Bifidobacterium in this PI-IBS model. Rifaximin alleviated visceral hypersensitivity, recovered intestinal barrier function, and inhibited low-grade inflammation in colon and ileum of PI-IBS mouse model. Moreover, rifaximin exerts anti-inflammatory effects with only a minimal effect on the overall composition and diversity of the gut microbiota in this model.


The emergence of co-occurring adolescent polysubstance use and depressive symptoms: A latent growth modeling approach.
This study tests competing models of the relation between depression and polysubstance use over the course of adolescence. Participants included a nationwide sample of adolescents (N = 3,604), ages 12 to 17 at study Wave 1, assessed annually for 3 years. Models were tested using cohort-sequential latent growth curve modeling to determine whether depressive symptoms at baseline predicted concurrent and age-related changes in drug use, whether drug use at baseline predicted concurrent and age-related changes in depressive symptoms, and whether initial levels of depression predicted changes in substance use significantly better than vice versa. The results suggest a transactional model such that early polysubstance use promotes early depressive symptoms, which in turn convey elevated risk for increasing polysubstance use over time, which in turn conveys additional risk for future depressive symptoms, even after accounting for gender, ethnicity, and household income. In contrast, early drug use did not portend risk for future depressive symptoms. These findings suggest a complicated pattern of interrelations over time and indicate that many current models of co-occurring polysubstance use and depressive symptoms may not fully account for these associations. Instead, the results suggest a developmental cascade, in which symptoms of one disorder promote symptoms of the other across intrapersonal domains.


Centrally administered neuromedin S inhibits feeding behavior and gastroduodenal motility in mice.
Neuromedin S (NMS) was recently identified as an endogenous ligand for the FM-4/TGR-1 receptor in the rat hypothalamus. No previous studies have examined the effect of NMS on gut motility. We examined the effects of intracerebroventricular administration of NMS on food intake in food-deprived and free-feeding mice, and on gastroduodenal motility by using a manometric method, and gastric emptying in mice. We found that NMS decreased food intake and the gastric emptying rate. It also disrupted the motor activity in the antrum and duodenum of conscious food-deprived mice. These results suggest that NMS influences gut motility as well as feeding behavior.


Behavioural characterisation of the alpha-mannosidosis guinea pig.
alpha-Mannosidosis is a lysosomal storage disorder resulting from a functional deficiency of the lysosomal enzyme alpha-mannosidase. This deficiency results in the accumulation of various oligosaccharides in the lysosomes of affected individuals, causing somatic pathology and progressive neurological degeneration that results in cognitive deficits, ataxia, and other neurological symptoms. We have a naturally occurring guinea pig model of this disease which exhibits a deficiency of lysosomal alpha-mannosidase and has a similar clinical presentation to human alpha-mannosidosis. Various tests were developed in the present study to characterise and quantitate the loss of neurological function in alpha-mannosidosis guinea pigs and to follow closely the progression of the disease. General neurological examinations showed progressive differences in alpha-mannosidosis animals from approximately 1 month of age. Significant differences were observed in hind limb gait width from 2 months of age and significant cognitive (memory and learning) deficits were observed from 3 months of age. Evoked response tests showed an increase in somatosensory P1 peak latency in alpha-mannosidosis guinea pigs from approximately 2 months of age, as well as progressive hearing loss using auditory brainstem evoked responses. The alpha-mannosidosis guinea pig therefore appears to exhibit many of the characteristics of the human disease, and will be useful in evaluating therapies for treatment of central nervous system pathology.


Requirement for TGFbeta receptor signaling during terminal lens fiber differentiation.
Several families of growth factors have been identified as regulators of cell fate in the developing lens. Members of the fibroblast growth factor family are potent inducers of lens fiber differentiation. Members of the transforming growth factor beta (TGFbeta) family, particularly bone morphogenetic proteins, have also been implicated in various stages of lens and ocular development, including lens induction and lens placode formation. However, at later stages of lens development, TGFbeta family members have been shown to induce pathological changes in lens epithelial cells similar to those seen in forms of human subcapsular cataract. Previous studies have shown that type I and type II TGFbeta receptors, in addition to being expressed in the epithelium, are also expressed in patterns consistent with a role in lens fiber differentiation. In this study we have investigated the consequences of disrupting TGFbeta signaling during lens fiber differentiation by using the mouse alphaA-crystallin promoter to overexpress mutant (kinase deficient), dominant-negative forms of either type I or type II TGFbeta receptors in the lens fibers of transgenic mice. Mice expressing these transgenes had pronounced bilateral nuclear cataracts. The phenotype was characterized by attenuated lens fiber elongation in the cortex and disruption of fiber differentiation, culminating in fiber cell apoptosis and degeneration in the lens nucleus. Inhibition of TGFbeta signaling resulted in altered expression patterns of the fiber-specific proteins, alpha-crystallin, filensin, phakinin and MIP. In addition, in an in vitro assay of cell migration, explanted lens cells from transgenic mice showed impaired migration on laminin and a lack of actin filament assembly, compared with cells from wild-type mice. These results indicate that TGFbeta signaling is a key event during fiber differentiation and is required for completion of terminal differentiation.


Initial Application of a Bicuspid Aortic Annuloplasty Ring in Pediatric Cardiac Surgery.
Aortic stenosis and aortic insufficiency (AI) are common valvular conditions that may necessitate repair or replacement of the aortic valve. Aortic valve replacement is associated with higher long-term complications and thus, a consistent, reliable method of repair is needed. This is especially true in the pediatric population where lifelong anticoagulation and development of recurrent aortic stenosisor aortic insufficiency are especially problematic. The Hemispherical Aortic Annuloplasty Reconstruction Technology ring has been developed and used for annular stabilization in adults with success, though its efficacy in the pediatric population has yet to be demonstrated. Herein, we discuss the use of a geometric ring in aortic valve repair for the pediatric patient.


Benign liver angiomyolipoma: a case study.
Hepatic angiomyolipoma is a rare mesenchymal tumor. It consists of vessels, fatty tissue and muscle tissue. These can appear in various ratios. While the kidney is the most common localization of angiomyolipoma, only about 300 cases have been described in the liver so far. It is a tumor of uncertain behavior. Most of the patients suffering from the lesion is asymptomatic. It is often preoperatively misdiagnosed using various imaging methods given its similarity to other hepatic tumors. Our 64 years old female patient was being examined for dull abdominal pains with no other symptoms. Her close relatives suffered from no malignancies. Imaging exams showed a liver lesion highly suspicious for hepatocellular carcinoma. However, the patient showed no elevation of typical oncomarkers. We performed left lateral sectionectomy. A grey solid focal lesion was found in the resected tissue. Histological and immunohistochemical evaluation determined the diagnosis of angiomyolipoma. The postoperative period was uncomplicated. The patient has been followed at an office for hepato-pancreato-biliary diseases, with no signs of recurrence until the present. Hepatic angiomyolipoma is a rare disease. The diagnostic process can be challenging as illustrated by the presented case. Even though the working diagnosis proved false, the chosen treatment was appropriate and delivered good results. Long-term postoperative follow-up is required.


Enhancing photosynthesis in plants: the light reactions.
In this review, we highlight recent research and current ideas on how to improve the efficiency of the light reactions of photosynthesis in crops. We note that the efficiency of photosynthesis is a balance between how much energy is used for growth and the energy wasted or spent protecting the photosynthetic machinery from photodamage. There are reasons to be optimistic about enhancing photosynthetic efficiency, but many appealing ideas are still on the drawing board. It is envisioned that the crops of the future will be extensively genetically modified to tailor them to specific natural or artificial environmental conditions.


Long-term survival in paraneoplastic Lambert-Eaton myasthenic syndrome.
To establish whether improved tumor survival in patients with Lambert-Eaton myasthenic syndrome (LEMS) and small-cell lung cancer (SCLC) was due to known prognostic risk factors or an effect of LEMS independently, perhaps as a result of circulating factors. We undertook a prospective observational cohort study of patients with LEMS attending Nottingham University Hospitals, UK, or via the British Neurological Surveillance Unit. In parallel, patients with a new diagnosis of biopsy-proven SCLC were enrolled, examined for neurologic illness, and followed up until death or study end. Between May 2005 and November 2014, we recruited 31 patients with LEMS and SCLC and 279 patients with SCLC without neurologic illness. Allowing for known SCLC survival prognostic factors of disease extent, age, sex, performance status, and sodium values, multivariate Cox regression analysis showed that the presence of LEMS with SCLC conferred a significant survival advantage independently of the other prognostic variables (hazard ratio 1.756, 95% confidence interval 1.137-2.709, p = 0.011). Improved SCLC tumor survival seen in patients with LEMS and SCLC may not be due solely to lead time bias, given that survival advantage remains after allowing for other prognostic factors and that the same degree of survival advantage is not seen in patients with paraneoplastic neurologic syndromes other than LEMS presenting before SCLC diagnosis.


