Research on High Precision Stiffness Modeling Method of Redundant Over-Constrained Parallel Mechanism.
Traditional stiffness modeling methods do not consider all factors comprehensively, and the modeling methods are not unified, lacking a global stiffness model. Based on screw theory, strain energy and the virtual work principle, a static stiffness modeling method for redundant over-constrained parallel mechanisms (PMs) with clearance was proposed that considers the driving stiffness, branch deformation, redundant driving, joint clearance and joint contact deformation. First, the driving stiffness and branch deformation were considered. According to the strain energy and Castiliano's second theorem, the global stiffness matrix of the ideal joint mechanism was obtained. The offset of the branch was analyzed according to the restraint force of each branch. The mathematical relationship between the joint clearance and joint contact deformation and the end deformation was established. Based on the probability statistical model, the uncertainty of the offset value of the clearance joint and the contact area of the joint caused by the coupling of the branch constraint force was solved. Finally, taking a 2UPR-RR-2RPU redundant PM as an example, a stiffness simulation of the mechanism was carried out using the finite element method. The research results show that the high-precision stiffness modeling method proposed in this paper is correct, and provides an effective method for evaluating the stiffness performance of the PM.


Licorice-induced hypertension: a case of pseudohyperaldosteronism due to jelly bean ingestion.
Hypertension is one of the most common problems encountered in the primary care setting. Numerous secondary causes of hypertension exist and are potentially reversible. The ability to screen for such causes and manage them effectively may spare patients from prolonged medical therapy and hypertensive complications. Licorice can cause hypertension and hypokalemia due its effects on cortisol metabolism. We report a case of jelly bean ingestion that highlights the presentation, pathophysiology and management of licorice-induced hypertension.


The electrolarynx: voice restoration after total laryngectomy.
The ability to speak and communicate with one's voice is a unique human characteristic and is fundamental to many activities of daily living, such as talking on the phone and speaking to loved ones. When the larynx is removed during a total laryngectomy (TL), loss of voice can lead to a devastating decrease in a patient's quality of life, and precipitate significant frustration over their inability to communicate with others effectively. Over the past 50 years there have been many advances in techniques of voice restoration after TL. Currently, there are three main methods of voice restoration: the electrolarynx, esophageal speech, and tracheoesophageal speech through a tracheoesophageal puncture (TEP) with voice prosthesis. Although TEP voice is the current gold standard for vocal rehabilitation, a significant minority of patients cannot use or obtain TEP speech for various reasons. As such, the electrolarynx is a viable and useful alternative for these patients. This article will focus on voice restoration using an electrolarynx with the following objectives: 1) To provide an understanding of the importance of voice restoration after total laryngectomy. 2) To discuss how the electrolarynx may be used to restore voice following total laryngectomy. 3) To outline some of the current electrolarynx devices available, including their mechanism of action and limitations. 4) To compare pros and cons of electrolaryngeal speech to TEP and esophageal speech.


Family and twin studies in systemic lupus erythematosus.
We have estimated how much of the total genetic predisposition to SLE may be attributable to genes outside the HLA region by comparing figures for concordance of SLE in monozygotic twins with those for concordance in HLA identical siblings in Australia. None of six dizygotic co-twins of white Australian SLE probands was concordant for SLE. One of four (25%) monozygotic co-twins of white Australian SLE probands was concordant for SLE which when added to previously published figures for Caucasoid populations gives an overall concordance rate for SLE in monozygotic twins of 25%. None of 18 HLA identical, same sex siblings of SLE probands, had definite SLE by the study criteria (i.e. less than 6%). The comparison of these figures shows that most of the genetic predisposition to SLE is attributable to genes outside the HLA region.


Performance of undergraduate dental students on ICDAS clinical caries detection after different learning strategies.
This study aimed to evaluate the effect of a digital learning tool on undergraduate dental students' performance in detecting dental caries using ICDAS. An experimental digital learning tool (DLT) was created using digital photographs of sound and carious teeth. Thirty-nine students were divided into three groups (n = 13) and each assessed 12 randomly allocated patients before and after learning strategies: G1, ICDAS e-learning program; G2, ICDAS e-learning program plus DLT; G3, no learning strategy. Students (n = 32) reassessed patients 2 weeks after training. Comparing before and after the learning strategies, any difference in the values of specificity and area under the ROC curve for all groups was found. Sensitivity was statistically significantly higher for G1 and G2. Comparing the groups, G2 showed a significant increase in sensitivity at the D2 and D3 thresholds. Spearman's correlations with the gold standard before and after the learning strategy were 0.60 and 0.61 for G1, 0.57 and 0.63 for G2, and 0.54 and 0.54 for G3, respectively. The Wilcoxon test showed a statistically significant difference between the values obtained before and after learning strategies for G1 and G2. Use of the DLT after the ICDAS e-learning program tended to increase the sensitivity of ICDAS used by undergraduate dental students. The DLT appeared to improve dental students' ability to use ICDAS.


Cloning and characterisation of a Heterodera glycines aminopeptidase cDNA.
An aminopeptidase full-length cDNA (Hg-amp-1) was cloned from the adult female soybean cyst nematode Heterodera glycines by heterologous screening of a cDNA library with a Caenorhabditis elegans EST sequence. The predicted open reading frame encoded an 882-amino acid protein containing the conserved zinc-binding domain and GAMEN motif that are characteristic of M1 family aminopeptidases. The putative protein lacks any subcellular targeting signals and displays strong similarity to puromycin-sensitive aminopeptidases from C. elegans, Drosophila and mammals. Hg-amp-1 is expressed in juvenile nematodes and both male and female adults, with highest expression in gravid females. In situ mRNA hybridisation localised the Hg-amp-1 transcript to the genital primordium of pre-parasitic juvenile nematodes and the reproductive tract of adult females. Suppression of Hg-amp-1 transcript level by RNA-interference led to a 61% reduction in the number of female nematodes parasitising soybean roots 21 days post infection with infective juvenile nematodes that had been exposed to double-stranded RNA.


Emerging roles of DNA repair factors in the stability of centromeres.
Satellite DNA sequences are an integral part of centromeres, regions critical for faithful segregation of chromosomes during cell division. Because of their complex repetitive structure, satellite DNA may act as a barrier to DNA replication and other DNA based transactions ultimately resulting in chromosome breakage. Over the past two decades, several DNA repair proteins have been shown to bind and function at centromeres. While the importance of these repair factors is highlighted by various structural and numerical chromosome aberrations resulting from their inactivation, their roles in helping to maintain genome stability by solving the intrinsic difficulties of satellite DNA replication or promoting their repair are just starting to emerge. In this review, we summarize the current knowledge on the role of DNA repair and DNA damage response proteins in maintaining the structure and function of centromeres in different contexts. We also report the recent connection between the roles of specific DNA repair factors at these genomic loci with age-related increase of chromosomal instability under physiological and pathological conditions.


Prevalence and etiological profile of chronic obstructive pulmonary disease in nonsmokers.
Tobacco smoking has been recognized as the most important risk factor for chronic obstructive pulmonary disease (COPD) for a long time, but recent studies have shown that nonsmokers also contribute to a significant proportion of COPD. This study was performed to find out the proportion of nonsmoker individuals among COPD patients and to determine various etiologies in nonsmoker COPD patients. This study was an observational cross-sectional study conducted in Department of Pulmonary Medicine, MLN Medical College, Allahabad. A total of 200 COPD patients, aged >18 years of either gender with COPD, diagnosed by clinical and spirometric criteria (GOLD guideline) were included in the study. Of the 200 COPD patients, the proportion of nonsmoker patients was 56.5%, and the smoker was 43.5%. Among 113 nonsmoker COPD patients, maximum number of patients (69.03%) belonged to low socioeconomic status but most important and statistically significant risk factor was exposure to biomass smoke (53.98%), other significant risk factors were treated pulmonary tuberculosis (32.74%), and long-standing asthma (14.16%). Risk factors that were not statistically significant were occupational exposure (9.73%), exposure to outdoor air pollution (3.54%), and lower respiratory tract infection during childhood (1.77%). The patients who were exposed to more than one risk factors, developed COPD at an earlier age. This study revealed that nonsmokers contribute a significant proportion of COPD patients. Multiple risk factors other than smoking also play a major role in the development of COPD, particularly exposure to biomass smoke, treated pulmonary tuberculosis, and long-standing asthma.


The importance of secondary trauma exposure for post-disaster mental disorder.
Interventions to treat mental disorders after natural disasters are important both for humanitarian reasons and also for successful post-disaster physical reconstruction that depends on the psychological functioning of the affected population. A major difficulty in developing such interventions, however, is that large between-disaster variation exists in the prevalence of post-disaster mental disorders, making it difficult to estimate need for services in designing interventions without carrying out a post-disaster mental health needs assessment survey. One of the daunting methodological challenges in implementing such surveys is that secondary stressors unique to the disaster often need to be discovered to understand the magnitude, type, and population segments most affected by post-disaster mental disorders. This problem is examined in the current commentary by analyzing data from the WHO World Mental Health (WMH) Surveys. We analyze the extent to which people exposed to natural disasters throughout the world also experienced secondary stressors and the extent to which the mental disorders associated with disasters were more proximally due to these secondary stressors than to the disasters themselves. RESULTS. Lifetime exposure to natural disasters was found to be high across countries (4.4-7.5%). 10.7-11.4% of those exposed to natural disasters reported the occurrence of other related stressors (e.g. death of a loved one and destruction of property). A monotonic relationship was found between the number of additional stressors and the subsequent onset of mental disorders CONCLUSIONS. These results document the importance of secondary stressors in accounting for the effects of natural disasters on mental disorders. Implications for intervention planning are discussed.