White matter integrity in dyskinetic cerebral palsy: Relationship with intelligence quotient and executive function.
Dyskinetic cerebral palsy (CP) is one of the most disabling motor types of CP and has been classically associated with injury to the basal ganglia and thalamus. Although cognitive dysfunction is common in CP, there is a paucity of published quantitative analyses investigating the relationship between white matter (WM) microstructure and cognition in this CP type. This study aims (1) to compare brain WM microstructure between people with dyskinetic CP and healthy controls, (2) to identify brain regions where WM microstructure is related to intelligence and (3) to identify brain regions where WM microstructure is related to executive function in people with dyskinetic CP and (4) to identify brain regions where the correlations are different between controls and people with CP in IQ and executive functions. Thirty-three participants with dyskinetic CP (mean ± SD age: 24.42 ± 12.61, 15 female) were age and sex matched with 33 controls. Participants underwent a comprehensive neuropsychological battery to assess intelligence quotient (IQ) and four executive function domains (attentional control, cognitive flexibility, goal setting and information processing). Diffusion weighted MRI scans were acquired at 3T. Voxel-based whole brain groupwise analyses were used to compare fractional anisotropy (FA) and of the CP group to the matched controls using a general lineal model. Further general linear models were used to identify regions where white matter FA correlated with IQ and each of the executive function domains. White matter FA was significantly reduced in the CP group in all cerebral lobes, predominantly in regions connected with the parietal and to a lesser extent the temporal lobes. There was no significant correlation between IQ or any of the four executive function domains and WM microstructure in the control group. In participants with CP, lower IQ was associated with lower FA in all cerebral lobes, predominantly in locations that also showed reduced FA compared to controls. Attentional control, goal setting and information processing did not correlate with WM microstructure in the CP group. Cognitive flexibility was associated with FA in regions known to contain connections with the frontal lobe (such as the superior longitudinal fasciculus and cingulum) as well as regions not known to contain tracts directly connected with the frontal lobe (such as the posterior corona radiata, posterior thalamic radiation, retrolenticular part of internal capsule, tapetum, body and splenium of corpus callosum). The widespread loss in the integrity of WM tissue is mainly located in the parietal lobe and related to IQ in dyskinetic CP. Unexpectedly, executive functions are only related with WM microstructure in regions containing fronto-cortical and posterior cortico-subcortical pathways, and not being specifically related to the state of fronto-striatal pathways which might be due to brain reorganization. Further studies of this nature may improve our understanding of the neurobiological bases of cognitive impairments after early brain insult.


Plasmonic Nanomaterials in Dark Field Sensing Systems.
Plasma nanoparticles offer promise in data storage, biosensing, optical imaging, photoelectric integration, etc. This review highlights the local surface plasmon resonance (LSPR) excitation mechanism of plasmonic nanoprobes and its critical significance in the control of dark-field sensing, as well as three main sensing strategies based on plasmonic nanomaterial dielectric environment modification, electromagnetic coupling, and charge transfer. This review then describes the component materials of plasmonic nanoprobes based on gold, silver, and other noble metals, as well as their applications. According to this summary, researchers raised the LSPR performance of composite plasmonic nanomaterials by combining noble metals with other metals or oxides and using them in process analysis and quantitative detection.


Complex regulation of Arabidopsis AGR1/PIN2-mediated root gravitropic response and basipetal auxin transport by cantharidin-sensitive protein phosphatases.
Polar auxin transport, mediated by two distinct plasma membrane-localized auxin influx and efflux carrier proteins/complexes, plays an important role in many plant growth and developmental processes including tropic responses to gravity and light, development of lateral roots and patterning in embryogenesis. We have previously shown that the Arabidopsis AGRAVITROPIC 1/PIN2 gene encodes an auxin efflux component regulating root gravitropism and basipetal auxin transport. However, the regulatory mechanism underlying the function of AGR1/PIN2 is largely unknown. Recently, protein phosphorylation and dephosphorylation mediated by protein kinases and phosphatases, respectively, have been implicated in regulating polar auxin transport and root gravitropism. Here, we examined the effects of chemical inhibitors of protein phosphatases on root gravitropism and basipetal auxin transport, as well as the expression pattern of AGR1/PIN2 gene and the localization of AGR1/PIN2 protein. We also examined the effects of inhibitors of vesicle trafficking and protein kinases. Our data suggest that protein phosphatases, sensitive to cantharidin and okadaic acid, are likely involved in regulating AGR1/PIN2-mediated root basipetal auxin transport and gravitropism, as well as auxin response in the root central elongation zone (CEZ). BFA-sensitive vesicle trafficking may be required for the cycling of AGR1/PIN2 between plasma membrane and the BFA compartment, but not for the AGR1/PIN2-mediated root basipetal auxin transport and auxin response in CEZ cells.


Pelvic tenderness is not limited to the prostate in chronic prostatitis/chronic pelvic pain syndrome (CPPS) type IIIA and IIIB: comparison of men with and without CP/CPPS.
We wished to determine if there were differences in pelvic and non-pelvic tenderness between men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) Type III and men without pelvic pain. We performed the Manual Tender Point Survey (MTPS) as described by the American College of Rheumatology on 62 men with CP/CPPS Type IIIA and IIIB and 98 men without pelvic pain. We also assessed tenderness of 10 external pelvic tender points (EPTP) and of 7 internal pelvic tender points (IPTP). All study participants completed the National Institutes of Health Chronic Prostatitis Symptom Inventory (NIH CPSI). We found that men with CPPS were significantly more tender in the MTPS, the EPTPS and the IPTPS. CPSI scores correlated with EPTP scale but not with IPTP scale or prostate tenderness. Prostatic tenderness was present in 75% of men with CPPS and in 50% of men without CPPS. Expressed prostatic fluid leukocytosis was not associated with prostatic tenderness. Men with CP/CPPS have more tenderness compared to men without CPPS. Tenderness in men with CPPS is distributed throughout the pelvis and not specific to the prostate.


Aberrant PTEN, PIK3CA, pMAPK, and TP53 expression in human scalp and face angiosarcoma.
Angiosarcoma is a rare, highly aggressive malignant tumor originating from endothelial cells that line the lumen of blood or lymphatic vessels. The molecular mechanisms of scalp and face angiosarcoma still need to be elucidated. This study aimed to investigate the expression of phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphorylated mitogen-activated kinase-like protein (pMAPK), and tumor protein p53 (TP53) in scalp and face angiosarcoma and to assess tumor tissue apoptosis.The expression and intracellular distribution of PTEN, PIK3CA, pMAPK, and TP53 proteins in 21 specimens of human scalp and face angiosarcoma and 16 specimens of human benign hemangioma were evaluated using immunohistochemistry. Tumor cell apoptosis was assessed by terminal deoxyribonucleotide transferase-mediated dUTP nick end-labeling staining.Significantly lower PTEN but higher PIK3CA, pMAPK, and TP53 immunostaining were detected in the angiosarcoma specimens than in the benign hemangioma specimens(P < .01). The angiosarcoma tissues exhibited significantly higher apoptosis indices than the benign hemangioma tissues (P < .01). The positive expression rates of PIK3CA, pMAPK, and TP53 were correlated with the degree of tumor differentiation in the human scalp and face angiosarcoma.The PI3K, MAPK, and TP53 pathways might be involved in angiosarcoma tumorigenesis in humans and may serve as therapeutic targets for the effective treatment of this malignancy.


Inhibition of guanylate cyclase and protein kinase G impairs retention for the passive avoidance task in the day-old chick.
Nitric oxide (NO) is a highly labile chemical messenger which has previously been implicated in memory processes in a variety of learning paradigms and species. However, there is only limited evidence to suggest which enzymes are acted upon by NO during the formation of memory. The present study investigates the role of guanylate cyclase (GC) and protein kinase G (PKG) in a form of passive avoidance learning known to be dependent on nitric oxide activity. It was determined that in vivo pharmacological inhibition of GC using either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one or 6-anilino-5,8-quinolinedione resulted in two transitory memory retention deficits centred around 40 and 120 min posttraining, respectively. In contrast, inhibition of PKG with N-[2-(methylamino)ehtyl]-5-isoquinoline-sulfornamide hydrochloride (H-8) resulted in a single temporary retention loss centered at 120 min posttraining. These temporary retention losses appear to be specific to memory since they were dose-dependent and could not be explained by nonspecific performance effects. Further, these results suggest that these agents inhibit memory retrieval rather than formation, since memory is subsequently available. The current findings indicate that guanylyl cyclase mediates two memory retrieval processes, the latter of which appears to be PKG-dependent. In contrast, since inhibition of NO results in a permanent retention loss, it is suggested that NO is required for memory formation through GC-independent processes.


Vagal nerve monitoring: a comparison of techniques in a canine model.
An optimal technique exists for intraoperative, electrophysiologic vagal nerve monitoring. Analogous to facial nerve monitoring during lateral skull base surgery, vagal nerve monitoring may be used at surgery involving the jugular foramen, the posterior cranial fossa, the infratemporal fossa, the parapharyngeal space, and the thyroid gland to decrease the incidence of iatrogenic injuries. Laryngeal electromyography (EMG) is an accurate test of vagal nerve function: four applications have been described for use intraoperatively. The purpose of this study was to compare the sensitivities of these techniques in a canine model in order to identify the optimal method of intraoperative vagal nerve monitoring. Four techniques of EMG vagal nerve monitoring were studied in dogs. The thyroarytenoid muscle (TA) was monitored directly in three techniques. Two methods used bipolar hookwire electrodes (L.A. Diagnostics, Los Angeles, CA) inserted in the TA percutaneously through the cricothyroid membrane or via direct laryngoscopy (DL). The third TA monitoring technique involved the use of an EMG endotracheal tube (Xomed-Treace, Jacksonville, FL). The fourth technique used a laryngeal surface EMG electrode (RLN Systems, Jefferson City, MO), laryngoscopically placed in the postcricoid space. After placing each monitoring device, the vagus nerve was identified bilaterally in the neck. The nerves were sequentially stimulated at a constant current of 4.1 Hz with increasing intensity (starting at 0.05 mAmps) to determine the minimum thresholds to stimulate vocal cord contraction. A positive response at the vocal cord was defined as a train of four contractions of > or = 50 mV. The lowest threshold for each technique in each dog was recorded. A positive response was obtained in 27 of 32 possible cases using a maximum boundary of 0.5 mAmps for stimulus intensity. Survival analysis was then used to generate Kaplan-Meier survival curves, allowing a comparison of the mean time needed to obtain a response. Log-rank chi statistics showed that the survival curves are inhomogenous (degrees of freedom [df] = 3, chi = 15.58, p < 0.001). The laryngeal surface electrode appears to offer the most sensitive method for vagal nerve monitoring. Four techniques of intraoperative, EMG vagal nerve monitoring were compared in a canine model. The results suggest that EMG recordings can be obtained successfully through a variety of techniques and that the laryngeal surface electrode appears to be the most sensitive technique in the canine model.


Irreversible adsorption-driven assembly of nanoparticles at fluid interfaces revealed by a dynamic surface tension probe.
Adsorption-driven self-assembly of nanoparticles at fluid interfaces is a promising bottom-up approach for the preparation of advanced functional materials and devices. Full realization of its potential requires quantitative understanding of the parameters controlling the self-assembly, the structure of nanoparticles at the interface, the barrier properties of the assembly, and the rate of particle attachment. We argue that models of dynamic surface or interfacial tension (DST) appropriate for molecular species break down when the adsorption energy greatly exceeds the mean energy of thermal fluctuations and validate alternative models extending the application of generalized random sequential adsorption theory to nanoparticle adsorption at fluid interfaces. Using a model colloidal system of hydrophobic, charge-stabilized ethyl cellulose nanoparticles at neutral pH, we demonstrate the potential of DST measurements to reveal information on the energy of adsorption, the adsorption rate constant, and the energy of particle-interface interaction at different degrees of nanoparticle coverage of the interface. These findings have significant implications for the quantitative description of nanoparticle adsorption at fluid interfaces.


The impact of pre-operative cholecystostomy on laparoscopic excision of choledochal cyst in paediatric patients.
This aim of this study was to identify the pre-operative risk factors for conversion during laparoscopic excision of choledochal cyst in paediatric patients. A retrospective single-centre study was carried out. All paediatric patients (< 18 years) who had undergone laparoscopic excision of choledochal cyst between 2004 and 2021 were reviewed. The outcome was conversion to open surgery and pre-operative factors that affected the conversion rate were analyzed. Sixty-one patients were included. Conversion was required in 24 cases (39.3%). There was no difference in the conversion rate between the first (before 2012, n = 30) and second (after 2012, n = 31) half of the series (36.7% vs. 42.0%, p = 0.674). Majority was type 1 cyst (86.8%) and the median cyst size was 4.6 cm (IQR: 2.2-6.4 cm). Antenatal diagnosis was available in 18 patients (29.5%). The median age at operation was 23.0 months (IQR: 8.0-72.0 months). Pre-operatively, 19 patients (31.1%) suffered from cholangitis and 5 (8.2%) of them required cholecystostomy. Comparing patients with successful laparoscopic surgery (L) and converted cases (C), there were no differences in the age at operation (p = 0.74), cyst size (p = 0.35), availability of antenatal diagnosis (p = 0.23) and cholangitic episodes (p = 0.40). However, a higher percentage of patients required cholecystostomy in the converted group (L vs. C = 2.7% vs. 16.7%, p = 0.05). Using logistic regression analysis, it was also a risk factor for conversion (OR = 3.5 [1.37-5.21], p = 0.05). Pre-operative cholecystostomy is a potential risk factor for conversion during laparoscopic excision of choledochal cyst in children.


Neuronal responses at the sight of objects in monkey basal forebrain subregions during operant visual tasks.
The basal forebrain appears to be important in cognitive function. It has been suggested that this region is composed of several cholinergic cell groups, mainly the medial septum, the diagonal band of Broca, and the nucleus basalis of Meynert. To elucidate the functional differences between these subregions, we have recorded single-unit activity from the periventricular areas involving the medial septum, the diagonal band of Broca (ms/dbB), and the substantia innominata (SI), including the nucleus basalis of Meynert, of an object-discriminating monkey. Of 226 ms/dbB and 439 SI neurons analyzed, 36 (15.9%) and 115 (26.2%), respectively, responded to the sight of some complex object. Thirteen (5.8%) ms/dbB and 80 (18.2%) SI neurons responded to virtually all objects and the ratio of these neurons in the SI was higher than that in the ms/dbB. The other 23 (10.2%) ms/dbB and 35 (8.0%) SI neurons responded preferentially to one or two of three categories (rewarding, aversive, or meaningless) of familiar or to unfamiliar objects, and response selectivity to one category of the ms/dbB neurons (15; 6.6%) was higher than that to the SI neurons (14; 3.2%). The results suggest that the SI, including the nucleus basalis of Meynert, may encode visual information about objects more broadly and participate more fully in visual attention than the ms/dbB region, which may be more closely related to learning.


Communication of cancer-related genetic and genomic information: A landscape analysis of reviews.
Cancer-related genetic and genomic testing (CGT) is changing cancer care by personalizing care options, leading to an era of precision medicine. Advances in and increased use of CGT add complexity to clinical communication. This landscape analysis assessed published reviews of communication issues related to CGT and discusses implications for practice and behavioral research. A comprehensive electronic literature search was conducted of peer-reviewed literature reviews on studies related to CGT communication published between January 2010 and January 2017, resulting in a final sample of 24 reviews. Reviews were categorized, with overlaps, into four domains across the genetic testing communication continuum. Reviews on CGT-related knowledge, attitudes, and perceptions (n = 8) found that despite substantial public interest, their knowledge and awareness remains low. Providers also reported insufficient knowledge and overall caution, particularly regarding direct-to-consumer (DTC) genetic testing. Reviews of decision-making about CGT and test uptake (n = 8) identified individual, interpersonal, and systems-level barriers to uptake. Reviews of patient-provider CGT communication (n = 8) revealed limited communication and little empirical research on outcomes of communication or efforts at improving clinical and family communication. There were mixed findings in reviews (n = 15) on the psychological and behavioral impact of CGT, and DTC testing particularly had little effect on behaviors. Taken together, there is very little extant research in CGT in minority and underserved communities. In order for scientific advances in CGT to translate into equitable, patient-centered care, behavioral research, including health literacy and communication, plays critical roles.


Seasonal influenza vaccination of the elderly.
The elderly are at increased risk of the complications of seasonal influenza. Annual vaccination is therefore recommended. However, two systematic reviews published by the Cochrane collaboration have highlighted a number of outstanding issues. This article examines whether annual influenza vaccination of the elderly and their regular contacts is still supported by the available scientific evidence. The randomised trials included in one of the Cochrane reviews suggest that influenza vaccination reduces the incidence of flu-like syndromes and laboratory-confirmed influenza in the elderly. There are no robust randomised trials specifically designed to assess whether vaccination of the elderly prevents influenza complications. Two case-control studies showed a statistical correlation between vaccination and a lower risk of death from influenza complications. Cohort studies have also shown that complications are less frequent when the vaccine strains correspond to circulating strains. Because of a patient selection bias, non-randomised studies seem to overestimate the efficacy of vaccination. Three randomised trials showed that vaccination of care home staff reduced mortality among elderly residents during seasonal flu epidemics. No such effect was observed in another trial, possibly because a large proportion (32%) of staff in the control institutions had also been vaccinated. In practice, influenza vaccination of the elderly with risk factors for complications is justified, especially for care home residents, their regular contacts and healthcare workers. Seasonal flu vaccination of healthy people over 65 provides limited benefit but its harm-benefit balance remains favourable. More studies of routine influenza vaccination of the elderly are needed.


The triple rule-out for acute ischemic stroke: imaging the brain, carotid arteries, aorta, and heart.
Ischemic stroke is commonly embolic, either from carotid atherosclerosis or from cardiac origin. These potential sources of emboli need to be investigated to accurately prescribe secondary stroke prevention. Moreover, the mortality in ischemic stroke patients due to ischemic heart disease is greater than that of age-matched controls, thus making evaluation for coronary artery disease important in this patient population. The purpose of this study was to evaluate the image quality of a comprehensive CTA protocol in patients with acute stroke that expands the standard CTA coverage to include all 4 chambers of the heart and the coronary arteries. One hundred twenty patients consecutively admitted to the emergency department with suspected cerebrovascular ischemia undergoing standard-of-care CTA were prospectively enrolled in our study. We used an original tailored acquisition protocol using a 64-section CT scanner, consisting of a dual-phase intravenous injection of iodinated contrast and saline flush, in conjunction with a dual-phase CT acquisition, ascending from the top of the aortic arch to the vertex of the head, then descending from the top of the aortic arch to the diaphragm. No beta blockers were administered. The image quality, attenuation, and CNRs of the carotid, aortic, vertebral, and coronary arteries were assessed. Carotid, aorta, and vertebral artery image quality was 100% diagnostic (rated good or excellent) in all patients. Coronary artery image quality was diagnostic in 58% of RCA segments, 73% of LAD segments, and 63% of LCX segments. When we considered proximal segments only, the diagnostic quality rose to 71% in the RCA, 83% in the LAD, and 74% in the LCX. Our stroke protocol achieved excellent opacification of the left heart chambers, the cervical arteries, and each coronary artery, in addition to adequate carotid and coronary artery image quality.


THE ASSOCIATION BETWEEN PRO AND ANTI-INFLAMMATORY MARKERS WITH THE COMPONENTS OF METABOLIC SYNDROME.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that is linked with increased circulating markers of oxidative stress and low-grade inflammation. The link between inflammation and MetS is not yet fully understood. We aim to evaluate the relationship between the levels of pro and anti-inflammatory markers such as apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), interleukin (IL) 6, tumor necrosis factor alpha (TNF-α), fibrinogen and complement component 3 (C3) and adiponectin and MetS/MetS components. This study was a case-control study conducted in an outpatient internal medicine clinic of the Ondokuz Mayıs University Internal Medicine Department. A total of 108 subjects (59 female, 49 male) who were not under any dietary restrictions and older than 17 years were selected and divided into two groups (54 with MetS and 54 healthy controls). Increased levels of IL-6, C3 and Apo-B/Apo-A1 ratios and decreased levels of Apo-A1 and TNF-α (except in patients with hypertriglyceridemia) were detected in the MetS group. Apo-A1 and TNF-α exhibited decreased levels, and IL-6, fibrinogen, C3 and Apo-B levels and Apo-B/Apo-A1 ratios increased as higher numbers of MetS criteria were met in the total study group. We found that inflammatory marker levels were not affected by an increased number of MetS criteria met in the MetS group although these levels increased in the control group with higher numbers of MetS components. The presence of a high number of MetS components does not have an additive pro-inflammatory contribution for subjects already diagnosed with MetS.