Triple therapy of warfarin, aspirin and a thienopyridine for patients treated with vitamin K antagonists undergoing coronary stenting. A review of the evidence.
Dual antiplatelet treatment of aspirin and a thienopyridine (either ticlopidine or clopidogrel) is the standard of care in patients undergoing coronary artery stenting (PCI-S). Such treatment however, is not generally applicable in patients with concomitant indication for vitamin K antagonists (VKA), in whom therefore the optimal treatment is currently undefined. According to the limited available evidence, the management of these patients is substantially variable, but triple therapy of VKA, aspirin and a thienopyridine is the most frequently adopted. Both VKA and dual antiplatelet treatment in fact are warranted to actually prevent systemic thromboembolism and stent thrombosis, although an increased haemorrhagic risk might be associated with such therapy. A substantial incidence of bleeding has been effectively observed with triple therapy in a few, small, retrospective, observational series. The risk of haemorrhage appears to increase with the duration of treatment, although concomitant factors (i.e., advanced age, presence of gastrointestinal lesions, excessive anticoagulation or traumatic manoeuvres), rather than the administration of numerous antithrombotic agents in itself, may play a role. As expected, no thromboembolic or thrombotic events have been generally reported with such treatment. Because of the limited and poor quality data currently available on the management of patients with an indication for VKA undergoing PCI-S, large-scale registries and clinical trials are warranted to determine the optimal antithrombotic treatment in this patient subset, which is foreseen to progressively increase over the next years.


Informing women on menopause and hormone therapy: Know The Menopause a multidisciplinary project involving local healthcare system.
Hormone therapy (HT) in the menopause is still a tricky question among healthcare providers, women and mass media. Informing women about hormone replacement therapy was a Consensus Conference (CC) organized in 2008: the project Know the Menopause has been launched to shift out the results to women and healthcare providers and to assess the impact of the cc's statement. And Findings: The project, aimed at women aged 45-60 years, was developed in four Italian Regions: Lombardy, Tuscany, Lazio, Sicily, each with one Local Health Unit (LHU) as "intervention" and one as "control". Activities performed were: survey on the press; training courses for health professionals; educational materials for target populations; survey aimed at women, general practitioners (GPs), and gynaecologists; data analysis on HT drugs' prescription. Local activities were: training courses; public meetings; dissemination on mass media. About 3,700 health professionals were contacted and 1,800 participated in the project. About 146,500 printed leaflets on menopause were distributed to facilitate the dialogue among women and health care professionals. Training courses and educational cascade-process activities: participation ranged 25- 72% of GPs, 17-71% of gynaecologists, 14-78% of pharmacists, 34-85% of midwives. 1,281 women interviewed. More than 90% believed menopause was a normal phase in life. More than half did not receive information about menopause and therapies. HT prescription analysis: prevalence fell from 6% to 4% in five years. No differences in time trends before-after the intervention. Major limitations are: organizational difficulties met by LHU, too short time for some local activities. A huge amount of information was spread through health professionals and women. The issue of menopause was also used to discuss women's wellbeing. This project offered an opportunity to launch a multidisciplinary, multimodal approach to menopause looking not only at pharmacological aspects, but also at quality of life and information.


Nucleotide excision by E. coli DNA polymerase I in proofreading and non-proofreading modes.
Escherichia coli DNA polymerase I exists in at least two distinct kinetic forms. When it binds to a template, the proofreading activity is usually switched off. As the enzyme progresses along the template, it becomes more and more competent for excision. This phenomenon introduces a link between fidelity and processivity. Processivity is best studied when the chain-length distributions of synthesized polymers are stationary. Even then, however, one cannot avoid multiple initiations on a given template by the same molecule of the enzyme. When synthesis is initiated with primers of lengths 15 or 20, a strange phenomenon is observed. It seems that the polymerase starts by hydrolyzing the primer down to a length of 7-10 nucleotides and only then starts to add nucleotides. It does so in a low-accuracy mode, suggesting that, while the exonuclease is clearly active, it does not contribute to proofreading. The warm-up of the proofreading function is therefore reinterpreted as a switch between two modes of behaviour: a mode 1 of low accuracy in which the 3'----5' exonuclease, while active, is uncoupled from the polymerase and does not contribute to proofreading, and a mode 2 of high accuracy in which the exonuclease is kinetically linked to the polymerase activity.


Combined smooth muscle and melanocytic differentiation in lymphangioleiomyomatosis.
Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal proliferation of immature-looking smooth muscle (SM)-like cells (LAM cells), leading to lung destruction and cyst formation. In addition to expressing some SM markers, scattered LAM cells express the melanocytic maker gp100, which is recognized by antibody HMB45, suggesting that at least a few LAM cells may have melanocytic differentiation. Here we immunostained 26 LAM samples for several melanocyte-related proteins. These studies showed that all LAM cells express tetraspanin CD63, a melanoma-associated protein that belongs to the transmembrane 4 superfamily. The majority of LAM cells also immunoreacted with PNL2, an antibody against a yet uncharacterized melanocytic antigen. Furthermore, we examined the co-expression of PNL2 and Ki-67, an indicator of cell proliferation, and found that PNL2-positive LAM cells showed a significantly lower proliferation rate compared with their negative counterparts. Our findings shed new light on the nature of the LAM cells by demonstrating their combined SM and melanocytic differentiation and the existence of subpopulations with different proliferative potential. Furthermore, these studies provided two new antibodies useful in the diagnosis of LAM.


Clinical Application of Multimodal Neuronavigation System in Neuroendoscope-Assisted Skull Base Chordoma Resection.
Skull base chordoma is a rare tumor arising from embryonic remnants of the notochord with invasive potential. Due to the destruction of osseous landmarks and invasion of surrounding structures, surgical resection is challenging. The authors explored the clinical value of a multimodal neuronavigation system in skull base chordoma resection using a neuroendoscope. Between January 2012 and January 2016, the authors utilized neuroendoscopy to excise skull base chordoma in 93 patients. The authors performed 45 operations assisted by multimodal neuronavigation (neuronavigation group) and 48 without intraoperative imaging guidance (control group). In the control group, 35 patients (73%) underwent gross total resection. In the neuronavigation group, all patients underwent gross total resection without radiographically identified bleeding. Only 1 patient (2%) in the neuronavigation group showed a temporary reduction in vision, which improved after symptomatic treatment. In contrast, there were 4 patients (8%) with postoperative complication, including 2 patients with intracranial hematoma and 2 with neurological deficits. Complication rates were higher than the neuronavigation group. In the follow-up period, 2 patients in the control group with subtotal resection had recurrence within 24 months, but without extracranial metastases. The multimodal neuronavigation system could contribute intraoperative real-time guidance for spatial relationships between lesions and adjacent neurovascular structures, as well as eroded and distorted anatomical landmarks through multiple image fusion and 3-dimensional reconstruction. It significantly improves surgical outcome and provides a new insight into the management of skull base chordomas.


Neural tracking of speech envelope does not unequivocally reflect intelligibility.
During listening, brain activity tracks the rhythmic structures of speech signals. Here, we directly dissociated the contribution of neural envelope tracking in the processing of speech acoustic cues from that related to linguistic processing. We examined the neural changes associated with the comprehension of Noise-Vocoded (NV) speech using magnetoencephalography (MEG). Participants listened to NV sentences in a 3-phase training paradigm: (1) pre-training, where NV stimuli were barely comprehended, (2) training with exposure of the original clear version of speech stimulus, and (3) post-training, where the same stimuli gained intelligibility from the training phase. Using this paradigm, we tested if the neural responses of a speech signal was modulated by its intelligibility without any change in its acoustic structure. To test the influence of spectral degradation on neural envelope tracking independently of training, participants listened to two types of NV sentences (4-band and 2-band NV speech), but were only trained to understand 4-band NV speech. Significant changes in neural tracking were observed in the delta range in relation to the acoustic degradation of speech. However, we failed to find a direct effect of intelligibility on the neural tracking of speech envelope in both theta and delta ranges, in both auditory regions-of-interest and whole-brain sensor-space analyses. This suggests that acoustics greatly influence the neural tracking response to speech envelope, and that caution needs to be taken when choosing the control signals for speech-brain tracking analyses, considering that a slight change in acoustic parameters can have strong effects on the neural tracking response.


[Successful desensitization using cisplatin after carboplatin-associated hypersensitivity reactions in 3 cases with recurrent ovarian carcinoma].
The standard chemotherapy for ovarian carcinoma is paclitaxel and carboplatin concomitant therapy. This combination is so frequently administered that a carboplatin-associated hypersensitivity reaction may occur after long-term treatment. Recently, we experienced carboplatin-associated hypersensitivity reactions in three cases. They showed symptoms of tachycardia, chest tightness, and dyspnea. We report these cases that could be readministered platinum agent using the cisplatin desensitization method. This method was relatively safe and successful for patients with platinum-sensitive disease.


Dimensions of Religiosity: The Effects of Attendance at Religious Services and Religious Faith on Discontinuity in Substance Use.
Previous studies have shown that religion plays an important role in substance misuse. This study examines the effects of the two widely used dimensions of religiosity-religious behavior measured by attendance at religious services and religious faith measured by the importance of religious faith-on cigarette, alcohol, and drug non-use in adulthood. The analysis was based on data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), Waves 1, 3, and 4. The sample was restricted to those who reported having used the substance in Wave 3 (ages 18-25). Four outcome variables (cigarette, alcohol, marijuana, and any illicit drugs) were generated indicating respondents' substance non-use in the past 30 days in Wave 4 (ages 25-32). The number of core sample sizes varied depending on the type of substance (N = 666-1,045). Logistic regression and propensity score matching (PSM) methods (the kernel matching and nearest-neighbor matching methods) were used. Church attendance frequency was significantly and positively associated with any kind of substance non-use in the past 30 days, whereas religious faith was related to the discontinuation of alcohol use only. After we controlled for the observables and confounding bias in the PSM models, results became weaker but remained statistically significant. Social and instrumental support offered by churches may help people abstain from substance use. Health professionals could consider establishing partnerships with religious communities to support substance users.


Ki-M8 monoclonal antibody reactive with an intracytoplasmic antigen of monocyte/macrophage lineage.
A monoclonal antibody (MoAb), Ki-M8, that reacts specifically with cells of the monocyte/macrophage system is described. On light and electron microscopic immunohistochemistry, Ki-M8 recognizes intracytoplasmatically localized antigens of mol wt 30,000 and 32,000, increasingly expressed during differentiation of monocytes into macrophages. Ki-M8 antigen is detectable on almost all known tissue macrophages and monocyte/macrophage-related cell lines after appropriate stimulation. In functional terms Ki-M8 significantly impairs the generation of oxygen radicals during an induced respiratory burst. Applied to acute nonlymphoblastic leukemias, a clear-cut differentiation of the monocytic phenotype and differentiation is possible on the basis of Ki-M8 immunoreactivity. Ki-M8 represents a reagent specific for the monocyte/macrophage system with regard to antigen distribution in normal and neoplastic cells as well as with regard to its influence on a typical monocyte/macrophage-related function.


The distribution of NCAM in the chick hindlimb during axon outgrowth and synaptogenesis.
We have determined the distribution and form of the neural cell adhesion molecule (NCAM) in the chick hindlimb from initial axon outgrowth (stage 17 1/2) until 3 days posthatching by immunohistological staining and sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblots. Axons stained intensely for NCAM at all ages, whereas nonneuronal limb components exhibited dynamic changes in staining. Mesenchymal cells in the sclerotome adjacent to the neural tube developed NCAM immunoreactivity in an anterior-posterior sequence which correlated with the sequence of axonal outgrowth. Low to moderate amounts of NCAM were detected within and surrounding presumptive nerve pathways, consistent with a permissive role for NCAM in axon extension, but not with a precise delineation of pathway boundaries. On myotubes immunoreactivity for NCAM remained low from stage 26 to 30 when it increased dramatically in both aneural and control limbs, indicating that its appearance is not triggered by nerve-dependent activity or trophic interactions. The increase was temporally associated with muscle cleavage and may encourage subsequent axon ramification as well as synaptogenesis. Staining remained high on muscle fibers during secondary myotube formation and only declined during the week before hatching when polyneuronal innervation is withdrawn and the mature synaptic pattern becomes stabilized. This loss of muscle NCAM occurred first on fast and then on slow muscle fibers. Together these results suggest that the timing of innervation may be controlled by the muscle, through NCAM expression, but that the subsequent suppression of muscle NCAM may occur as a result of nerve-mediated activity.


The transformation of hormonal stress responses throughout puberty and adolescence.
Prepubertal rats display heightened hormonal stress reactivity compared with adults in that levels of ACTH and corticosterone take twice as long (i.e. 40-60 min) to return to baseline following an acute stressor. Despite this substantial change in stress responsiveness, and the critical nature of the adolescence period of development, the maturation of the hormonal stress response from the time of pubertal onset to adulthood has not been thoroughly investigated. To examine this, we measured ACTH, corticosterone, and testosterone in 30-, 40-, 50-, 60-, and 70-day-old (i.e. spanning pubertal and adolescent development) male rats before and after a 30 min session of restraint stress. We found that the adult-like ACTH stress response develops between 50 and 60 days of age, while the corticosterone response changes between 30 and 40 days of age. We also found that adrenal corticosterone concentrations paralleled the plasma corticosterone response following restraint, suggesting that stress-induced adrenal corticosterone synthesis decreases during adolescent development and may, at least in part, contribute to the differential stress response observed before and after puberty. Finally, stress leads to increases in testosterone secretion, but only after 50 days of age. Collectively, these results indicate that shifts in hormonal stress responses occur throughout adolescent maturation and that these responses show distinct developmental profiles.


Stability of Alprostadil in 0.9% Sodium Chloride Stored in Polyvinyl Chloride Containers.
The stability of alprostadil diluted in 0.9% sodium chloride stored in polyvinyl chloride (VIAFLEX) containers at refrigerated temperature, protected from light, is reported. Five solutions of alprostadil 11 mcg/mL were prepared in 250 mL 0.9% sodium chloride polyvinyl chloride (PL146) containers. The final concentration of alcohol was 2%. Samples were stored under refrigeration (2°C to 8°C) with protection from light. Two containers were submitted for potency testing and analyzed in duplicate with the stability-indicating high-performance liquid chromatography assay at specific time points over 14 days. Three containers were submitted for pH and visual testing at specific time points over 14 days. Stability was defined as retention of 90% to 110% of initial alprostadil concentration, with maintenance of the original clear, colorless, and visually particulate-free solution. Study results reported retention of 90% to 110% initial alprostadil concentration at all time points through day 10. One sample exceeded 110% potency at day 14. pH values did not change appreciably over the 14 days. There were no color changes or particle formation detected in the solutions over the study period. This study concluded that during refrigerated, light-protected storage in polyvinyl chloride (VIAFLEX) containers, a commercial alcohol-containing alprostadil formulation diluted to 11 mcg/mL with 0.9% sodium chloride 250 mL was stable for 10 days.


Dysembryogenetic spinal tumours in adults without dysraphism.
The authors report 15 patients with spinal intradural dysembryogenetic tumours with clinical onset in adult age in the absence of clinical and radiological signs of dysraphism. The series includes seven lipomas, four epidermoid cysts, three dermoid cysts and one teratoma. The tumour site was the thoracic region in three cases, the lumbar cord and conus in six, the cauda equina in four and the filum terminale in two. Among 14 patients operated upon, the surgical removal was complete in eight cases, subtotal in two and partial in four. Recurrence was noticed only in one subtotally resected thoracic epidermoid cyst. Magnetic resonance imaging allows a precise diagnosis of these lesions, mainly of small lipomas and dermoids of the conus and filum, where a tethered conus is responsible for clinical symptoms. Dysembryogenetic spinal rumours that become symptomatic in adult age may require surgical treatment. Reduction of the mass and release of any associated tethered neural elements are the goal of surgery for spinal lipomas, whereas epidermoid and dermoid cysts require a more radical treatment. However, even partial resections to avoid neural damage result in a good clinical outcome and very low risk of recurrence.


A model for oral health gradients in children: using structural equation modeling.
Detecting the underlying socioeconomic and behavioral determinants is essential for reducing oral health disparities in children. To test a conceptual model in children to explore the interaction amongst social, environmental, behavioral factors and oral health outcomes. This analytic cross-sectional study was performed in 2014-2015 in Shiraz, Iran. The sampling was conducted using a multistage stratified design to represent the whole 6-year-olds in Shiraz County. Participants were 830, 6-year-old first grade primary schoolchildren and their parents. Children were examined to register decayed, missing and filled teeth (dmft) and simplified oral hygiene index (OHI-S). Parents were asked for data on socio-cultural risk factors, oral health behaviors and children's oral health related quality of life (C-OHRQoL). Data on environmental risk factors were collected from several sources. The proposed model, a development of Peterson's, was tested using structural equation modeling (SEM). The tested model could empirically demonstrate the wide range of social and behavioral factors affecting C-OHRQoL. Socioeconomic status (SES) affected the OHRQoL of children through several pathways. Tooth brushing frequency, use of oral health services and consuming cariogenic foods were the mediators, through which SES affected dmft and subsequently C-OHRQoL. Using the modified Petersen's model and SEM, the paths in which different distal and proximal factors affect oral health outcomes in children could be clearly identified. It showed that addressing the underlying social, economic and behavioral determinants is essential for reducing oral health disparities among Iranian children.


Reparative cartilaginous callus in subarticular osteonecrosis of bone. A histopathological study of the femoral head.
A histopathologic study of a series of 346 resected femoral heads with gross osteonecrosis secondary to trauma, steroid therapy, idiopathic or other disease processes demonstrated the production of significant cartilaginous callus tissue at fracture clefts in 19 specimens (5.5%). Although subarticular fracture clefts were commonly present in such specimens, the formation of cartilaginous callus occurred only when one of the two opposing surfaces at the fracture cleft consisted of viable bone. Usually this was osseous tissue that originally had composed a portion of the infarct but had undergone revascularization. In another group of five cases from the same series, fragmentation of all tissue superior to the layer of cartilaginous callus had occurred by the time of surgery. The previously formed cartilaginous callus layer then became the actual weightbearing surface. Pathologically, callus must be differentiated from the cartilaginous tuft phenomenon of exposed intra-articular bone.


The adaptor protein ARH escorts megalin to and through endosomes.
Megalin is an endocytic receptor that binds multiple ligands and is essential for many physiological processes such as brain development and uptake of proteins by the kidney tubule, yolk sac, and thyroid. The cytoplasmic tail of megalin contains two FXNPXY motifs. Autosomal recessive hypercholesterolemia (ARH) is an adaptor protein that binds to the FXNPXY motif of the low-density lipoprotein receptor as well as clathrin and AP-2. We found that ARH also binds to the first FXNPXY motif of megalin in two-hybrid, pull-down and coimmunoprecipitation assays. ARH colocalizes with megalin in clathrin coated pits and in recycling endosomes in the Golgi region. When cells are treated with nocodazole, the recycling endosomes containing megalin and ARH disperse. On internalization of megalin, ARH and megalin are first seen in clathrin coated pits followed by sequential localization in early endosomes and tubular recycling endosomes in the pericentriolar region followed by their reappearance at the cell surface. Expression of ARH in Madin-Darby canine kidney cells expressing megalin mini-receptors enhances megalin-mediated uptake of 125I-lactoferrin, a megalin ligand. These results show that ARH facilitates endocytosis of megalin, escorts megalin along its endocytic route and raise the possibility that transport through the endosomal system is selective and requires interaction with specific adaptor proteins.


Clinical pathway of elderly persons with lowered mood in the health care services.
Elderly persons with mild depression are notable consumers of somatic health services. This study describes the typical clinical pathway including institutional care of two groups, depressed and non-depressed elderly persons, in different stages of the health care system, and compares possible changes in the use of health care services between the two groups. We also compare differences in morbidity and mortality between depressed and non-depressed persons. The depressed group of 50 persons in our follow-up study were selected randomly from among those persons who were diagnosed as having symptoms of depression, as shown in the Zung Self-Rating Depression Scale (n = 109). Persons (n = 50) who were not diagnosed as suffering from depression and who showed no signs of cognitive impairment (n = 833) were likewise chosen at random as a control group. We found that people suffering from symptoms of depression utilized institutional care, home health care and the outpatient clinics more than non-depressed people. Depressed people were more likely to suffer cardiovascular (p < 0.023) and pulmonary diseases (p < 0.04) than non-depressed controls. The mortality among depressed people was significantly higher than that in the control group. The results of our study give reason to believe that home-care staff are in a key position to identify depressed subjects. They have to understand the relationship between depression and the effect of various diseases on health and functional capacity. It is also important to ensure efficient communication between those responsible for health care.