Intestinal geohelminthiasis in the developing world.
Intestinal parasitic helminths such as roundworms (Ascaris lumbricoides), hookworms (Ancylostoma doudenale and Necator americanus) and whipworm (Trichuris trichiura) are common in the developing world. Strongyloides stercoralis, though not so common, also contributes to health problems. The prevalence of intestinal worm infestation in India varies from 5% to 76%, which is similar to that in other developing countries. These parasitic infestations are acquired by ingestion, inhalation or penetration of the skin by the infective forms. Ascaris causes many intestinal and respiratory symptoms and plays an important role in precipitating protein-energy malnutrition in undernourished children. Hookworms cause anaemia and hypoproteinaemia. In areas where hookworm infestation is endemic, 90% of pregnant mothers are anaemic. Trichuriasis as a causative agent of human disease has only recently gained attention. Heavy infestation with T. trichiura can result in severe colitis and significant blood loss. This in turn can lead to impaired cognitive functions which are reversible on treatment. Though not as widely prevalent as the other geohelminths in India, Strongyloides stercoralis infestation can be fatal in debilitated and immunosuppressed children. So far, the impact of these parasites on the health of children has been underestimated and concentrated efforts to minimize the worm load and its consequences have not been given due importance in our health policies. This article reviews the pathophysiology, clinical impact and control options of the most commonly prevalent geohelminths in the developing world.


Wnt signaling in the stem cell niche.
All the cells present in the blood are derived from the hematopoietic stem cell (HSC). Because mature blood cells have a limited life span, HSCs must perpetuate themselves through self-renewal to maintain a functional hematopoietic compartment for the lifetime of an organism. This review focuses on studies that identify the Wnt signaling pathway as a mediator of HSC self-renewal and maintenance and analyzes its potential influence in context of the HSC niche. The Wnt signaling pathway has emerged as a potential regulator of self-renewal for HSCs. Recent findings have demonstrated that Wnt signaling can directly promote HSC self-renewal and ability to reconstitute the hematopoietic system of lethally irradiated mice. The recent findings that osteoblasts are an important regulatory component of the HSC microenvironment, and that elements of the Wnt signaling pathway can influence osteoblast frequency, raise the possibility that Wnt signaling may influence HSC function indirectly through the niche as well. In this review, the authors evaluate the experimental evidence for a direct role of Wnt signaling HSCs as well as an indirect role through its influence on the HSC niche. Defining the mechanism of action of Wnt signaling in HSC maintenance in context of the surrounding microenvironment and determining how this signal may integrate with other niche derived signals represents the next challenge HSC biology.


[Celiac disease - disease of children and adults: symptoms, disease complications, risk groups and comorbidities].
About 1% of human population suffers from celiac disease (CD) and it is one of the most commonly diagnosed autoimmune disorders. Until recently it was believed that CD affects mainly children, but as the newest studies show, up to 60% recently diagnosed patients are adults, often over the age of 60. CD's medical signs are nonspecific. Atypical course of the disease with extraintestinal symptoms is being increasingly observed. The disease may also be asymptomatic over many years. The studies show that the average diagnosis of CD takes more than 10 years since the first symptoms appear. Nonspecific medical signs cause undiagnosed patients suffering from CD to visit gastroenterologists, endocrinologists, allergists, gynaecologists and other medical specialists. However, most frequently general practitioners have the first encounter with patients suffering from CD, therefore they are able to recognize symptoms of the disease at the earliest and refer the patient to a gastroenterologist. Early diagnosis and beginning of the treatment reduce complications of untreated CD. The aim of this paper is to show general practitioners symptoms, disease complications, risk groups and comorbidities of CD.


Dependency between consecutive local conformations helps assemble protein structures from secondary structures using Go potential and greedy algorithm.
Discretization of protein conformational space and fragment assembly methods simplify the search of native structures. These methods, mostly of Monte Carlo and genetic-type, do not exploit, however, the fact that short fragments describing consecutive parts of proteins are conformation-dependent. Yet, this information should be useful in improving ab initio and comparative protein structure modeling. In a preliminary study, we have assessed the possibility of using greedy algorithms for protein structure reconstruction based on the assembly of fragments of four-residue length. Greedy algorithms differ from Monte Carlo and genetic approaches in that they grow a polypeptide chain one fragment after another. Here, we move one step further in complexity, and provide strong evidence that the dependence between consecutive local conformations during assembly makes possible the reconstruction of protein structures from their secondary structures using a Go potential. Overall our procedure can reproduce 20 protein structures of 50-164 amino acids within 2.7 to 6.5 A RMSd and is able to identify native topologies for all proteins, although some targets are stabilized by very long-range interactions.


[Risk factors for a complicated disease course in children with measles admitted to a Philippine university hospital].
To analyse the correlation of specific risk factors and measles complications in children admitted to a Philippine university medical centre. Retrospective cross-sectional study. Department of Pediatrics, De La Salle University Medical Center at Dasmarinas, a suburb of Manila, the Philippines. Information was collected on patients under 16 admitted for measles from January 1993 to May 1996, using a data collection form. Of the 180 patients included in this study, 8 (4%) died during the hospital stay, and 172 left the hospital in good condition. 61 Patients (34%) had complicated measles (pneumonia, gastroenteritis, and (or) encephalitis). Age under 2 years and stay in the service ward (as opposed to the private ward) were significantly related to complicated measles. No significant relation was found for the presence of associated illnesses or malnutrition. More severe complications were seen at an early age than in industrialised countries where the frequency appears to increase with age. Malnutrition possibly contributes less to severity of the disease than environmental factors such as hygiene and social class.


Life-Threatening Contraceptive-Related Pulmonary Embolism in a 14-Year-Old Girl with Hereditary Thrombophilia.
The prothrombotic effect of combined oral contraceptives (COCs) is well-established, with a 3-6-fold increased risk of VTE compared to non-users. When initiation of COCs is considered, it is therefore of paramount importance to carefully evaluate all other potential risk factors for VTE. Based on a case of life-threatening COC-associated pulmonary embolism in a girl heterozygous for the prothrombin G20210A mutation and with a family history of thrombotic disease, we discuss the importance of assessing not just the genotype but also the phenotype when considering initiation of COCs in patients with thrombophilia. A 14-year-old girl presented with acute onset of chest pain and dyspnea followed by syncope. She was hypoxic and hemodynamically compromised at admission. Computed tomography pulmonary angiography revealed a large central "saddle" pulmonary embolism causing nearly total occlusion of the right pulmonary artery, and several minor peripheral embolisms bilaterally. She was successfully treated with thrombolysis (alteplase) followed by aPTT-adjusted heparin infusion until adequate anticoagulation with warfarin was achieved. Two years earlier, the patient had been found heterozygote for the prothrombin G20210A mutation, and 9 months before admission she had initiated use of second-generation COCs. Hereditary thrombophilia and a family history of early-onset venous thromboembolism (VTE) each pose an increased risk of VTE and should be considered as separate, irreversible risk factors. Other contraceptive methods should be used when treatment with COCs is expected to result in an unacceptable high risk of VTE.


The role of Rac1 and Rac2 in bacterial killing.
The small Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 have distinct roles in regulating neutrophil chemotaxis; however, little is known about their possible unique roles in mediating bacterial killing. To elucidate the relative roles of Rac1 and Rac2 in regulating neutrophil-mediated bacterial killing, we utilized the previously described mice model in which mouse neutrophils are deficient in either Rac1, Rac2, or both isoforms. We demonstrate here that while both Rac isoforms are required for normal neutrophil chemotaxis and bacterial killing, they have non-overlapping roles in bacterial phagocytosis and NADPH oxidase function.


Nutrition and the science of disease prevention: a systems approach to support metabolic health.
Progress in nutritional science, genetics, computer science, and behavioral economics can be leveraged to address the challenge of noncommunicable disease. This report highlights the connection between nutrition and the complex science of preventing disease and discusses the promotion of optimal metabolic health, building on input from several complementary disciplines. The discussion focuses on (1) the basic science of optimal metabolic health, including data from gene-diet interactions, microbiome, and epidemiological research in nutrition, with the goal of defining better targets and interventions, and (2) how nutrition, from pharma to lifestyle, can build on systems science to address complex issues.


Cholinergic alterations by exposure to pesticides used in control vector: Guppies fish (Poecilia reticulta) as biological model.
Spinosad and temephos are two of the most used pesticides in Mexico for the control of vector causing disease such as dengue, chikungunya and Zika. The aim of this study was to compare the neurotoxic effects of these two pesticides using guppy fish (Poecilia reticulata) as a model organism. Guppies were exposed for 7 and 21 days to technical grade temephos and spinosad at 1.0 and 0.07 g/L, respectively, (10 and 0.5 mg/L of active substance; concentrations recommended by the Ministery of Health of the State (Secretaría de Salud de Nayarit (SSN) Mexico)). Subsequently, acetylcholinesterase activity (AChE) and acetylcholine concentrations (ACh) in muscle tissue were determined. Temephos exposure decreased AChE activity and increased ACh concentration, whereas exposure to spinosad only increased ACh concentration. Though cholinergic alterations were more severe in fish exposed to temephos, both pesticides were equally lethal during the first seven days after exposure. Nonetheless, temephos was more lethal after 21 days.


Influence of high altitude exposure on the immune system: a review.
High altitude may be defined as elevations as low as 1500 meters to those as high as 8800 meters. Very few studies have been conducted so far at high altitude for the specific purpose of monitoring different immune parameters in humans. Military personnel and mountaineers may be required to perform in environmental extremes such as high altitude. The stressors they experience are numerous and varied, e.g., high altitude, humidity and the availability of food and water, prolonged moderate to heavy physical activities, limited or inadequate sleep, increased susceptibility to infection and injury, etc. In this article we review the immunological consequences of high altitude exposure.