Consumer Mobile Health Apps: Current State, Barriers, and Future Directions.
This paper discusses the current state, barriers, and future directions of consumer-facing applications (apps). There are currently more than 165,000 mobile health apps publicly available in major app stores, the vast majority of which are designed for patients. The top 2 categories are wellness management and disease management apps, whereas other categories include self-diagnosis, medication reminder, and electronic patient portal apps. Apps specific to physical medicine and rehabilitation also are reviewed. These apps have the potential to provide low-cost, around-the-clock access to high-quality, evidence-based health information to end users on a global scale. However, they have not yet lived up to their potential due to multiple barriers, including lack of regulatory oversight, limited evidence-based literature, and concerns of privacy and security. The future directions may consist of improving data integration into the health care system, an interoperable app platform allowing access to electronic health record data, cloud-based personal health record across health care networks, and increasing app prescription by health care providers. For consumer mobile health apps to fully contribute value to health care delivery and chronic disease management, all stakeholders within the ecosystem must collaborate to overcome the significant barriers.


New strategy for the synthesis of iminoglycitols from amino acids.
A novel strategy for the enantioselective synthesis of polyhydroxypiperidines, which can be considered as iminoglycitols or 2,6-dideoxyazasugars, was developed. alpha-Benzolsulfonylamino esters served as a C(2)N building block while 2-bromo-3-(bromomethyl)oxazoles and -thiazoles contributed a C3-unit to the final piperidine ring. At first a dihydropyridine ring was established via alkylation and bromine-lithium exchange. The keto group of the resulting 5,6-dihydro[1,3]oxazolo- and 5,6-dihydro[1,3]thiazolo[4,5-c]pyridin-7(4H)-ones was reduced and, after alkylation reactions, the azole ring was cleaved, thus providing heteroatom substituents for the target piperdines. Protected 5-amino-3,4-dihydroxy and 5-amino-3-hydroxy-4-thiohydroxypiperdines were obtained in the talose series while Mitsunobu reaction of the intermiediates provided access to the altrose series.


Primary care assessment instruments for patients at risk of, or with, persistent pain: opportunistic findings from a systematic literature review.
Early identification in primary care settings of individuals with, or at-risk of, developing persistent pain, is important to limit development of disability. There is little information to assist primary care providers to choose or deliver relevant, efficient, and soundly constructed assessment instruments for this purpose. We recently published the findings of a literature review, which produced a compendium of assessment instruments to identify adults with, or at-risk of developing, persistent pain of noncancer origin. This paper reports on instruments opportunistically identified during this review which may be appropriate to primary health care settings for early identification of such patients. One hundred sixteen potentially useful instruments were initially identified in the review, measuring pain severity, psychological distress, functional capacity, quality of life or multidimensional constructs of persistent pain. Following a series of steps, 45 instruments were shortlisted, with sound clinical utility and strong psychometric properties. Of these, 16 instruments were appropriate to primary health care settings because of simple wording, brief items, short administration time, and ease of scoring. No one assessment instrument captured all constructs of persistent pain. The 16 instruments provide a broad choice for primary care clinicians to assist with early identification of adults at risk of, or with persistent pain.


Spirituality, Happiness, and Psychological Well-being in 13- to 15-year olds: A Cross-country Longitudinal RCT Study.
Based on a study of 5339 adolescents from 60 schools across 15 countries, this paper reports on the effect of spirituality on their happiness and psychological well-being. A customized spiritual program was administered and post-treatment outcome variable scores of the experimental group were higher. Adolescents from relatively affluent nations, boys, Christians, and those who self-practiced scored higher post-test. This makes a case for nominating spirituality as an important developmental variable for 13- to 15-year olds.


Studies of hypoxemia and pulmonary hemodynamics in acute myocardial infarction.
On 55 patients with acute myocardial infarction blood gas changes and A-aDO2 while breathing room air were observed for a period of 5 weeks. PaO2 during the 35% O2 inhalation was measured on admission and 5 weeks later for comparisons with the PaO2 while breathing room air. Pulmonary circulatory hemodynamics was measured in 29 cases on admission using Swan-Ganz's right heart flow directed catheter 7F, and the catheter was kept in the pulmonary artery in 13 cases for a maximum of 9 days. The mean PaO2 while breathing room air on admission was 66.7 mmHg in the 55 cases. It was 52.3 mmHg in the heart failure group and 74.9 mmHg in the non-heart failure group, showing prominent hypoxemia in the heart failure group. The mean PaO2 recovered to normal (84.1 mmHg and 87.0 mmHg) 5 weeks later. Inhalation of 35% O2 was performed for 20 minutes on admission and 5 weeks later. The elevation of PaO2 during the oxygen inhalation on admission was smaller than that 5 weeks later, significantly smaller in the heart failure group (P less than 0.001). The mean A-aDO2 on admission was higher in the heart failure group (58.1 mmHg) than in the non-heart failure group (34.8 mmHg). PaO2 showed significant correlations with cardiac index and SvO2. Although it was significantly correlated with PA diast. and TPR, no correlation with CVP was observed. Hypoxemia in acute myocardial infarction is caused by the following process: the onset of myocardial infarction causes low output, leading to left ventricular failure. As the result of elevated left atrial pressure and pulmonary venous pressure, intestinal pulmonary edema develops provoking ventilation-perfusion inequality, intra-pulmonary shunting, and diffusing defect.


Anthocyanins from a single botanical source can be used as a replacement for hemalum and eosin.
For various reasons, histologists in several parts of the world have tried to replace hematoxylin and eosin with locally available plant dyes of the anthocyanin family. Blue or violet nuclear stains have been created by combining an anthocyanin with iron or aluminum ions at low pH. Obtaining a pink or red cytoplasmic counterstain, however, has not been achieved previously, even with a red solution of anthocyanin, because the chemistry of the colorant does not allow bonding to cytoplasmic materials and collagen. We used two extracts from the petals of common mallow, Malva sylvestris, to create both a blue nuclear stain and a red counterstain. The two extracts contained two chemically distinct types of anthocyanins. The first extract contains vic-hydroxyls capable of complexing aluminum ions; its flavylium core is cationic. The second type lacks vic-hydroxyls on its core structure, but includes pendant glucosides that contain a malonic acid ester with a free carboxyl substituent. The precise identity of the first anthocyanin currently is unknown, but likely is one or more of the common anthocyanins such as cyanidin, delphinidin or petunidin, which complex readily with aluminum. The second anthocyanin is malonated malvidin, which does not complex with aluminum, but is anionic at the pH used here. The overall visual effect of applying the two anthocyanin extracts is remarkably similar to that of hemalum plus eosin.


Defining the structure-function relationships of bluetongue virus helicase protein VP6.
The VP6 protein of bluetongue virus possesses a number of activities, including nucleoside triphosphatase, RNA binding, and helicase activity (N. Stauber, J. Martinez-Costas, G. Sutton, K. Monastyrskaya, and P. Roy, J. Virol. 71:7220-7226, 1997). Although the enzymatic functions of the protein have been documented, a detailed structure and function study has not been completed and the oligomeric form of the protein in solution has not been described. In this study, we have characterized VP6 activity by creating site-directed mutations in the putative functional helicase domains. Mutant proteins were expressed at high levels in an insect cell by using recombinant baculoviruses purified and analyzed for ATP binding, ATP hydrolysis, and RNA unwinding activities. UV cross-linking experiments indicated that the lysine residue in the conserved motif AXXGXGK(110)V is directly involved in ATP binding, whereas mutant R(205)Q in the arginine-rich motif ER(205)XGRXXR bound ATP at a level comparable to that of the wild-type protein. The RNA binding activity was drastically altered in the R(205)Q mutant and was also affected in the K(110)N mutant. Helicase activity was altered in both mutants. The mutation E(157)N in the DEXX sequence, presumed to act as a Walker B motif, showed an intermediate activity, implying that this motif does not play a crucial role in VP6 function. Purified protein demonstrated stable oligomers with a ring-like morphology in the presence of nucleic acids similar to those shown by other helicases. Gel filtration chromatography, native gel electrophoresis, and glycerol gradient analysis clearly indicated multiple oligomeric forms of VP6.


The burden of symptoms among community-dwelling older persons with advanced chronic disease.
Little is known about the frequency and range of symptoms experienced by community-dwelling older persons with advanced chronic disease who are not enrolled in hospice. The objectives of our study were to determine (1) the prevalence of a range of symptoms among older persons with advanced chronic disease and (2) whether the prevalence of symptoms is similar across diagnoses. This was a cross-sectional study of the symptoms reported by 226 community-dwelling persons 60 years or older with advanced chronic obstructive pulmonary disease (COPD), cancer, or congestive heart failure (CHF). Symptoms were assessed using the Edmonton Symptom Assessment System. Virtually all participants (86%) experienced at least 1 symptom that rated moderate or severe, and most (69%) experienced 2 or more symptoms. The symptoms reported by the greatest proportion of participants were limited activity (61%), fatigue (47%), and physical discomfort (38%). Participants with COPD had a higher unadjusted mean +/- SD number of moderate or severe symptoms (3.3 +/- 2.1) than did participants with cancer (2.6 +/- 1.8; P = .03) or CHF (2.0 +/- 1.7; P<.001). After we adjusted for sociodemographic factors, compared with participants with CHF, participants with cancer experienced 38% (95% confidence interval, 9%-75%) more moderate or severe symptoms and participants with COPD experienced 71% (95% confidence interval, 37%-114%) more moderate or severe symptoms. Most community-dwelling older persons with advanced COPD, cancer, or CHF experienced multiple moderate or severe symptoms. The clinical care of community-dwelling older persons with advanced chronic illnesses would be enhanced by the identification and alleviation of the range of symptoms they experience.


Persistence of O6-guanine DNA adducts in styrene-exposed lamination workers determined by 32P-postlabelling.
A modified 32P-postlabelling method was used for the detection of styrene-specific DNA adducts in lamination workers. The persistence of O6-styrene DNA adducts was studied in DNA from lymphocytes and granulocytes of an exposed and a control group. We compared O6-adduct levels obtained from a sampling prior to vacation, after 2 weeks of vacation and after an additional 1 month of work. In granulocytes, there was no significant difference in adduct levels between the control and the exposed groups in any individual samplings. In lymphocytes of laminators the detected adduct levels were significantly higher (5.4 adducts/10(8) nucleotides) than those in the controls (1.0 adduct/10(8) nucleotides). The 2 week interruption of exposure did not influence the total O6-adduct level (4.9 adducts/10(8) nucleotides in the first sampling versus 5.1 adducts/10(8) nucleotides in the second), indicating very slow removal of the specific O6-styrene adducts from DNA.


[The cost of tests and their informational content].
The trade-off between the cost of a test and its information content are presented in this paper. In cost-effectiveness analysis, the ratio of diagnostic costs, including the risks of testings, to the number of cases detected provides and index of diagnostic benefit. This ratio may be useful under conditions of uncertainty.


Experimental Identification of Smartphones Using Fingerprints of Built-In Micro-Electro Mechanical Systems (MEMS).
The correct identification of smartphones has various applications in the field of security or the fight against counterfeiting. As the level of sophistication in counterfeit electronics increases, detection procedures must become more accurate but also not destructive for the smartphone under testing. Some components of the smartphone are more likely to reveal their authenticity even without a physical inspection, since they are characterized by hardware fingerprints detectable by simply examining the data they provide. This is the case of MEMS (Micro Electro-Mechanical Systems) components like accelerometers and gyroscopes, where tiny differences and imprecisions in the manufacturing process determine unique patterns in the data output. In this paper, we present the experimental evaluation of the identification of smartphones through their built-in MEMS components. In our study, three different phones of the same model are subject to repeatable movements (composing a repeatable scenario) using an high precision robotic arm. The measurements from MEMS for each repeatable scenario are collected and analyzed. The identification algorithm is based on the extraction of the statistical features of the collected data for each scenario. The features are used in a support vector machine (SVM) classifier to identify the smartphone. The results of the evaluation are presented for different combinations of features and Inertial Measurement Unit (IMU) outputs, which show that detection accuracy of higher than 90% is achievable.


[A healthy and active ageing by preparation and complex care (author's transl)].
Today it is possible and necessary to show the way for a healthy and active ageing under our social conditions. This way means the preparation for the age and the pension. This is only possible by the unit of positive personal attitudes, motivations and behaviour with adequate social planning. There are many examples of the macrobiotic, gerohygiene, geropsychology and sports medicine. There are also results and experiences of the whole life and the effects of extreme situations of the life to take into consideration for the indication for the preparation and complex care. Some methodical theses and postulates for training-programmes for the preparation on age and pension are worked out. Such programmes should be carried out for groups, which are especially endangered by their work: workers and leading works.


[Blood conservation in thoracic aortic surgery with total cardiopulmonary bypass].
In thoracic aortic surgery, a large number of homologous transfusions sometimes cause systemic inflammatory response, which may lead to pulmonary dysfunction, renal dysfunction and brain edema. To predict the need for homologous blood transfusion in aortic surgery, we use blood transfusion index (preoperative Ht x body weight) to predict the magnitude of homologous transfusion. From Dec 1997 to May 2000, 59 consecutive patients were underwent thoracic aortic graft replacement with total cardiopulmonary bypass. These patients were divided in 2 groups, who were underwent graft replacement without blood transfusions, and who needed blood transfusions. Each group was compared in age, sex, emergency, Ht, CPB time, blood transfusion index and operative mortality. Forty patients (67.7%) did not required blood transfusion. In elective cases (32 cases), 84.3% were underwent operation without blood transfusion. There was no significant difference between 2 groups in terms of age and mean bypass duration. Blood transfusion index was significantly higher in transfusion group (2,320 +/- 784) compared with that in not transfusion group (1,445 +/- 706). Blood transfusion index was useful preoperative parameter to predict the need for homologous transfusion.


Surgical management of tennis elbow.
To ascertain whether there were any differences in the outcome of release of the common extensor origin and release of the common extensor origin and drilling of the lateral epicondyle in the management of recalcitrant tennis elbow. One hundred and eleven patients (125 elbows; 40 males, median age: 47 years; 71 females, median age: 45 years) entered the study. The minimum follow-up period was 2 years (average follow-up: 52.8 months). Patients were reviewed at 2 and 6 or 8 weeks, and 3 and 6 months after surgery. If a complication ensued, or if a patient did not report improvements, they were followed up for at least 1 year postoperatively. Two years after the recruitment period had ended, telephone interviews were performed. We used a 1 to 10 scale when enquiring about pain, both preoperative and postoperative, with 1 as the best score and 10 the worst. We also determined patient satisfaction, grip strength, and elbow function. Seventy-five percent of patients had excellent or good results, with 73% of them being satisfied with the results of surgery. There was no statistical significance in the outcome of the 2 procedures (chi-square, p=0.488). There were no statistically significant differences between the 2 procedures regarding pain, satisfaction, elbow function, and grip strength. Release of the common extensor origin at the elbow is a relatively simple operation, and produces reliable long term relief of tennis elbow pain in at least 70% of patients.


The Golgi-localized, gamma ear-containing, ARF-binding (GGA) protein family alters alpha synuclein (α-syn) oligomerization and secretion.
Several age-related neurodegenerative disorders are associated with protein misfolding and aggregation of toxic peptides. α-synuclein (α-syn) aggregation and the resulting cytotoxicity is a hallmark of Parkinson's disease (PD) as well as dementia with Lewy bodies. Rising evidence points to oligomeric and pre-fibrillar forms as the pathogenic species, and oligomer secretion seems to be crucial for the spreading and progression of PD pathology. Recent studies implicate that dysfunctions in endolysosomal/autophagosomal pathways increase α-syn secretion. Mutation in the retromer-complex protein VPS35, which is involved in endosome to Golgi transport, was suggested to cause familial PD. GGA proteins regulate vesicular traffic between Golgi and endosomes and might work as antagonists for retromer complex mediated transport. To investigate the role of the GGAs in the α-syn oligomerization and/or secretion process we utilized protein-fragment complementation assays (PCA). We here demonstrate that GGAs alter α-syn oligomer secretion and α-syn oligomer-mediated toxicity. Specifically, we determined that GGA3 modifies extracellular α-syn species in an exosome-independent manner. Our data suggest that GGA3 drives α-syn oligomerization in endosomal compartments and thus facilitates α-syn oligomer secretion. Preventing the early events in α-syn oligomer release may be a novel approach to halt disease spreading in PD and other synucleinopathies.


Evaluation of the effectiveness of photobiomodulation therapy as an alternative method to local anesthesia injection in pediatric dentistry.
The idea of receiving local anesthesia (LA) via an injection is a major source of dental fear and anxiety. In children, dental anxiety is considered the main reason for avoiding dental treatments. Moreover, there are potential complications during/after LA administration. Thus, it is necessary to search for painless, low-risk, and nonpharmacological anesthetic approaches. This study was performed to evaluate the effectiveness of photobiomodulation (PBM) therapy as an alternative method to LA injection for conventional restorative treatments in pediatric patients. This was a split-mouth randomized clinical study. The study included 15 children between 6 and 12 years old. Each child had 2 similar contralateral caries lesions in the first permanent molars in the same jaw, total (30) teeth. For each child, one tooth was treated under conventional LA injection and the other was treated under PBM-based anesthesia. The Wong-Baker's Faces Pain Scale was used for reporting the pain and discomfort levels at the end of the treatments. Data statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 20. Mann-Whitney U-test was used to compare between the groups. The PBM-based anesthesia group recorded a mean pain score of 2.27 ± 1.28. The conventional LA group recorded a mean pain score of 1.73 ± 0.7. The difference between the groups was not statistically significant (P = 0.168). PBM-based anesthesia may be an optional alternative to LA injection for conventional restorative treatments in children with dental anxiety, needle phobia, or special needs, and it deserves further studies and improvement.


Combination of oxymatrine (Om) and astragaloside IV (As) enhances the infiltration and function of TILs in triple-negative breast cancer (TNBC).
Triple-negative breast cancer (TNBC) is the most aggressive subtype and has a poor response to treatment due to an immunosuppressive microenvironment. Chinese Medicine effective constituents such as oxymatrine (Om) and astragaloside IV (As) have shown promise in cancer treatment by providing anti-fibrosis and immune-enhancing effects. However, the potential combined effect of Om and As on TNBC and its mechanism is still uncertain. This study focuses on exploring the impact of Om and As on enhancing the immunosuppressive microenvironment of TNBC and uncovering the potential mechanism behind it. In this study, a trans-Cancer associated fibroblasts (CAFs) infiltration system of T cells was utilized to investigate the potential benefits of Om, while the impact of As on the morphology and quantity of mitochondria in T cells was examined in a co-culture system with tumor cells. Further to investigate the combined effects of Om and As on tumor suppression and immunosuppressive microenvironment improvement, this study established an in situ TNBC mouse model with 4 T1-luc. In vitro, our findings indicate that Om can effectively suppress the activation of CAFs by downregulating the expression of FAP and α-SMA, and also promoting the infiltration of T cells trans CAFs. It was discovered that the mitochondrial activity of T cells could be improved by increasing the number of mitochondria and cristae. In vivo, the optimal ratio of Om and As (2:1) was found to increase the apoptosis rate of tumor cells in a co-culture system and enhance the infiltration of CD4+ and CD8+ T cells, as confirmed by Flow Cytometry results. Our study suggests that Om and As could enhance the immune system's ability to treat TNBC by improving the infiltration and increasing the anti-tumor function of TILs. This intervention may lead to a promising therapeutic direction for the treatment of TNBC.