Exploratory factor analysis of the reintegration to normal living index in a stroke population.
The reintegration to normal living index (RNLI) is a global assessment of patient quality of life often utilized in stroke populations. Previous studies in various general disability samples have consistently reported a two-factor solution for the RNLI. Despite its common use with stroke patients, the RNLI has not been psychometrically evaluated in an exclusively stroke sample. This study is believed to represent the first factor analysis of the RNLI using a sample comprised exclusively of individuals who have survived cerebral infarct. The aim of this study is to evaluate the psychometric properties of the RNLI in assessing quality of life of stroke survivors. We retrospectively examined RNLI scores of 928 adults with strokes of varying severities as part of a multidisciplinary, interinstitutional collaboration across an academic medical center, acute care hospital, and rehabilitation center. We utilized a principal component factor analysis to evaluate the factor structure of the RNLI. Mean RNLI scores ±SD for the sample were 75.26 ± 19.85, ranging between 20 and 100. The Cronbach α was .94. A scree test for factor retention strongly suggested a single factor solution, explaining 64.50% of the total variance. Previous factor analyses on the RNLI utilizing general disability samples commonly report a two-factor solution. Our data support the presence of a single factor solution across the RNLI within a large sample comprised exclusively of stroke survivors. This suggests that the RNLI acts as more of a unitary measure of quality of life within a stroke sample relative to other disabled samples.


[Prenatal screening for cleft lip].
Echography is a medical imaging technique based on the transmission to and the reflection of ultrasound from biological tissues. Used in obstetrics it can detect minor as well as more severe fetal pathologies well before birth. The prenatal diagnosis of facial clefts and their precise anatomic evaluation give the surgeon vital information for a prenatal consultation that will greatly aid parents and medical personnel in treating and caring for the infant.


Consequences of rapid fertility decline in the Republic of Korea: issues and solutions.
During the last 3 decades, efforts to deal with population problems in Korea have focused largely on reducing population growth. The national population control program has been a major means of achieving this goal. Between the early 1960s and 1990, evidence from a national survey indicates that the percent of current use of contraception rose from about 12% to 80% and the total fertility rate fell to 1.6. representing 1 of the most rapid fertility transitions in the developing world. In conjunction with this rapid reduction in fertility, mortality also improved significantly during this period. Thus, Korea has virtually completed the demographic transition from high birth and death rates to low birth and death rates during the same period. It is widely recognized that Korea has reached demographic maturity and has also achieved remarkable economic development at the same time. The world's demographic history shows that the demographic transition which almost every industrialized country has gone through from a predominantly rural, illiterate society with high birth and death rates, to a predominantly rural, illiterate society with high birth and death rates, to a predominantly urban, educated society with low birth and death rates usually takes well over a century, but in Korea, that process has taken only a few decades. On the other hand, the consequences of a rapid fertility decline bring about various demographic and social issues which we have to take into consideration for future socioeconomic development policy concerning the well-being of the Korean people. Some of issues for policy consideration can be broadly summarized as follows: 1) gradual imbalance of sex ratio at birth due to traditional son preference behavior; 2) latent effect of inevitable population aging and increasing dependency burden on behalf of the elderly for the public sector; 3) changes in family life cycle and rapid transformation form a large to a small family; 4) increasing demand for now social roles for women, supported by easing of child care burdens within households.


Clinical signs and laboratory markers in predicting progression to AIDS in HIV-1 infected patients.
In a prospective longitudinal study 89 men with HIV-1 infection were observed for a mean time of 51 months with regard to clinical signs and laboratory findings predictive of progression to AIDS/opportunistic infection (OI). In a bivariate regression analysis the clinical signs showing a significant relation to AIDS development were: dermatitis of the face, yellow toe nail changes, hairly leukoplakia and oral candidiasis. The laboratory findings significantly associated with progression to AIDS were: decrease of the relative and absolute number of CD4 lymphocytes, decrease of the CD4/CD8 ratio, HIV p24 antigenaemia, lack of anti-HIV p24, elevated erythrocyte sedimentation rate, anaemia and elevated serum-beta-2-microglobulin. The relative number (%) of CD4 cells was found superior to the absolute number and the CD4/CD8 ratio. In a multivariate regression analysis decrease of CD4 lymphocytes and lack of anti-HIV p24 were independently associated with subsequent AIDS/OI development.


Effects of neural mobilizations through movement representation techniques for the improvement of neural mechanosensitivity of the median nerve region: a randomized controlled trial.
The main objective was to compare the effects of neural mobilization (NM), NM performed through mirror therapy (MT), NM performed through action observation (AO) training and finally classic rehabilitation program (mobility and strength) exercises on neural mechanosensitivity, widespread of proximal and distal pain and pressure pain thresholds (PPT). The second objective was to assess the effects of these interventions on handgrip strength, conditioned pain modulation, motor imagery ability and temporal summation. Single-blinded randomized controlled trial. Fifty-four healthy subjects were randomly assigned to each group. Neural mechanosensitivity, widespread pain and PPT were the main variables. The secondary variables included handgrip strength, conditioned pain modulation, motor imagery ability and temporal summation. All groups showed significant differences in time*factor for neural mechanosensitivity (p = 0.001), PPT in the dermatome of the median nerve (p = 0.007), PPT at carpal tunnel (p < 0.05) and proximal widespread (p = 0.01). No differences were found for distal widespread, conditioned pain modulation, handgrip strength motor imagery ability or temporal summation (p > 0.05). There is an absence of statistically significant differences between groups. NM through movement representation techniques can reduce mechanosensitivity and mechanical hyperalgesia in the median nerve dermatome and forearm, although no differences were found between groups.


Enigmatic MELK: The controversy surrounding its complex role in cancer.
The Ser/Thr protein kinase MELK (maternal embryonic leucine zipper kinase) has been considered an attractive therapeutic target for managing cancer since 2005. Studies using expression analysis have indicated that MELK expression is higher in numerous cancer cells and tissues than in their normal, nonneoplastic counterparts. Further, RNAi-mediated MELK depletion impairs proliferation of multiple cancers, including triple-negative breast cancer (TNBC), and these growth defects can be rescued with exogenous WT MELK, but not kinase-dead MELK complementation. Pharmacological MELK inhibition with OTS167 (alternatively called OTSSP167) and NVS-MELK8a, among other small molecules, also impairs cancer cell growth. These collective results led to MELK being classified as essential for cancer proliferation. More recently, in 2017, the proliferation of TNBC and other cancer cell lines was reported to be unaffected by genetic CRISPR/Cas9-mediated MELK deletion, calling into question the essentiality of this kinase in cancer. To date, the requirement of MELK in cancer remains controversial, and mechanisms underlying the disparate growth effects observed with RNAi, pharmacological inhibition, and CRISPR remain unclear. Our objective with this review is to highlight the evidence on both sides of this controversy, to provide commentary on the purported requirement of MELK in cancer, and to emphasize the need for continued elucidation of the functions of MELK.


Titanium Oxo Cluster with Six Peripheral Ferrocene Units and Its Photocurrent Response Properties for Saccharides.
A unique titanium oxo cluster with a ferrocene ligand was synthesized and characterized by single crystal X-ray analysis. Six ferrocene carboxylates coordinate to a D3d Ti6O6 core to be a redox active cluster 1, [Ti6O6(OiPr)6(O2CFc)6]. An analogue 2, [Ti6O6(OiPr)6(O2CiBu)6], where the redox active ferrocene group is replaced by isobutyrate, is also reported as a contrast. The six ferrocene moieties in 1 are structurally identical to give a main redox wave at E1/2 = 0.62 V in dichloromethane investigated by cyclic voltammetry. Photocurrent responses using electrodes of clusters 1 and 2 were studied, and the response properties of 1 are better than those of 2. The electronic spectra and theoretical calculations indicate that charge transfer occurs from ferrocene to Ti(IV) in 1, and the presence of the ferrocene moiety gives efficient electron excitation and charge separation. Cluster 1 is a cooperative system of TiO cluster and redox active ferrocene. Photocurrent response properties of an electrode of 1 for four saccharides, glucose, fructose, maltose, and sucrose, were tested, and only reducing sugars were responsive. The electrode of 2 is also photocurrent responsive to saccharides, but the current densities are lower than those of redox active 1.


3D Orientational Control in Self-Assembled Thin Films with Sub-5 nm Features by Light.
While self-assembled molecular building blocks could lead to many next-generation functional organic nanomaterials, control over the thin-film morphologies to yield monolithic sub-5 nm patterns with 3D orientational control at macroscopic length scales remains a grand challenge. A series of photoresponsive hybrid oligo(dimethylsiloxane) liquid crystals that form periodic cylindrical nanostructures with periodicities between 3.8 and 5.1 nm is studied. The liquid crystals can be aligned in-plane by exposure to actinic linearly polarized light and out-of-plane by exposure to actinic unpolarized light. The photoalignment is most efficient when performed just under the clearing point of the liquid crystal, at which the cylindrical nanostructures are reoriented within minutes. These results allow the generation of highly ordered sub-5 nm patterns in thin films at macroscopic length scales, with control over the orientation in a noncontact fashion.


7,8-dihydro retinals outperform the native retinals in conferring photosensitivity to visual opsin.
The visual pigment rhodopsin presents an astonishing photochemical performance. It exhibits an unprecedented quantum yield (0.67) in a highly defined and ultrafast photoisomerization process. This triggers the conformational changes leading to the active state Meta II of this G protein-coupled receptor. The responsible ligand, retinal, is covalently bound to Lys-296 of the protein in a protonated Schiff base. The resulting positive charge delocalization over the terminal part of the polyene chain of retinal creates a conjugation defect that upon photoexcitation moves to the opposite end of the polyene. Shortening the polyene as in 5,6-dihydro- or 7,8-dihydro analogues might facilitate photoisomerization of a 9-Z and an 11-Z bond. Here we describe pigment analogues generated with bovine opsin and 11-Z 7,8-dihydro retinal or 9-Z 7,8-dihydro retinal. Both isomers readily generate photosensitive pigments that differ remarkably in spectral properties from the native pigments. In addition, in spite of the more flexible 7,8 single bond, both analogue pigments exhibit strikingly efficient photoisomerization while largely maintaining the activity toward the G-protein. These results bear upon the activation of ligand-gated signal transducers such as G protein-coupled receptors.