Noninvasive visualization of in vivo drug delivery of poly(L-glutamic acid) using contrast-enhanced MRI.
Biomedical imaging is valuable for noninvasive investigation of in vivo drug delivery with polymer conjugates. It can provide real-time information on pharmacokinetics, biodistribution, and drug delivery efficiency of the conjugates. Noninvasive visualization of in vivo drug delivery of polymer conjugates with contrast-enhanced magnetic resonance imaging (MRI) was studied with paramagnetically labeled poly(L-glutamic acid) in an animal tumor model. Poly(L-glutamic acid) is a biocompatible and biodegradable drug carrier for diagnostics and therapeutics. Poly(L-glutamic acid)-1,6-hexanediamine--(Gd-DO3A) conjugates with molecular weights of 87, 50, and 28 kDa and narrow molecular weight distributions were prepared and studied in mice bearing MDA-MB-231 human breast cancer xenografts. Contrast-enhanced MRI resulted in real-time and three-dimensional visualization of blood circulation, pharmacokinetics, biodistribution, and tumor accumulation of the conjugates, and the size effect on these pharmaceutics properties. The conjugate of 28 kDa rapidly cleared from the circulation and had a relatively lower tumor accumulation. The conjugates with higher molecular weights exhibited a more prolonged blood circulation and higher tumor accumulation. The difference between the conjugates of 87 and 50 kDa was not significant. Contrast-enhanced MRI is effective for noninvasive real-time visualization of in vivo drug delivery of paramagnetically labeled polymer conjugates.


Cinacalcet in peritoneal dialysis patients: one-center experience.
Secondary hyperparathyroidism is the target of several therapeutic strategies, including the use of cinacalcet. Most studies were done only in hemodialysis patients, with few data from peritoneal dialysis patients. The aim of our work was to evaluate the effectiveness of cinacalcet in secondary hyperparathyroidism in a one-center peritoneal dialysis patients. A retrospective study was performed in 27 peritoneal dialysis patients with moderate to severe secondary hyperparathyroidism (PTHi > 500 pg/mL with normal or elevated serum calcium levels) treated with cinacalcet. Demographic, clinical and laboratory parameters at the beginning of cinacalcet therapy, second, fourth, sixth months after and at the time it was finished were analyzed. Patients were under peritoneal dialysis at 30.99 ± 16.58 months and were treated with cinacalcet for 15.6 ± 13.4 months; 21 (77.8%) patients showed adverse gastrointestinal effects; PTHi levels at the beginning of cinacalcet therapy were 1145 ± 449 pg/mL. The last PTHi levels under cinacalcet therapy was 1131 ± 642 pg/mL. PTHi reduction was statistically significant at 2 months after the beginning of cinacalcet (p = 0.007) but not in the following evaluations. It is necessary the development of new forms of cinacalcet presentation, in order to avoid gastrointestinal effects adverse factors and to improve therapeutic adherence.


An in silico model of LINE-1-mediated neoplastic evolution.
Recent research has uncovered roles for transposable elements (TEs) in multiple evolutionary processes, ranging from somatic evolution in cancer to putatively adaptive germline evolution across species. Most models of TE population dynamics, however, have not incorporated actual genome sequence data. The effect of site integration preferences of specific TEs on evolutionary outcomes and the effects of different selection regimes on TE dynamics in a specific genome are unknown. We present a stochastic model of LINE-1 (L1) transposition in human cancer. This system was chosen because the transposition of L1 elements is well understood, the population dynamics of cancer tumors has been modeled extensively, and the role of L1 elements in cancer progression has garnered interest in recent years. Our model predicts that L1 retrotransposition (RT) can play either advantageous or deleterious roles in tumor progression, depending on the initial lesion size, L1 insertion rate and tumor driver genes. Small changes in the RT rate or set of driver tumor-suppressor genes (TSGs) were observed to alter the dynamics of tumorigenesis. We found high variation in the density of L1 target sites across human protein-coding genes. We also present an analysis, across three cancer types, of the frequency of homozygous TSG disruption in wild-type hosts compared to those with an inherited driver allele. Source code is available at https://github.com/atallah-lab/neoplastic-evolution. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Regulation of amylase gene expression in diabetic mice is mediated by a cis-acting upstream element close to the pancreas-specific enhancer.
We localized the cis-acting sequences that mediate the regulation of a pancreatic amylase gene, Amy-2.2, in diabetic mice. We constructed three hybrid genes containing sequences from the 5'-flanking region of the amylase gene upstream of the heterologous elastase promoter linked to the CAT structural gene. These constructs were transferred to the germ line of transgenic mice by microinjection of fertilized eggs. The amylase sequences had two effects on expression of the elastase promoter: Basal expression was increased, and expression in diabetic animals was reduced to approximately 2% of basal levels. A 30-bp amylase fragment was sufficient to transfer both of these regulatory functions to the elastase promoter. Sequences within this 30-bp fragment are included in the binding site for the pancreatic nuclear protein PTF1. The close association of the PTF1-binding site and the regulatory functions is consistent with a mechanism based on interference with activation by PTF1 in diabetic pancreas. PTF1-binding activity is not reduced in diabetic pancreas. The data presented here demonstrate that the 5'-flanking region of the pancreatic amylase gene contains a novel insulin-dependent element (IDE) that mediates the loss of expression in diabetic animals.


Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor.
Human genetic data have associated angiotensin-converting enzyme (ACE) with Alzheimer disease (AD), and purified ACE has been reported to cleave synthetic amyloid beta-protein (Abeta) in vitro. Whether deficiency in ACE activity, arising from genetic alteration or pharmacological inhibition, can decrease Abeta degradation and allow Abeta accumulation in intact cells is unknown. We cloned ACE from human neuroblastoma cells and showed that it had posttranslational processing and enzymatic activity typical of the endogenous protease. Cellular expression of ACE promoted degradation of naturally secreted Abeta40 and Abeta42, leading to significant clearance of both species. Using site-directed mutagenesis, we determined that both active sites within ACE contribute to Abeta clearance, and an ACE construct bearing mutations in each catalytic domain had no effect on Abeta levels. Pharmacological inhibition of ACE with a widely prescribed drug, captopril, promoted the accumulation of cell-derived Abeta in the media of beta-amyloid precursor-protein expressing cells. Together, these results show that ACE can lower the levels of secreted Abeta in living cells and that this effect is blocked by inhibiting the protease's activity with an ACE inhibitor. This work, combined with the genetic studies, supports the hypothesis that ACE may modulate the susceptibility to and progression of AD via degradation of Abeta. Our data encourage further analyses of the ACE gene for disease association and raise the question of whether currently prescribed ACE inhibitors could elevate cerebral Abeta levels in humans.


Use of GenoType® MTBDRplus assay to assess drug resistance and mutation patterns of multidrug-resistant tuberculosis isolates in northern India.
The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is a major public health problem. The diagnosis of MDR-TB is of paramount importance in establishing appropriate clinical management and infection control measures. The aim of this study was to evaluate drug resistance and mutational patterns in clinical isolates MDR-TB by GenoType® MTBDRplus assay. A total of 350 non-repeated sputum specimens were collected from highly suspected drug-resistant pulmonary tuberculosis (PTB) cases; which were processed by microscopy, culture, differentiation and first line drug susceptibility testing (DST) using BacT/ALERT 3D system. Among a total of 125 mycobacterium tuberculosis complex (MTBC) strains, readable results were obtained from 120 (96%) strains by GenoType® MTBDRplus assay. Only 45 MDR-TB isolates were analysed for the performance, frequency and mutational patterns by GenoType® MTBDRplus assay. The sensitivity of the GenoType® MDRTBplus assay for detecting individual resistance to rifampicin (RIF), isoniazid (INH) and multidrug resistance was found to be 95.8%, 96.3% and 97.7%, respectively. Mutation in codon S531L of the rpoB gene and codon S315T1 of katG genes were dominated in MDR-TB strains, respectively (P < 0.05). The GenoType® MTBDRplus assay is highly sensitive with short turnaround times and a rapid test for the detection of the most common mutations conferring resistance in MDR-TB strains that can readily be included in a routine laboratory workflow.


Apatite associated destructive arthritis.
Twelve patients, 11 women and one man, aged 66-83, with a distinctive type of destructive arthropathy are described. The principal joints affected were the shoulders (ten) and knees (seven). Clinical features included pain on use, large cool effusions, instability and rapid progression. Radiographs showed attrition of bone and cartilage with a paucity of reparative changes. Synovial fluids were viscous, with low cell counts, and stained positively for the presence of apatite-containing particles. Extensive calcific material was seen in the synovium of the four patients biopsied, and on the radiographs in seven. Most patients had some associated or preceding joint disorder. The literature on similar cases is reviewed, and the possible role of crystals and other aetiological factors is discussed. It is suggested that a characteristic form of large-joint atrophy can occur in elderly patients at a number of joint sites and in several different clinical settings.


PHARMACEUTICAL BENEFITS ADVISORY COMMITTEE RECOMMENDATIONS IN AUSTRALIA.
The aim of this study was to examine submissions made to the Pharmaceutical Benefits Advisory Committee (PBAC) and assess whether the predicted financial impact was associated with a recommendation. The second objective was to assess whether the financial and utilization estimates for listing the proposed medicine were reliable. Data were extracted from public summary documents of major submissions considered by the PBAC from 2012 to 2014. Information collected included whether submissions were accepted, rejected, or deferred; estimated use; and financial impact. For those submissions that were recommended in 2012 and listed on the Pharmaceutical Benefits Scheme (PBS) by January 2014, a comparison was made between predicted and actual use and cost in 2014, based on PBS utilization. In 2012 to 2014, the PBAC considered 142 unique major submissions; of those, 65 were recommended for listing. A higher financial cost to the government was a statistically significant factor in predicting rejection (p = .004 for cost > AUD 30 million Australian dollars [20.7 million Euros] compared with cost-saving). Of the submissions that were recommended in 2012 and listed by 2014, the actual use was higher than predicted for 5/19 medications. The estimated cost was outside the predicted bracket of cost for 10/19 medications, with 8/19 medications having threefold underestimated expenditure, and 2/19 items having lower than predicted expenditure. This study highlights that the predicted financial impact of a medication to the PBS budget is associated with a PBAC recommendation and also highlights that predicted use may not reflect actual prescribing practices.