Breaking up and making up: The secret life of the vacuolar H+ -ATPase.
The vacuolar ATPase (V-ATPase; V1 Vo -ATPase) is a large multisubunit proton pump found in the endomembrane system of all eukaryotic cells where it acidifies the lumen of subcellular organelles including lysosomes, endosomes, the Golgi apparatus, and clathrin-coated vesicles. V-ATPase function is essential for pH and ion homeostasis, protein trafficking, endocytosis, mechanistic target of rapamycin (mTOR), and Notch signaling, as well as hormone secretion and neurotransmitter release. V-ATPase can also be found in the plasma membrane of polarized animal cells where its proton pumping function is involved in bone remodeling, urine acidification, and sperm maturation. Aberrant (hypo or hyper) activity has been associated with numerous human diseases and the V-ATPase has therefore been recognized as a potential drug target. Recent progress with moderate to high-resolution structure determination by cryo electron microscopy and X-ray crystallography together with sophisticated single-molecule and biochemical experiments have provided a detailed picture of the structure and unique mode of regulation of the V-ATPase. This review summarizes the recent advances, focusing on the structural and biophysical aspects of the field.


The delayed bloodstream clearance of Plasmodium falciparum parasites after M5717 treatment is attributable to the inability to modify their red blood cell hosts.
M5717 is a promising antimalarial drug under development that acts against multiple stages of the life cycle of Plasmodium parasites by inhibiting the translation elongation factor 2 (PfeEF2), thereby preventing protein synthesis. The parasite clearance profile after drug treatment in preclinical studies in mice, and clinical trials in humans showed a notable delayed clearance phenotype whereby parasite infected red blood cells (iRBCs) persisted in the bloodstream for a significant period before eventual clearance. In a normal P. falciparum infection iRBCs sequester in the deep circulation by cytoadherence, allowing them to avoid surveillance and clearance in the spleen. We found that M5717 blocks parasite modification of their host red blood cells (RBCs) by preventing synthesis of new exported proteins, rather than by directly blocking the export of these proteins into the RBC compartment. Using in vitro models, we demonstrated that M5717 treated ring/trophozoite stage iRBCs became less rigid, and cytoadhered less well compared to untreated iRBCs. This indicates that in vivo persistence of M5717 treated iRBCs in the bloodstream is likely due to reduced cytoadherence and splenic clearance.


Nutrient enhancement of allelopathic effects of exotic invasive on native plant species.
Many ecosystems may suffer from both nutrient enrichment and exotic plant invasions simultaneously. Much has been known that nutrient inputs can promote growth and expansion of exotic invasive plants in wetlands, and that allelopathic effects of the exotic invasive plants can inhibit the growth of coexisting native plants, contributing to their invasion success. Thus, we hypothesized that allelopathic effects of exotics on natives in invaded ecosystems can be enhanced by nutrient enrichment. To test this hypothesis, we conducted two greenhouse hydroponic experiments. One is the monoculture experiment in which a widespread exotic invasive perennial Alternanthera philoxeroides and a native perennial Ludwigia peploides subsp. stipulacea in monoculture were subjected to five levels of nutrient supply. The other is the mixture experiment in which the two species in mixture were subjected to five levels of nutrient supply, each with and without activated carbon addition. Both A. philoxeroides and L. peploides grew better under higher level of nutrient availability in monoculture experiment. In the mixture experiment, A. philoxeroides formed less total and root biomass while L. peploides formed more in response to activated carbon addition and all of the responses had larger degree at higher level of nutrient availability, indicating A. philoxeroides had significant allelopathic effects on L. peploides and the effects was significantly enhanced by nutrient enrichment. Such results support our hypothesis and reveal a novel mechanism for exotic plant invasion in eutrophicated and invaded wetlands, i.e. nutrient enhancement of allelopathic effects of exotics on natives.


Parkinson's disease and the effect of lexical factors on vowel articulation.
Lexical factors (i.e., word frequency and phonological neighborhood density) influence speech perception and production. It is unknown if these factors are affected by Parkinson's disease (PD). Ten men with PD and ten healthy men read CVC words (varying orthogonally for word frequency and density) aloud while audio recorded. Acoustic analysis was performed on duration and Bark-scaled F1-F2 values of the vowels contained in the words. Vowel space was larger for low-frequency words from dense neighborhoods than from sparse ones for both groups. However, the participants with PD did not show an effect of density on dispersion for high-frequency words.


Social determinants of good hand-washing practice (GHP) among adolescents in a rural Indian community.
A cross-sectional study was conducted in 5 randomly selected villages to assess prevalence of good hand-washing practice (GHP) among adolescents, and describe the social determinants. The prevalence of adolescent GHP was 32.1% (95% CI = 27.1, 37.1). Logistic regression established 5 significant positive predictors-maternal GHP, presence of sanitary latrine, availability of soap at hand-washing locations, in-house water supply, and higher per capita income. Our research provides a scope for better understanding of the socioeconomic determinants of GHP in a rural Indian setting, and may find implications in the Total Sanitation Campaign launched by Government of India.


Global Threats From Preventable Injuries.
Preventable injuries kill thousands of the world's population every day and injure millions each year. Road traffic crashes and opioid drug misuse are major causes of these injuries. Increased efforts are needed to promote strong policies, develop new prevention strategies, and protect workers from these global public health threats.


A novel cDNA transcript inversely regulated to osteocalcin in differentiating osteoblast-like cells.
In vitro MC3T3-E1 osteoblastic cells differentiate from a preosteoblastic to a mature osteoblastic phenotype constitutively expressing osteocalcin. For this process cell contacts seem to be an essential prerequisite. Using differential display of mRNA from subconfluent and confluent MC3T3-E1 cultures, we isolated and cloned a novel cDNA transcript, named Mc2, exhibiting an open reading frame of 162 bp and without extensive homologies to sequences in the EMBL database. The presence of the Mc2 mRNA was verified in primary mouse osteoblasts. Mc2 mRNA was upregulated during the transition of MC3T3-E1 cell cultures from subconfluence to confluence. In long-term cultures, Mc2 mRNA expression reached a maximum between days 8 and 12, and decreased again on day 21, when osteocalcin expression significantly increased. Treatment of these cells with by 3,3',5-triiodo-l-thyronine resulted in an inhibition of the culture time-dependent upregulation of Mc2 mRNA, whereby osteocalcin mRNA was highly expressed. This inverse regulation of Mc2 and osteocalcin mRNAs was also found in ROS 17/2.8 cells and in mouse bone marrow stromal cells. Transfection experiments showed that uncontrolled expression of a Mc2-GFP vector led to increased cell death in MC3T3-E1 cells. The transient upregulation of Mc2 mRNA in osteoblast-like cells and its interesting inverse regulation to osteocalcin suggest an important role in osteoblastic differentiation.


Graves orbitopathy: update on diagnosis and therapy.
Graves orbitopathy (GO) is an autoimmune disorder representing the most frequent extrathyroidal manifestation of Graves disease. It is rare, with an age-adjusted incidence of approximately 16.0 cases per 100,000 population per year in women and 2.9 cases per 100,000 population per year in men. GO is an inflammatory process characterized by edema and inflammation of the extraocular muscles and an increase in orbital connective tissue and fat. Despite recent progress in the understanding of its pathogenesis, GO often remains a major diagnostic and therapeutic challenge. It has become increasingly important to classify patients into categories based on disease activity at initial presentation. A Hertel exophthalmometer measurement of >2 mm above normal for race usually categorizes a patient as having moderate-to-severe GO. Encouraging smoking cessation and achieving euthyroidism in the individual patient are important. Simple treatment measures such as lubricants for lid retraction, nocturnal ointments for incomplete eye closure, prisms in diplopia, or botulinum toxin injections for upper-lid retraction can be effective in mild cases of GO. Glucocorticoids, orbital radiotherapy, and decompression/rehabilitative surgery are generally indicated for moderate-to-severe GO and for sight-threatening optic neuropathy. Future therapies, including rituximab aimed at treating the molecular and immunological basis of GO, are under investigation and hold promise for the future.


[Eosinophil apoptosis and asthma].
Eosinophils play an important role in airway inflammation in asthma. Eosinophils are believed through the release of their mediators to develop the irreversible structural airway changes. Dysregulation of apoptosis can lead to pathological accumulation of eosinophils in bronchial tissue. Apoptosis (programmed cell death) leads to the characteristic morphologic changes including reduction of the cellular volume, blebbing of the membrane, condensation of the nuclear chromatin, DNA laddering, mitochondrial dysregulation and finally to apoptotic bodies. Apoptosis can be induced by oncogenes, specific ligands and some cytokines. On the other hand IL-5, IL-3 and GM-CSF (granulocyte-macrophage-colony stimulating factor) dramatically increase the life span of eosinophils. Glucocorticoids promote eosinophil apoptosis and totally reverse the delayed death cased by beta2-agonists.


[Biological weapons and biological defence in Denmark].
Biological weapons have been known for centuries, and since World War II, offensive programs have accelerated the development of these weapons considerably. The anthrax attacks in the fall 2001 and speculations regarding the research and development of Iraqi bioweapons have been causes for concern. The effect of biological weapons may be overwhelming, in particular when one is dealing with a contagious agent. The National Centre for Biological Defence provides a preparedness capability through evidence-based research and practical operational capabilities.


Identifying Individuals With Mild Cognitive Impairment Using Working Memory-Induced Intra-Subject Variability of Resting-State EEGs.
Individuals with mild cognitive impairment (MCI) are at high risk of developing into dementia (e. g., Alzheimer's disease, AD). A reliable and effective approach for early detection of MCI has become a critical challenge. Although compared with other costly or risky lab tests, electroencephalogram (EEG) seems to be an ideal alternative measure for early detection of MCI, searching for valid EEG features for classification between healthy controls (HCs) and individuals with MCI remains to be largely unexplored. Here, we design a novel feature extraction framework and propose that the spectral-power-based task-induced intra-subject variability extracted by this framework can be an encouraging candidate EEG feature for the early detection of MCI. In this framework, we extracted the task-induced intra-subject spectral power variability of resting-state EEGs (as measured by a between-run similarity) before and after participants performing cognitively exhausted working memory tasks as the candidate feature. The results from 74 participants (23 individuals with AD, 24 individuals with MCI, 27 HC) showed that the between-run similarity over the frontal and central scalp regions in the HC group is higher than that in the AD or MCI group. Furthermore, using a feature selection scheme and a support vector machine (SVM) classifier, the between-run similarity showed encouraging leave-one-participant-out cross-validation (LOPO-CV) classification performance for the classification between the MCI and HC (80.39%) groups and between the AD vs. HC groups (78%), and its classification performance is superior to other widely-used features such as spectral powers, coherence, and the complexity estimated by Katz's method extracted from single-run resting-state EEGs (a common approach in previous studies). The results based on LOPO-CV, therefore, suggest that the spectral-power-based task-induced intra-subject EEG variability extracted by the proposed feature extraction framework has the potential to serve as a neurophysiological feature for the early detection of MCI in individuals.


Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China.
Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor, has been shown to be effective in treatment of diabetic peripheral neuropathic pain and approved for the management of patients with diabetic peripheral neuropathic pain (DPNP) in the United States, European Union, and many other countries. This study assessed the efficacy and safety of duloxetine in Chinese patients with diabetic peripheral neuropathic pain. This double-blind, randomized, placebo-controlled, flexible-dose study treated adult patients with diabetic peripheral neuropathic pain and baseline Brief Pain Inventory (BPI) 24-hour average pain severity ratings ≥ 4 with duloxetine 60 mg to 120 mg once daily or placebo for 12 weeks. Dose adjustments of duloxetine or matching placebo were based upon investigator's judgment of clinical response. Change from baseline to endpoint in BPI average pain was the primary efficacy outcome. Secondary outcome measures included BPI-severity and -Interference, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, EuroQol: 5 Dimensions, Athens Insomnia Scale, and safety measures. Of 215 patients randomized, 88.4% and 82.1% of patients in placebo and duloxetine groups, respectively, completed the study. Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups (P = 0.124). Duloxetine- treated patients showed significantly greater pain reduction compared with those in placebo group at weeks 1, 2, and 4 (P = 0.004, P = 0.009, and P = 0.006, respectively), but not at weeks 8 (P = 0.125) and 12 (P = 0.107). Duloxetine-treated patients experienced statistically significant improvement in Patient Global Impression of Improvement, Clinical Global Impression of Severity, area under the curve for pain relief, BPI-severity pain right now, and BPI-interference walking ability. Patients treated with duloxetine 120 mg once daily showed significantly greater pain reduction on the Brief Pain Inventory average pain score relative to placebo. Duloxetine-treated patients reported nausea, somnolence, anorexia, and dysuria significantly more than placebo. Although the primary study endpoint was not achieved, the overall observed response pattern suggests the efficacy of duloxetine in the treatment of Chinese patients with diabetic peripheral neuropathic pain. The safety profile for duloxetine is similar to that reported in other global trials.


Circadian and homeostatic variation in sustained attention.
Human performance is modulated by circadian rhythms and homeostatic changes. Changes in efficiency in the performance of many tasks might be produced by variation in a basic cognitive process, such as sustained attention. This cognitive process is the capacity to respond efficiently to the environment during prolonged periods (from minutes to hours). There are three indices of sustained attention: general stability of efficiency, time on task stability, and short-term stability. The objective of this work was to analyze circadian and homeostatic influences on the indices of sustained attention. Participants were nine undergraduate female student volunteers (mean age 17.67 yrs, SD = 1.00, range 16-19 yrs) who attended school from 07:00-13:30 h, Monday to Friday. They were assessed while adhering to a modified 28 h constant-routine protocol during which feeding, room temperature, motor activity, and room illumination were controlled. Rectal temperature was recorded each minute, and indices of sustained attention were assessed hourly through a continuous performance task (CPT). General stability was measured as standard deviation of correct responses and reaction time, time on task stability was measured as the linear regression of correct responses and reaction time throughout the task, and short-term stability was measured as hit runs and error runs. Rectal temperature showed circadian variation; subjective somnolence and tiredness increased, while general performance and all indices of sustained attention declined throughout the 28 h recording session. General stability exhibited circadian variation, whereas time on task did not. Short-term stability showed circadian variations in short-error runs, long-error runs, and short-hit runs, but long-hit runs did not. There was a 26 sec short interval at the beginning of the task, characterized by a very high efficiency level of performance. Execution during this safe period was not affected by time awake and did not show circadian variation. Overall, these results suggest a dissociation of the effects of circadian and homeostatic factors on the indices of sustained attention. General stability, short- and long-error runs, and short-hit runs were modulated by both a homeostatic factor and a circadian effect, while long-hit runs and time on task stability were modulated only by a homeostatic factor and did not show circadian variation. There was also a 26 sec "safe period" that seems to be independent of circadian and homeostatic influences. These results suggest that performance at work deteriorates at the end of a shift due to a decrease in general stability, an increase in error runs, decrease of long-hit runs, and decline with time on task. Night shiftworkers are exposed to an additional deterioration of performance during the nighttime due to a decrease in general stability and an increase in error runs.


Assessing the blinking state of fluorescent quantum dots in free solution by combining fluorescence correlation spectroscopy with ensemble spectroscopic methods.
The current method for investigating the blinking behavior is to immobilize quantum dots (QDs) in the matrix and then apply a fluorescent technique to monitor the fluorescent trajectories of individual QDs. So far, no method can be used to directly assess the blinking state of ensemble QDs in free solution. In this study, a new method was described to characterize the blinking state of the QDs in free solution by combining single molecule fluorescence correlation spectroscopy (FCS) with ensemble spectroscopic methods. Its principle is based on the observation that the apparent concentration of bright QDs obtained by FCS is less than its actual concentration measured by ensemble spectroscopic method due to the QDs blinking. We proposed a blinking index (Kblink) for characterizing the blinking state of QDs, and Kblink is defined as the ratio of the actual concentration (Cb,actual) measured by the ensemble spectroscopic method to the apparent concentration (Cb,app) of QDs obtained by FCS. The effects of certain factors such as laser intensity, growth process, and ligands on blinking of QDs were investigated. The Kblink data of QDs obtained were successfully used to characterize the blinking state of QDs and explain certain experimental results.


[Study on serum erythropoietin levels in patients with hematologic malignancies].
To study whether hematologic malignancy patients with anemia have a lower erythropoietin (EPO) response. Serum EPO levels were detected by ELISA in patients with hematologic malignancies and with iron deficiency anemia (IDA). Eighty patients with hematologic malignancies, including 13 multiple myeloma (MM), 7 chronic lymphocytic leukemia (CLL) and 60 non-Hodgkin's lymphoma (NHL) were studied. Thirty of them had anemia(21 NHL,6 MM and 3 CLL). Twenty patients with IDA were studied as the control. Hematologic malignancy patients with anemia had higher EPO levels [(97.8 +/- 183.9) IU/L] than those with normal Hb values [(27.8 +/- 85.4) IU/L; P <0.01]. In patients with IDA, serum EPO response was inversely correlated with Hb level (r= -0.5, P <0.05) , but no such inverse correlation was found in the hematologic malignancy patients with anemia (r = -0.14). After corrected for Hb level, the serum EPO levels were significantly lower in anemic patients with hematologic malignancies than in IDA patients (P = 0.032) , indicating a decreased EPO response in the former group. Anemia associated with hematologic malignancy might result from an inappropriately low EPO response. EPO treatment for these patients may be beneficial.


Simultaneous cranial subarachnoid hemorrhage and spinal subdural hematoma.
We report a rare case of simultaneous cranial subarachnoid and spinal subdural hematoma (SDH) in a 42-year-old man who was on Warfarin therapy after cardiac bypass surgery. Computed tomography at presentation revealed a cranial subarachnoid hemorrhage, and spinal Magnetic Resonance Imaging (MRI) showed a spinal SDH extending from the T6 to L5 segments. He had paraparesis due to spinal cord compression. The patient was managed conservatively due to his poor general condition and was infused with intravenous steroid therapy, but he experienced sudden cardiac arrest 5 hours later after being admitted to the hospital. This case is of interest because of its first presentation of spinal subdural hematoma and cranial subarachnoid hemorrhage simultaneously and it is also the second longest vertebral segmental spread in the literature.


High-speed atomic force microscopy directly visualizes conformational dynamics of the HIV Vif protein in complex with three host proteins.
Vif (viral infectivity factor) is a protein that is essential for the replication of the HIV-1 virus. The key function of Vif is to disrupt the antiviral activity of host APOBEC3 (apolipoprotein B mRNA-editing enzyme catalytic subunit 3) proteins, which mutate viral nucleic acids. Inside the cell, Vif binds to the host cell proteins Elongin-C, Elongin-B, and core-binding factor subunit β, forming a four-protein complex called VCBC. The structure of VCBC-Cullin5 has recently been solved by X-ray crystallography, and, using molecular dynamics simulations, the dynamics of VCBC have been characterized. Here, we applied time-lapse high-speed atomic force microscopy to visualize the conformational changes of the VCBC complex. We determined the three most favorable conformations of this complex, which we identified as the triangle, dumbbell, and globular structures. Moreover, we characterized the dynamics of each of these structures. Our data revealed the very dynamic behavior of all of them, with the triangle and dumbbell structures being the most dynamic. These findings provide insight into the structure and dynamics of the VCBC complex and may support efforts to improve HIV treatment, because Vif is essential for virus survival in the cell.