Multiple sources of endogenous opioid peptide involved in the hypoglycemic response to 15 Hz electroacupuncture at the Zhongwan acupoint in rats.
A decrease in plasma glucose levels was observed in rats which received electroacupuncture (EA) stimulation at the Zhongwan acupoint. In the present study, the role of the adrenal gland in this hypoglycemic response to EA at high frequency (15 Hz) was investigated on adrenalectomized (ADX) normal rats. There was a sharper decrease in plasma glucose by EA stimulation in the fasting ADX group than in the fasting sham-operated group. Naloxone blocked this hypoglycemic response to EA stimulation in rats which received ADX. Stimulation of EA failed to elicit an increase in plasma beta-endorphin and insulin levels in ADX rats. Similar results were observed in sham and ADX mice. EA stimulation of ADX mice can reduce plasma glucose levels. Furthermore, naloxone abolished the hypoglycemic response to EA stimulation in mice. Such a hypoglycemic response to EA stimulation was also observed in micro-opioid receptor knockout mice (MOR-KOM). Mediation by another opioid peptide should also be considered in future experiments. We conclude that multiple sources of endogenous opioid peptide participated in the lowering of plasma glucose in rats induced by EA stimulation at higher frequency (15 Hz) at the Zhongwan acupoint. Increase in beta-endorphin levels from the adrenal gland enhances the secretion of insulin, there by reducing plasma glucose levels, and is partially involved in this EA stimulation.


Neurophysiological and BOLD signal uncoupling of giant somatosensory evoked potentials in progressive myoclonic epilepsy: a case-series study.
In progressive myoclonic epilepsy (PME), a rare epileptic syndrome caused by a variety of genetic disorders, the combination of peripheral stimulation and functional magnetic resonance imaging (fMRI) can shed light on the mechanisms underlying cortical dysfunction. The aim of the study is to investigate sensorimotor network modifications in PME by assessing the relationship between neurophysiological findings and blood oxygen level dependent (BOLD) activation. Somatosensory-evoked potential (SSEP) obtained briefly before fMRI and BOLD activation during median-nerve electrical stimulation were recorded in four subjects with typical PME phenotype and compared with normative data. Giant scalp SSEPs with enlarger N20-P25 complex compared to normal data (mean amplitude of 26.2 ± 8.2 μV after right stimulation and 27.9 ± 3.7 μV after left stimulation) were detected. Statistical group analysis showed a reduced BOLD activation in response to median nerve stimulation in PMEs compared to controls over the sensorimotor (SM) areas and an increased response over subcortical regions (p < 0.01, Z > 2.3, corrected). PMEs show dissociation between neurophysiological and BOLD findings of SSEPs (giant SSEP with reduced BOLD activation over SM). A direct pathway connecting a highly restricted area of the somatosensory cortex with the thalamus can be hypothesized to support the higher excitability of these areas.


[Clinical audit on the use of expensive systemic antifungals in the Besançon University Hospital].
The continuous improvement policy for healthcare quality requires practice evaluation. The principle of a clinical audit is to compare practice to guidelines. Prescription guidelines on antifungal agent use has been available in our hospital since 2003. It was updated in 2005 and 2006. The aim of this study was to assess compliance to guidelines, with an audit of prescriptions: amphotericin B lipid formulation, voriconazole and caspofungin, expensive antifungals concerned by the budget allowance correlated to activity, subject to supplementary reimbursement to the coded Homogeneous Group of Diseases. The assessment criteria were: relevance of the indication, absence of a better alternative, complying to recommended dosage, loading dose and timing. This retrospective study dealt with all prescriptions of all departments, from January to May 2007. Hundred and eighteen prescriptions were retrospectively analyzed for 81 patients. The rate of overall conformity was 54%. Antifungal therapy was justified for 113 prescriptions (96%). In 30% of the cases, a more efficient alternative was advised, cheaper or less toxic. The dosage and the charge dosing were right in 92% and 80% of the cases respectively. This audit allowed assessing good-use of antifungals. We showed an over-prescription of caspofungin and sometimes insufficient regimen of voriconazole dosages for children. Reporting these audit results and development of new international guidelines stress the need to update local recommendations regularly.


Bupivacaine-eluting soy protein structures for controlled release and localized pain relief: An in vitro and in vivo study.
Burn pain is known to be excruciating, and while burn care has greatly advanced, treatment for burn-related pain is lacking. Current pain relief methods include systemic administration of analgesics, which does not provide high drug concentration at the wound site. In the present study, soy protein was used as the base material for bupivacaine-loaded hybrid wound dressings. The effect of the formulation on the drug release profile was studied using high performance liquid chromatography, and the cytotoxicity was tested on human fibroblasts. A second-degree burn model in rats was used to quantify the efficacy of the wound dressings in vivo, using the Rat Grimace Scale. All tested films exhibited high biocompatibility, and the drug release profiles showed rapid release during the initial 5 hr and a continuous slower release for another 24 hr. Significant pain relief was achieved in the animal trials, proving a decrease of 51-68% in pain levels during days 1-3 post-burn. Hence, the results indicate a safe and controlled bupivacaine release for a period of more than 24 hr, effectively treating pain caused by second-degree burns. The understanding of the formulation-properties effects, together with our in vivo study, enables to advance this field toward tailorable systems with high therapeutic potential.


Calcium ions modulate regulation of smooth muscle contraction mediated by phosphorylation of myosin regulatory light chains.
The effect of calcium ions on conformational changes of F-actin initiated by decoration of thin filaments with phosphorylated and dephosphorylated heavy meromyosin from smooth muscles was studied by fluorescence polarization spectroscopy. It is shown that heavy meromyosin with phosphorylated regulatory light chains (pHMM) promotes structural changes of F-actin which are typical for the "strong" binding of actin to the myosin heads. Heavy meromyosin with dephosphorylated regulatory light chains (dpHMM) causes conformational changes of F-actin which are typical for the "weak" binding of actin to the myosin heads. The presence of calcium enhances the pHMM effect and attenuates the dpHMM effect. We propose that a Ca2+-dependent mechanism exists in smooth muscles which modulates the regulation of actin--myosin interaction occurring via phosphorylation of myosin regulatory light chains.


Outbreak of multiresistant OXA-24- and OXA-51-producing Acinetobacter baumannii in an internal medicine ward.
Here we describe the clinical, microbiological, epidemiological, and molecular characterization of an outbreak of multidrug-resistant Acinetobacter baumannii (MRAB) involving 5 patients admitted to the internal medicine ward of our hospital. Over a 6-week period, 5 MRAB isolates were recovered from 5 patients, including 1 with fatal meningitis, 3 with skin and soft tissue infections, and 1 with respiratory colonization. One sample obtained during environmental monitoring in the ward was A. baumannii-positive. According to the pulsed-field gel electrophoresis typing results, the strains isolated from all patients and the environmental sample belonged to a single clone, identified as ST79 by multilocus sequence typing. The blaOXA-24 and blaOXA-51 carbapenemases were detected in all isolates. Four patients died, but only the death of the meningitis patient was probably related to the A. baumannii infection. The infection source was probably the hands of the healthcare workers because the outbreak strain was isolated from the surface of a serum container. The results of the present study revealed the importance of strict adherence to control measures by all healthcare workers because the consequences of noncompliance can be very serious.


Regression Models on Riemannian Symmetric Spaces.
The aim of this paper is to develop a general regression framework for the analysis of manifold-valued response in a Riemannian symmetric space (RSS) and its association with multiple covariates of interest, such as age or gender, in Euclidean space. Such RSS-valued data arises frequently in medical imaging, surface modeling, and computer vision, among many others. We develop an intrinsic regression model solely based on an intrinsic conditional moment assumption, avoiding specifying any parametric distribution in RSS. We propose various link functions to map from the Euclidean space of multiple covariates to the RSS of responses. We develop a two-stage procedure to calculate the parameter estimates and determine their asymptotic distributions. We construct the Wald and geodesic test statistics to test hypotheses of unknown parameters. We systematically investigate the geometric invariant property of these estimates and test statistics. Simulation studies and a real data analysis are used to evaluate the finite sample properties of our methods.


Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a common autoimmune systemic inflammatory disease affecting approximately 1% of the worldwide population. The interaction of genetic and environmental factors results in a cascade of immune reactions, which ultimately lead to the development of synovitis, joint damage, and structural bone damage. These, in turn, lead to pain, disability, and emotional, social, and economic challenges. A number of extraarticular manifestations and comorbidities are present in patients with RA, which result in increased mortality. The American College of Rheumatology and European League Against Rheumatism recently published updated disease classification criteria in an effort to identify RA earlier so that effective treatment can be employed to prevent irreversible changes.


Landau-Kleffner syndrome: an uncommon dealt with case in Southeast Asia.
An 11-year-old boy was admitted with fever followed by convulsions. He had developed aphasia subsequent to this illness. His birth history was unremarkable, and he had normal growth and development including of language, hearing and vision. His neurological examination was normal except for aphasia. Investigations including cerebrospinal fluid study and MRI were normal. However, EEG was abnormal and the boy was diagnosed as a case of Landau-Kleffner syndrome (LKS) and treated with sodium valproate, levetiracetam and steroids. He responded well to treatment and has been on follow-up for the last 4 months. We present this case of LKS to increase awareness about early diagnosis and to highlight the importance of appropriate management for a better outcome.


Effects of pH on the association between the inhibitor cystatin and the proteinase chymopapain.
Cysteine proteinases are involved in many aspects of physiological regulation. In humans, some cathepsins have shown another function in addition to their role as lysosomal proteases in intracellular protein degradation; they have been implicated in the pathogenesis of several heart and blood vessel diseases and in cancer development. In this work, we present a fluorometric and computational study of the binding of one representative plant cysteine proteinase, chymopapain, to one of the most studied inhibitors of these proteinases: chicken cystatin. The binding equilibrium constant, Kb, was determined in the pH range between 3.5 and 10.0, revealing a maximum in the affinity at pH 9.0. We constructed an atomic model for the chymopapain-cystatin dimer by docking the individual 3D protein structures; subsequently, the model was refined using a 100 ns NPT molecular dynamics simulation in explicit water. Upon scrutiny of this model, we identified 14 ionizing residues at the interface of the complex using a cutoff distance of 5.0 Å. Using the pKa values predicted with PROPKA and a modified proton-linkage model, we performed a regression analysis on our data to obtain the composite pKavalues for three isoacidic residues. We also calculated the electrostatic component of the binding energy (ΔGb,elec) at different pH values using an implicit solvent model and APBS software. The pH profile of this calculated energy compares well with the experimentally obtained binding energy, ΔGb. We propose that the residues that form an interchain ionic pair, Lys139A from chymopapain and Glu19B from cystatin, as well as Tyr61A and Tyr67A from chymopapain are the main residues responsible for the observed pH dependence in the chymopapain- cystatin affinity.


Capsule endoscopy and push enteroscopy in the diagnosis of obscure gastrointestinal bleeding.
In obscure gastrointestinal (GI) bleeding, it is often difficult to detect the bleeding sites located in the small bowel with conventional radiological, scintigraphic or angiographic techniques. Push enteroscopy and capsule endoscopy are currently considered to be the most effective diagnostic procedures. The aim of this study was to compare the detection rates between capsule endoscopy and push enteroscopy. From May 2002 through January 2003, we prospectively examined by capsule endoscopy 39 patients with suspected small bowel diseases, in particular GI bleeding of unknown origin in Renji Hospital. Among them, 32 complained of obscure recurrent GI bleeding. Between January 1993 and October 1996, we used push enteroscopy on 36 patients who suffered from unexplained GI bleeding. All patients had prior normal results on gastroscopy, colonoscopy, small bowel barium radiography, scintigraphy and/or angiography. M2A capsule endoscopy disclosed abnormal small bowel findings in 26 (82%) out of 32 patients. Twenty-one of them had significant pathological findings explaining their clinical disorders. Diagnostic yield was therefore 66% (21 of 32 patients). Definite bleeding sites diagnosed by capsule endoscopy in 21 patients included angiodysplasia (8), inflammatory small-bowel (5), small-bowel polyps (4), gastrointestinal stromal tumour (2), carcinoid tumour and lipoma (1), and hemorrhagic gastritis (1). Push enteroscopy detected the definite sources of bleeding in 9 (25%) of the 36 patients. Patients with definite bleeding sources included angiodysplasias (2), leiomyosarcoma (2), leiomyoma (1), lymphoma (1), Crohn's disease (1), small-bowel polyps (1) and adenocarcinoma of ampulla (1). Suspected bleeding sources were shown by push enteroscopy in two additional patients (6%), and in other five patients (16%) by capsule endoscopy. The present study of patients with obscure GI bleeding showed that capsule endoscopy significantly superior to push enteroscopy in detecting GI bleeding (P < 0.001). Capsule endoscopy is safe and painless, and should become the initial diagnostic choice for patients with obscure GI bleeding.


20(S)-protopanaxadiol promotes the migration, proliferation, and differentiation of neural stem cells by targeting GSK-3β in the Wnt/GSK-3β/β-catenin pathway.
Active natural ingredients, especially small molecules, have recently received wide attention as modifiers used to treat neurodegenerative disease by promoting neurogenic regeneration of neural stem cell (NSC) in situ. 20(S)-protopanaxadiol (PPD), one of the bioactive ingredients in ginseng, possesses neuroprotective properties. However, the effect of PPD on NSC proliferation and differentiation and its mechanism of action are incompletely understood. In this study, we investigated the impact of PPD on NSC proliferation and neuronal lineage differentiation through activation of the Wnt/glycogen synthase kinase (GSK)-3β/β-catenin pathway. NSC migration and proliferation were investigated by neurosphere assay, Cell Counting Kit-8 assay, and EdU assay. NSC differentiation was analyzed by Western blot and immunofluorescence staining. Involvement of the Wnt/GSK3β/β-catenin pathway was examined by molecular simulation and Western blot and verified using gene transfection. PPD significantly promoted neural migration and induced a significant increase in NSC proliferation in a time- and dose-dependent manner. Furthermore, a remarkable increase in antimicrotubule-associated protein 2 expression and decrease in nestin protein expression were induced by PPD. During the differentiation process, PPD targeted and stimulated the phosphorylation of GSK-3β at Ser9 and the active forms of β-catenin, resulting in activation of the Wnt/GSK-3β/β-catenin pathway. Transfection of NSCs with a constitutively active GSK-3β mutant at S9A significantly hampered the proliferation and neural differentiation mediated by PPD. PPD promotes NSC proliferation and neural differentiation in vitro via activation of the Wnt/GSK-3β/β-catenin pathway by targeting GSK-3β, potentially having great significance for the treatment of neurodegenerative diseases.


The effect of isolation methods and the use of different enzymes on islet yield and in vivo function.
The ability to isolate high-yield pure and viable islets from human cadaver pancreas donors is dependent on donor factor as well as isolation factors. The aim of this study was to examine factors influencing islets recovery and in vivo function with an emphasis on donor and isolation methods as well as to compare the effectiveness of Liberase, widely used in clinical islet isolation, with Serva for the isolation of pure functional islets. The results of 123 islet isolations using Liberase for digestion were compared with those of 113 isolations with Serva. Islet equivalents per gram of tissue were similar between Liberase and Serva (3620 +/- 1858 vs. 4132 +/- 2104, p < 0.2) as well as the percent purity (75 +/- 16 vs. 74 +/- 15, p < 0.9). In vivo function of islets from 71 isolations (Liberase = 45, Serva = 26) were further tested by transplantation into NOD-SCID mice following short-term culture (< 6 days, n = 71). Our data show that both Liberase- and Serva-isolated islets showed similar function results following short-term culture. These data demonstrate that there is no difference in islet yield, purity, and function between the two enzymes. However, when these 71 isolations were analyzed for in vivo function with emphasis on donor factors, cold ischemia time (12.0 +/- 5.3 vs. 15.0 +/- 5.7, p < 0.04), islet integrity (1.6 +/- 0.7 vs. 1.3 +/- 0.5, p < 0.05), and female gender were the only factors that correlated with in vivo function. We also compared the mechanical-shaking method for islets isolation with hand-shaking methods. Our results show that although there is no different in islet yield, purity, and integrity between different enzymes using the same method, hand-shaking method yields more islets with better integrity than mechanical-shaking method.


Photocleavable Peptide-Poly(2-hydroxyethyl methacrylate) Hybrid Graft Copolymer via Postpolymerization Modification by Click Chemistry To Modulate the Cell Affinities of 2D and 3D Materials.
Controlling the surface properties of engineered materials to enhance or reduce their cellular affinities remains a significant challenge in the field of biomaterials. We describe a universal technique for modulating the cytocompatibilities of two-dimensional (2D) and three-dimensional (3D) materials using a novel photocleavable peptide-grafted poly(2-hydroxyethyl methacrylate) (PHEMA) hybrid. The reversible addition-fragmentation chain transfer copolymerization of HEMA and propargyl acrylate was successfully controlled. The resultant alkyne-containing PHEMA was then used to modify the azide-terminated oligopeptides [Arg-Gly-Asp-Ser (RGDS)] with a photolabile 3-amino-3-(2-nitrophenyl)propanoic acid moiety via the copper-catalyzed alkyne-azide click chemistry. This strategy was readily used to decorate the surfaces of both hydrophilic and hydrophobic materials with RGDS peptides due to the high film-forming abilities of the PHEMA unit. The resultant thin film acted as an effective scaffold for improving cell adhesion and growth of NIH/3T3 fibroblasts and MC3T3-E1 osteoblast-like cells in vitro. In addition, UV irradiation of the surface led to the detachment of cells from the material surface accompanied by the photocleavage of RGDS grafts and enabled the 2D-patterning of cells and cell sheet engineering. The applicability of this system to 3D materials was investigated, and the cell adhesion was remarkably enhanced on a 3D-printed poly(lactic acid) object. This facile, biocompatible, and photoprocessable peptide-vinyl polymer hybrid system is valuable for its ability to advance the fields of tissue engineering, cell chips, and regenerative medicine.


Regulation of growth hormone secretion by the growth hormone releasing hexapeptide (GHRP-6).
Growth hormone (GH) secretion is regulated by a complex system of central and peripheral signals. Recently, a new GH-releasing hexapeptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) called GHRP-6 which specifically releases GH has been studied. In the present work the mechanism of action of GHRP-6 has been addressed in experimental animal models as well as in obese subjects. GHRP-6 releases GH independently of the hypothalamic factors GHRH and somatostatin and is a powerful GH releaser in obesity.


Phosphine and phosphine oxide groups in metal-organic frameworks detected by P K-edge XAS.
Phosphine metal-organic frameworks (P-MOFs) are crystalline porous coordination polymers that contain phosphorus functional groups within their pores. We present the use of X-ray absorption spectroscopy (XAS) at the P K-edge to determine the phosphine to phosphine oxide ratio in two P-MOFs with MIL-101 topology. The phosphorus oxidation state is of particular interest as it strongly influences the coordination affinity of these materials for transition metals. This method can determine the oxidation state of phosphorus even when the material contains paramagnetic nuclei, differently from NMR spectroscopy. We observed that phosphine in LSK-15 accounts for 72 ± 4% of the total phosphorus groups and that LSK-12 contains only phosphine oxide.


Inattentiveness, parental smoking and adolescent smoking initiation.
To examine how adolescents' inattentive behaviour, together with parental smoking patterns, predicts smoking initiation by age 14. DESIGN, SETTINGS: A prospective, longitudinal study: baseline at ages 11-12, follow-up at age 14. A population-based sample of Finnish twins, born 1983-1987, with parents and classroom teachers as additional informants. Two groups were formed, allocating the co-twins of each family into separate groups: the study sample and a replication sample. Twin individuals (n = 4552), aged 11-12 at baseline and 14 (average 14.04 years) at follow-up. At baseline, inattentiveness was assessed with the Multidimensional Peer Nomination Inventory (MPNI, Teacher Form) and parental smoking with individual questionnaires completed by each twins' parents; at the age 14 follow-up, adolescent smoking was assessed with a self-report questionnaire. At age 14, 57% reported never having smoked, 34% had experimented with cigarettes and 9% were current smokers. Inattentiveness and parental smoking additively predicted both experimental and current smoking in adolescence. The effects were independent of each other. The risk related to inattentiveness itself is high, but in combination with the effects of parental smoking, the probability of current smoking can rise as high as 38%, compared with 5% without these two risk factors. For prevention purposes, parental commitment to non-smoking should be emphasized.