Vibrational characteristics of harp soundboards.
Harps exist in different forms, from large factory-made concert harps to small hand-made folk harps. This variety presents both a challenge and an opportunity for acousticians. The musical quality of a harp depends on many factors, but key among these is the soundboard. This work sets out to define some general desirable qualities of a harp soundboard. First, in order to understand the relationship between the vibrational behavior of a bare soundboard and that of a completed instrument, a 36-string harp was built from scratch. Measurements were made at each stage of construction, and the results showed how the bare soundboard properties affect those of the finished harp. Second, the soundboards of several harps of different sizes were assessed by measuring the admittances along the string bar. These data showed that one relationship crucial to the quality of the soundboard is that between the modal shapes and modal frequencies of the soundboard, and the position and fundamental frequencies of the strings attached to it. A general statement is made about this relationship, one which should be of use to harp makers.


Validation of the Greek version of the Accommodation and Enabling Scale for Eating Disorders (AESED).
Eating disorders-related research has shown that families, in order to alleviate family conflict and stress, accommodate the symptoms of individuals with eating disorders. It has been argued that by tolerating or alleviating symptoms, the latter may gradually be reinforced or even fully accepted, as the family becomes increasingly "trapped" in specific eating patterns, weight control behaviors, and body shape worries. The Accommodation and Enabling Scale for Eating Disorders was created in 2009, aiming to assess family adaptability of individuals with eating disorders. The purpose of the present research was to test the psychometric properties of the Greek version of the scale in a sample of parents of individuals with eating disorders. The translation procedure was carried out based on the forward-backward method, while the study was conducted at the Eating Disorders Clinic of the First Psychiatric Clinic of Aiginiteion Hospital. The convenience sampling methods were used for the sample's recruitment. Respondents reported on their basic demographic characteristics, and completed the General Health Questionnaire-28, and the Accommodation and Enabling Scale for Eating Disorders. The final study's sample consisted of 125 parents of individuals with eating disorders (69.6% women), with a mean age of 55.2 years. Factor analysis revealed a five-factor model, similar to that of the original version of the scale, with the model explaining 63.3% of the total variance. Internal consistency was judged to be high, with Cronbach's coefficient a being 0.93 for the scale's total score, while Cronbach's α for the five subscales ranged from 0.78 to 0.90. Convergent validity was tested with the Spearman's coefficient rho, which revealed a statistically significant correlation of the weighted scale with the General Health Questionnaire (rho=0.33, p<0.5). The results showed that the Greek version of the Accommodation and Enabling Scale for Eating Disorders is a valid and reliable tool for assessing the adaptability of families of people suffering from eating disorders. Application of the tool to larger samples will validate its psychometric properties on a larger scale.


[Biochemical study on the thyrotropic activity in urinary immunoreactive-human chorionic gonadotropin of patients with trophoblastic disease].
We have studied the biochemical properties of urinary immunoreactive-human Chorionic Gonadotropin (IR-hCG) using the human thyroid gland in vitro slice method to investigate the thyrotropic activity in purified IR-hCG of patients with thyroid hyperfunction associated with trophoblastic disease. IR-hCG was extracted using a kaolin-acetone-alcohol concentration and purified by DEAE Cellulose, Sephadex G-100 and DEAE Sephacel column chromatographies according to Nishimura et al. with slight modifications. The substance with thyrotropic activity (hCT) was found in 3 cases of trophoblastic disease with hyperthyroidism among the 14 cases investigated. HCT consists of two dissimilar subunits, namely, hCT alpha-subunit and hCT beta-subunit like hCG, whose molecular weights are estimated at about 15,000 and 20,000 respectively and have carbohydrate moiety bound to concanavalin A. The thyrotropic activity was shown by the recombinant hybrid molecules, hCT beta-subunit and hCG alpha-subunit, whereas no potency was found in hCT beta-subunit only. The carboxyterminal residues of hCT (Ile-Leu-Pro-Glu) were not digested by carboxypeptidases Band Y. These results suggest that hCT is an intrinsic activity of hCG and cross-reacts immunologically, while the amino acid residues of the carboxyterminus of the hCT beta-subunit are different from those of the hCG beta-subunit.


Implantation in coronary circulation induces morphofunctional transformation of radial grafts from muscular to elastomuscular.
The purpose of this research was to investigate the in vivo morphofunctional changes induced in the radial artery (RA) by its use as coronary artery bypass conduit by comparing the morphological features and vasoreactivity of the native RA versus the coronary RA graft in the same patient. Ten years after surgery, 10 patients were submitted to intravascular ultrasound examination of the RA graft of the controlateral (in situ) RA and of the internal thoracic artery (ITA) graft and to vasoactive challenges with acetylcholine and serotonin. Quantitative angiographic assessment showed that the mean diameter of the RA coronary grafts was significantly larger than that of the in situ RA and of the ITA (2.89+/-0.40 mm RA grafts, 2.14+/-0.52 mm in situ RA, 2.25+/-0.53 mm ITA grafts; P<0.001). The in situ RA demonstrated a typical muscular architecture, whereas RA coronary grafts showed a clear reduction of the thickness of the medial layer and had a less well-defined muscular component of the media with interposition of elastic tissue. Serotonin endovascular infusion elicited a strong spastic reaction in in situ RAs; the same challenge induced only moderate constriction in RA and ITA coronary grafts. Implantation in the coronary circulation leads to major anatomic and vasoreactive modifications of the RAs that tend to lose the morphofunctional features of a muscular conduit and assume those of an elastomuscular artery, such as the ITA.


[Migraine--the repercussions on functioning and quality of life, treatment and the doctor-patient relationship in Israel].
Migraines are a common illness affecting the functioning and quality of life of its sufferers. Research indicates that doctors tend to underrate the severity of this ailment and as such, do not always provide an adequate solution, including specific migraine treatment. The survey aimed to examine the repercussions of migraines on functioning, quality of life, widespread treatment of the disease and the doctor-patient relationship in Israel. The survey was conducted by means of a telephone poll consisting of 200 women suffering from migraines and treated with drugs. It was found that migraines, despite current treatment, impair the patient's functioning, lead to work absenteeism (51%) and have a negative effect on social life and leisure activities (80%). To our surprise, only half of the patients complained of their migraine attacks to their family physician, less than half of them (48%) take prescription drugs and only 10% are treated with medication prescribed specifically for migraines (Triptan). This survey shows that in Israel there is room for improvement in each one of the examined fields for the well-being of the patient, the patient's family, social environment and work place.


Brain atrophy predicts mortality after mechanical thrombectomy of proximal anterior circulation occlusion.
Brain atrophy is associated with an inferior functional outcome in patients undergoing mechanical thrombectomy (MT) for acute ischemic stroke. We hypothesized that brain atrophy determined from pre-interventional non-contrast-enhanced CT scans would also be linked to increased mortality in this cohort. A total of 204 patients treated with MT for acute occlusions of the internal carotid artery (ICA) or the M1 segment of the middle cerebral artery (M1) at Tampere University Hospital, Finland between 2013 and 2017 were retrospectively studied. Brain atrophy index (BAI), masseter muscle surface area and density, chronic ischemic lesions, and white matter lesions were evaluated from pre-interventional CT studies. Logistic regression was applied in analyzing the association of BAI with 3-month mortality. Median age at baseline was 69.9 years (IQR 15.6) and mortality at 3 months was 13.2% (n=27). BAI, measured with excellent reproducibility (intraclass correlation coefficient ≥0.894, p<0.001), was significantly associated with age (r=0.54), white matter lesions (r=0.43), dental status (r=-0.31), masseter area (r=-0.24), masseter density (r=-0.28), and chronic ischemic lesions (r=0.24) (p≤0.001 for all). In univariable analysis, BAI demonstrated a strong association with mortality (OR 2.02, 95% CI 1.34 to 3.05, per 1 SD increase), and none of the other factors associated with mortality remained as significant when included in the same multivariable model. The results remained similar when extending the follow-up up to 2.5 years. Brain atrophy predicts 3-month mortality after MT of the ICA or the M1 independent of age, masseter sarcopenia, chronic ischemic lesions, or white matter lesions.


Irradiated tumor cell vaccine for treatment of an established glioma. I. Successful treatment with combined radiotherapy and cellular vaccination.
Rats bearing a 5-day intracranial (i.c.) syngeneic glioma were treated with a subcutaneous (s.c.) vaccination consisting of irradiated glioma cells or a multimodality approach composed of radiotherapy plus s.c. vaccination. Vaccination of rats harboring a T9 glioma with 5 x 10(6) irradiated T9.F glioma cells (a clone derived from the T9 glioblastoma cell line) resulted in a marked enhancement of i.c. glioma growth and a significant decrease in survival. Histopathology of the tumors from vaccinated rats revealed a massive glioma composed of healthy tumor tissue lacking any marked inflammation, edema or hemorrhage. Analysis of the tumor-infiltrating mononuclear cells indicated that gliomas from vaccinated rats contained a 10-fold greater lymphoid infiltrate per milligram of tumor as compared to tumors from non-vaccinated rats, suggesting that the vaccination had induced immune cells to localize to the i.c. glioma. Combined treatment consisting of 15 Gy of whole head irradiation of the 5-day glioma followed by vaccination with T9.F cells resulted in a significant increase in survival compared to that of non-treated rats, 45% of which remained tumor-free. Microscopic evaluation in survivors of the tumor implantation site revealed the presence of hemosiderin-laden macrophages and other mononuclear cells, with the absence of tumor cells within the residual lesion. When survivors were challenged s.c. with viable T9.F glioma cells, a delayed-type hypersensitivity (DTH) reaction appeared at the challenge site. T cells purified from these rats proliferated and secreted Th(1)-associated cytokines when stimulated with irradiated T9.F glioma cells, and lysed T9.F target cells. In contrast, when these rats were challenged s.c. with the unrelated MadB106 adenocarcinoma, tumor formation was observed. These findings indicate that the treatment of an established i.c. glioma with a cellular vaccination alone may induce enhanced tumor growth; however, when the vaccination is combined with radiation therapy, the results are beneficial in terms of increased survival time or complete remission that is accompanied by the development of tumor-specific cellular immunity.